Ravi Kishore Narra, MD

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell lymphoproliferative disease characterized by a unique set of pathologic and epidemiologic features. The disease is characterized by the presence of multinucleate giant cells called Hodgkin Reed-Sternberg (HRS) cells.¹ Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the relative rarity of the malignant cells within affected tissues. The HRS cells, which usually account for only 0.1% to 10% of the cells, induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which then constitute the majority of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, it was not until the 1990s that it was conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B cells.

Due to the development of highly effective therapies for Hodgkin lymphoma, cure is a reasonable goal for most patients. Because of the high cure rate, late complications of therapy must be considered when selecting treatment. This article reviews the clinical features and treatment options for advanced stage and relapsed/refractory Hodgkin lymphoma. A previously published article reviewed the epidemiology, etiology/pathogenesis, pathologic classification, initial workup, and staging evaluation of Hodgkin lymphoma, as well as the prognostic stratification and treatment of patients with early-stage Hodgkin lymphoma.³ 

PRESENTATION, INITIAL EVALUATION, AND PROGNOSIS

Overall, classical Hodgkin lymphoma (cHL) usually presents with asymptomatic mediastinal or cervical lymphadenopathy. At least 50% of patients will have stage I or II disease.⁴ A mediastinal mass is seen in most patients with nodular sclerosis cHL, at times showing the characteristics of bulky (> 10 cm) disease. Constitutional, or B, symptoms (fever, night sweats, and weight loss) are present in approximately 25% of all patients with cHL, but 50% of advanced stage patients. Between 10% and 15% of patients will have extranodal disease, most commonly involving lung, bone, and liver. Lymphocyte-predominant Hodgkin lymphoma (LPHL) is a rare histological subtype of Hodgkin lymphoma that is differentiated from cHL by distinct clinicopathological features. The clinical course and treatment approach for LPHL are dependent upon the stage of disease. The clinicopathological features of LPHL are discussed in the early-stage Hodgkin lymphoma article.³

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified as early stage favorable, early stage unfavorable, and advanced stage. For advanced stage Hodgkin lymphoma patients, prognosis can be defined using a tool commonly referred to as the International Prognostic Score (IPS). This index consists of 7 factors: male gender, age 45 years or older, stage IV disease, hemoglobin < 10.5 g/dL, white blood cell (WBC) count > 15,000/μL, lymphopenia (absolute lymphocyte count < 600 cells/μL or lymphocytes < 8% of WBC count), and serum albumin < 4 g/dL.⁵ In the original study by Hasenclever et al,⁵ the 5-year freedom from progression (FFP) ranged from 42% to 84% and the 5-year overall survival (OS) ranged from 56% to 90%, depending on the number of factors present. This scoring system, however, was developed using a patient population treated prior to 1992. Using a more recently treated patient population, the British Columbia Cancer Agency (BCCA) found that the IPS is still valid for prognostication, but outcomes have improved across all IPS groups, with 5-year FFP now ranging from 62% to 88% and 5-year OS ranging from 67% to 98%.⁶ This improvement is likely a reflection of improved therapy and supportive care. Table 1 shows the PFS and OS within each IPS group, comparing the data from the German Hodgkin Study Group (GHSG) and BCCA group.^5,6

 A closer evaluation of the 7 IPS variables was performed using data from patients enrolled in the Eastern Cooperative Oncology Group (ECOG) 2496 trial.⁷ This analysis revealed that, though the original IPS remained prognostic, its prognostic range has narrowed. Age and stage of disease remained significant for FFP, while age, stage of disease, and hemoglobin level remained significant for OS. An alternative prognostic index, the IPS-3, was constructed using age, stage, and hemoglobin levels. IPS-3, which identifies 4 risk groups, performed as a better tool for risk prediction for both FFP and OS, suggesting that it may provide a simpler and more accurate risk assessment than the IPS in advanced HL.⁷

High expression of CD68 is associated with adverse outcomes, whereas high FOXP3 and CD20 expression on tumor cells are predictors of superior outcomes.⁸ A recent study found that CD68 expression was associated with OS. Five-year OS was 88% in those with less than 25% CD68 expression, versus 63% in those with greater than 25% CD68 expression.⁹

Roemer and colleagues evaluated 108 newly diagnosed cHL biopsy specimens and found that almost all cHL patients had concordant alteration of PD-L1 (programmed death ligand-1) and PD-L2 loci, with a spectrum of 9p24.1 alterations ranging from low level polysomy to near uniform 9p24.1 amplification. PD-L1/PD-L2 copy number alterations are therefore a defining pathobiological feature of cHL.¹⁰ PFS was significantly shorter for patients with 9p24.1 amplification, and those patients were likely to have advanced disease suggesting that 9p24.1 amplification is associated with less favorable prognosis.¹⁰ This may change with the increasing use of PD-1 inhibitors in the treatment of cHL.

High baseline metabolic tumor volume and total lesion glycolysis have also been associated with adverse outcomes in cHL. While not routinely assessed in practice currently, these tools may ultimately be used to assess prognosis and guide therapy in clinical practice.¹¹

 

ADVANCED STAGE HODGKIN LYMPHOMA

FRONTLINE THERAPY

First-line Chemotherapy 

Chemotherapy plays an essential role in the treatment of advanced stage Hodgkin lymphoma. In the 1960s, the MOPP regimen (nitrogen mustard, vincristine, procarbazine, prednisone) was developed, with a 10-year OS of 50% and a progression-free survival (PFS) of 52% reported in advanced stage patients. The complete remission (CR) rate was 81%, and 36% of patients who achieved CR relapsed later.¹² This chemotherapy regimen is associated with a significant rate of myelosuppression and infertility as well as long-term risk of secondary myelodysplasia and acute leukemias.^13,14 This led to the development of newer regimens such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine).¹⁵ In a randomized trial, ABVD showed improved failure-free survival (FFS) over MOPP (61% versus 50% at 5 years) but similar OS (66%–73%).¹⁶ In light of these findings, and considering the lower rate of infertility and myelotoxicity, ABVD became the standard of care for advanced stage cHL in the United States.

The Stanford V regimen was developed in an attempt to further minimize toxicity.¹⁷ Stanford V is a condensed, 12-week chemotherapy regimen that includes mechlorethamine, doxorubicin, vinblastine, etoposide, prednisone, vincristine, and bleomycin, followed by involved-field radiation therapy (IFRT). Subsequent trials compared the Stanford V and ABVD regimens and showed similar OS, freedom from treatment failure (FFTF), and response rates.^18,19 The ABVD regimen was noted to have higher pulmonary toxicity, while other toxicities such as lymphopenia and neuropathy were higher with the Stanford V regimen. In addition, Stanford V requires patients to receive radiation therapy (RT) to original sites of disease larger than 5 cm in size and contiguous sites. 

Another regimen which has been studied extensively for advanced stage Hodgkin lymphoma, and is considered a standard of care in some parts of the world, is escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). In the HD9 study (n = 1196), the GHSG evaluated BEACOPP, escalated BEACOPP, and COPP/ABVD in advanced stage Hodgkin lymphoma.²⁰ All arms of the study included 30 Gy RT to sites of bulky disease or residual disease. This study showed improved OS and FFTF with escalated BEACOPP, but at the cost of higher rates of toxicity. At 10 years, FFTF was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for COPP/ABVD, baseline BEACOPP, and escalated BEACOPP, respectively (P < 0.001). The rate of secondary acute leukemia 10 years after treatment was 0.4% for COPP/ABVD, 1.5% for BEACOPP, and 3.0% for escalated BEACOPP. However, 3 subsequent randomized trials did not confirm a survival benefit with escalated BEACOPP relative to ABVD. In the HD 2000 trial (n = 295)²¹ and in a trial by Viviani and colleagues (n = 331),²² an improvement in OS was not demonstrated in favor of escalated BEACOPP. These studies also confirmed a higher rate of toxicities as well as secondary malignancies associated with the escalated BEACOPP regimen. In the EORTC20012 Intergroup trial (n = 549), 8 cycles of ABVD was compared with 4 cycles of escalated BEACOPP followed by 4 cycles of baseline BEACOPP, without radiation, in patients with clinical stage III or IV Hodgkin lymphoma with IPS score ≥ 3. Both regimens resulted in statistically similar FFS (63.7% in ABVD × 8 versus 69.3% in BEACOPP 4+4) and OS (86.7% in ABVD × 8 vs 90.3% in BEACOPP 4+4).²³

In the United States, ABVD (6–8 cycles) is commonly used, although escalated BEACOPP (particularly for patients with an IPS of 4 or higher) and Stanford V are considered appropriate as well.²⁴ In the North American Intergroup study comparing ABVD to Stanford V, and in the trial by Viviani et al, ABVD was associated with a 5- to 7-year FFS of 73% to 79% and OS of 84% to 92%.^19,22 Given these excellent results, as well as the potential to cure patients with second-line therapy consisting of autologous hematopoietic cell transplantation (auto-HCT), the general consensus among most U.S. hematologists and oncologists is that ABVD remains the treatment of choice, and that the improved FFS/PFS with escalated BEACOPP is not outweighed by the additional toxicity associated with the regimen. There may, however, be a role for escalated BEACOPP in select patients who have a suboptimal response to ABVD as defined by interim positron emission tomography (iPET) scan (see below).

