Emerging Treatments In Acute Myeloid Leukemia (AML)
Course Authors
Mary-Elizabeth M. Percival, M.D., M.S. and Roland B. Walter, M.D., Ph.D., M.S.
Dr. Percival is Assistant Professor of Medicine, University of Washington School of Medicine, and Assistant Member, Fred Hutchinson Cancer Research Center, and Dr. Walter is Associate Professor of Medicine, University of Washington School of Medicine, and Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
Within the past 12 months, Dr. Percival has received clinical trial support from FLXBio and Dr. Walter has been a consultant to Agios Therapeutics, Amphivena Therapeutics, AstraZeneca, Covagen AG, Emergent Biosolutions, Janssen R&D, Pfizer and Seattle Genetics; received clinical trial/lab support from AbbVie, ADC Therapeutics, Amgen, Amphivena Therapeutics, Arog Pharmaceuticals, Celator, Covagen, Pharmcyclics, Seattle Genetics and Stemline Therapeutics; and has ownership interest in Amphivena Therapeutics.
Albert Einstein College of Medicine, CCME staff, and interMDnet staff have nothing to disclose relevant to this activity.
Estimated course time: 1 hour(s).
Albert Einstein College of Medicine – Montefiore Medical Center designates this enduring material activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™.
Physicians should claim only the credit commensurate with the extent of their participation in the activity.
In support of improving patient care, this activity has been planned and implemented by Albert Einstein College of Medicine-Montefiore Medical Center and InterMDnet. Albert Einstein College of Medicine – Montefiore Medical Center is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.
 
Learning Objectives
Upon completion of this Cyberounds®, you should be able to:
Describe standard treatments for newly diagnosed AML for adults of all ages, including induction chemotherapy and allogeneic hematopoietic cell transplantation (HCT);
List the areas in which new treatments are needed;
Appreciate the importance of targeted therapies, such as small molecule inhibitors or antibodies, as an adjunct to standard AML treatments.
 
This program will discuss several investigational agents for the treatment of AML.
Background
Acute myeloid leukemia (AML) is a relatively uncommon but difficult-to-treat hematologic malignancy. AML is defined by the World Health Organization (WHO) as the presence of 20% or greater myeloblasts and/or monoblasts/promonocytes and/or megakaryoblasts in the blood or bone marrow, or the localized accumulation of myeloid blasts in tissues ("myeloid sarcoma"); in some cases associated with specific cytogenetic abnormalities, the diagnosis can be made regardless of the blast count. According to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the estimated incidence of AML in the United States is 19,950 new cases in 2016, which would account for 1.2% of all new cancer cases. Without any treatment, or with supportive care alone, patients with AML have a life expectancy on the order of weeks to months. With AML-directed, typically aggressive treatments, however, some patients can be cured of their disease.
Unlike the advances in solid tumors, where new drugs are approved on a regular basis, the changes in the landscape of AML therapy have been slower and more limited. For many adults, particularly those under the age of 60 at diagnosis, treatment outcomes have gradually improved over the last 20-30 years. Arguably, however, much of this progress is secondary to better supportive care and advances in allogeneic hematopoietic cell transplant (HCT), which have allowed the use of aggressive therapy for an increasing proportion of patients. By comparison, the lack of new drug approvals has left "7+3", first introduced in 1973, as the standard induction regimen for AML. Indeed, though other drugs are used off-label and all-trans retinoic acid (ATRA) was approved in 1995 for the treatment of the rare AML subtype, acute promyelocytic leukemia (APL), gemtuzumab ozogamicin (GO) remains the only drug approved for the treatment of AML in the past 40 years.
GO is a first-generation antibody-drug conjugate targeting CD33, which is frequently expressed on AML cells. After accelerated U.S. marketing approval in 2000, this drug was voluntarily withdrawn in most countries in 2010 after the U.S. Food & Drug Administration (FDA)-mandated confirmatory post-marketing trial failed to confirm clinical benefit in unselected adults with AML and raised concern over increased early mortality; subsequently, criticisms have been leveled at the study design (including the study population and choice of the anthracycline dose in the experimental arm), and public pleas have been made to reconsider its approval status.
