Novel therapeutic strategies for AML in 2012

Abstract

During the last four decades, much progress has been made in understanding the molecular pathogenesis of acute myeloid leukemia and in identifying prognostic factors predictive of outcome. However, progress in therapy has been much slower. Since the initial description of the combination of an anthracycline and cytarabine for induction, few major advances have changed the standard of care. Furthermore, these few advances apply to younger patients and those with inherently more favorable disease biology. Intensification of post-remission cytarabine improves the cure rate of patients in first complete remission (CR). Daunorubicin dose intensification improves outcome in younger patients. Finally, allogeneic hematopoietic cell transplantation is an effective strategy for many patients in first CR. The discovery of drugs with novel mechanisms of action which are directly at specific molecular targets is among the most exciting areas of research and holds great promise for the development of effective treatment.

Keywords:

• Acute leukemia
• Induction and consolidation
• New agents

Introduction

Among younger patients (less than ages 55–60 years of age) with newly diagnosed acute myeloid leukemia (AML), cytotoxic chemotherapy with the combination of an anthracycline and cytarabine results in complete remission (CR) in approximately 60 to 80%.1^–3 However, only approximately 40 to 45% of patients achieving CR remain alive at 5 years and considerably less when all patients and not just those achieving CR are considered. Among older patients (more than 55–60 years of age), the CR rate is approximately 40–50% and only approximately 10–15% remain alive at 5 years. Interestingly, the major advances, other than hematopoietic cell transplantation (HCT), benefit those with more favorable disease. Intensive consolidation chemotherapy often including intermediate- or high-dose cytarabine, is now standard post-remission therapy for younger patients, but is only effective for those with favorable- or intermediate-cytogenetic risk disease. Such an approach does not appear benefit those patients with unfavorable-risk cytogenetics or older adults.4 Allogeneic HCT is a potentially curative approach for many patients in first CR, but the graft-versus-leukemia (GVL) effect is only modestly effective in patients with unfavorable-risk disease. Reduced-intensity conditioning (RIC) HCT and alternative donors have expanded the population of patients who can potentially benefit from the GVL effect. However, the transplant-related mortality associated with both fully myeloablative as well as RIC HCT remains a major limitation. Recent insights into the molecular genetics of AML have led to rapid drug discovery. Although few of these novel agents have yet to change the natural history of patients with AML, it is likely that the burgeoning number of exciting molecularly directed agents will do so in the very near future.

New Prognostic Factors: Incorporating Molecular Genetics

The presence of a number of recently described gene mutations has an important influence on outcome in AML after conventional chemotherapy and may guide therapy. Patients with a normal karyotype comprise approximately 45% of adults with AML. Such patients whose leukemic cells do not express the FLT3-ITD mutation, but do express the NPM1 mutation may not benefit from HCT in a donor-versus-donor analysis, but such conclusions warrant further studies.5 A recent donor–no donor analysis suggests that such patients may indeed benefit.6 Patients with core binding factor (CBF) leukemias represent a group of population for whom allogeneic HCT has not generally been recommended. However, patients whose leukemia cells express a mutation in c-KIT appear to have a considerably less favorable outcome than those patient with CBF AML without a c-KIT mutation and may be considered for transplantation or other novel approaches such as a tyrosine kinase inhibitor.7,8 The c-KIT mutation among patients with the inv(16) chromosomal abnormality appears to have less or no impact. Patients with a bi-allelic CEBPalpha mutation appear to have a reasonably good outcome with conventional chemotherapy and may not benefit from allogeneic HCT. Patients with unfavorable-risk cytogenetics and other mutations which confer a poor prognosis with conventional chemotherapy do not have a favorable outcome with chemotherapy alone and may benefit from allogeneic HCT.9 The outcome of patients with FLT3-ITD mutations appears to depend on the allelic ratio. Novel potent FLT3 inhibitors such as AC220 (discussed below) have been developed and are in clinical trials in combination with cytotoxic chemotherapy. The benefit from allogeneic HCT has not been clearly established among such patients although most clinicians recommend such an approach.10 Conflicting results have been published evaluating the influence of IDH mutations. It is clear that the impact on outcome depends on the patient population and the presence of other cooperating mutations.

