Did you arrive here by via search engine?
Click here to view the original version of this article

Click to Print This Page
(This section will not print)

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.(1) 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.(2) 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.(3) Arguably, however, much of this progress is secondary to better supportive care and advances in allogeneic hematopoietic cell transplant (HCT),(4) 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.(5)(6)

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.(7) 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.(8) 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.(9)(10) Issues with the glacial pace of drug approval and unrealistic expectations of efficacy by regulatory bodies, among others, have been reviewed previously.(7)(10)

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.(12)

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).(13) 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.(14)(15)(17) 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.(18) 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.(19)

Remission is assessed with bone marrow evaluation around day 28 following induction chemotherapy, primarily using morphologic criteria,(20) 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.(21)(22)(23) Induction chemotherapy is followed by 3-4 cycles of post-remission ("consolidation") chemotherapy, which, in the United States, is most frequently high-dose cytarabine.(24)(25)(26)

In many patients, allogeneic HCT should be considered during first complete remission.(27) 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.(20)(28)

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.(29) 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).(29) 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.(30)

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.(31)(32)(33) 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.(34)(35)(36) Generally, patients older than age 60 or 65 are considered elderly, though that definition may not be espoused by patients themselves.(37) Geriatric assessments have been studied and predict outcomes in older patients, but these are not widely utilized.(38) This population is significant, considering that the median age of diagnosis with AML is 67,(2) but many physicians do not treat elderly patients beyond providing supportive or palliative care.(39) 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.(40)(41)(42)(43)(44) 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).(45)

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.(46) 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.(47) 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.(48) The treatment of APL has been revolutionized by the combination of two non-chemotherapy agents: ATRA and arsenic trioxide (ATO).(49)(50) The cure rate, using this combination in patients with low-risk APL, is in excess of 90%, obviating the need for chemotherapy.(51) 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).(52)(53)(54)

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%,(2) 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).

Table 1. Areas In Which New AML Therapies Are Needed.

Areas Under Investigation Why New Treatments Are Needed
Upfront induction treatment Overall survival rate for AML is only 25%
Treatment of MRD Presence of MRD is an important negative prognostic factor for patients with or without subsequent allogeneic HCT
Less intensive induction therapies Less fit patients may not be able to tolerate induction chemotherapy, but hypomethylating agents are unlikely to lead to cure
Treatment of relapsed/refractory AML Prognosis of relapsed/refractory AML is poor, so new drugs are needed to help patients achieve remission and to bridge to allogeneic HCT
Maintenance (after completion of consolidation and/or post-HCT) Relapses of AML are most likely within the first 2-3 years after completion of planned treatment

Abbreviations: measurable residual disease (MRD); hematopoietic cell transplant (HCT).

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.(55) 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.(56) 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).(56) 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).(56) 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].(56) 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.

Table 2. Emerging Treatments for AML.

Drug Mechanism Phase of Testing in AML Notes on Activity/Approval
CPX-351 Liposomal formulation of cytarabine and daunorubicin in a fixed 5:1 molar ratio 3 (completed) Positive results in randomized trial vs. 7+3 in older adults; likely to be FDA-approved in 2017
Sorafenib Multikinase inhibitor with activity against FLT3 3 (completed) Approved for renal cancer, but available off-label for AML
Midostaurin Multikinase inhibitor with activity against FLT3 3 (completed) Positive results in randomized trial (versus placebo in combination with 7+3 for newly diagnosed FLT3-mutated patients); likely to be FDA-approved in 2017
Quizartinib Second-generation FLT3 inhibitor 3 (not yet started) Randomized trial (versus placebo in combination with 7+3 for newly diagnosed FLT3-mutated patients) proposed
Crenolanib Second-generation FLT3 inhibitor 3 (not yet started) Randomized trial (versus placebo in combination with mitoxantrone/cytarabine for relapsed/refractory FLT3-mutated patients)
Gilteritinib (ASP2215) FLT3 and AXL inhibitor 3 (not yet started) Randomized trial (versus salvage chemotherapy for relapsed/refractory FLT3-mutated patients)
AG120 IDH1 inhibitor 2 (ongoing) Phase 1 combination with induction therapy ongoing; phase 1b/2 combination with azacitidine ongoing
AG221 IDH2 inhibitor 3 (ongoing) Randomized trial ongoing (versus conventional care)
Venetoclax (ABT-199) BCL2 inhibitor 2 (ongoing) Approved for relapsed CLL; combination studies with low-intensity therapy ongoing in AML
SGN-CD33A Antibody-drug conjugate targeting CD33 3 (ongoing) Randomized trial (versus placebo in combination with azacitidine/decitabine in older newly diagnosed patients)
AMG330 Bi-specific T cell engaging antibody targeting CD33 1 (ongoing) Single-agent first-in-human continuous IV infusion for 28 days
MGD006 dual-affinity retargeting (DART) antibody against CD123 1 (ongoing) Single-agent first-in-human

Abbreviations: Food and Drug Administration (FDA).

