Leukemia, Myelodysplasia, Transplantation

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Introduction

Acute myeloid leukemia (AML) comprises a heterogeneous group of disorders characterized by proliferation of clonal, abnormally differentiated hematopoietic progenitor cells of myeloid lineage that infiltrate the bone marrow, blood, and other tissues.¹ In most cases, AML is rapidly fatal if left untreated. Over the past 2 decades, our understanding of the underlying disease biology responsible for the development of AML has improved substantially. We have learned that biological differences drive the various clinical, cytogenetic, and molecular subentities of AML; distinguishing among these subentities helps to identify optimal therapies, while offering improved clinical outcomes for select groups. After years of stagnation in therapeutic advances, 4 new drugs for treating AML were approved by the US Food and Drug Administration (FDA) in 2017. In this article, we review key features of AML diagnosis and management in the context of 2 case presentations.

Epidemiology and Risk Factors

An estimated 21,380 new cases of AML were diagnosed in the United States in 2017, constituting roughly 1.3% of all new cases of cancer.² Approximately 10,590 patients died of AML in 2017. The median age of patients at the time of diagnosis is 68 years, and the incidence is approximately 4.2 per 100,000 persons per year. The 5-year survival for AML has steadily risen from a meager 6.3% in 1975 to 17.3% in 1995 and 28.1% in 2009.² The cure rates for AML vary drastically with age. Long-term survival is achieved in approximately 35% to 40% of adults who present at age 60 years or younger, but only 5% to 15% of those older than 60 years at presentation will achieve long-term survival.³

Most cases of AML occur in the absence of any known risk factors. High-dose radiation exposure, chronic benzene exposure, chronic tobacco smoking, and certain chemotherapeutics are known to increase the risk for AML.⁴ Inconsistent correlations have also been made between exposure to organic solvents, petroleum products, radon, pesticides, and herbicides and the development of AML.⁴ Obesity may also increase AML risk.⁴

Two distinct subcategories of therapy-related AML (t-AML) are known. Patients who have been exposed to alkylating chemotherapeutics (eg, melphalan, cyclophosphamide, and nitrogen mustard) can develop t-AML with chromosomal 5 and/or 7 abnormalities after a latency period of approximately 4 to 8 years.⁵ In contrast, patients exposed to topoisomerase II inhibitors (notably etoposide) develop AML with abnormalities of 11q23 (leading to MLL gene rearrangement) or 21q22 (RUNX1) after a latency period of about 1 to 3 years.⁶ AML can also arise out of other myeloid disorders such as myelodysplastic syndrome and myeloproliferative neoplasms, and other bone marrow failure syndromes such as aplastic anemia.⁴ Various inherited or congenital conditions such as Down syndrome, Bloom syndrome, Fanconi anemia, neurofibromatosis 1, and dyskeratosis congenita can also predispose to the development of AML. A more detailed listing of conditions associated with AML can be found elsewhere.⁴

Molecular Landscape

The first cancer genome sequence was reported in an AML patient in 2008.⁷ Since then, various elegantly conducted studies have expanded our understanding of the molecular abnormalities in AML. The Cancer Genome Atlas Research Network analyzed the genomes of 200 cases of de novo AML in adults.⁸ Only 13 mutations were found on average, much fewer than the number of mutations in most adult cancers. Twenty-three genes were commonly mutated, and another 237 were mutated in 2 or more cases. Essentially, all cases had at least 1 nonsynonymous mutation in 1 of 9 categories of genes: transcription-factor fusions (18%), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), spliceosome-complex genes (14%), and cohesin-complex genes (13%).