Treatment outcomes have gradually improved over the last 20-30 years.
Other drugs with a diverse spectrum of targets and mechanisms, including tipifarnib (farnesyltransferase inhibitor), laromustine (alkylator), clofarabine (purine antimetabolite) and decitabine (hypomethylating agent), have failed to gain approval for the treatment of AML in the U.S. The reasons for these failures are complex. For some of the drugs, problems with clinical trial design, which are not unique to AML, include small phase 2 studies and clinical heterogeneity of patient populations. The choice of endpoint(s) may also have contributed, but criteria besides overall survival time (OS) improvements, including event-free survival (EFS), may be used more frequently in the future. Further, while our increasing knowledge of the molecular heterogeneity of AML may lead to new therapeutic targets, it is simultaneously challenging to determine how patients with various unique combinations of mutations will respond to therapy. Issues with the glacial pace of drug approval and unrealistic expectations of efficacy by regulatory bodies, among others, have been reviewed previously.
This Cyberounds® will review the current standard therapy for AML, including special cases such as treatment of the elderly or medically less fit and those with APL, before identifying areas where new strategies and drugs are needed and examining emerging treatments for AML. Importantly, the National Comprehensive Cancer Network (NCCN) guidelines for AML highlight that participation in a clinical trial, if available, should be the first treatment choice for all patients.
Standard Therapy
Medically Fit Patients
For medically fit patients, the standard therapy for the past four decades is so-called 7+3 therapy, consisting of seven days of cytarabine administered by continuous infusion (100-200 mg/m2/day) combined with three days of an anthracycline (daunorubicin or idarubicin). The dose of daunorubicin has been studied extensively, with large randomized studies demonstrating that a dose of 90 mg/m2 leads to better outcomes than a dose of 45 or 60 mg/m2. However, a more recent randomized trial showed no difference for daunorubicin at 90 mg/m2 and 60 mg/m2 (the dose currently considered standard in 7+3) except perhaps in patients with FLT3-ITD mutated AML. Alternatively, some centers use regimens containing high-dose cytarabine (doses >1 g/m2) during induction therapy. One recent large, randomized study indicates that such regimens (e.g. FLAG-Ida, which combines fludarabine, cytarabine, G-CSF, and idarubicin) have more robust anti-leukemic activity than 7+3, although reduced relapse rates and improved relapse-free survival (RFS) may not translate into longer OS because of increased toxicity.
Remission is assessed with bone marrow evaluation around day 28 following induction chemotherapy, primarily using morphologic criteria, though assessment of measurable ("minimal") residual disease (MRD) by examination of immunophenotypic or cytogenetic/molecular abnormalities is increasingly important in determining subsequent treatment strategies and outcomes. Induction chemotherapy is followed by 3-4 cycles of post-remission ("consolidation") chemotherapy, which, in the United States, is most frequently high-dose cytarabine.
In many patients, allogeneic HCT should be considered during first complete remission. The European LeukemiaNet prognostic classification combines molecular and cytogenetic data from diagnosis, and patients with intermediate or adverse risk AML are typically referred for allogeneic HCT. The benefits of better anti-leukemic activity of allogeneic HCT relative to chemotherapy are weighed against increased risks of morbidity and mortality related to transplant.
Because donor identification is time-consuming, HLA-typing is often performed soon after the time of AML diagnosis once initial prognostic information is available. Sibling typing can occur simultaneously, after appropriate initial medical screening, as matched related donors still remain the preferred donor source. If siblings are not available or are not HLA-matched, a worldwide search of unrelated donors should be initiated for patients, followed by umbilical cord blood and haploidentical searches if necessary. The choice of conditioning regimen before transplant is affected by patient age and donor source. Myeloablative regimens, which may further reduce the leukemic cell burden, can be used for younger patients; both myeloablative and non-myeloablative conditioning will allow for a beneficial graft-versus-leukemia effect.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) attempted to standardize one aspect of allogeneic HCT in patients with myeloid malignancies by randomizing patients to HCT with reduced-intensity conditioning or myeloablative conditioning. The study was stopped early by an independent data safety monitoring board after 272 patients were enrolled of a planned 356 because the myeloablative conditioning arm demonstrated a lower rate of relapse at 18 months (13.5% vs. 48.3% in the reduced-intensity arm), though the OS difference was not statistically significant (77.4% in the myeloablative arm vs. 67.7% in the reduced-intensity arm). Critics of the study argue that it should not have been closed early because the primary endpoint (overall survival at 18 months) was not reached, but the results nonetheless argue that patients with myeloid malignancies who can tolerate a myeloablative regimen prior to HCT should receive it. The choice of reduced-intensity conditioning regimen may also be important, and another abstract presented at the American Society of Hematology meeting in 2015 demonstrated that outcomes were superior in a retrospective analysis for patients receiving fludarabine and melphalan, as opposed to fludarabine and busulfan.