Brentuximab vedotin is an anti-CD30 antibody-drug conjugate (ADC) consisting of an anti-CD30 antibody linked to monomethyl auristatin E (MMAE), a potent antitubulin agent. CD30 is highly expressed on HRS cells and also in anaplastic large cell lymphoma. Upon binding to CD30, the ADC/CD30 complex is then internalized and directed to the lysosome, where the ADC is proteolytically cleaved, releasing MMAE from the antibody. MMAE then disrupts microtubule networks within the cell, leading to G2/M cycle arrest and apoptosis. CD30 is consistently expressed on HRS cells. In addition to being studied in the relapsed/refractory setting (described below), brentuximab has been studied in the first-line setting. In a phase 1 trial, brentuximab combined with ABVD was associated with increased pulmonary toxicity, while brentuximab + AVD had no significant pulmonary toxicity, with an excellent CR rate (96%), suggesting that substituting brentuximab for bleomycin may be an effective strategy. In addition to possibly being more efficacious, this strategy would also have the benefit of eliminating the risk of bleomycin pulmonary toxicity.²⁵ Based on this data, a large international phase 3 study (the ECHELON-1 trial) comparing ABVD versus brentuximab + AVD in advanced stage cHL patients was recently completed. This study enrolled 1334 patients, and preliminary results were recently announced. With a median follow-up of 24 months, the brentuximab + AVD arm had a 4.9% absolute improvement in PFS relative to the ABVD arm (82.1% versus 77.2%). The brentuximab + AVD arm had an increased incidence of febrile neutropenia, managed with growth factors and peripheral neuropathy requiring dose adjustments, whereas the ABVD arm had an increased rate and severity of pulmonary toxicity.²⁶ Further follow-up will be required to determine whether this will translate into a survival benefit. See Table 2 for a summary of recent large randomized prospective phase 3 trials in advanced stage Hodgkin lymphoma. 

 

Alternative Regimens in Older Patients

Patients older than 60 years of age often have poor tolerance for ABVD and especially escalated BEACOPP. This results in increased treatment-related mortality and reduced overall dose intensity, with higher relapse rates and poor OS. In an attempt to improve on the results of treatment of elderly patients with Hodgkin lymphoma, alternative regimens have been explored. One example is PVAG (prednisone, vinblastine, doxorubicin, gemcitabine). With this regimen, the 3-year OS was 66% and PFS was 58%. One patient out of 59 died from treatment-related toxicity, which is much improved over the historical figures for elderly patients with Hodgkin lymphoma.²⁷ Another commonly used approach in practice is to simply omit bleomycin from ABVD. In the early-stage setting (GHSG HD-13 trial), this regimen (referred to as AVD) led to 89.6% PFS at 5 years, compared to 93.5% with ABVD.²⁸ It therefore stands to reason that this should be a reasonable option in older or more frail advanced stage cHL patients as well.

Brentuximab has been evaluated as a single-agent therapy for first-line therapy of elderly patients with Hodgkin lymphoma. In a phase 2 study, 27 patients (63% with advanced stage disease) were treated, with a 92% overall response rate and 73% CR rate. However the median duration of remission was disappointing at only 9.1 months.²⁹ Based on this data, single-agent brentuximab appears to be a reasonable and well tolerated option for frail or elderly patients, although with the caveat that long-term disease control is relatively uncommon.

RESPONSE-ADAPTED FRONTLINE THERAPY USING INTERIM PET SCAN

In recent years, response-adapted treatment approaches have been extensively researched in cHL using iPET. The goal is to reduce toxicity by minimizing therapy in those who achieve negative iPET and/or to intensify treatment for patients with suboptimal response on iPET. Gallamini et al evaluated the prognostic role of an early iPET scan in advanced Hodgkin lymphoma patients (n = 190) treated with ABVD. This study found that patients with positive iPET had a 2-year PFS of 12.8% versus 95.0% in patients with negative iPET. This result was highly statistically significant (P < 0.0001). This study also showed that PET-2 (iPET after 2 cycles of ABVD) superseded the prognostic value of the IPS at diagnosis.³⁰ As a result, numerous subsequent studies have been pursued using iPET for risk-adapted treatment in cHL.

A critical element to the conduct of iPET risk-adapted treatment for cHL is the interpretation of the iPET. In hopes of standardizing iPET interpretation in clinical trials, a scoring system called the Deauville score was developed. The Deauville score ranges from 1 to 5 (Table 3).

 For risk-adapted trials in cHL, a Deauville score of 1 to 3 is generally considered a negative iPET, whereas a score of 4 or 5 is considered a positive iPET.^31,32

The SWOG (Southwest Oncology Group) S0816 trial (n = 358) evaluated iPET-adapted treatment after 2 cycles of ABVD in stage III or IV Hodgkin lymphoma patients. Patients with positive iPET (Deauville score 4 to 5; n = 60) received escalated BEACOPP for 6 cycles, whereas iPET-negative (Deauville score 1 to 3; n = 271) patients continued to receive 4 more cycles of ABVD. The 2-year PFS was 64% for iPET-positive patients.³³ This PFS was much higher than the expected 15% to 30% from prior studies such as Gallamini et al,³⁰ suggesting that the treatment intensification may have been of benefit.

In the HD0801 study (n = 519), newly diagnosed advanced Hodgkin lymphoma patients with positive iPET after 2 cycles of ABVD (n = 103) received early ifosfamide-containing salvage therapy followed by high-dose therapy with autologous stem cell rescue. The 2-year PFS was 76% for PET-2–positive patients, comparable with PET-2–negative patients who had PFS of 81%.³⁴ Again, this result for iPET-positive patients was much better than expected based on the historical control from Gallamini et al, suggesting that the treatment intensification may have been beneficial. It should be emphasized, however, that neither HD0801 nor S0816 were randomized prospective trials; rather, all iPET-positive patients were assigned to an intensified treatment approach.

In the HD18 trial (n = 1100), patients with advanced stage cHL started therapy with escalated BEACOPP and underwent an iPET after 2 cycles. For those with a positive iPET, rituximab was added to escalated BEACOPP in the experimental arm (n = 220) for cycles 3 through 8. The control group (n = 220) continued to receive 6 more cycles of escalated BEACOPP. In the 2 groups, the 3-year PFS was similar (91.4% in escalated BEACOPP, 93% in rituximab + escalated BEACOPP), suggesting no significant benefit with addition of rituximab.³⁵ This study also calls into question whether iPET provides useful information for patients receiving intensive therapy such as escalated BEACOPP, and indicates that the historical control data for iPET-positive patients from Gallamini et al may not be consistently reproduced in other prospective trials. As a result, nonrandomized trials that implement an iPET risk-adapted approach should be interpreted with caution. See Table 4 for a summary of recent trials in advanced stage Hodgkin lymphoma using iPET scan to guide therapy. 

 

RADIATION THERAPY IN FRONTLINE TREATMENT

In patients with advanced stage Hodgkin lymphoma, IFRT to initial bulky sites of disease may be incorporated into frontline therapy to improve local control. However, whether this provides a survival benefit and which patients benefit most from consolidative RT remain unclear.

The European Organization for Research and Treatment of Cancer (EORTC) completed a randomized study in advanced stage Hodgkin lymphoma patients who achieved complete or partial remission after MOPP-ABV.³⁶ Patients in CR were randomly assigned to receive no further treatment versus IFRT (24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites). Patients in partial remission (PR) were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites. Among the CR patients, the 5-year event-free survival (EFS) was 79% to 84% and did not differ for those who received radiation versus those who did not. Five-year OS was 85% to 91% and also did not differ between the 2 groups. However, among the patients in PR after chemotherapy, the 5-year EFS was 79% and the 5-year OS was 87%, which is better than expected for PR patients, indicating a possible benefit to RT in patients with a partial response after chemotherapy. In the GHSG HD12 trial, patients with advanced stage Hodgkin lymphoma who had a residual lesion by computed tomography (CT) (but not analyzed by PET) had a very subtle improvement in FFTF (90% versus 87%) in favor of consolidation with IFRT, but again no survival benefit was seen.³⁷

The EORTC and HD12 studies described above utilized CT scan for assigning remission status following chemotherapy, and it is now well known that many patients with residual masses (by CT) after chemotherapy may in fact be cured, as such residual radiographic abnormalities may simply be composed of fibrosis. PET scan is more accurate than CT in identifying patients who truly have residual active disease following chemotherapy. As a result, the EORTC study discussed above and the GHSG HD12 trial are of limited relevance in the modern era, in which patients routinely undergo PET scan at the end of therapy. Restricting IFRT to sites that remain PET-positive after completing chemotherapy may be a reasonable strategy that would allow for the avoidance of RT in many patients, and may obviate the need for aggressive second-line therapy (eg, high-dose therapy and autologous hematopoietic cell transplant [auto-HCT]). This approach was taken in the GHSG HD15 trial (n = 2182) in which advanced stage patients were treated with 3 variations on the BEACOPP regimen (8 cycles of escalated BEACOPP, 6 cycles of escalated BEACOPP, or 8 cycles of baseline BEACOPP, randomized in a 1:1:1 ratio). Patients with a residual mass of 2.5 cm or greater on CT scan then underwent a PET scan; if the lesion was PET positive, it was treated with 30 Gy of IFRT. This overall strategy was very effective, with 5-year FFTF rates of 84.4%, 89.3%, and 85.4%, respectively. The OS rates were 91.9%, 95.3%, and 94.5%, respectively. For patients with lesions that remained PET positive after chemotherapy, the PFS rate was 86.2% at 48 months, whereas patients in PR with persistent mass ≥ 2.5 cm but with negative PET had a PFS of 92.6%, similar to that of patients in CR.³⁸ With this approach of BEACOPP followed by PET-guided radiation, the proportion of patients receiving RT was reduced from 71% (in the HD9 study) to only 11% in the HD15 study,³⁸ with no apparent loss in overall efficacy when comparing the results of the 2 studies.