In another study, samples from 1540 patients from 3 prospective trials of intensive chemotherapy were analyzed to understand how genetic diversity defines the pathophysiology of AML.⁹ The study authors identified 5234 driver mutations from 76 genes or genomic regions, with 2 or more drivers identified in 86% of the samples. Eleven classes of mutational events, each with distinct diagnostic features and clinical outcomes, were identified. Acting as an internal positive control in this analysis, previously recognized mutational and cytogenetic groups emerged as distinct entities, including the groups with biallelic CEBPA mutations, mutations in NPM1, MLL fusions, and the cytogenetic entities t(6;9), inv(3), t(8;21), t(15;17), and inv(16). Three additional categories emerged as distinct entities: AML with mutations in genes encoding chromatin, RNA splicing regulators, or both (18% of patients); AML with TP53 mutations, chromosomal aneuploidies, or both (13%); and, provisionally, AML with IDH2R172 mutations (1%). An additional level of complexity was also revealed within the subgroup of patients with NPM1 mutations, where gene–gene interactions identified co-mutational events associated with both favorable or adverse prognosis.

Further supporting this molecular classification of AML, a study that performed targeted mutational analysis of 194 patients with defined secondary AML (s-AML) or t-AML and 105 unselected AML patients found that the presence of mutations in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 (all members of the chromatin or RNA splicing families) was highly specific for the diagnosis of s-AML.¹⁰ These findings are particularly clinically useful in those without a known history of antecedent hematologic disorder. These mutations defining the AML ontogeny were found to occur early in leukemogenesis, persist in clonal remissions, and predict worse clinical outcomes. Mutations in genes involved in regulation of DNA modification and of chromatin state (commonly DNMT3A, ASXL1, and TET2) have also been shown to be present in preleukemic stem or progenitor cells and to occur early in leukemogenesis.³ Unsurprisingly, some of these same mutations, including those in epigenetic regulators (DNMT3A, ASXL1, and TET2) and less frequently in splicing factor genes (SF3B1, SRSF2), have been associated with clonal hematopoietic expansion in elderly, seemingly healthy adults, a condition termed clonal hematopoiesis of indeterminate potential (CHIP).^3,11,12 The presence of CHIP is associated with increased risk of hematologic neoplasms and all-cause mortality, the latter being possibly driven by a near doubling in the risk of coronary heart disease in humans and by accelerated atherosclerosis in a mouse model.^11,13,14

Clinical Presentation and Work-up

Case Patient 1

A 57-year-old woman with a history of hypertension presents to the emergency department with complaints of productive cough and fevers for the previous 3 days. Examination reveals conjunctival pallor, gingival hyperplasia, and decreased breath sounds at the posterior right lung field. Investigations reveal a white blood cell (WBC) count of 51,000/µL with 15% blasts, a hemoglobin of 7.8 g/dL, and a platelet count of 56 × 10³/µL. Peripheral blood smear is notable for large myeloblasts with occasional Auer rods. Chest radiograph shows a consolidation in the right lower lobe.

Case Patient 2

A 69-year-old man presents to his primary care physician for evaluation of worsening fatigue for the previous 4 months. Ten years prior to presentation, he had received 6 cycles of RCHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) as treatment for diffuse large B-cell lymphoma. Conjunctival pallor, patches of purpura over the extremities, and mucosal petechiae are noted on examination. Laboratory analyisis reveals a WBC count of 2400/µL with 12% blasts, hemoglobin of 9.0 g/dL, and platelet count of 10 × 10³/µL. Peripheral smear shows dysplastic myeloid cells and blasts.

Clinical Features

Patients with AML typically present with features secondary to proliferation of blasts (ie, findings of bone marrow failure and end organ damage).^4,5 Fatigue, pallor, dizziness, dyspnea, and headaches occur secondary to anemia. Easy and prolonged bruising, petechiae, epistaxis, gingival bleeding, and conjunctival hemorrhages result from thrombocytopenia. Bleeding from other sites such as the central nervous system and gastrointestinal tract occurs but is uncommon. Patients may also present with infections resulting from unrecognized neutropenia. Constitutional symptoms including anorexia, fevers, and weight loss are frequently reported, while organomegaly (hepatomegaly and/or splenomegaly) is seen in about a quarter of patients.⁴ Infiltration of blasts into almost every organ has been noted, a condition known as myeloid (or granulocytic) sarcoma.¹⁵ This condition is more commonly found in patients with blastic, monoblastic, or myelomonocytic variants of AML, and is known as isolated myeloid sarcoma if no concurrent marrow or blood involvement is identified. In the absence of induction chemotherapy, systemic involvement occurs in a matter of weeks to months following such presentation.¹⁶

