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Characterization of Resistant AML After Venetoclax and Hypomethylation Failure

By: Lauren Harrison, MS
Posted: Tuesday, March 10, 2020

Older patients who are newly diagnosed with acute myeloid leukemia (AML) and fail to respond to front-line venetoclax plus hypomethylating therapy typically have high-risk disease biology such as therapy-related AML, secondary AML, complex cytogenetics, FTL3-ITD, mutated TP53, and mutated N/KRAS. These high-risk features tend to decrease the likelihood of response and confer a worse overall survival, reported Abhishek Maiti, MBBS, of The University of Texas MD Anderson Cancer Center at the 2019 American Society for Hematology (ASH) Annual Meeting & Exposition (Abstract 738) and published in the journal Blood.

This retrospective study analyzed patients from November 2014 through February 2019 who had newly diagnosed AML and enrolled in clinical trials studying venetoclax plus hypomethylating agents. Patients included in the present study developed refractory AML or relapse after initial response to treatment. In total, 103 patients with AML were identified, and 41 of them developed refractory AML or relapsed. The median age of patients was 74 years, and a median of 4 cycles of therapy was received.

After initial venetoclax and hypomethylation therapy, 46% of patients had achieved a complete response, whereas 20% had primary refractory disease. Patients who had an initial response relapsed after a median of 5.3 months; after disease failure, the median overall survival for all 41 patients was 2.4 months. After treatment failure, 24 patients (3 with primary refractory AML, 21 with relapsed AML) received salvage therapy, and 5 of them responded.

Patients with mutated NPM1 and mutated IDH1/2 who relapsed were found to have adverse-risk cytogenetics or co-occurring mutations in TP52, N/KRAS, FLT3, and/or KIT. Two of the five patients with FLT3 mutations responded to salvage therapy, which included a FLT3 inhibitor. Of 11 patients with RAS mutations, 3 responded to salvage therapy, whereas 1 of 6 patients with mutated TP53 responded to salvage therapy.

Disclosure: For full disclosures of the study authors, visit ashpublications.org.


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