UPFRONT STEM CELL TRANSPLANTATION 

To further improve outcomes of patients with advanced Hodgkin lymphoma with high-risk disease, high-dose therapy with auto-HCT has been explored as part of frontline therapy. While this has been shown to be feasible in such patients,³⁹ randomized trials have not shown a clear benefit in terms of FFS or OS with upfront auto-HCT. ^40,41 Therefore, auto-HCT is not considered a standard component of frontline therapy for cHL patients who achieve CR by PET/CT scan.

RELAPSED AND REFRACTORY HODGKIN LYMPHOMA 

Depending on the stage, risk factors, and frontline regimen utilized, between 5% and 40% of patients with Hodgkin lymphoma can be expected to experience either primary induction failure or a relapse after attaining remission with frontline therapy.³ Primary refractory Hodgkin lymphoma, which occurs in up to 5% to 10% of patients, is defined as progression or no response during induction treatment or within 90 days of completing treatment. In cases where remission status is in question, an updated tissue biopsy is recommended. Biopsy is also recommended in cases in which new sites of disease have appeared or if relapse has occurred after a durable period of remission. Restaging is recommended at the time of relapse. 

 

For younger patients with relapsed/refractory Hodgkin lymphoma, the standard of care in most cases is second-line (or salvage) chemotherapy followed by high-dose therapy and auto-HCT. For patients not felt to be candidates for auto-HCT, options include conventional second-line chemotherapy alone, salvage radiotherapy, novel agents such as brentuximab or immune checkpoint inhibitors, and/or participation in clinical trials. 

CONVENTIONAL MULTI-AGENT CHEMOTHERAPY REGIMENS

Numerous conventional regimens have been shown in phase 2 studies to be active in relapsed and refractory Hodgkin lymphoma. These include platinum-based regimens, gemcitabine-based regimens, and alkylator-based regimens. No randomized trials in Hodgkin lymphoma have been conducted comparing these regimens. In general, regimens are chosen based on the patient’s age, performance status, comorbidities, and whether auto-HCT is being considered. 

In the United States, platinum-based regimens such as ICE (ifosfamide, carboplatin, etoposide),⁴² DHAP (dexamethasone, cisplatin, high-dose cytarabine),⁴³ ESHAP (etoposide, methylprednisolone, high-dose cytarabine, cisplatin),⁴⁴ GDP (gemcitabine, cisplatin, dexamethasone),⁴⁵ and GCD (gemcitabine, carboplatin, dexamethasone)⁴⁶ are all considered appropriate second-line therapy options for patients being considered for auto-HCT, due to their high response rates and because autologous hematopoietic stem cell collection remains feasible after these regimens. Response rates range from 60% to 88%, with CR rates between 17% and 41%, and toxic death rates generally well below 5%.

Other gemcitabine-based regimens such as IGEV (ifosfamide, gemcitabine, vinorelbine) and GVD (gemcitabine, vinorelbine, liposomal doxorubicin) are also effective.^47,48 GVD is an excellent choice since it is a generally well-tolerated outpatient regimen with a 60% response rate even in heavily pretreated patients.⁴⁸ Stem cell collection remains feasible after both IGEV and GVD as well. ABVD can produce CR in approximately 20% to 50% of patients initially treated with MOPP.^49–51 In practice, however, most patients today with relapsed or refractory Hodgkin lymphoma have already received ABVD as part of their first-line therapy, and retreatment with ABVD is not a good option because it would be associated with prohibitively high cumulative doses of doxorubicin. 

These multi-agent chemotherapy regimens may not be tolerated well in patients over age 65 to 70 years or those with significant underlying comorbidities. In recent years, bendamustine has emerged as one of the most active conventional agents for cHL, with overall response rates of 53% to 58% in heavily pre-treated patients.^52,53 Bendamustine can generally be tolerated even in elderly patients as well.

Some centers, particularly in Europe, investigated aggressive salvage regimens such as mini-BEAM (carmustine, etoposide, cytarabine, melphalan)⁵⁴ or dexa-BEAM (BEAM plus dexamethasone).⁵⁵ These regimens, however, are associated with significant hematologic toxicity and high (2%–5%) treatment-related mortality. As a result, these are rarely used in the United States.

For patients who have progressed after (or are not candidates for) platinum- and/or gemcitabine-based therapy, older alkylator-based regimens such as MOPP, C-MOPP, or ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) can be considered.^56–58 However, these regimens are associated with significant bone marrow suppression, and autologous hematopoietic stem cell collection may no longer be feasible after such regimens. Therefore, these regimens should only be given to patients not felt to be auto-HCT candidates, or patients for whom autologous hematopoietic stem cell collection has already been completed. Weekly vinblastine or single-agent gemcitabine are palliative chemotherapy options, with response rates in the 60% to 80% range. Patients can sometimes be maintained on such low-intensity palliative regimens for 6 to 12 months or longer.^59,60

BRENTUXIMAB VEDOTIN

Several trials are evaluating incorporation of brentuximab into second-line therapy in transplant-eligible patients. These approaches have used brentuximab prior to, concurrent with, or following platinum-based chemotherapy.⁶¹ While there is currently no consensus on the optimal way to incorporate brentuximab into salvage therapy, it is possible that the use of brentuximab or other novel agents in salvage therapy may allow for avoidance of conventional chemotherapy in some patients. In addition, this may translate into more patients proceeding to auto-HCT in a PET negative state. PET negativity prior to auto-HCT is a powerful predictor of long-term remission after auto-HCT, so any intervention that increases the rate of PET negativity prior to auto-HCT would be expected to improve outcomes with auto-HCT.^62–65

For patients not being considered for autoHCT, or those for whom platinum-based salvage therapy was ineffective, single-agent brentuximab is an excellent option. In 2 phase 2 studies, an overall response rate (ORR) of 60% to 75% (including a CR rate of 22%–34%) was seen in relapsed and refractory Hodgkin lymphoma patients.⁶⁶ The US Food and Drug Administration (FDA) approved brentuximab vedotin in August 2011 for treatment of relapsed and refractory Hodgkin lymphoma, after a failed auto-HCT, or in patients who are not auto-HCT candidates and who have received at least 2 prior chemotherapy regimens. With more extended follow-up, it has become clear that a proportion of patients who achieve CR to brentuximab may maintain remission long-term—58% at 3 years and 38% at 5 years.⁶⁷ These patients may in fact be cured, in many cases without having undergone allogeneic HCT (allo-HCT) after brentuximab.

 

PD-1 (IMMUNE CHECKPOINT) INHIBITORS

As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.⁶⁸ Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.⁶⁹ In general, these agents are well tolerated, although patients must be monitored closely for

inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.^70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.⁷²

AUTOLOGOUS STEM CELL TRANSPLANTATION 

Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.^55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.⁷⁴

A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.⁵⁵ This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.⁷³ 

The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions. 

The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.⁷⁵ Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,⁷⁶ chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.⁷⁷ This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.⁷⁸

IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).^79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.⁸¹

 

Prognostic Factors Associated with Outcome with Auto-HCT

The factor most consistently associated with improved outcome for patients with relapsed and refractory Hodgkin lymphoma who undergo auto-HCT is the disease status at transplant.^63,77 Those in a second CR, versus a chemo-sensitive relapse (but not CR), versus a chemo-refractory relapse have DFS rates of 60% to 70%, 30% to 40%, and 10% to 20%, respectively.⁶³ The duration between remission and relapse also has important prognostic significance. Late relapse (> 1 year after completion of frontline therapy) is associated with better outcomes as compared to early relapse.⁵⁵ Other factors with prognostic significance at relapse include anemia, time to relapse and clinical stage, B symptoms, extranodal disease, number of prior chemotherapy regimens, and performance status.^42,82 The prognostic impact of pretransplant disease status has been confirmed by studies using functional imaging (eg, FDG-PET or gallium scans). In a report by Moskowitz et al, patients with negative functional imaging following second-line therapy had a 77% EFS post-auto-HCT versus 33% in those whose functional imaging remained positive.⁶² Very similar findings have been reported by other groups.^63–65

Post-Auto-HCT Brentuximab Maintenance

In the multicenter, randomized, double-blinded phase 3 AETHERA trial (n = 329), brentuximab (n = 165) was compared with placebo (n = 164) in patients with unfavorable risk relapsed or primary refractory cHL who had undergone autologous transplant. Eligible patients had at least 1 of the following risk factors for progression after auto-HCT: primary refractory Hodgkin lymphoma (failure to achieve complete remission), relapsed Hodgkin lymphoma with an initial remission duration of less than 12 months, or extranodal involvement at the start of pre-transplantation salvage chemotherapy. Patients were required to have CR, PR, or stable disease after pretransplant salvage chemotherapy with adequate kidney, liver, and bone marrow function. Patients who previously received brentuximab were excluded. Patients received 16 cycles of brentuximab or placebo once every 3 weeks starting 30 to 45 days after transplant. The PFS was significantly improved in the brentuximab group when compared to the placebo group (hazard ratio 0.57; P = 0.0013) after a median observation time of 30 months. Median PFS was 42.9 months in the brentuximab group versus 24.1 months in the placebo group; estimated 2-year PFS rates were 63% in the brentuximab group and 51% in the placebo group. OS was not significantly different between the study groups (~85%), presumably due to the fact that patients in the control group who relapsed likely went on to receive brentuximab as a subsequent therapy.⁸³

PRIMARY REFRACTORY HODGKIN LYMPHOMA 

Patients with primary refractory Hodgkin lymphoma have a poor outcome. Salvage therapy using conventional chemotherapy and/or RT results in long-term DFS in 10% or fewer of such patients.^13,84 Given these poor outcomes with conventional salvage therapy, auto-HCT is considered to be the standard of care for this subset of patients. The GHSG retrospectively analyzed the prognostic factors and outcomes of patients with primary refractory Hodgkin lymphoma. The 5-year freedom-from-second-failure and the 5-year OS were reported to be 31% and 43%, respectively, for those patients treated with auto-HCT. Patients with poor functional status at time of transplant, age greater than 50 years, and failure to attain a temporary remission had a 0% 5-year OS, as compared to 55% in patients without any of these risk factors.⁸⁵ A large retrospective European study showed that patients with chemo-resistant disease who underwent transplant had a 19% survival at 5 years.⁶³ Hence, even patients with primary refractory Hodgkin lymphoma have some chance of achieving long-term survival following auto-HCT. 