Laboratory analysis will usually demonstrate derangements in peripheral blood cell lines. At least half of patients have a total WBC count less than 5000/µL, a platelet count less than 50 × 10³/µL, or both at the time of diagnosis.^4,17 Approximately 10% of patients present with hyperleukocytosis and a WBC count greater than 100,000/µL, which can be associated with leukostasis.⁵ Additionally, spontaneous electrolyte derangement consistent with tumor lysis syndrome and coagulation abnormalities found in disseminated intravascular coagulation may be noted, even before initiation of therapy.

Work-Up of Suspected AML

Bone marrow biopsy and aspirate, along with touch preparations of the core biopsy sample, are crucial in the workup of suspected AML. At least 200 WBCs on blood smears and 500 nucleated cells on spiculated marrow smears should be counted.³ Reactivity with specific histochemical stains (myeloperoxidase, Sudan black B, or naphthyl AS-D-chloroacetate), presence of Auer rods, and reactivity to monoclonal antibodies against epitopes present on myeloblasts (eg, CD13, CD33, CD117) help distinguish myeloblasts from lymphoblasts.⁴ Flow cytometric analysis helps in confirming myeloid lineage; blasts generally express CD34 and HLA-DR, markers of immature hematopoietic precursors, and dim CD45 (common leukocyte antigen). One or more lymphoid antigens may be aberrantly expressed as well. Of note, in about 2% to 3% of acute leukemia cases, immunohistochemistry and/or flow cytometry findings demonstrate immature cells with features of both myeloid and lymphoid lineages (biphenotypic) or different populations of myeloid and lymphoid leukemia cells (bilineal). These leukemias are termed mixed-phenotype acute leukemia and are typically treated with either AML or acute lymphoblastic leukemia regimens.¹⁸

Cytogenetics, as assessed through conventional karyotype and fluorescence in situ hybridization (FISH), constitutes an essential part of the work-up. Eight balanced translocations and inversions and their variants are included in the World Health Organization (WHO) category “AML with recurrent genetic abnormalities,” while 9 balanced rearrangements and multiple unbalanced abnormalities in the presence of a blast count ≥ 20% are sufficient to establish the diagnosis of “AML with myelodysplasia-related changes.”^3,19 Various other gene rearrangements thought to represent disease-initiating events are recognized as well, but these rearrangements do not yet formally define WHO disease categories.³ FISH can help detect RUNX1-RUNX1T1, CBFB-MYH11, KMT2A (MLL), and MECOM (EVI1) gene fusions, as well as chromosomal changes like 5q, 7q, or 17p, especially when fewer than 20 metaphases are assessable (due to failure of culture) by conventional cytogenetic methods.³

As certain molecular markers help with disease prognosis and the selection of personalized therapies, testing for these markers is recommended as part of a complete work-up of AML. The current standard of care is to test for nucleophosmin (NPM1), fms-like tyrosine kinase 3 (FLT3), and CEBPA mutations in all newly diagnosed patients.¹RUNX1 mutation analysis should also be considered as its presence defines a provisional WHO subcategory.¹⁹ In the case of FLT3, the analysis should include both internal tandem duplications (FLT3-ITD, associated with worse prognosis especially at high allelic ratio) and tyrosine-kinase domain mutations (FLT3-TKD; D835 and I836), especially now that FLT3 inhibitors are regularly used.²⁰ Most academic centers now routinely use next-generation sequencing–based panels to assess multiple mutations.