Post-transplant treatment and maintenance strategies, e.g., with the DNA methyltransferase inhibitor azacitidine ("hypomethylating agent") or small molecule inhibitors, are under active investigation. Patients with any evidence of residual disease at follow-up bone marrow assessments often receive treatment with hypomethylating agents. The value of these strategies is not firmly established, but more post-transplant strategies are needed for residual disease, as well as maintenance, to prevent relapse.
Less Fit Patients
While there is no absolute age cut-off for consideration of intensive therapy in AML, age is considered a negative prognostic indicator in terms of outcomes. Age is a contributor to treatment-related mortality, and additionally, older patients have a decreased rate of achieving complete remission than younger patients. Generally, patients older than age 60 or 65 are considered elderly, though that definition may not be espoused by patients themselves. Geriatric assessments have been studied and predict outcomes in older patients, but these are not widely utilized. This population is significant, considering that the median age of diagnosis with AML is 67, but many physicians do not treat elderly patients beyond providing supportive or palliative care. The current standard in the community is for older patients with high-risk myelodysplastic syndrome or AML to receive low-intensity treatment with hypomethylating agents. With median survival estimates of less than 12 months, outcomes generally remain unsatisfactory, and major effort is spent trying to improve these outcomes with novel treatment approaches.
The proposed ELN guidelines suggest that older age should not by itself determine if a patient is to receive less intensive therapy; instead, a second factor will also be required, including patient-related (ECOG performance status 3-4 not related to AML or significant co-morbidities not related to AML) or disease-related (ELN adverse-risk cytogenetics/genetics).
Though selection bias likely plays an important role in patient treatment assignment, large-scale data from the Swedish Acute Leukemia Registry suggest that older patients do benefit from intensive treatment. This implies that the primary source of morbidity and mortality is the AML itself, rather than the treatment for AML, even when the treatment is intensive. Consistent with this conclusion, a large retrospective analysis of 1079 patients indicated that survival is better with intensive induction than non-intensive therapy in older patients with co-morbidities. Thus, we posit that intensive chemotherapy is likely the best treatment option for most patients, but newer therapies that combine efficacy and tolerability are needed for those patients who cannot tolerate induction.
APL
APL is an uncommon subtype of AML, which accounts for <5% of all AML cases and is classically characterized by a translocation between chromosome 15 and chromosome 17, leading to a fusion protein PML-RARA. The treatment of APL has been revolutionized by the combination of two non-chemotherapy agents: ATRA and arsenic trioxide (ATO). The cure rate, using this combination in patients with low-risk APL, is in excess of 90%, obviating the need for chemotherapy. However, patients with high-risk disease (defined as a white blood cell count >10,000/? 1/4 l at diagnosis) may still require cytoreduction, including initial treatment with an anthracycline (most commonly idarubicin) or another drug (such as GO).
Age is considered a negative prognostic indicator in terms of outcomes.
Because of the high risk of coagulopathy-associated morbidity and mortality in untreated APL and in light of the non-toxic nature of ATRA, patients with clinically suspected APL should be started on oral ATRA, while waiting for definitive testing to return (usually with fluorescence in situ hybridization testing for the 15;17 translocation), which is commonly available within 24 hours. With the incorporation of ATO into frontline therapy for APL, the treatment options for relapsed patients have become very limited.