SALVAGE RADIOTHERAPY

The GHSG performed a retrospective analysis of the efficacy of salvage RT in patients with refractory or first-relapsed Hodgkin lymphoma. Five-year FFTF and OS rates were 28% and 51%, respectively. Patients with a limited-stage relapse and without B symptoms were more likely to benefit from salvage RT.⁸⁶ Campbell et al reported on 81 patients undergoing salvage RT for persistent or recurrent Hodgkin lymphoma after chemotherapy. The 10-year FFTF and OS rates were 33% and 46%, respectively.⁸⁷ Similarly, Wirth et al reported a 5-year FFS of 26% and 5-year OS of 57%. These figures were 36% and 75%, respectively, in patients whose relapse was limited to supradiaphragmatic nodal sites without B symptoms.⁸⁸ RT therefore may be a useful strategy for a subset of patients who relapse following chemotherapy, particularly those with a limited-stage relapse, without B symptoms, and those with relapsed disease after a CR, as opposed to those with a partial response or lack of response to the prior chemotherapy regimen. 

INVESTIGATIONAL AGENTS AND NOVEL COMBINATIONS

Several biological therapies are emerging as options for the treatment of refractory or relapsed disease. These therapies consist of monoclonal antibodies and ADCs that target cell surface antigens, or small molecules that inhibit key intracellular pathways within neoplastic cells. 

 

Rituximab

Rituximab is a chimeric anti-CD20 monoclonal antibody used widely in B-cell non-Hodgkin lymphomas. The CD20 molecule is typically highly expressed in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Two studies (one in relapsed patients, the other in a mixture of relapsed and previously untreated patients) showed significant activity of rituximab in relapsed NLPHL, with ORRs ranging from 94% to 100%, CR rates ranging from 41% to 53%, and median duration of remission in the 10- to 33-month range.^89,90 In cHL, CD20 is expressed in HRS cells in 20% to 30% of cases. In such cases, single-agent rituximab has also shown activity. There is also evidence that rituximab may be effective even in cases in which the HRS cells are CD20-negative, presumably by virtue of depleting reactive B lymphocytes from the microenvironment, which may enhance anti-tumor immunity, or by eliminating a putative CD20-expressing Hodgkin lymphoma stem cell.^91,92

Lenalidomide

Lenalidomide is an immunomodulatory drug that has multiple modes of action, including direct induction of apoptosis in tumor cells, antiangiogenic effects, and the activation of immune cells, such as natural killer cells and T cells. Lenalidomide has been shown to modify many features of the microenvironment of HRS cells and has demonstrated activity in other B-cell neoplasms. As a result, lenalidomide has been evaluated in relapsed and refractory Hodgkin lymphoma patients. A multicenter phase 2 study by Fehniger et al included 35 patients, 87% of whom had previously undergone HCT and 55% of whom were refractory to the last therapy.⁹³ All patients were given lenalidomide 25 mg/day from days 1 to 21 of a 28-day cycle until disease progression. One patient was noted to achieve CR, 6 achieved PR, and 5 had stable disease lasting more than 6 months, for an ORR of 19% and a “cytostatic overall response rate” of 33%. The median duration of CR/partial remission was 6 months, with the median time-to-treatment failure in responders (including those with stable disease > 6 months) being 15 months. Similarly, in another study, Böll et al evaluated 12 patients across 4 German centers with relapsed or refractory disease who were treated with oral lenalidomide for 21 days in a 28-day cycle. No radiological evidence of disease progression after 2 cycles of lenalidomide was seen in any of the enrolled patients. ORR was noted to be 50%, with 6 patients with stable disease and 5 patients achieving PR after 2 cycles.⁹⁴

Novel Brentuximab Combination Therapies

Brentuximab plus bendamustine. The combination of brentuximab and bendamustine was tested as an outpatient regimen in a phase 1/2 study (n = 55) in primary refractory Hodgkin lymphoma or after first relapse. The CR rate of the combination was 74%, with an overall objective response (CR + PR) of 93%. The CR rates were 64% and 84%, respectively, for refractory and relapsed patients. The PFS at 12 months was 80%, establishing this combination therapy as an effective salvage regimen with durable response.⁹⁵

Brentuximab plus nivolumab. Preliminary results have recently been presented from 2 studies^96,97 evaluating the combination of brentuximab and nivolumab. While this combination would still be considered investigational, these studies showed very encouraging ORRs of 90% to 100% and a CR rate of 62% to 66%. Longer follow-up is needed to determine whether these responses are durable and to document the toxicity profile of this combination.

Mammalian Target of Rapamycin Inhibitors

Two mammalian target of rapamycin (mTOR) inhibitors, everolimus and temsirolimus, are currently available in the United States. While neither drug currently has FDA approval for Hodgkin lymphoma, everolimus was evaluated in a phase 2 trial in a heavily pretreated group of relapsed/refractory patients. An ORR of 47% was seen, with a median time to progression of 7.2 months.⁹⁸

ALLOGENEIC STEM CELL TRANSPLANTATION 

Historically, patients who relapse after having an auto-HCT generally had a poor outcome, with a median survival of 2 to 3 years after failure of auto-HCT.⁹⁹ These patients may be offered palliative chemotherapy (see above), treatment with novel agents (see above), or enrollment in a clinical trial. Select patients may benefit from a second hematopoietic stem cell transplant, most commonly an allo-HCT. However, rare patients with late relapse after auto-HCT may be considered for a second auto-HCT, with a minority of such patients achieving a durable remission after the second auto-HCT.^100,101 Because relapse or progressive disease occurs most commonly in the first several months following auto-HCT, patients are more often considered for allo-HCT than a second auto-HCT. In addition, a second auto-HCT may not be feasible due to impaired bone marrow reserve and/or concerns for development of secondary myelodysplasia or acute myeloid leukemia.

 

Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).^102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression. 

More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).^104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.¹⁰⁵

Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.^107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.

Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.¹⁰⁹ Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease. 

These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.¹¹⁰ Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.^111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone. 

Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.⁶⁷ For such patients, avoiding the risks of allo-HCT is a desirable goal.

 

For those who relapse or progress after auto-HCT, a reasonable strategy therefore is to treat initially with brentuximab, unless the patient is already known to have responded poorly to brentuximab, or already has significant neuropathy. Those who achieve a CR to brentuximab are then observed. A subset of those patients will remain in remission at 5 years without further therapy. For those who relapse, or who achieve less than a CR to brentuximab, additional treatment (with brentuximab re-treatment being one option) followed by a reduced-intensity allo-HCT is a reasonable consideration. This approach has the theoretical advantages of (1) avoiding the risk of allo-HCT in the subset potentially cured by brentuximab, (2) getting patients to allo-HCT with fewer comorbidities (due to a lower total exposure to conventional chemotherapy pre-transplant), and (3) applying allo-HCT in the setting of sensitive disease/lower disease burden (due to the high efficacy of brentuximab). The results of a small study suggest that brentuximab may in fact be a very effective “bridge” to allotransplant. Chen et al¹¹³ reported on 18 patients with relapsed/refractory Hodgkin lymphoma (17 of whom had previously undergone auto-HCT) who were treated on brentuximab vedotin clinical trials. The data were retrospectively evaluated to determine the efficacy and safety of subsequent reduced-intensity allo-HCT. Remarkably, at 1 year the OS was 100%, PFS was 92%, and nonrelapse mortality was 0% with a median follow-up of 14 months. Hence, brentuximab is safe for use prior to reduced-intensity allo-HCT in heavily pre-treated patients and appears to be associated with very favorable post-transplant outcomes, particularly in comparison to older studies of allo-HCT in the era prior to brentuximab.

SUMMARY

Currently, cure is possible for the majority of patients diagnosed with advanced stage Hodgkin lymphoma. The challenge to the clinician is to provide curative treatment with the lowest risk of serious toxicities. Which regimen will best provide this balance of risk and benefit needs to be assessed based on the relapse risk, age, frailty, and comorbidity profile for an individual patient. For many patients with relapsed or refractory Hodgkin lymphoma, cure remains possible using approaches based on hematopoietic stem cell transplantation, RT, and/or brentuximab. In addition, there are now numerous conventional chemotherapy agents, RT strategies, and exciting newer agents such as PD-1 inhibitors, that can provide significant clinical benefit even when cure is not feasible.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

 

 

PATHOLOGIC CLASSIFICATION

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

 

 

INITIAL EVALUATION AND STAGING

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

 

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

 

 

EARLY-STAGE NLPHL

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

 

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

 

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

 

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

 

 

PATHOLOGIC CLASSIFICATION

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

 

 

INITIAL EVALUATION AND STAGING

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

 

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

 

 

EARLY-STAGE NLPHL

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

 

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

 

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

 

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.