By considering gene interactions, this approach provides the physician with a more nuanced understanding of the prognosis and informs the selection of therapies either at the time of diagnosis or at the time of relapse.^9,21,22 Mutations of TP53 and ASXL1, for example, are consistently associated with worse prognosis and are now included along with FLT3, NPM1, CEBPA, and TP53 in the National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) risk stratification schemas (Table 1).³

Diagnosis and Classification

A marrow or blood blast (myeloblasts, monoblasts, megakaryoblasts, or promonocytes [considered blast equivalents]) count of ≥ 20% is required for AML diagnosis.^3,19 The presence of t(15;17), t(8;21), inv(16), or t(16;16), however, is considered diagnostic of AML irrespective of blast count.^3,19 The previously used French-American-British (FAB) classification scheme has been replaced by the WHO classification (Table 2), which takes into account the morphologic, cytogenetic, genetic, and clinical features of the leukemia.

Six groups of AML are recognized under this scheme. “AML with recurrent genetic abnormalities” accounts for about 20% to 30% of all AML cases and contains the most distinct genetic abnormalities of prognostic significance.^19,23 AML with t(8;21) and AML with inv(16) or t(16;16), the 2 forms of core-binding factor AML seen in about 10% to 15% of patients, fall under this group and have a relatively good prognosis. The presence of c-KIT mutation is, however, an adverse prognostic feature in these core-binding factor AMLs.²⁴ Overall, this group includes 8 cytogenetically defined abnormalities, 1 molecular abnormality (AML with mutated NPM1), and 2 other provisional entities (AML with biallelic mutations of CEBPA and AML with mutated RUNX1).

The category “AML with myelodysplasia-related changes” includes AML that has evolved out of an antecedent myelodysplastic syndrome, has ≥ 50% dysplasia in 2 or more lineages, or has myelodysplasia-related cytogenetic changes (eg, –5/del(5q), –7/del(7q), ≥ 3 cytogenetic abnormalities).¹⁹ “Therapy-related myeloid neoplasm,” or therapy-related AML, is diagnosed when the patient has previously received cytotoxic agents or ionizing radiation.¹⁹

Cases which do not meet the criteria for 1 of the previously mentioned categories are currently classified as “AML, not otherwise specified.” Further subclassification is pursued as per the older FAB scheme; however, no additional prognostic information is obtained in doing so.^3,19 Myeloid sarcoma is strictly not a subcategory of AML. Rather, it is an extramedullary mass of myeloid blasts that effaces the normal tissue architecture.¹⁶ Rarely, myeloid sarcoma can be present without systemic disease involvement; it is important to note that management of such cases is identical to management of overt AML.¹⁶

Finally, myeloid proliferations related to Down syndrome include 2 entities seen in children with Down syndrome.¹⁹Transient abnormal myelopoiesis, seen in 10% to 30% of newborns with Down syndrome, presents with circulating blasts that resolve in a couple of months. Myeloid leukemia associated with Down syndrome is AML that occurs usually in the first 3 years of life and persists if not treated.¹⁹

Case 1 Continued

The presence of 15% blasts in the peripheral blood is concerning for, but not diagnostic of, AML. On the other hand, the presence of Auer rods is virtually pathognomonic for AML. Gingival hyperplasia in this patient may be reflective of extramedullary disease. Cytogenetics from the peripheral blood and marrow aspirate show inv(16) in 20 of 20 cells. Molecular panel is notable for mutation in c-KIT. As such, the patient is diagnosed with core-binding factor AML, which per the ELN classification is considered a favorable-risk AML. The presence of c-KIT mutation, however, confers a relatively worse outcome.

Case 2 Continued

Presence of pancytopenia in a patient who previously received cytotoxic chemotherapy is highly concerning for therapy-related myeloid neoplasm. The presence of 12% blasts in the peripheral blood does not meet the criteria for diagnosis of AML. However, marrow specimens show 40% blasts, thus meeting the criteria for an AML diagnosis. Additionally, cytogenetics are notable for the presence of monosomy 7, while a next-generation sequencing panel shows a mutation in TP53. Put together, this patient meets the criteria for therapy-related AML which is an adverse-risk AML according to the ELN classification.