Induction Chemotherapy: New Beginnings

A large randomized trial conducted by the Eastern Cooperative Oncology Group tested daunorubicin dose intensification in younger patients with newly diagnosed AML. Daunorubicin in a daily dose of 90 mg/m²/day for 3 days was compared with 45 mg/m²/day for 3 days each in combination with standard dose cytarabine given for 7 days.11 This resulted in a significantly better CR rate in the 90 mg arm (70·6 vs 57·3%: P = 0·001) without any addition toxicity. Survival at a median of 24 months was also improved (23·7 vs 15·7 months: P = 0·003). The benefit was not observed in those patients with unfavorable-risk cytogenetics or in those with FLT3-ITD mutations. The Haemato-Oncology Foundation for Adults in the Netherlands group has also demonstrated a benefit for high-dose daunorubicin in patients up to age 65 years. These two studies have changed the standard of care. Whether the 90 mg dose is more effective than a dose of 60 mg is not known. However, the 90 mg dose is not more toxic even among older adults. Three studies have explored the addition of antibody directed chemotherapy with the immunoconjugate, gemtuzumab ozogamicin, a humanized anti-CD33 monoclonal antibody which is chemically linked to the potent toxin calicheamicin. In a large study reported by the Medical Research Council, 1113 patients were randomized to one of three induction regimens, either Daunorubicin plus Ara-C or Daunorubicin plus cytarabine and Etoposide or FLAG-Ida, with or without GO at a dose of 3 mg/m².12 There was no improvement in CR rate or OS. However, there was a significant OS benefit among patients with favorable-risk cytogenetics. Due to toxicity issues and lack of sufficient efficacy in a second trial carried out by the Southwest Oncology Group, S0106, evaluating the benefits of GO in induction when combined with chemotherapy in younger patients,13 the drug was removed from the market. However, most recently, the Acute Leukemia French Association performed a randomized trial in patients ages 50–70 and showed a benefit for adding three doses of GO (total dose of 9 mg/m²) to conventional induction chemotherapy for those with favorable-risk cytogenetics and to a lesser extent those with intermediate-risk cytogenetics, but not among those with unfavorable-risk disease.14 Whether these studies provide sufficiently definitive data to establish GO as a new standard of care for CBF AML or other patients remains a subject for debate.

Consolidation Chemotherapy: Are Less Intensive Regimens as Effective?

Standard consolidation chemotherapy for younger adults often includes high-dose cytarabine.4 However, the optimal dose and schedule and number of cycles have not been established and the addition of other agents is not beneficial. The Medical Research Council has conducted a randomized comparison of two cytarabine doses, 3 versus 1·5 g/m², following CR induced with an intensive triple-drug induction, which showed no apparent benefit for the higher dose of cytarabine. These results suggest that a new standard may be established if additional studies confirm these results.15 Randomized trials conducted by the Haemato-Oncology Foundation for Adults in the Netherlands and Japanese Adult Leukemia Study Group groups also suggest that reduced doses of cytarabine in consolidation are as effective as and less toxic than higher-doses which have become routine in clinical practice.

Hematopoietic Cell Transplantation

In general, patients with favorable-risk cytogenetics do not benefit from HCT and patients with unfavorable-risk cytogenetics do appear to benefit. The role of allogeneic HCT in intermediate-risk patients may depend on a specific molecular genetic genotype. Several important recent advances in allogeneic HCT have occurred. Firstly, there is evidence which suggests that TRM has decreased during the past 30 years related to a change in incidence in organ damage, infections and graft-versus-host disease.16 Secondly, the outcome for transplantation from well-matched unrelated donors appears to be associated with similar outcomes as those associated with matched related donors even among patients with high-risk disease.¹⁷17,18 Thirdly, the introduction of RIC allogeneic HCT, whereby the chemotherapy administered as conditioning is not intensive and myeloablative and the benefits rely more on the putative GVL effect, has expanded the population of patients who may not otherwise have had the opportunity to benefit.

Drug Discovery: a Myriad of New Promising Agents

A wide variety of new agents with unique mechanisms of action has been discovered. These include antisense oligonucleotides,19 CPX-351 (a liposomal formation of a fixed molar ratio of daunorubicin and cytarabine),20 DOT1L inhibitors (histone H3K79 methyltransferase inhibitor) which appears to target MLL,21 FLT3 inhibitors such as Sorafenib22 and AC220,23 novel purine analogs such as Clofarabine24 and Sapacitabine25 and elacytarabine [elaidic ester of cytarabine which is independent of the hENT1 (human equilibrative nucleoside transporter 1) transporter which facilitates transfer of cytarabine across the cell membrane].26 The purine nucleoside Clofarabine induced CR in 38% of previously untreated adults aged ⩾60 years with at least 1 adverse prognostic factor (age ⩾70 years, antecedent hematologic disorder, PS of at least 2, and/or intermediate or poor-risk karyotype) with a 30-day all cause mortality rate of 10%.24 The overall response rate was 42% among patients with poor-risk cytogenetics. CPX-351 is a liposomal formulation of a 5∶1 fixed molar ratio of daunorubicin and Ara-C.27 Among previously untreated adults aged 60–75, receiving CPX-351, the overall response rate was 66·7% with a CR rate of 40·5%. The 30- and 60-day mortality rates were 3 and 4·7%, respectively, compared to 7·3 and 14·6% for patients treated with conventional cytotoxic chemotherapy in a randomized trial. Further studies of these agents alone exploring alternative doses and schedules or combined other novel agents or chemotherapy are underway. The heterogeneity of AML will mandate close collaboration among both clinical investigators and laboratory-based scientists for the design of studies with exciting new therapies directed at specific molecular targets in AML.

Table 1. New agents in acute myeloid leukemia

Agent	Mechanism	Comments
XIAP antisense oligo19	Apoptosis inhibitor	Effective with chemotherapy
CPX-35120	Liposomal fixed ratio of daunorubicin and cytarabine	High response rate and reduced mortality, particularly in therapy-related AML
DOT1L inhibitor21	Histone H3K79 methyltransferase	Preclinical data against MLL
Sorafenib22/AC22023	Multi-kinase inhibitor	CRs with single agent
Clofarabine24	Nucleoside analog	Effective in older adults with unfavorable progostic factors
Sapacitabine25	Nucleoside analog	CRs with single agent
Elacytarabine26	Eliadic ester of cytarabine	Modest remission rate in advanced disease