INTRODUCTION

Hodgkin lymphoma, previously known as Hodgkin’s disease, is a B-cell malignancy with unique pathological and epidemiological features for which highly effective therapies exist. The disease is characterized by the presence of mononuclear and multinucleate giant cells called Hodgkin and Reed-Sternberg (HRS) cells.¹

Hodgkin lymphoma is unique compared to other B-cell lymphomas because of the scarcity of the malignant cells in the tumor tissue. The HRS cells usually account for only 0.1% to 10% of the cells in the affected tissues, and the HRS cells induce accumulation of nonmalignant lymphocytes, macrophages, granulocytes, eosinophils, plasma cells, and histiocytes, which constitute more than 90% of tumor cellularity.² Although the disease was first described by Sir Thomas Hodgkin in 1832, in part because of this unique histopathology, not until 1991 was it conclusively demonstrated that HRS cells are in fact monoclonal germinal center–derived B-cells. This article reviews management and frontline treatment options for limited-stage classical Hodgkin lymphoma and nodular lymphocyte predominant Hodgkin lymphoma. Treatment of advanced stage and relapsed/refractory Hodgkin lymphoma will be discussed in a separate article.

EPIDEMIOLOGY

Hodgkin lymphoma accounts for 0.5% of all malignancies and 11.7% of all lymphomas among adults in the United States.³ The incidence of Hodgkin lymphoma has been steadily increasing over the past 4 decades and was estimated to be 8260 cases in the United States in 2017, with a slight male predominance. Hodgkin lymphoma is expected to cause 1070 deaths in 2017, accounting for 0.2% of all cancer deaths.³ First-degree relatives of patients with Hodgkin lymphoma have a 3- to 9-fold increased risk of having the disease compared to the general population,⁴ and monozygotic twin siblings of Hodgkin lymphoma patients have a greatly increased risk for developing the disease—up to 100-fold—compared to normal cohorts.⁵ The incidence is highest among Caucasians, African Americans, and Hispanics, and lower in Asians and American Indians.³ Hodgkin lymphoma incidence shows a bimodal peak distribution, with 1 peak between the ages of 15 and 44 years, and another peak after age 65 years.⁶

ETIOLOGY/PATHOGENESIS

The cause of Hodgkin lymphoma is unknown. Epstein-Barr virus (EBV) infection is present in up to 40% of Hodgkin lymphoma cases, suggesting a role of this virus in the pathogenesis of some cases. The risk of EBV-positive Hodgkin lymphoma was found to be higher following an episode of infectious mononucleosis, while the risk of EBV-negative Hodgkin lymphoma remained unchanged.⁷ The incidence of Hodgkin lymphoma is 5 to 14 times higher in HIV-infected patients than in noninfected patients.⁸ It is not considered an AIDS-defining illness, but has become more frequent with the growth and aging of the HIV-positive population.^9,10 Hodgkin lymphoma patients with HIV typically have CD4 lymphocyte counts greater than 200 cells/μL,¹¹ with the incidence of Hodgkin lymphoma actually declining with lower CD4 lymphocyte counts.¹² HIV-related Hodgkin lymphoma tends to have an aggressive course, with high rates of EBV positivity.¹³ The incidence of Hodgkin lymphoma is 1.8 times higher among smokers, and the risk appears to increase with duration of smoking.^14,15

The cell of origin of Hodgkin lymphoma, while long suspected to be the HRS cell, remained unproven until the 1990s when micro-dissection and single-cell polymerase chain reaction techniques allowed for confirmation that the HRS cell was in fact a monoclonal germinal center derived B cell.^16,17 These HRS cells lack immunoglobulin due to defective transcription regulation and not due to crippling mutations.^18,19 The cellular infiltrate in Hodgkin lymphoma appears to play a decisive role in allowing the HRS cells to survive by providing an environment that suppresses cytotoxic immune responses as well as by providing cellular interactions and cytokines that support their growth and survival. The extensive inflammatory infiltrate in classical Hodgkin lymphoma is comprised of T helper 2 (Th2) and regulatory T cells and lacks T helper 1 (Th1) cells, CD8 cytotoxic T cells, and natural killer cells.²⁰ The HRS cells escape apoptosis by several mechanisms which include latent EBV infection and constitutive nuclear factor (NF)-kB pathways, as well as other deregulated signaling pathways that promote survival, such as EBV nuclear antigen 1 (EBNA1) protein, EBV latent infection membrane protein 1 (LMP1), and LMP2.^21,22

Genetic alterations in the 9p24 locus which encodes PD-L1/PD-L2 are nearly universally present in classical Hodgkin lymphoma and are now considered a disease-defining feature.²³

 

 

PATHOLOGIC CLASSIFICATION

According to the 2008 World Health Organization (WHO) classification, Hodgkin lymphoma has 2 clearly defined entities: classical Hodgkin lymphoma (cHL), which accounts for approximately 95% cases, and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which accounts for the remaining cases.²⁴ These 2 entities differ in their clinical, pathological, and biological features, which in turn affect prognosis and treatment options. Classical Hodgkin lymphoma is characterized by a paucity of HRS cells surrounded by a background of mixed inflammatory infiltrate comprised of histiocytes, small lymphocytes, eosinophils, neutrophils, plasma cells, fibroblasts, and collagen. Depending on the particular combinations of these elements and the specific features of the neoplastic cells, cases can be subclassified into several cHL subtypes: the nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted types.²⁵

The diagnosis of cHL is made based on a combination of morphology of HRS cells and the other cells infiltrating the tissue, combined with immunohistochemical staining. Because of the rare nature of the malignant (clonal) cell in Hodgkin lymphoma specimens, flow cytometry is generally of little value. The HRS cells in cHL are CD30-positive and CD45 negative in virtually all cases, and CD15-positive in 85% of cases.²⁶ B-cell antigens are typically negative except for CD20, which is positive in about 20% cases.²⁷

Nodular sclerosis Hodgkin lymphoma (NSHL) is the most common subtype of cHL, accounting for 65% to 75% of cases. It is common among young adults and tends to involve the mediastinal, supraclavicular, and cervical lymph nodes. NSHL is characterized by the presence of collagen bands that divide the lymphoid tissue into circumscribed nodules. This subtype usually presents as stage I or II disease, typically with neck and/or mediastinal disease, and evidence of EBV infection is present in approximately 10% to 40% of North American cases.⁷ Patients diagnosed with NSHL generally have a very good prognosis.

Mixed cellularity Hodgkin lymphoma (MCHL) constitutes about 20% to 25% of cHL cases. It affects a somewhat older population, with a median age at diagnosis of 38 years. The typical bimodal age distribution is not seen with MCHL. MCHL has a male predominance (70%), and is more frequent in HIV-infected patients (70% of whom also have EBV infection). Lymphoid tissues have classic HRS cells and significant inflammatory infiltrates. Approximately 50% of patients with MCHL present as stage III or IV with abdominal lymphadenopathy or splenic involvement, and B symptoms are frequent.²⁴

Lymphocyte-rich Hodgkin lymphoma (LRHL) is uncommon, accounting for only 3% to 5% of cases of cHL.²⁸ The disease usually presents at an older age and has a 2:1 male predominance. HRS cells are commonly seen and a large number of reactive lymphocytes are also present. Although on the basis of morphology and immunohistochemistry LRHL belongs to the cHL group, clinically it more closely resembles LPHL. Patients usually present at early stage and rarely have B symptoms. LRHL carries an excellent prognosis, with a greater than 90% PFS after 5 years.^23,29

Lymphocyte-depleted Hodgkin lymphoma (LDHL) is the least common form of cHL, accounting for less than 5% of cases. Many cases previously placed in this category are now recognized as diffuse large B-cell lymphoma (DLBCL), anaplastic large-cell lymphoma (ALCL), or NSHL with lymphocyte depletion.³⁰ HRS cells are frequently seen, but reactive inflammatory cells are relatively sparse. EBV infection is seen in up to 90% of cases, commonly associated with HIV-infected individuals. Advanced-stage and symptomatic disease are more common. Prognosis is slightly worse compared to other categories.

NLPHL accounts for approximately 5% of cases of Hodgkin lymphoma. It has a unimodal age distribution, with the peak incidence in the fourth decade, and male predilection of 3:1.²⁸ NLPHL is characterized by large primary lymphoid follicles, with polytypic small B lymphocytes and extensive meshworks of follicular dendritic cells. The lymphocytic/histiocytic (L and H), or “popcorn,” cells scattered within the nodules differ from classic HRS cells, both in their morphology and in their biochemical profile, being frequently negative for CD15, CD30 and for the EBV genome, and usually positive for B-cell antigens such as CD20, suggesting that L and H cells may be immunoglobulin-synthesizing monoclonal B cells. CD45 is also typically positive in NLPHL, in distinction from cHL. NLPHL has an indolent course compared to cHL, and long-term survival is common.^19,31 NLPHL commonly presents with limited-stage disease. NLPHL may eventually transform into a more aggressive lymphoma, such as diffuse large B-cell lymphoma (including centroblastic, immunoblastic, or T-cell/histiocyte–rich subtypes), at a rate of 4% to 12%. This can occur even 15 to 20 years after the initial diagnosis of NLPHL.^32,33 In a recent large retrospective study of 222 patients with NLPHL, the rate of transformation to DLBCL was 7.6%, with a median time to transformation of 35 months. Overall survival was not adversely affected in patients undergoing transformation compared to those without transformation.³⁴

PRESENTATION

Classical Hodgkin lymphoma usually presents with asymptomatic mediastinal or cervical lymphadenopathy. Half of patients present with stage I or stage II disease.³⁵ A mediastinal mass is seen in most patients with NSHL, at times with bulky disease, with “bulky” defined as a mediastinal mass measuring one-third or more of the maximal thoracic diameter on chest x-ray, or 10 cm on computed tomography (CT) scan. Systemic symptoms, or "B" symptoms—fevers (> 38°C), drenching night sweats, and unexplained weight loss (> 10% of baseline body weight over the preceding 6 months or less)—are detected in approximately 25% of patients. Between 10% and 15% will have extranodal disease, most commonly involving lung, bone, and liver. NLPHL usually presents with limited-stage disease without B symptoms; it typically has a more indolent presentation and clinical course than cHL.