Management

The 2 most significant factors that must be considered when selecting AML therapies are the patient’s suitability for intensive chemotherapy and the biological characteristics of the AML. The former is a nuanced decision that incorporates age, performance status, and existing comorbidities. Treatment-related mortality calculators can guide physicians when making therapy decisions, especially in older patients (≥ 65 years). Retrospective evidence from various studies suggests that older, medically fit patients may derive clinically comparable benefits from intensive and less intensive induction therapies.²⁵^–²⁷ The biological characteristics of the leukemia can be suggested by morphologic findings, cytogenetics, and molecular information, in addition to a history of antecedent myeloid neoplasms. Recently, an AML composite model incorporating an augmented Hematopoietic Cell Transplantation–specific Comorbidity Index (HCT-CI) score, age, and cytogenetic/molecular risks was shown to improve treatment decision-making about AML; this model potentially could be used to guide patient stratification in clinical trials as well.²⁸ The overall treatment model of AML is largely unchanged otherwise. It is generally divided into induction, consolidation, and maintenance therapies.

Induction Therapy

In patients who can tolerate intensive therapies, the role of anthracycline- and cytarabine-based treatment is well established. However, the choice of specific anthracycline is not well established. One study concluded that idarubicin and mitoxantrone led to better outcomes as compared to daunorubicin, while another showed no difference between these agents.^29,30 A pooled study of AML trials conducted in patients aged 50 years and older showed that while idarubicin led to a higher complete remission rate (69% versus 61%), the overall survival (OS) did not differ significantly.³¹ As for dosing, daunorubicin given at 45 mg/m² daily for 3 days has been shown to have lower complete remission rates and higher relapse rates than a dose of 90 mg/m² daily for 3 days in younger patients.^32–34 However, it is not clear whether the 90 mg/m² dose is superior to the frequently used dose of 60 mg/m².³⁵ A French study has shown comparable rates of complete remission, relapse, and OS between the 60 mg/m² and 90 mg/m² doses in patients with intermediate or unfavorable cytogenetics.³⁶

If idarubicin is used, a dose of 12 mg/m² for 3 days is considered the standard. In patients aged 50 to 70 years, there were no statistically significant differences in rates of relapse or OS between daunorubicin 80 mg/m² for 3 days versus idarubicin 12 mg/m² for 3 days versus idarubicin 12 mg/m² for 4 days.³⁷As for cytarabine, the bulk of the evidence indicates that a dose of 1000 mg/m² or higher should not be used.³⁸ As such, the typical induction chemotherapy regimen of choice is 3 days of anthracycline (daunorubicin or idarubicin) and 7 days of cytarabine (100–200 mg/m² continuous infusion), also known as the 7+3 regimen, which was first pioneered in the 1970s. In a recent phase 3 trial, 309 patients aged 60 to 75 years with high-risk AML (AML with myelodysplasia-related changes or t-AML) were randomly assigned to either the 7+3 regimen or CPX-351 (ie, nano-liposomal encapsulation of cytarabine and daunorubicin in a 5:1 molar ratio).³⁹A higher composite complete response rate (47.7% versus 33.3%; P = 0.016) and improved survival (9.56 months versus 5.95 months; hazard ratio [HR] 0.69, P = 0.005) were seen with CPX-351, leading to its approval by the FDA in patients with high-risk AML.

The 7+3 regimen has served as a backbone onto which other drugs have been added in clinical trials—the majority without any clinical benefits—for patients who can tolerate intensive therapy. In this context, the role of 2 therapies recently approved by the FDA must be discussed. In the RATIFY trial, 717 patients aged 18 to 59 years with AML and a FLT3 mutation were randomly assigned to receive standard chemotherapy (induction and consolidation therapy) plus either midostaurin or placebo; those who were in remission after consolidation therapy received either midostaurin or placebo in the maintenance phase.⁴⁰The primary endpoint was met as midostaurin improved OS (HR 0.78, P = 0.009). The benefit of midostaurin was consistent across all FLT3 subtypes and mutant allele burdens, regardless of whether patients proceeded to allogeneic stem cell transplant (allo-SCT). Based on the results of RATIFY, midostaurin was approved by the FDA for treatment of AML patients who are positive for the FLT3 mutation. Whether more potent and selective FLT3 inhibitors like gilteritinib, quizartinib, or crenolanib improve the outcomes is currently under investigation in various clinical trials.²⁰