Areas In Which New Treatments Are Needed
Despite some improvements over time, the five-year survival rate for AML has remained remarkably low at approximately 25%, though mediating factors such as age and cytogenetic/molecular risk status can help sub-classify patients and determine the treatment algorithm at the time of diagnosis. Increasing evidence indicates that the prognostic information can be refined based on response to chemotherapy, with data on remission status and presence of MRD being useful to help determine benefit from further chemotherapy and/or allogeneic HCT.
Five major areas in which new approaches are needed for the treatment of AML include: (1) upfront induction treatment; (2) treatment of patients with suboptimal remissions (i.e., patients with MRD); (3) less intensive options for adults unable or unwilling to tolerate induction; (4) treatment of relapsed disease; and (5) maintenance following completion of chemotherapy or transplantation (Table 1).
In the remainder of this Cyberounds®, we will discuss emerging treatments that aim to address these deficiencies in our current armamentarium.
Novel Formulations
The drug CPX-351 combines cytarabine and daunorubicin in a fixed 5:1 molar ratio within a liposomal carrier (Table 2). CPX-351 was designed to achieve synergistic cytotoxic drug levels. The drug has been studied primarily in older patient populations, both in the upfront setting and for patients with relapsed/refractory disease. A phase 2 trial randomized 126 older newly-diagnosed AML patients to CPX-351 (at 100 units/m2 on days 1, 3 and 5) or 7+3 chemotherapy (with daunorubicin 60mg/m2 on days 1-3 and cytarabine 100 mg/m2 daily as a continuous IV infusion on days 1-7) in a 2:1 fashion; though patients receiving CPX-351 had higher response rates, the OS and EFS were not significantly different. A planned subgroup analysis of patients with secondary AML showed a significant increase in OS with a hazard ratio of 0.46 (p=0.01) in favor of CPX-351; median OS was 6.1 months in the 7+3 arm and 12.1 months in the CPX-351 arm. This patient population formed the basis for the phase 3 study.
The phase 3 study (NCT01696084) was recently reported in abstract form, and described 309 older patients with newly diagnosed poor-risk AML who were randomized 1:1 to CPX-351 vs. 7+3 in the same dosing pattern as the phase 2 study. Patients had to be 60-75 years of age and have unfavorable risk, untreated AML (with prior cytotoxic treatment for a prior malignancy or rheumatologic disease, antecedent hematologic disorder, or AML with MDS-related cytogenetic abnormalities).
Approximately 25% of patients with AML carry a mutation in FMS-like kinase 3 (FLT3).
Responses, EFS and OS were all superior in the CPX-351 arm (median OS 9.56 vs. 5.95 months, HR = 0.69, p=0.005). Grade 3-5 adverse events were high in both arms (92 vs. 91%) without any significant differences, with the most common toxicity being febrile neutropenia (68% in CPX-351 arm vs. 71% in 7+3 arm). Count recovery appeared to be slightly slower in the CPX-351 arm [median time to absolute neutrophil count (ANC) ??JPY500/ml after one induction was 35 days vs. 29 days for 7+3; the timing was similar for platelet recovery]. Based on the positive phase 3 results, CPX-351 has been granted breakthrough designation for AML by the FDA, and regulatory paperwork is being submitted by the manufacturer. Approval of CPX-351 by the FDA will likely be limited to older patients, but opens the door for this effective drug in other therapeutic applications.
Small Molecule Inhibitors
Tyrosine Kinase ("FLT3") Inhibitors
Approximately 25% of patients with AML carry a mutation in FMS-like kinase 3 (FLT3), primarily an internal tandem duplication, though tyrosine kinase domain mutations are also described; the mutational frequency is slightly higher in patients with normal karyotype. Such mutations lead to a proliferative phenotype, since FLT3 signaling is involved in the maintenance of cell division and differentiation. Blocking signaling through FLT3 and its membrane-bound receptor has been an attractive target under investigation for over a decade. Earlier multi-kinase inhibitors with activity against FLT3 signaling, such as lestaurtinib, had a toxic side effect profile that precluded aggressive dosing in combination with chemotherapy.
