Timothy S. Fenske

Article Type

Article

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Fri, 01/04/2019 - 10:51

Author(s)

Ravi Kishore Narra, MD

Jasleen Randhawa, MD

Timothy S. Fenske

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.

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Hospital Physician: Hematology/Oncology - 12(5)

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