The development of gemtuzumab ozogamicin (GO) has been more complicated. GO, an antibody-drug conjugate comprised of a CD33-directed humanized monoclonal antibody linked covalently to the cytotoxic agent calicheamicin, binds CD33 present on the surface of myeloid leukemic blasts and immature normal cells of myelomonocytic lineage.⁴¹ The drug first received an accelerated approval in 2000 as monotherapy (2 doses of 9 mg/m² 14 days apart) for the treatment of patients 60 years of age and older with CD33-positive AML in first relapse based on the results of 3 open-label multicenter trials.^41,42However, a confirmatory S0106 trial in which GO 6 mg/m² was added on day 4 in newly diagnosed AML patients was terminated early when an interim analysis showed an increased rate of death in induction (6% versus 1%) and lack of improvement in complete response, disease-free survival, or OS with the addition of GO.⁴³ This study led to the withdrawal of GO from the US market in 2010. However, 2 randomized trials that studied GO using a different dose and schedule suggested that the addition of GO to intensive chemotherapy improved survival outcomes in patients with favorable and intermediate-risk cytogenetics.^44,45 The results of the multicenter, open-label phase 3 ALFA-0701 trial, which randomly assigned 271 patients aged 50 to 70 years with newly diagnosed AML to daunorubicin and cytarabine alone or in combination with GO (3 mg/m² on days 1, 4, and 7 during induction and day 1 of 2 consolidation courses), showed a statistically significant improvement in event-free survival (17.3 months versus 9.5 months; HR 0.56 [95% confidence interval 0.42 to 0.76]).⁴⁵ Again, the survival benefits were more pronounced in patients with favorable or intermediate-risk cytogenetics than in those with unfavorable cytogenetics. The results of this trial led to the re-approval of GO in newly diagnosed AML patients.  

For patients who cannot tolerate intensive therapies, the 2 main therapeutic options are low-dose cytarabine (LDAC) and the hypomethylating agents (HMA) azacitidine and decitabine. A phase 3 trial of decitabine versus mostly LDAC (or best supportive care, BSC) demonstrated favorable survival with decitabine (7.7 months versus 5.0 months).⁴⁶ In the AZA-AML-001 trial, azacitidine improved median survival (10.4 months versus 6.5 months) in comparison to the control arm (LDAC, 7+3, BSC).⁴⁷ Emerging data has also suggested that HMAs may be particularly active in patients with unfavorable-risk AML, a group for which LDAC has been shown to be especially useless.⁴⁸As such, HMA therapies are generally preferred over LDAC in practice. Finally, it is pertinent to note that GO can also be used as monotherapy based on the results of the open-label phase 3 AML-19 study in which GO demonstrated a survival advantage over BSC (4.9 months versus 3.6 months, P = 0.005).⁴⁹

Postremission or Consolidation Therapy

There is no standard consolidation therapy for AML at present. In general, for patients who received HMA in the induction phase, the same HMA should be continued indefinitely until disease progression or allo-SCT.³ For those who received intensive chemotherapy in the induction phase, the consensus is to use cytarabine-based consolidation therapies. Cytarabine given as a single agent in high-doses has generally led to similar outcomes as multiagent chemotherapy.⁵⁰ In this regard, cytarabine regimens, with or without anthracycline, at 3000 mg/m² have similar efficacy as an intermediate dose of 1000 mg/m².³⁸A total of 2 to 4 cycles of post-remission therapy is considered standard.³ Intensified post-remission chemotherapy has not been associated with consistent benefit in older AML patients or those with poor-risk disease. In recent years, measurable residual disease (MRD) assessment has emerged as a potentially useful tool in risk stratification and treatment planning, with various studies suggesting that MRD status in complete remission is one of the most important prognostic factors.⁵¹ Prospective studies confirming the significance of MRD as a marker for therapy selection are awaited. Finally, maintenance chemotherapy is not part of standard AML treatment.³