More recently, however, data from the multi-kinase inhibitors, sorafenib and midostaurin, suggest a benefit of such inhibitors when added to standard induction chemotherapy in younger adults with AML. Sorafenib in combination with induction chemotherapy has shown improvements in younger AML patients unselected for FLT3 mutation status, albeit with more toxicity including higher rates of fever, diarrhea, bleeding, cardiac events and hand-foot rash. Specifically, a randomized, double-blind, placebo-controlled phase 2 trial was performed in Germany combining 7+3 induction followed by high-dose cytarabine consolidation with or without sorafenib in 276 untreated AML patients age 18-60 years at diagnosis. The median EFS was 9 months in the placebo group versus 21 months in the sorafenib group; OS was not reached in either group after three years of follow-up. An exploratory subgroup analysis of the 46 patients with FLT3-ITD mutations showed a trend towards improved RFS and OS in the patients who received sorafenib.
Interestingly, a similar German trial was performed in 211 newly diagnosed AML patients over the age of 60, which showed no difference in EFS and OS in the sorafenib group. A high early death rate in the sorafenib group was noted (17% vs. 7% in the placebo arm; p=0.052), suggesting that any potential anti-leukemic effect was counterbalanced by increased toxicity; as a result, patients in the sorafenib group were much more likely to receive less chemotherapy and to stop maintenance early. A subgroup analysis of FLT3-ITD mutated patients also showed no survival benefit to sorafenib.
Midostaurin was granted breakthrough designation by the FDA and is likely to be approved in late 2016 or early 2017.
It is conceivable, but currently unproven, that the benefit of kinase inhibition may be more pronounced in a patient population selected for FLT3 mutation status. Early results from the international phase 3 randomized RATIFY trial, investigating the combination of 7+3 chemotherapy with or without midostaurin during induction, post-remission and maintenance therapy in 717 newly diagnosed FLT3-mutated patients under the age of 60, demonstrated a clear OS benefit in the midostaurin arm. After a median follow up of 57 months for surviving patients, the median OS was 74.7 months in the midostaurin arm and 26.0 months in the placebo arm, despite the fact that complete remission rates were similar in both arms (59% vs. 54%, p=0.018). The rate of grade 3 or higher adverse events was similar in both arms, and the benefit of midostaurin was seen across all FLT3 subgroups when patients were stratified by allelic ratio at diagnosis. Both multi-kinase inhibitors are being explored for post-HCT maintenance, sorafenib primarily retrospectively and midostaurin prospectively (in the randomized RADIUS trial; NCT01883362). Midostaurin was granted breakthrough designation by the FDA in February 2016, and is likely to be approved in late 2016 or early 2017.
More potent and specific second-generation FLT3 inhibitors are under development as well, including quizartinib, crenolanib and gilteritinib (ASP2215). Quizartinib has a high response rate as a single-agent in relapsed/refractory FLT3-ITD mutated AML (53% response rate in the phase 1 dose-escalation study, which was replicated in phase 2 studies as well). Studies are ongoing with quizartinib in a variety of other realms as well, including as maintenance after allogeneic HCT. A phase 3 randomized double-blind placebo-controlled study of quizartinib in combination with 7+3 chemotherapy for newly diagnosed FLT3-ITD patients will begin accrual shortly (QuANTUM-R-First; NCT02668653).
Crenolanib is in a similar phase of testing, with an active phase 1 study in combination with 7+3 induction in newly diagnosed FLT3-mutated patients (NCT02283177) as well as a large randomized phase 3 study proposed but not yet underway (in combination with mitoxantrone and cytarabine induction chemotherapy for relapsed/refractory FLT3-mutated patients; NCT02298166). Crenolanib may be better tolerated with decreased myelosuppression and the ability to overcome resistance mutations.
The newest inhibitor in the class is gilteritinib (ASP2215), a dual FLT3 and AXL inhibitor, which may have particular activity in resistance mutations with an overall response rate of 57% in the phase 1/2 study. A phase 3 registration trial comparing single-agent ASP2215 versus salvage chemotherapy in relapsed/refractory FLT3-mutated patients is under development (NCT02421939). It is too soon to tell whether these more selective inhibitors will lead to survival improvements and FDA approval, or whether some of the off-target effects of the "dirtier" and less selective tyrosine kinase inhibitors like sorafenib and midostaurin are actually responsible for the clinical benefit seen in combination with chemotherapy.
