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Recent Progress in AML
Why I Am Optimistic About Recent Progress in AML

Released: March 22, 2016

Expiration: March 21, 2017

Farhad Ravandi
Farhad Ravandi, MD
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After decades with few new drugs available for patients with acute myeloid leukemia (AML), treatment options are changing at last. What follows is my perspective on some of the most promising treatment approaches in AML for 2016.

FLT3 Inhibitors
Better understanding of the biology and mechanisms of leukemogenesis has provided us with potential targets for drug development—several of these targets (eg, FLT3, IDH1, IDH2, BCL2, CD33) are actionable (they have agents that target them), and these targeted agents will potentially be available for incorporation in our treatment strategies.

For example, in a plenary presentation at the 2015 ASH annual meeting in Orlando, Florida, results were presented from a large, multinational randomized trial examining the potential benefit of including an FLT3 kinase inhibitor, midostaurin, in the frontline treatment of younger patients with AML. Data from this study demonstrated an improvement in survival in patients who received the drug in addition to traditional cytotoxic chemotherapy. 

This not only has implications for the standard therapy of this population—the FDA recently granted midostaurin breakthrough therapy status based on this trial—but it also provides further impetus for the continued clinical development of other, perhaps more potent, FLT3 inhibitors such as quizartinib and gilteritinib. Trials of other FLT3 inhibitors such as sorafenib have previously hinted at the potential benefit of incorporating targeted therapies in chemotherapy regimens for AML, as has already been demonstrated in patients with Philadelphia chromosome–positive acute lymphoblastic leukemia, where the incorporation of tyrosine kinase inhibitors such as imatinib and dasatinib has significantly improved outcomes. 

Minimal Residual Disease
Another area of significant recent development in AML is monitoring and treating minimal residual disease (MRD). It can be argued that we are close to the ceiling of achievable benefits using DNA-interacting traditional cytotoxic agents, with dose increases or adding newer cytotoxic agents to currently available regimens offering limited further gains. Better standardized and reliable assays for detecting MRD can identify leukemic cells left behind after treatment with cytotoxic regimens, which are likely to be inherently resistant to such agents. Recent development of agents such as molecularly targeted inhibitors (eg, the BCL2 inhibitor venetoclax, the histone deacetylase inhibitor pracinostat, and the IDH2 inhibitor AG-221) and monoclonal antibody–based therapies, with alternative mechanisms of action against these cells, can potentially assist us in eradicating minimal residual leukemia, thereby improving relapse-free survival and potentially OS. The challenge is likely to be the development of clinical trials that can convincingly prove their utility in an acceptable time frame.

Demethylating Agents
Advances in treatment for the elderly population, who account for the majority of patients with AML and are less able to tolerate intensive cytotoxic agents, include the introduction of demethylating agents such as decitabine and azacitidine, providing alternative tools for therapy that may prove effective in combination with molecularly targeted agents such as venetoclax and pracinostat as well as antibody-based drugs. These strategies already look promising with early trials reporting limited toxicity as well as a high rate of durable responses. 

Final Thoughts
These are just a few highlights of the many interesting and important recent data showing promise in the management of AML, with the potential to provide our patients with improved outcomes. 

Please leave a comment and let me know what recent data you are integrating into your clinical practice.
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Which of the following agents in development for AML do you most anticipate having the greatest impact on your practice?
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