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AML Targeted Therapy
Acute Myeloid Leukemia: Will Understanding the Biology Lead to Better Outcomes?

Released: March 26, 2015

Expiration: March 24, 2016

Farhad Ravandi
Farhad Ravandi, MD
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Treatment of patients with acute myeloid leukemia (AML) has not changed significantly in the past few decades, with continued use of cytarabine and anthracyclines as the backbone of induction therapy, followed by selection of patients for transplantation in first remission based on their cytogenetics and molecular findings at diagnosis. Improvements in patient outcomes during this time have been, for the most part, due to the optimization of the dose of cytarabine and anthracyclines in the induction and consolidation regimens, as well as better supportive care. Most of these advances, however, have been of greater benefit in younger patients, whereas most of the patients with AML are older than 60 years of age with poorer outcomes.

Advances in AML research have led to increased understanding of the mechanisms of carcinogenesis in general and leukemogenesis, in particular. Numerous frequently occurring molecular mutations, including FLT3-ITD (which confers unfavorable risk), NPM1 (which confers favorable risk), and others, as well as specific cytogenetic abnormalities, are considered specific disease entities in AML. We are beginning to develop specific treatment strategies for these, best exemplified by acute promyelocytic leukemia, with t(15;17) and the molecular abnormality PML-RARA, which is now curable in almost all patients with standard-risk disease with the combination of all-trans retinoic acid and arsenic trioxide.

New Targets, New Therapies
The identification of potential targets such as FLT3, IDH, and BCL2 has led to testing of a wide range of new agents now in clinical trials for first-line and relapsed or refractory AML, alone or in combination with other current and novel therapies. FLT3 tyrosine kinase inhibitors, for example, have shown benefit in trials in patients with newly diagnosed and relapsed or refractory AML (sorafenib, midostaurin, quizartinib, crenolanib), particularly in patients with the FLT3-ITD mutation. Phase III trials in these agents are ongoing. The first-in-class isocitrate dehydrogenase 2 inhibitor AG-221 showed a 56% response rate in a mostly AML patient population in a phase I trial, and a phase II study with the BCL2 agonist venetoclax (ABT-199) showed activity in patients with relapsed/refractory AML, particularly in patients with IDH mutations. Researchers are exploring other targeted agents for AML as well, including the anti-CD33 monoclonal antibody–based therapies such as gemtuzumab, lintuzumab, and the more novel agent SGN-CD33A, proteasome inhibitors, and cell cycle inhibitors, in addition to nucleoside analogues, immunotherapies, and other agents such as vosaroxin, volasertib, and CPX-351 (a 5:1 molar combination of cytarabine and daunorubicin encapsulated in a lipid envelope).

Improved outcomes for patients with AML enrolled on trials investigating these agents have made pretreatment cytogenetic and molecular analysis imperative for all patients. Researchers are also studying improved techniques for detecting minimal residual disease after initial therapy to better gauge treatment efficacy. Better identification of patient molecular mutations and cytogenetic abnormalities, matched with the availability of these novel targeted agents for such a highly heterogeneous disease, makes participation in a clinical trial of enormous importance for practicing physicians and their patients with AML.

Many of the novel targeted agents are directed toward specific molecular abnormalities, and as such, their identification at a reputable laboratory at the time of diagnosis is likely to influence choice of treatment on various nationally available clinical trials, both at the time of initial therapy and at relapse. Furthermore, the availability of this information may help guide post-remission strategies on various national studies involving the use of these targeted agents.

At my institution, a comprehensive panel of known molecular mutations is performed in addition to the standard cytogenetics at the time of initial diagnosis. We use this information not only to select patients for appropriate clinical trials (for example, those including FLT3 inhibitors or specific studies for core binding factor leukemias or APL), but also to decide on the best post-remission strategy. Furthermore, we use the information at the time of relapse to select clinical trials of appropriate targeted inhibitors for the appropriate patients. With this strategy, we have been able to improve the overall outcome of patients (compared to our historical data) both after initial treatment and at the time of relapse.

Your Thoughts?
What impact have new molecular targets in AML made in your practice? Let us know with your comments below and in the poll question on this page.

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