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.(9) 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.(57)

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.(58)(59)(59) 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.(58) 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.(60) A subgroup analysis of FLT3-ITD mutated patients also showed no survival benefit to sorafenib.(60)

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.(61) 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).(61) 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.(61) Both multi-kinase inhibitors are being explored for post-HCT maintenance, sorafenib primarily retrospectively(62)(63)(64) 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).(65) Studies are ongoing with quizartinib in a variety of other realms as well, including as maintenance after allogeneic HCT.(66) 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.(67)

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.(68) 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.(69)(70) 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%,(71) whereas a phase 1 study of the IDH1 inhibitor showed an overall response rate of 36%.(72) 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.(71)

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.(71) There is also a report of an IDH1 inhibitor leading to differentiation syndrome.(73) 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?(74)

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.(75) 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.(76) 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).(77) 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.(78)

More recently, several studies have investigated GO in addition to intensive chemotherapy in adults with newly diagnosed AML.(6) 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.(6) 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.(79) 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.(80) 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.(81) 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).(82) 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).(83) 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.(84) 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.(84) Importantly, oral arsenic allows for patients to be outpatient more frequently and subsequently decreases healthcare-related costs.(85)(86)

Table 3. Emerging Treatments for APL.

Drug Mechanism Phase of Testing in AML Notes on Activity/Approval
Oral arsenic Heavy metal which leads to differentiation in APL 3 (complete) Randomized non-inferiority trial (versus IV arsenic)
Liposomal ATRA Liposomal formulation of ATRA 2 (complete) Not approved in U.S.
Tamibarotene Synthetic retinoid 2 (complete) Studied for maintenance and in relapsed patients

ATRA formulations have also been modified. Successful early studies of liposomal ATRA showed promising single-agent activity.(87) Tamibarotene, a novel synthetic retinoid, has been studied for APL maintenance and in the setting of relapse after treatment with ATRA and ATO.(88)(89) 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.(88) 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.(48)

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.