Role of Stem Cell Transplant

AML is the most common indication for allo-SCT. The availability of alternative donor strategies, which include mismatched, unrelated, haplo-identical, and cord blood donor sources, and the development of non-myeloablative and reduced-intensity conditioning (RIC) regimens (which take advantage of graft-versus-leukemia effect while decreasing cytotoxicity from myeloablative regimens) have expanded the possibility of allo-SCT to most patients under the age of 75 years.³ The decision to perform transplant is now largely based upon assessment of the risk (nonrelapse mortality) to benefit (reduction in risk of relapse) ratio, as determined by both disease-related features (cytogenetics, molecular profile) and clinical characteristics of the donor (type, availability, match) and the recipient (comorbidities, performance status).³ In a meta-analysis of 24 prospective trials involving more than 6000 AML patients in first complete remission, allo-SCT was associated with a significant survival benefit in patients with intermediate- and poor-risk AML but not in patients with good-risk AML.⁵² In line with this, good-risk AML patients are generally not recommended for transplant in first complete remission. For patients with normal karyotype who were said to have de novo AML (historically an intermediate-risk AML group), superior OS was demonstrated with transplant over intensive chemotherapy in those patients with either FLT3-ITD mutations or those with the molecular profile characterized by negativity for mutations in NPM1/CEBPA/FLT3.⁵³ For patients with primary refractory disease and high-risk AML, transplant is probably the only curative option.

The choice of conditioning regimen is guided by several factors, including the subtype of AML, disease status, donor-recipient genetic disparity, graft source, comorbidities in the recipient (ie, tolerability for intensive conditioning regimen), as well as the reliance on graft-versus-leukemia effect as compared to cytotoxic effect of the regimen. The BMT CTN 0901 trial, which randomly assigned 218 patients aged 18 to 65 years to RIC (typically fludarabine/busulfan) or myeloablative regimens, showed an advantage for myeloablative regimens.⁵⁴ The trial demonstrated a lower risk of relapse (13.5% versus 48.3%, P < 0.01) and higher rates of relapse-free survival (67.7% versus 47.3%, P < 0.01) and OS (67.7% versus. 77.4%, P = 0.07) at 18 months despite higher treatment-related mortality (15.8% versus 4.4%, P = 0.02) and a higher rate of grade 2 to 4 acute graft-versus-host disease (44.7% versus 31.6%, P = 0.024). At present, a RIC regimen is generally recommended for older patients or those with a higher comorbidity burden, while the myeloablative regimen is recommended for younger, fit patients.

Relapsed/Refractory Disease

The treatment of relapsed and refractory AML constitutes a major challenge, with OS estimated around 10% at 3 years.⁵⁵ Currently, there is no standard salvage therapy in this setting, thus underscoring the need for clinical trials. For younger, fitter patients, the typical approach is to use intensive chemotherapy to achieve a second complete remission followed by a stem cell transplant. In younger patients, a second complete remission is achievable in about 55% of patients, although this rate is lower (~20%–30%) in more unselected patients.^56,57 About two thirds of those who achieve complete remission may be able to proceed to transplant.⁵⁷ For older patients where transplant is not possible, the goal is to use less intensive therapies that help with palliation. HMAs (azacitidine, decitabine) are used and have complete remission rates of 16% to 21% and median survival of 6 to 9 months in older patients.³ LDAC is another option in this setting. The recent approval of GO in this setting has further expanded the options. This approval was based on the outcomes of the phase 2 single-arm MyloFrance-1 study in which single-agent GO administered at 3 mg/m² on days 1, 4, and 7 led to complete remission in 15 of 57 patients.⁵⁸