IDH Inhibitors
A smaller subset of AML patients, approximately 15-20%, carries mutations in isocitrate dehydrogenase 1 or 2 (IDH1 and IDH2), with a prevalence that increases with age. These mutations are associated with a poor prognosis in normal karyotype AML and are an attractive target for targeted drug development. Inhibitors of IDH2 are slightly farther in clinical testing, with a phase 1/2 study of the IDH2 inhibitor, AG221, demonstrating an overall response rate of 41%, whereas a phase 1 study of the IDH1 inhibitor showed an overall response rate of 36%. Combination trials with hypomethylating agents (NCT02677922) and induction chemotherapy (NCT02632708) are ongoing; additionally, in IDH2-mutated patients, a phase 3 multicenter open-label trial has begun accrual, randomizing patients to AG221 versus conventional care regimens (IDHENTIFY; NCT02577406). The inhibitors seem to be well-tolerated, with side effects of indirect hyperbilirubinemia and nausea reported most frequently.
It typically takes several cycles before patients achieve best response; also, a relatively large percentage of patients have stable disease with normalization of peripheral blood counts, including normalization of peripheral blood neutrophils and transfusion independence, but with persistent circulating and marrow blasts, leading to an as-yet-unsubstantiated hypothesis that these patients may have "smoldering" AML. There is also a report of an IDH1 inhibitor leading to differentiation syndrome. No public data exist to date that confirm that this improvement in peripheral counts is equivalent to a remission, and a major question remains regarding IDH inhibitors: is there a substantial benefit to patients given single-agent inhibitors in the relapsed/refractory setting instead of conventional salvage chemotherapy?
BCL2 Inhibitors
Recent preclinical studies have indicated that BCL2 inhibitors may have a role in the treatment of AML, since BCL2 overexpression is frequently detected in AML cells. The BCL2 inhibitor, venetoclax (ABT-199), was recently approved for the treatment of relapsed chronic lymphocytic leukemia based on remarkable activity demonstrated in an open-label study, particularly for patients with adverse risk markers. A phase 1b open-label dose-escalation study of venetoclax in combination with decitabine or azacitidine in older treatment-naA?ve AML patients showed an overall response rate of around 70% (NCT02203773). Further combination studies with venetoclax are ongoing in AML patients.
Immunotherapy
Gemtuzumab Ozogamicin
CD33 is commonly expressed on the surface of AML cells, and the antibody-drug conjugate GO was designed to target CD33-expressing leukemia cells. GO initially received accelerated U.S. marketing approval for adults age >60 with relapsed CD33+ AML who were not candidates for cytotoxic chemotherapy based on data from three phase 2 trials showing overall response rate [CR/CR with incomplete platelet recovery (CRp)] of approximately 30%. Subsequent studies have confirmed single agent activity of GO in newly diagnosed and relapsed/refractory non-APL AML, but overall response rates have usually not exceeded 25-35% and were occasionally very low, except in APL, for which GO has been found to be exquisitely effective.
More recently, several studies have investigated GO in addition to intensive chemotherapy in adults with newly diagnosed AML. While these studies used GO in different schedules, a meta-analysis of all 3,325 patients on these trials showed that GO significantly reduced relapse risk and improved survival, with benefits seen primarily in patients with favorable cytogenetics and also, to a lesser extent, in those with intermediate but not adverse cytogenetics. These findings are complemented by a randomized trial showing that GO provided a very modest benefit over best supportive care and hydroxyurea in untreated older adults considered "unfit" for intensive chemotherapy. As mentioned before, GO was withdrawn from most commercial markets in 2010 and, despite repeated calls by many leukemia experts, has not (yet) been reintroduced.