Footnotes

1Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 2016;127:2391-405.
2SEER Stat Fact Sheets: Acute Myeloid Leukemia (AML). n.d. (Accessed June 29, 2016, at http://seer.cancer.gov/statfacts/html/amyl.html.)
3Percival ME, Tao L, Medeiros BC, Clarke CA. Improvements in the early death rate among 9380 patients with acute myeloid leukemia after initial therapy: A SEER database analysis. Cancer 2015;121:2004-12.
4Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med 2010;363:2091-101.
5Clarke WT, Marks PW. Gemtuzumab ozogamicin: is there room for salvage? Blood 2010;116:2618-9.
6Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol 2014;15:986-96.
7Lancet JE. New agents: great expectations not realized. Best Pract Res Clin Haematol 2013;26:269-74.
8Othus M, van Putten W, Lowenberg B, et al. Relationhip between event-free survival and overall survival in acute myeloid leukemia: A report from SWOG, HOVN/SAKK, and MRC/NCRI. Haematologica 2016.
9Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med 2012;366:1079-89.
10Ding L, Ley TJ, Larson DE, et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012;481:506-10.
12O'Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 2.2013. J Natl Compr Canc Netw 2013;11:1047-55.
13Yates JW, Wallace HJ, Jr., Ellison RR, Holland JF. Cytosine arabinoside (NSC-63878) and daunorubicin (NSC-83142) therapy in acute nonlymphocytic leukemia. Cancer Chemother Rep 1973;57:485-8.
14Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 2009;361:1249-59.
15Lee JH, Joo YD, Kim H, et al. A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. Blood 2011;118:3832-41.
17Burnett AK, Russell NH, Hills RK, et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML induction: results from the UK NCRI AML17 trial in 1206 patients. Blood 2015;125:3878-85.
18Burnett AK, Russell NH, Hills RK, United Kingdom National Cancer Research Institute Acute Myeloid Leukemia Study G. Higher daunorubicin exposure benefits FLT3 mutated acute myeloid leukemia. Blood 2016;128:449-52.
19Burnett AK, Russell NH, Hills RK, et al. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the medical research council AML15 trial. J Clin Oncol 2013;31:3360-8.
20Dohner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010;115:453-74.
21Wood BL. Principles of minimal residual disease detection for hematopoietic neoplasms by flow cytometry. Cytometry B Clin Cytom 2016;90:47-53.
22Othus M, Wood BL, Stirewalt DL, et al. Effect of measurable ('minimal') residual disease (MRD) information on prediction of relapse and survival in adult acute myeloid leukemia. Leukemia 2016.
23Grimwade D, Freeman SD. Defining minimal residual disease in acute myeloid leukemia: which platforms are ready for "prime time"? Blood 2014;124:3345-55.
24Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med 1994;331:896-903.
25Lowenberg B, Pabst T, Vellenga E, et al. Cytarabine dose for acute myeloid leukemia. N Engl J Med 2011;364:1027-36.
26Lowenberg B. Sense and nonsense of high-dose cytarabine for acute myeloid leukemia. Blood 2013;121:26-8.
27Appelbaum FR. Indications for allogeneic hematopoietic cell transplantation for acute myeloid leukemia in the genomic era. Am Soc Clin Oncol Educ Book 2014:e327-33.
28Cornelissen JJ, Gratwohl A, Schlenk RF, et al. The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach. Nat Rev Clin Oncol 2012;9:579-90.
29Scott BL, Pasquini MC, Logan B, et al. Results of a Phase III Randomized, Multi-Center Study of Allogeneic Stem Cell Transplantation after High Versus Reduced Intensity Conditioning in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML): Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0901. Blood 2015;126:LBA-8.
30Damlaj M, Alkhateeb HB, Hefazi M, et al. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing. Biol Blood Marrow Transplant 2016;22:1431-9.
31Craddock C, Labopin M, Robin M, et al. Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2016;101:879-83.
32Platzbecker U, Wermke M, Radke J, et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2012;26:381-9.
33Schroeder T, Frobel J, Cadeddu RP, et al. Salvage therapy with azacitidine increases regulatory T cells in peripheral blood of patients with AML or MDS and early relapse after allogeneic blood stem cell transplantation. Leukemia 2013;27:1910-3.
34Walter RB, Othus M, Borthakur G, et al. Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment. J Clin Oncol 2011;29:4417-23.
35Krug U, Rollig C, Koschmieder A, et al. Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes. Lancet 2010;376:2000-8.
36Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome. Cancer 2006;106:1090-8.
37Schiffer CA. "I am older, not elderly," said the patient with acute myeloid leukemia. J Clin Oncol 2010;28:521-3.
38Klepin HD, Geiger AM, Tooze JA, et al. Geriatric assessment predicts survival for older adults receiving induction chemotherapy for acute myelogenous leukemia. Blood 2013;121:4287-94.
39Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol 2015;94:1127-38.
40Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562-9.
41Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223-32.
42Dombret H, Seymour JF, Butrym A, et al. International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015;126:291-9.
43Thepot S, Itzykson R, Seegers V, et al. Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. Am J Hematol 2014;89:410-6.
44Itzykson R, Thepot S, Quesnel B, et al. Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine. Blood 2011;117:403-11.
45Estey E. Acute myeloid leukemia: 2016 Update on risk-stratification and management. Am J Hematol 2016;91:824-46.
46Juliusson G, Antunovic P, Derolf A, et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009;113:4179-87.
47Sorror M, Storer B, Elsawy M, et al. Relative benefit for intensive versus non-intensive induction therapy for patients with newly diagnosed acute myeloid leukemia (AML) using a composite, age-comorbidity-cytogenetic model. EHA Learning Center 2016:Abstract LB580.
48Coombs CC, Tavakkoli M, Tallman MS. Acute promyelocytic leukemia: where did we start, where are we now, and the future. Blood Cancer J 2015;5:e304.
49Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21.