 

 

INITIAL EVALUATION AND STAGING

The initial workup includes a complete blood count (CBC), erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and chemistry studies to evaluate renal function and liver function. Fine-needle aspiration will usually fail to identify the infrequent HRS cells, and instead only reveal the reactive background of inflammatory cells. Generous (large gauge) core needle biopsies may provide diagnosis effectively in some cases, but in general, an excisional lymph node biopsy is preferred to ensure an accurate diagnosis and avoid the need for repeated biopsy procedures. In cases where an excisional biopsy would be difficult or risky, a core needle biopsy procedure is a reasonable first step, with the understanding that a subsequent surgical procedure may still be necessary.

Baseline imaging includes CT scans of the neck, chest, abdomen, and pelvis. Use of positron emission tomography (PET) scanning is now standard in the initial evaluation and assessment of treatment response in Hodgkin lymphoma.³⁶ Due to the increased sensitivity of PET or PET/CT scan, additional lesions may be identified that were not seen on conventional CT scans. This will alter the staging, and potentially the treatment plan, in up to 25% to 30% of patients.^37,38 PET/CT scan performed during initial evaluation also facilitates optimal interpretation of post-therapy PET/CT scans and is therefore strongly encouraged as a part of the initial staging evaluation.³⁹

Recent studies have shown that bone marrow biopsy is not routinely needed in the initial staging of cHL. A study of 454 patients concluded that bone marrow biopsy would not have altered the stage in any stage I or II patients. It was further concluded that overall treatment strategy would not have been altered for any of the patients.⁴⁰ Based on this study and others, it is now clear that FDG-PET has a high sensitivity, and when PET scan is negative (in the bone marrow and skeleton), a bone marrow biopsy provides little additional value. For patients with significant cytopenias, a bone marrow biopsy is reasonable. Such patients may benefit from a bilateral biopsy, which increases the probability of demonstrating bone marrow involvement by 16% to 33%.^41,42 Techniques such as staging laparotomy and lymphangiography are now considered obsolete.

Hodgkin lymphoma is staged according to the Ann Arbor staging system (Table 1). The original Ann Arbor staging was published in 1971,⁴³ and in 1989 the “Cotswold modifications” extended the definitions of stage IV disease and the suffix “X” was added to denote bulky disease.⁴⁴ Both systems were developed for the staging of Hodgkin lymphoma, but are now used for staging non-Hodgkin lymphoma as well.

PROGNOSTIC FACTORS

For the purposes of prognosis and selection of treatment, Hodgkin lymphoma is commonly classified into early-stage favorable, early-stage unfavorable, and advanced stage. Early-stage Hodgkin lymphoma refers to patients with Ann Arbor stage I or stage II disease. With early-stage Hodgkin lymphoma, the prognosis varies significantly based on factors such as the presence of B symptoms, elevated erythrocyte sedimentation rate ([ESR] > 50 mm/hr), number of nodal sites involved, older age, and a large mediastinal mass. For this reason, most clinical trials to evaluate treatment strategies for early-stage Hodgkin lymphoma are based on various combinations of these risk factors. The definition of early-stage unfavorable Hodgkin lymphoma varies across different clinical trial study groups, and it is important to understand the definition in interpreting the results of these trials (Table 2).^45,46

In the German Hodgkin Study Group (GHSG) trials, early-stage Hodgkin lymphoma is stratified into a high risk (“unfavorable”) group defined by any of the following: a large mediastinal mass (one third of maximum thoracic diameter), extra-nodal disease, 3 or more nodal areas, and an ESR of > 50 mm/hr in asymptomatic patients or > 30 mm/hr in patients with B symptoms. Low-risk (“favorable”) patients lack all of these factors.⁴⁷ The European Organization for Research and Treatment of Cancer (EORTC) defines the unfavorable prognostic group as older than 50 years of age, large mediastinal adenopathy (maximum width on a chest radiograph of at least one third of the internal transverse diameter of the thorax at the level of T5 through T6 or any mass of ≥ 10 cm in the largest dimension), an ESR of 50 mm/hr and no B symptoms, or with an ESR of 30 mm/hr in those who have B symptoms, and/or 4 or more regions of involvement.⁴⁸ The National Cancer Institute of Canada (NCIC) Clinical Trials Group and the Eastern Cooperative Oncology Group (ECOG) define high-risk groups as presence of B symptoms, bulky disease with a mediastinal mass width of at least one third of the maximum chest wall diameter, or any mass greater than 10 cm, and patients with intra-abdominal disease.^49,50

Gene-expression profiling in Hodgkin lymphoma has identified a gene signature of tumor-associated macrophages that was able to identify patients with a higher risk for primary treatment failure. In an independent cohort of patients, an increased number of CD68-positive macrophages was correlated with inferior outcomes.^51,52 Studies such as these underscore the importance of the tumor “microenvironment” (ie, the nonmalignant cells within a tumor) in determining the overall clinical behavior of a malignancy. While quantification of CD68-positive macrophages has potential to be applied to routine clinical practice, prospective data using CD68 as a tool for risk-adapted therapy is lacking.

 

Genetic alterations and amplifications in the 9p24.1 locus have recently been found to be a defining genetic feature of cHL. Amplification of 9p24.1 has been associated with unfavorable outcomes. Amplification of 9p24.1 (which includes the loci encoding the PD-L1 and PD-L2 genes) is more common in patients with advanced stage disease and is associated with shorter PFS.²³

A recent study attempted to integrate several different prognostic factors in cHL patients who were treated with ABVD (adriamycin [doxorubicin], bleomycin, vinblastine, and dacarbazine) and underwent an interim PET (iPET) scan after 2 cycles of ABVD. Focusing on those with a negative iPET scan, it was found that expression of CD68 and PD-1 in microenvironment cells, and STAT1 negativity in HRS cells identified a subset of PET-2 negative patients with a 3-year PFS significantly lower than that of the remaining PET-2 negative population (64% versus 95%). The algorithm correctly predicted the response to treatment in more than half of the patients who had relapse or disease progression despite a negative PET-2 scan. It therefore appears feasible, using tissue biomarkers at diagnosis, to identify patients at increased risk for poor outcome, even if the iPET scan is negative.⁵³

ROLE OF PET/CT IN ASSESSMENT OF RESPONSE TO THERAPY

PET/CT has been increasingly used for response assessment at various stages in lymphoma in recent years. Almost all types of lymphomas are fluorodeoxyglucose (FDG) avid; however, Hodgkin lymphoma is FDG avid in 97% to 100% of cases. In 2009, a 5-point scale was developed to score PET images with regard to treatment response, either partway through treatment (iPET) or at the end of therapy.⁵⁴ It was recommended as the standard reporting tool at the First International Workshop on PET in Lymphoma in Deauville, France, in 2009, and is thus now referred to as the Deauville score. A score of 1 is given if there is no uptake, 2 if the uptake ≤ mediastinum, 3 if > mediastinum but ≤ liver, 4 if uptake moderately higher than liver, 5 if uptake is markedly higher than liver and/or new lesions. X designates new areas of uptake unlikely to be related to lymphoma. In most trials, a score of 1 or 2 is considered a complete response and a score of 4 or 5 is considered a treatment failure. A score of 3 is sometimes considered a complete response, depending on the study. The Deauville criteria have been widely used in newer clinical trials utilizing response-adapted treatment as defined by PET response. PET/CT is recommended for staging and restaging at the end of therapy, in clinical practice, and clinical trials. Interim PET/CT scan, while commonly performed in clinical practice, is only recommended if the results will alter therapy (eg, if that information will result in the clinician omitting radiation therapy [RT] or altering the chemotherapy plan).

Early studies of iPET showed that achieving PET negativity early in the course of treatment was strongly associated with PFS and overall survival.⁵⁵ Subsequent studies confirmed the importance of achieving a negative iPET. As a result, considerable efforts have been put into designing response-adapted treatment approaches using iPET (see Treatment section), with some of these approaches now being listed in the National Comprehensive Cancer Network (NCCN) guidelines and being used in standard practice.

TREATMENT

EVOLUTION OF TREATMENT

The treatment of Hodgkin lymphoma has evolved over the past century, starting with the discovery of RT as effective treatment in the early 20th century. Long-term survival of patients with Hodgkin lymphoma treated with involved-field radiation therapy (IFRT) was first reported in the 1960s.^56,57 Outcomes improved further with the introduction of combined modality treatment (CMT) using chemotherapy and RT, with the overall 5-year relative survival for patients with Hodgkin lymphoma (all stages) treated in 2006–2012 being 85.4% to 87.3%.³ Since the majority of patients are now cured with modern therapy, treatment-related complications have become an important competing cause of mortality. Recent studies have therefore focused on maintaining efficacy while reducing toxicities, and refining the process of selecting patients who might benefit from more aggressive therapy. While RT was the first treatment modality shown to be curative for Hodgkin lymphoma,^56,57 multiple subsequent studies showed that CMT is superior to RT alone in terms of relapse-free survival.^58–63 In the GHSG H8-F trial, the estimated 5-year event-free survival and overall survival rates were significantly higher after 3 cycles of MOPP-ABV (mechlorethamine, vincristine, procarbazine, and prednisone combined with doxorubicin, bleomycin, and vinblastine) plus IFRT than after subtotal nodal radiotherapy alone. The 10-year overall survival estimates were 97% and 92%, respectively (P = 0.001).⁶⁴ As a result, CMT replaced RT alone as the standard of care for limited-stage Hodgkin lymphoma. However, for elderly or infirm patients, or those with other comorbidities making them poor chemotherapy candidates, RT alone may be a very reasonable option.⁶⁵ More recently, an increasing body of evidence has accumulated to support the use of chemotherapy alone in early stage cHL. This literature has consistently shown that omission of RT is associated with a modest increase in relapse, without a clear compromise in long-term overall survival. For some patients, the trade-off in terms of avoiding radiation (and the associated late effects) may be worth the small increase in relapse risk, since long-term survival does not appear to be substantially worse with chemo-therapy alone. Table 3 and Table 4 provide a summary of recent key studies which have defined treatment options for early-stage cHL.^48,66–71