SGN-CD33A
Issues with GO, including non-uniform drug conjugation, extrusion of the toxic moiety via drug transporters and its current unavailability, have made room for the introduction of SGN-CD33A, an antibody-drug conjugate also targeting CD33 designed to address these limitations. No direct comparisons have been performed between GO and SGN-CD33A in patients, but SGN-CD33A is under active investigation as single agent, as well as in combination with azacitidine or decitabine; in these combinations, a composite response rate of 76% in a phase 1 study among 53 patients with a median age of 75 years (range 60 to 87) has been observed. Based on these data, a pivotal phase 3 randomized trial recently opened for accrual, randomizing newly diagnosed older patients to SGN-CD33A vs. placebo in combination with azacitidine or decitabine (NCT02785900). Simultaneously, a phase 1b trial is underway examining SGN-CD33A in combination with 7+3 chemotherapy (NCT02326584), as well as a phase 1/2 trial to examine the safety and efficacy of SGN-CD33A both before and after allogeneic HCT in AML patients (NCT02614560).
Bispecific Antibodies
Bispecific antibodies have garnered considerable interest following the approval of the CD19-directed bispecific T-cell-engaging (BiTE) antibody blinatumomab for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia in late 2014. CD33 is the target for the BiTE antibody, AMG330, which recently entered phase 1 testing after promising preclinical data (NCT02520427). An alternative structure of a bispecific antibody, a so-called dual-affinity retargeting (DART) antibody, forms the basis for MGD006, which targets CD123 and CD3 and has also entered phase 1 testing (NCT02152956). For both compounds, no clinical data are yet available.
Other Areas of Consideration
APL
The choices for treatment in APL are likely to change since the advent of chemotherapy-free induction with ATRA and ATO; the cure rate for low-risk disease patients is in excess of 90%. Nonetheless, a number of interesting drugs may modify the treatment of APL upfront or may have utility in the setting of relapse (Table 3).
Recent preclinical studies have indicated that BCL2 inhibitors may have a role in the treatment of AML.
Oral arsenic is perhaps the best studied, with the completion of a randomized phase 3 trial versus an IV ATO formulation in 242 patients with APL receiving induction and maintenance. Oral arsenic (tetra-arsenic tetra-sulfide) confirmed non-inferiority to IV arsenic with disease-free survival of 98.1% vs. 95.5% at two years; CR rate and OS were not significantly different. Importantly, oral arsenic allows for patients to be outpatient more frequently and subsequently decreases healthcare-related costs.
ATRA formulations have also been modified. Successful early studies of liposomal ATRA showed promising single-agent activity. Tamibarotene, a novel synthetic retinoid, has been studied for APL maintenance and in the setting of relapse after treatment with ATRA and ATO. The overall response rate after relapse was 64%; notably, the patient cohort was quite small at 14 total, which speaks to the success of the current induction regimen with ATRA/ATO. Importantly, however, the major cause of death in APL, which is otherwise a highly curable subtype of AML, remains early mortality from complications such as bleeding diathesis or differentiation syndrome.
New Directions
Though few drugs have actually been approved for the treatment of AML in the last 40 years, active clinical investigation is ongoing. Two candidates discussed herein are expected to gain FDA approval in 2017 because of a significant OS benefit in randomized phase 3 studies, which will be the first drugs approved for AML in over a decade. One drug is the liposomal formulation of cytarabine and daunorubicin in a fixed molar ratio (CPX-351), which will be approved for newly diagnosed older patients (??JPY60 years) with adverse risk AML. The second is the multi-kinase inhibitor midostaurin, which will be indicated for patients with FLT3 mutations during induction and consolidation chemotherapy. However, the indications for both drugs may expand, as further clinical trials are ongoing (e.g., a randomized study of post-HCT maintenance with midostaurin in FLT3-mutated patients) and as clinical experience is gained.
The current treatment algorithm for fit patients with newly diagnosed AML is intensive induction chemotherapy followed by consolidation +/- allogeneic HCT. However, many patients do not fit into this sequence, whether because of age, patient preference, disease characteristics, or co-morbidities, among other issues. New drugs and directions are needed to successfully treat (and cure) many patients who have just received a diagnosis of AML. With many emerging agents on the horizon for both AML and APL (Tables 2 and 3), we have the potential to significantly improve outcomes for patients. For example, patients with MRD after induction or other high-risk features may end up receiving prolonged maintenance therapy, possibly with an oral agent such as midostaurin. While it is too soon to recommend maintenance or other changes to the current algorithm for AML patients, we anticipate that the coming years will bring additional approaches to the treatment of AML.