50Lo-Coco F, Di Donato L, Gimema, Schlenk RF, German-Austrian Acute Myeloid Leukemia Study G, Study Alliance L. Targeted Therapy Alone for Acute Promyelocytic Leukemia. N Engl J Med 2016;374:1197-8.
51Platzbecker U, Avvisati G, Cicconi L, et al. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol 2016.
52Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012;120:1570-80; quiz 752.
53Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009;27:504-10.
54Burnett AK, Russell NH, Hills RK, et al. Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): results of a randomised, controlled, phase 3 trial. Lancet Oncol 2015;16:1295-305.
55Lancet JE, Cortes JE, Hogge DE, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood 2014;123:3239-46.
56Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol 2016;34.
57Levis M, Ravandi F, Wang ES, et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011;117:3294-301.
58Rollig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol 2015;16:1691-9.
59Ravandi F, Cortes JE, Jones D, et al. Phase I/II study of combination therapy with sorafenib, idarubicin, and cytarabine in younger patients with acute myeloid leukemia. J Clin Oncol 2010;28:1856-62.
60Serve H, Krug U, Wagner R, et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: results from a randomized, placebo-controlled trial. J Clin Oncol 2013;31:3110-8.
61Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand)-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Blood (ASH Annual Meeting Abstracts) 2015;126:6.
62De Freitas T, Marktel S, Piemontese S, et al. High rate of hematological responses to sorafenib in FLT3-ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation. Eur J Haematol 2016;96:629-36.
63Brunner AM, Li S, Fathi AT, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol 2016.
64Chen YB, Li S, Lane AA, et al. Phase I trial of maintenance sorafenib after allogeneic hematopoietic stem cell transplantation for fms-like tyrosine kinase 3 internal tandem duplication acute myeloid leukemia. Biol Blood Marrow Transplant 2014;20:2042-8.
65Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol 2013;31:3681-7.
66Sandmaier BM, Khaled SK, Oran B, Gammon G, Trone D, Frankfurt O. Results of a Phase 1 Study of Quizartinib (AC220) As Maintenance Therapy in Subjects with Acute Myeloid Leukemia in Remission Following Allogeneic Hematopoietic Cell Transplantation. Blood 2014;124:428.
67Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood 2014;123:94-100.
68Levis MJ, Perl AE, Altman JK, et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). J Clin Oncol 2015;33.
69Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. J Clin Oncol 2010;28:2348-55.
70Paschka P, Schlenk RF, Gaidzik VI, et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010;28:3636-43.
71Stein EM, DiNardo C, Altman JK, et al. Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2 That Promotes Differentiation of Myeloid Cells in Patients with Advanced Hematologic Malignancies: Results of a Phase 1/2 Trial. Blood 2015;126:323.
72DiNardo C, De Botton S, Pollyea DA, et al. Molecular Profiling and Relationship with Clinical Response in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Potent Inhibitor of Mutant IDH1, in Addition to Data from the Completed Dose Escalation Portion of the Phase 1 Study. Blood 2015;126:1306.
73Kc B, DiNardo CD. Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120. Clin Lymphoma Myeloma Leuk 2016.
74Pascka P, Schlenk R, Weber D, et al. Outcome of patients with refractory or relapsed AML with IDH1 and IDH2 mutations after conventional salvage therapy: a study of the German-Austrian AML Study Group (AMLSG). EHA Learning Center 2016;S809.
75Irish JM, Anensen N, Hovland R, et al. Flt3 Y591 duplication and Bcl-2 overexpression are detected in acute myeloid leukemia cells with high levels of phosphorylated wild-type p53. Blood 2007;109:2589-96.
76Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 2016;374:311-22.
77DiNardo C, Pollyea D, Pratz K, et al. A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ??JPY to 65 Years and Not Eligible for Standard Induction Therapy. Blood 2015;126:327.
78Laszlo GS, Estey EH, Walter RB. The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev 2014;28:143-53.
79Amadori S, Suciu S, Selleslag D, et al. Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial. J Clin Oncol 2016;34:972-9.
80Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: a novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood 2013;122:1455-63.
81Fathi A, Erba H, Lancet J, et al. SGN-CD33A in combination with hypomethylating agents: a novel, well-tolerated regimen with high remission rate in older patients with AML. EHA Learning Center 2016.
82Krupka C, Kufer P, Kischel R, et al. CD33 target validation and sustained depletion of AML blasts in long-term cultures by the bispecific T-cell-engaging antibody AMG 330. Blood 2014;123:356-65.
83Al-Hussaini M, Rettig MP, Ritchey JK, et al. Targeting CD123 in acute myeloid leukemia using a T-cell-directed dual-affinity retargeting platform. Blood 2016;127:122-31.
84Zhu HH, Wu DP, Jin J, et al. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: a multicenter randomized controlled trial. J Clin Oncol 2013;31:4215-21.
85Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM. The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy. Cancer 2016;122:1160-8.
86Jiang H, Liang GW, Huang XJ, et al. Reduced medical costs and hospital days when using oral arsenic plus ATRA as the first-line treatment of acute promyelocytic leukemia. Leuk Res 2015;39:1319-24.
87Tsimberidou AM, Tirado-Gomez M, Andreeff M, et al. Single-agent liposomal all-trans retinoic acid can cure some patients with untreated acute promyelocytic leukemia: an update of The University of Texas M. D. Anderson Cancer Center Series. Leuk Lymphoma 2006;47:1062-8.
88Sanford D, Lo-Coco F, Sanz MA, et al. Tamibarotene in patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid and arsenic trioxide. Br J Haematol 2015;171:471-7.
89Shinagawa K, Yanada M, Sakura T, et al. Tamibarotene as maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled trial. J Clin Oncol 2014;32:3729-35.