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

Menin inhibitors (MENINi) show promise for relapsed or refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangements (KMT2Ar) and nucleophosmin 1 mutations (NPM1c). Outcomes after MENINi failure are poorly understood. To characterize the mutational landscape and subsequent outcomes, we conducted a multicenter retrospective study of adults from 4 US centers with R/R AML after MENINi failure (relapse after response or primary refractory). The 84 patients (63% KMT2Ar, n = 53; 23% NPM1c, n = 19) who received MENINi were heavily pretreated: 86% (n = 72) had previous intensive chemotherapy (IC) and 77% venetoclax (VEN; n = 67). After MENINi failure, 40% of patients (n = 34) received supportive care. For the treated patients (n = 50), common regimens included hypomethylating agent (HMA)/VEN (26%, n = 13), clinical trial (26%, n = 13), and gilteritinib-based therapy (18%, n = 9). The complete response (CR)/CR with incomplete hematologic recovery (CRi) rate for nontrial therapies was 19% (n = 7); overall response rate was 32% (n = 12). All CR/CRi occurred with HMA/VEN (n = 2, 15%), IC + VEN (n = 4, 67%), or MENINi switching (bleximenib to revumenib, n = 1 [50%]). No patient with FLT3-ITD mutation responded to gilteritinib (0/6 gilteritinib-naïve). Median overall survival from start of next therapy was 4.4 months and superior for patients who achieved CR/CRi, (15.4 vs 3.4 months, P = .048). Outcomes after MENINi failure are poor, but responses occur with VEN-based regimens or MENINi switching. FLT3-ITD, WT1, and MEN1 mutations are associated with resistance.