 

 

EARLY-STAGE NLPHL

NLPHL usually presents with limited-stage disease without B symptoms and has an indolent course with a slightly better prognosis compared to cHL.⁷² Due to the rarity of the disease, treatment guidelines are mostly based on retrospective analyses from single or multi-institution studies or subgroup analyses, often with relatively short follow-up. These studies must be interpreted with caution because of the possibility of inaccuracies in the pathologic diagnosis, small sample sizes, and selection bias. Treatment options for limited-stage NLPHL include observation, single-agent rituximab, IFRT (or involved-site radiation therapy [ISRT]) alone, or CMT.⁴⁶

Historically, patients with limited-stage NLPHL have been treated with RT alone, with 80% to 85% PFS and 85% to 95% overall survival rates.^73–75 Patients who relapse or progress after RT in general can successfully undergo salvage therapy.⁷⁴ In one study, rates of PFS and overall survival were similar among patients who had limited-field, regional-field, or extended-field RT,⁷⁵ indicating that IFRT is preferred. Studies comparing RT alone and CMT are limited. The GHSG HD7 trial included a subset of NLPHL patients, with a trend towards improved freedom from treatment failure (96% versus 83%) favoring CMT. This, however, did not translate into improved overall survival.⁴⁷ A retrospective analysis of the British Columbia Cancer Agency database compared patients with limited-stage NLPHL treated with RT alone to patients who received 2 cycles of ABVD followed by RT. A significant improvement in PFS (91% versus 65%) and overall survival (93% versus 84%) was seen, favoring CMT.⁷⁶

Chemotherapy alone is not recommended for limited-stage NLPHL since studies evaluating chemotherapy alone are quite limited and indicate relatively high rates of treatment failure. Given that the malignant cells in NLPHL are CD20-positive, single-agent rituximab has also been studied in this disease, including a study as frontline therapy in limited-stage patients. In this phase 2 trial in newly diagnosed patients with stage IA disease, an overall response rate (ORR) of 100% was seen, with an 85% complete response (CR) rate.⁷⁷ At 3 years, overall survival was 100% and PFS was 81%, indicating that the responses with single-agent rituximab are less durable than those with RT.

Advani et al evaluated rituximab followed by observation versus rituximab (R) followed by maintenance rituximab (MR) for 2 years in 39 new or previously treated patients. At 4 weeks the ORR was 100% (with CR in 67%, and partial response in 33%). At a median follow up of 9.8 years for R alone, and 5 years for R+MR, median PFS was 3 and 5.6 years, respectively (P = 0.26). Estimated 5-yr PFS and overall survival in patients treated with R versus R+MR were 39.1% and 95.7% versus 58.9% and 85.7%, with Pvalues of 0.26 (PFS) and 0.38 (overall), respectively. Maintenance rituximab therefore appears to prolong remission, although the results did not quite reach statistical significance.⁷⁸ Even though rituximab does not appear to be curative in NLPHL, it is a reasonable option for patients with early-stage NLPHL who are not good candidates for definitive RT. Whether combining rituximab with RT or CMT might further improve outcomes in early-stage NLPHL has not yet been determined.

In children, surgery alone may lead to long-term remission or possibly cure of limited-stage NLPHL. In a European multicenter retrospective study, 58 patients underwent surgery for limited-stage NLPHL. Among the 51 patients who achieved complete remission following surgery, 67% remained progression-free and 100% were alive at a median follow up of 43 months.⁷⁹ In adults, there is no data to support surgical treatment alone for NLPHL. Finally, observation may be a reasonable option in elderly or infirm patients for whom NLPHL is unlikely to affect life expectancy. For younger patients, given the excellent outcome with modern therapy and the long-term risk of transformation of NLPHL into an aggressive non-Hodgkin lymphoma, observation is generally not recommended.

The NCCN recommends RT (ISRT or IFRT, 30–36 Gy) as the preferred treatment for stage IA and IIA non-bulky NLPHL. In patients with stage IA disease with complete excision of solitary nodule, observation may be appropriate. A course of chemotherapy with ISRT with or without rituximab is recommended for patients with stage IB or IIB disease, or patients with stage IA or IIA bulky disease.

 

FIRST-LINE TREATMENT OF LIMITED-STAGE CHL

Early-Stage Favorable cHL

There is lack of consensus regarding the ideal treatment approach for patients with early-stage favorable cHL. However, there are several excellent options available, with overall survival rates exceeding 90%. Most of these regimens involve CMT, although some chemotherapy-alone approaches have been evaluated as well. Concurrent with the demonstration of excellent long-term remission rates with CMT, it became apparent that the long-term survival and quality of life of these patients is determined in large part by the risk of serious (and potentially fatal) treatment-related toxicities. Such toxicities consist primarily of secondary malignancies and cardiovascular events, and can continue to cause significant morbidity and mortality even 2 to 3 decades after treatment.^80–82 As a result, treatment decisions for these patients are complicated and require balancing efficacy against risk of late complications.

In the United States, until recently, CMT was generally considered the standard of care, with robust long-term data regarding efficacy. The most commonly used regimen has been ABVD for 2 to 4 cycles followed by IFRT. In some German studies, escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) has been used, but this is not a general standard of care in the United States for early-stage patients.

More recent data suggests that the rate of serious late complications in Hodgkin lymphoma patients is decreasing, likely due to less extensive radiation fields, lower radiation doses, and a movement away from the MOPP regimen to ABVD.^83,84 For patients who meet the “favorable” criteria set forth in the GHSG HD10 trial (see Table 2), 2 cycles of ABVD followed by 20 Gy of IFRT is an attractive option, with efficacy preserved and a low anticipated rate of late effects.⁶⁶ With this approach, and with long-term (10 years) follow up, all 4 arms had similar PFS (87%) and overall survival (94%), whether 2 or 4 cycles of ABVD were given. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure or overall survival. Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT.^66,71

In recent years, in an attempt to reduce late effects further, regimens consisting of chemotherapy alone have been investigated. In a study by Meyer et al, at 12 years the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal RT; the rates of freedom from disease progression were 87% and 92% in the 2 groups; and the rates of event-free survival were 85% and 80%, respectively.⁵⁰ However, it is important to note that this study did not include a CMT arm for the early favorable patients, and did not utilize modern RT techniques. Nevertheless, this early study and others⁶⁰ suggested that chemotherapy alone may be a reasonable option for some early-stage cHL patients, particularly for patients who are felt to be at increased risk for late toxicities from RT. As a result, additional studies have been conducted evaluating CMT versus chemotherapy alone for early-stage cHL. Many of these studies have incorporated interim PET/CT scan to develop a response-adapted approach to decide which patients are least likely to benefit from RT.

The HD-13 study was a follow-up study for HD-10, looking at deletion of bleomycin, dacarbazine, or both from the ABVD backbone. The ABD arm was closed early, because of an excess rate of treatment failure. Among the 1243 patents assigned to either the ABVD or AVD arm at 5 years of follow-up, there was 4.3% difference in PFS. This study was not able to demonstrate that 2 cycles of AVD was noninferior to 2 cycles of ABVD, each followed by 30 Gy IFRT, even though there was no difference in all 4 groups. It confirmed 2 cycles of ABVD as the preferred regimen in early favorable Hodgkin lymphoma, when CMT is the plan of care. However, for patients over age 60 to 65 years, or those with underlying cardiac or pulmonary comorbidities, bleomycin has significant risk of toxicity. In that setting, AVD is a safer option, with only a very modest decrease in 5-year PFS.

Based on the observation that iPET scan is highly predictive of outcome in Hodgkin lymphoma,^55,85 several trials have employed the use of an iPET scan to guide therapy. It is hoped that such studies will lead to new PET-directed treatment algorithms in which patients who require more aggressive therapy (eg, with CMT, or escalated BEACOPP) can be identified, and the remaining patients can be safely treated less aggressively (eg, with chemotherapy alone).

In the EORTC H10 trial, performed to evaluate treatment adaptation on the basis of iPET scan results in stage I and II Hodgkin lymphoma, a control arm received standard combined modality treatment (3 or 4 cycles of ABVD with INRT) irrespective of PET scan results. In the experimental arm, patients with a negative PET scan after 2 cycles of ABVD continued with 1 or 2 cycles of ABVD and did not receive RT. The iPET-positive patients received either standard treatment with ABVD plus INRT or escalated BEACOPP plus INRT. The iPET-negative patients received either ABVD only or ABVD plus INRT. The final results of this study, published recently, showed that in the iPET-positive patients the 5-year PFS was improved from 77.4% with standard ABVD plus INRT to 90.6% with escalated BEACOPP plus INRT (P = 0.002). In iPET-negative patients, 5-year PFS in the favorable group was 99% versus 87.1% in favor of ABVD plus INRT. The H10 study suggested that PET results after 2 cycles of ABVD can be integrated into treatment planning, In iPET-negative patients, the study was technically not able to demonstrate the noninferiority of the ABVD only regimen, owing to a higher risk of relapse if INRT is omitted, particularly in the favorable group.⁴⁸ However, this study does show that excellent outcomes can be obtained with omission of RT in patients with a negative iPET scan. This study provides a cautionary lesson though, in that the increase in relapse rate associated with omission of RT was more substantial (12%) for favorable versus unfavorable early-stage patients (2.5%), and this difference was only apparent after longer (5 years) follow-up. Despite this, chemotherapy alone is considered a reasonable treatment option, especially for patients felt to be at increased risk for late toxicities of RT or for patients who wish to avoid the risks of RT, with over 99% of patients alive at 5 years.

