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Targeted AML Therapies
A New Paradigm: Targeted Therapies for Acute Myeloid Leukemia

Released: October 15, 2018

Expiration: October 14, 2019

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After a prolonged period of stagnation where the progress in treating patients with acute myeloid leukemia (AML) was limited at best, we have seen significant advances in the current understanding of the biology of the disease and the molecular processes underlying its pathogenesis. This has already been translated into the discovery and development of a number of new agents with promising activity, some of which have been recently approved by the FDA for clinical use.

The initial description of the transmembrane receptor, FLT3, and its role in normal and malignant hematopoiesis dates back several decades, and that research has contributed to the investigation of inhibitors of FLT3 kinase activity evaluated in clinical trials for the past 15-20 years. However, no FLT3 inhibitors arrived in the clinic until FDA approval in 2017 of midostaurin in combination with chemotherapy in the initial therapy of patients with FLT3-mutated AML, supported by results from the RATIFY trial. In that phase III trial of younger patients with newly diagnosed FLT3-mutated AML (N = 717), patients in the midostaurin combination cohort had a median OS of 74.7 months vs 25.6 months in the group with chemotherapy alone.

Researchers are investigating a number of more potent FLT3 inhibitors, including quizartinib, gilteritinib, and crenolanib, in randomized trials designed to determine their efficacy in patients with relapsed FLT3-mutated AML and in the frontline setting. Gilteritinib is currently under FDA Priority Review, and quizartinib received a Breakthrough Therapy designation earlier this year.

Other recurring molecular aberrations in AML have been targets for drug development. Mutations of the genes encoding for the IDH enzymes have been described in approximately 20% of patients with AML, and enasidenib and ivosidenib, inhibitors of IDH2 and IDH1, respectively, have been evaluated in large phase I and II studies and have been recently approved by the FDA for the treatment of patients with relapsed IDH2 or IDH1 mutated AML, respectively. Both oral drugs are relatively nontoxic and well-tolerated in general, with an ORR of approximately 40%. Potential benefits of combining these drugs with chemotherapy or with hypomethylating agents are being investigated in ongoing trials.

Venetoclax, a potent inhibitor of the BCL2 protein important in the regulation of the cellular apoptotic mechanisms, is approved for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p deletion, who have received at least 1 previous therapy. Initial studies in relapsed AML showed modest activity, but studies combining venetoclax with low-dose cytarabine or with the hypomethylating agents decitabine or azacytidine have demonstrated impressive activity in untreated elderly patients with AML. These combinations have been well tolerated, producing response rates at least comparable to those achieved by cytarabine/anthracycline-based induction regimens, and these responses have been durable. Ongoing clinical trials will further establish the role of these regimens in the frontline therapy of elderly and unfit patients with AML, but it is likely that these regimens will have a significant role in this setting.

Other targeted strategies that may have potential promise are antibody-based agents. The reapproval of gemtuzumab ozogamicin for frontline therapy of patients with AML in combination with chemotherapy has generated further interest in monoclonal antibody–toxin conjugates, and numerous such agents are in development. Furthermore, with the success of immunotherapy in solid tumors and the efficacy of blinatumomab in acute lymphoblastic leukemia, several immune-reactivating antibodies and bispecific antibodies directed at myeloid-specific antigens are undergoing evaluation in early-phase clinical trials. These agents will likely be of interest also in the management of measurable residual disease due to their alternative mechanism of action compared with agents commonly used for induction and consolidation in AML.

Overall, with the availability of several drugs with promising activity, the outlook for patients with AML is improving significantly. Many challenges remain, including ways to rapidly identify patients who will likely benefit from specific strategies, and novel designs of trials that would quickly demonstrate the potential efficacy and benefit of multiple drugs in development.

I invite you to join my colleagues and me as we discuss these and other exciting therapeutic advances in AML at our Friday Satellite Symposium in San Diego, “Moving Toward Precision Therapy for Patients With AML: Clinical Challenges and Future Directions,” on November 30, 2018, preceding the 60th ASH Annual Meeting and Exposition. Please click HERE for further details and registration information.

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