Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Menin inhibitors (MENINi) offer a promising treatment for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and NPM1 mutations (NPM1c).
• Understanding treatment outcomes following MENINi failure is crucial for managing R/R AML patients.

Purpose of the Study:

• To investigate the mutational landscape and subsequent treatment outcomes in adult patients with R/R AML after MENINi failure.
• To identify effective treatment strategies and prognostic factors in this challenging patient population.

Main Methods:

• A multicenter retrospective study involving 84 adult patients from 4 U.S. centers diagnosed with R/R AML post-MENINi failure.
• Data collection included patient demographics, prior treatments (intensive chemotherapy, venetoclax, stem cell transplantation), subsequent therapies, and clinical outcomes.
• Genomic profiling was analyzed to identify mutations associated with treatment resistance.

Main Results:

• Patients were heavily pre-treated, with 86% receiving prior intensive chemotherapy and 77% prior venetoclax.
• Following MENINi failure, 40% received supportive care, while 60% received further treatment, commonly hypomethylating agent/venetoclax (HMA/VEN) or gilteritinib-based therapy.
• The overall response rate (ORR) for non-trial therapies was 32%, with complete remission/complete remission with incomplete hematologic recovery (CR/CRi) achieved primarily with HMA/VEN, intensive chemotherapy plus VEN, or MENINi switching.
• No FLT3-mutant patients responded to gilteritinib.
• Median overall survival (mOS) from the start of next therapy was 4.4 months, significantly longer for patients achieving CR/CRi (15.4 months) compared to non-responders (3.4 months).
• FLT3-ITD, WT1, and MEN1 mutations were associated with resistance.

Conclusions:

• Outcomes for R/R AML patients after MENINi failure are generally poor.
• Venetoclax-based regimens and switching to a different menin inhibitor show potential for achieving responses.
• Identifying specific mutations like FLT3-ITD, WT1, and MEN1 is important for predicting resistance to MENINi therapy.