Elias Jabbour, MD
Although there has been a paucity of drug advances for patients with acute myeloid leukemia (AML) during the past several decades, novel cytotoxic and targeted agents in the pipeline appear likely to provide new options for treating certain individuals with the malignancy, according to experts who participated in an OncLive Peer Exchange®
The panel members highlighted recent evidence showing the promise of emerging therapies for specific subgroups of patients during the program, “Moving Toward Precision Medicine in Adult Acute Myeloid Leukemia,” and stated that determining the optimal clinical settings for each agent will be the next steps for incorporating novel drugs into practice.
“Use of next-generation sequencing technology has generated a plethora of novel insights into the genetics of AML, providing important information about dysregulated signaling involved in leukemic transformation and leading to new therapeutic targets,” said Elias Jabbour, MD, who served as moderator for the program. “After a dearth of new therapies available for acute myeloid leukemia over the last few decades, we are transitioning into a new era with several promising strategies in late-stage development.”
Novel Chemotherapy Formulation
CPX-351 (Vyxeos) is a liposomal formulation of cytarabine and daunorubicin (molar ratio 5:1), which is designed to optimize synergy of the agents and improve incorporation and release of the drugs into the bone marrow. A phase III trial1 showed that patients with high-risk AML who received CPX-351 (100 units/m2
on days 1, 3, and 5) had significantly improved overall and event-free survival (EFS), including a subset of patients who had previously failed therapy with a hypomethylating agent, compared with participants who received standard 7+3 chemotherapy (cytarabine 100 mg/m2
/d x 7 days, daunorubicin 60 mg/m2
on days 1, 2, 3). Furthermore, outcomes following allogeneic transplantation were better in patients who achieved remission with CPX-351 than for those treated with 7+3 chemotherapy.Harry P. Erba, MD, PhD,
said that the data may define new approaches for high-risk patients 60 to 75 years old with secondary AML and possi- bly for other subgroups. “The way we develop future drugs in AML is going to change dramatically because I think we are going to, for the first time in 30 or 40 years, have new standards of care for subsets of our patients,” said Erba.Mark J. Levis, MD, PhD,
indicated that, although overall survival (OS) appears to be similar between CPX-351 and 3+7 chemotherapy in younger patients, CPX-351 may be less toxic in certain combination therapies. However, Erba cautioned that CPX-351 was associated with greater myelosuppression in a phase IIb trial of patients younger than 60 years in their first relapse, which should be considered when contemplating combinations of CPX-351 with myelosuppressive agents.
Targeted Therapies in Development
Approximately 24% of patients with AML are believed to harbor FLT3 mutations, most of which are internal tandem duplication (ITD) aberrations. Additionally, point mutations have been described in the kinase domain (TKD) of the FLT3 protein. These mutations are associated with an increased risk for early and multiple relapses in AML, and have therefore emerged as an attractive therapeutic target. The eld of FLT3 inhibitors has grown “very crowded,” with several likely obtaining approval during the next few years, according to Levis.
Midostaurin, a FLT3 inhibitor effective against the ITD and TKD mutations, is the rst FLT3-targeted therapy to improve OS in a randomized phase III study. The FDA is evaluating the multikinase small-molecule inhibitor under the agency’s break-through therapy and priority review programs. In the RATIFY trial, midostaurin with standard chemotherapy and as single-agent maintenance therapy reduced risk for mortality by 23% compared with chemotherapy plus placebo in newly diagnosed patients with FLT3
-mutated AML, with similar improvements in survival reported among TKD, high-ITD, and low-ITD mutation subgroups.Richard M. Stone, MD,
who presented the RATIFY results at the 2015 American Society of Hematology Annual Meeting, noted that patients who received midostaurin followed by allogeneic transplantation at rst remission fared particularly well, with a plateau and a survival curve in the 60% to 70% range. Stone stated that although administering midostaurin early in treatment (prior to allogeneic transplantation) would likely be most effective, early results from the ongoing RADIUS trial (NCT01883362) showed that midostaurin was safe following allogeneic transplantation.