With greater elucidation of the molecular characteristics of AML, the emergence of more effective targeted therapies is possible. Enasidenib, an inhibitor of mutant isocitrate dehydrogenase 2 (IDH2) protein that promotes differentiation of leukemic myeloblasts, recently received regulatory approval based on a single-arm trial. The overall response rate in this study was 38.5%, including a composite complete remission rate of 26.6% at a dose of 100 mg daily.⁵⁹ IDH differentiation syndrome, akin to the differentiation syndrome seen in acute promyelocytic leukemia, occurred in approximately 12% of the patients, with the most frequent manifestations being dyspnea, fever, pulmonary infiltrates, and hypoxia.⁶⁰

Survival of patients who relapse following transplant is particularly poor. A recent Center for International Blood and Marrow Transplant Research study found a 3-year OS ranging from a dismal 4% for those who present with early relapses (within 1 to 6 months) post-transplant to a more modest 38% for those who relapsed ≥ 3 years after their first transplant.⁶¹ The German Cooperative Transplant Study Group have suggested that azacitidine or chemotherapy followed by donor-lymphocyte infusions might improve responses over chemotherapy alone.⁶² Ipilimumab-based CTLA-4 blockade was reported to produce responses in a small cohort of patients, which was particularly notable in patients presenting with extramedullary manifestations of relapse.⁶³ In patients who are otherwise fit but have a florid relapse, a second transplant can sometimes be sought, but the value of a different donor for second transplant is unclear.³

Case 1 Conclusion

Given his relatively young age, suitability for intensive therapy, and the presence of a core- binding factor abnormality, the patient is treated with an induction regimen containing daunorubicin, cytarabine, and GO (7+3 + GO). He achieves complete remission. This is followed by consolidation chemotherapy with high-dose cytarabine and GO. Allo-SCT is reserved for later should the AML relapse. Note that dasatinib, a c-KIT inhibitor, can be added to the treatment regimens as per the results of the CALGB 10801 protocol.⁶⁴ Also, autologous SCT, instead of allo-SCT, can be considered in rare situations with relapsed core-binding factor AML (especially with inv(16) AML, younger patients, longer time in complete remission prior to relapse, and use of GO).

Case 2 Conclusion

The patient is deemed suitable for intensive chemotherapy. As such, CPX-351 is given in induction and consolidation and complete remission is achieved. Because he has adverse-risk AML, an allo-SCT is planned, but the patient relapses before it can be performed. Following 3 courses of decitabine therapy, the patient achieves complete remission once again but declines transplant. He maintains remission for an additional 4 months but then the leukemia progresses. Clinical trials are recommended to the patient, but he decides to pursue hospice care.

Conclusion

AML is the most common acute leukemia in adults. As defined currently, AML represents a group of related but distinct myeloid disorders that are characterized by various chromosomal, genetic, and epigenetic alterations. Early diagnosis and treatment can help prevent the emergence or manage the detrimental effects of its various complications such as leukostasis and tumor lysis syndrome. Improvements in supportive care, incremental treatment advances, and the wide adoption of allo-SCT for less than favorable cases have significantly improved survival of AML patients since the initial design of combinatorial (7+3) induction chemotherapy, particularly in patients presenting at a younger age. HMAs and the emergence of targeted therapies like FLT-3 and IDH2 inhibitors have added to our therapeutic armamentarium. Despite these advances, long-term survival rates in AML patients continue to be only approximately 40% to 50%. Older patients (particularly those over age 65 at the time of diagnosis), those with relapsed disease, and those with AML with certain unfavorable genetic abnormalities continue to have dismal outcomes. The design of newer targeted therapies, epigenetic agents, and immunotherapies will hopefully address this unmet need.

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Issue

Hospital Physician: Hematology/Oncology - 13(4)a

Publications

MDedge Hematology and Oncology

Hospital Physician: Hematology/Oncology

Topics

Leukemia, Myelodysplasia, Transplantation

Read more about Acute Myeloid Leukemia

Sections

Case-Based Review

Clinical Review

Author(s)

Pankit Vachhani, MD

Elizabeth A. Griffiths, MD