Outcomes of relapsed or refractory acute myeloid leukemia after menin inhibition failure
Kuo‐Kai Chin, Brian Ball, Yasmin Abaza, Jessica K. Altman, Rahul Thakur, Moiez Ali, Andriy Derkach, Mark B. Geyer, Aaron D. Goldberg, Tamanna Haque, Meghan C. Thompson, Jae H. Park, Martin S. Tallman, Sheng F. Cai, Eunice S. Wang, Ibrahim Aldoss, Eytan M. Stein
Abstract
ABSTRACT: 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.