 

Similar results were shown in the RAPID trial, in which patients with limited-stage cHL underwent 3 cycles of ABVD followed by PET assessment.⁶⁷ Patients with a negative PET (n = 426) were then randomized to RT (n = 209) versus no further therapy (n = 211). At a median of 60 months of follow-up, 3-year PFS was 94.6% in the RT group and 90.8% in the chemotherapy alone group. Similar to the H10 trial, it was concluded that chemotherapy alone was statistically inferior to CMT in terms of PFS. However, also similar to the H10 trial, the RAPID trial demonstrated that excellent results can be obtained in early-stage cHL patients with omission of RT, if iPET scan is negative after 3 cycles of ABVD, as there was no survival difference. These findings indicate that, when relapses occur as a result of omission of RT, such patients can be effectively treated later.

In the ongoing GHSG HD16 trial, patients with early-stage favorable cHL will be randomly assigned to a standard approach (ABVD × 2 cycles followed by 20-Gy IFRT) versus an experimental approach in which they receive ABVD for 2 cycles and then undergo PET scan. If the PET remains positive, they will receive 20-Gy IFRT. If the PET is negative, they will receive no further therapy. This trial could ultimately define ABVD for 2 cycles as a treatment option.

It is clear from these studies that omission of RT results in a somewhat higher rate of relapse but can be considered in selected patients. However, taking a less aggressive frontline approach may also be justified by the fact that, for those who do relapse, successful salvage therapies are available. Aggressive salvage therapy with autologous stem cell transplantation historically can cure approximately 50% of relapsed patients. With new and emerging therapies for relapsed disease, such as brentuximab vedotin and the PD-1 inhibitors (eg, nivolumab and pembrolizumab), the ability to cure relapsed patients may improve even more, further calling into question the practice of applying CMT uniformly for early-stage patients undergoing first-line therapy. Unfortunately, there is insufficient data from large randomized studies with long-term follow-up to fully address this issue currently, and there remains some controversy around this issue. NCCN recommends restaging PET/CT after 3 cycles of ABVD if a chemotherapy alone treatment modality is chosen. If the Deauville score is 1 or 2, either observation or 1 additional cycle of ABVD is recommended.⁴⁶

Early-Stage Unfavorable cHL

In the United States, historically early-stage unfavorable Hodgkin lymphoma has been treated with CMT, most commonly 4 to 6 cycles of ABVD followed by consolidative RT. With this approach one can expect a 5-year PFS of approximately 80% to 85%.^58,64,86 The GHSG HD8 trial showed that RT volume size reduction from extended-field to involved-field after COPP + ABVD chemotherapy for 2 cycles produced similar results and less toxicity in patients with early-stage unfavorable cHL.⁸⁶ The GHSG trial HD11 established ABVD for 4 cycles plus 30-Gy IFRT as a standard for early unfavorable Hodgkin lymphoma. The freedom from treatment failure at 5 years was 85.0%, and overall survival was 94.5%.⁶⁸

In the HD14 study by the GHSG, patients with early unfavorable cHL were treated with 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD, versus 4 cycles of ABVD. All patients then received 30 Gy of consolidative IFRT. A 5-year PFS of 95% was seen in the experimental arm, compared with 89% in the standard (ABVD) arm. As expected, this regimen was associated with more acute hematologic toxicity, and there was no difference between the 2 regimens with respect to overall survival or fertility.⁶⁹ Given the lack of improved survival and increased toxicity, ABVD has remained the standard chemotherapy regimen for early unfavorable cHL in the United States. NCCN recommends a restaging PET scan after 2 cycles of ABVD and to continue with 2 to 4 cycles of ABVD or escalated BEACOPP with or without ISRT based on Deauville scores.

Another viable treatment option is the Stanford V regimen, a condensed, 12-week regimen that includes mechlorethamine, doxorubicin, vinblastine, prednisone, vincristine, etoposide, and bleomycin, followed by IFRT.⁸⁷ In a randomized phase 3 trial conducted by ECOG (E2496), patients with stage I/II Hodgkin lymphoma with bulky mediastinal disease or advanced-stage disease were randomized to ABVD × 6 to 8 cycles versus Stanford V. RT was given (36 Gy) for those with bulky mediastinal disease or to sites of disease greater than 5 cm in the Stanford V arm. In a subset analysis focusing only on those with stage I/II bulky mediastinal disease, the 5-year failure free survival was 85% versus 79% and the 5-year overall survival was 96% versus 92% for the ABVD versus Stanford V arms, respectively. These differences were not statistically significant.⁷⁰ While the Stanford V regimen has the advantages of a 12-week treatment duration and a lower cumulative amount of bleomycin and doxorubicin, the Stanford V arm had higher rates of grade 3 lymphopenia and grade 3 to 4 peripheral neuropathies. In addition, Stanford V requires that most patients undergo RT (to original sites of disease measuring 5 cm or more plus contiguous areas). As a result, the investigators concluded that ABVD × 4 cycles plus IFRT remains the standard of care for patients with early unfavorable Hodgkin lymphoma with bulky mediastinal disease.

 

Other regimens have been studied in hopes of reducing toxicity, including the EVE regimen (epirubicin, vinblastine, and etoposide). This regimen was compared to ABVD in early unfavorable Hodgkin lymphoma patients, with all patients undergoing the same RT program. No differences were observed between the ABVD and EVE arms in terms of complete remission rate and overall survival. However, patients who received EVE had a significantly worse outcome than those who received ABVD in terms of relapse-free survival and failure-free survival.⁸⁸ EBVP (epirubicin, bleomycin, vinblastine, and prednisone) followed by IFRT was less efficacious compared with MOPP/ABV–type therapy.⁵⁸

An area of active investigation is whether RT can be safely omitted in patients with early- stage unfavorable cHL. The EORTC H10 study showed that, for patients with a negative iPET scan (after 2 cycles), the 5-year PFS rates were 92.1% versus 89.6% for ABVD plus INRT versus ABVD alone, respectively. While this technically did not meet criteria for noninferiority of ABVD alone, this study demonstrated that, for those with negative iPET, ABVD × 6 cycles (without radiation) can result in long-term remission in a high proportion (89%) of patients. For iPET-positive patients, 2 cycles of escalated BEACOPP were given followed by 30 Gy of IFRT on the experimental arm. This resulted in a 5-year PFS of 90.6% versus 77.4%, suggesting this may be a preferred approach for early-stage unfavorable patients with a positive iPET.⁴⁸ Even though the noninferiority of ABVD alone could not be established based on the statistical design of the study, the current NCCN guidelines recommend restaging after 2 cycles of ABVD for stage I or II unfavorable cHL and using that iPET as a guide, based on Deauville scores. For scores 1–3, ABVD × 2 cycles (total 4 cycles) plus ISRT or AVD × 4 (total 6) with or without ISRT is recommended. For a Deauville score of 4, escalated BEACOPP × 2 cycles or ABVD × 2 cycles (total 4) followed by ISRT is recommended. If the Deauville score is 5, further treatment decisions should be made based on repeat biopsy results. A follow up PET/CT is recommended for Deauville scores of 4 and 5 to confirm complete response.⁴⁶

LATE EFFECTS AND THE EVOLUTION OF RADIATION THERAPY

The RT given in Hodgkin lymphoma has evolved considerably over the years, from extended field or subtotal nodal fields developed in the 1960s, to the more focused involved-field or even involved-site radiation commonly given now. This approach reduces radiation volumes, and it already is becoming evident that the relative risk of breast cancer among young females receiving mediastinal RT for Hodgkin lymphoma is declining.⁸⁹ Cardiac dose is reduced significantly with IFRT compared to older radiation techniques as well. The extent of radiation may be reduced even further with involved-nodal/involved site or intensity-modulated approaches.⁹⁰

With new RT techniques allowing for more focused therapy and lower doses of radiation, models predict that the rate of long-term complications will decline further.^91,92 Furthermore, response-adapted (ie, PET-directed) approaches, as discussed in detail earlier in the article, are expected to increasingly allow for identification of patients who can safely avoid radiation entirely, which will hopefully lead to an even lower rate of late complications of therapy.

MONITORING FOR RELAPSE

A number of recent studies have shown that, for patients who achieve complete remission with first-line therapy, performing repeated scheduled surveillance imaging does not improve outcomes. In fact, most relapses are detected by the patient (due to symptoms or recurrence of lymph node enlargement). It is rare that a relapse would be detected by surveillance imaging alone. Furthermore, surveillance that includes routine imaging has not been associated with improved survival.⁹³ As a result, it is now recommended that patients undergo regular follow-up with symptom review, physical exam, and basic laboratory studies. Imaging studies should be obtained as needed for patients who develop signs, symptoms, exam findings, or laboratory values concerning for relapse.

More important than scheduled surveillance imaging for relapse is monitoring for late effects of therapy. These fall into several broad categories such as cardiovascular disease (coronary disease, congestive heart failure, valvular disease, carotid artery disease), pulmonary disease, hypothyroidism, and secondary malignancies. Aggressive surveillance for breast cancer is especially warranted in female patients who underwent chest radiation.⁴⁶

CONCLUSION

Hodgkin lymphoma is characterized pathologically by the presence of HRS cells accompanied by a polymorphous cellular infiltrate. It is a disease with a bimodal age distribution, several pathologic subtypes, and numerous treatment options. Overall, the prognosis for patients with early-stage disease is excellent, and although a majority of patients can now be cured, further studies are needed to optimize treatment such that short- and long-term treatment-related toxicities are minimized, without compromising disease control and cure.