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We report a case of acute myeloid leukemia (AML) with a KMT2A-rearrangement complicated by isolated central nervous system (CNS) relapse during menin inhibitor–based therapy. A 50-year-old man presented with marked leukocytosis (white blood cells, 39.3 × 10⁹/L) and circulating blasts and was diagnosed with t(6;11)(q27;q23) KMT2A–AFDN translocation AML (left panel: diagnostic bone marrow aspirate, 40× Wright-Giemsa stain, block arrows: blasts; thin arrows: erythroid precursors; flow plots demonstrate CD34⁺ blasts). He was treated on a clinical trial with the menin inhibitor ziftomenib combined with standard induction therapy. Baseline evaluation showed no evidence of CNS involvement. Complete remission with incomplete hematologic recovery was achieved after 4 cycles.

Five months into therapy, he developed progressive neurologic symptoms. Cerebrospinal fluid (CSF) examination demonstrated leukemic blasts (right panel: 40× CSF cytology Diff-Quik, block arrows: blasts; thin arrows: lymphocytes; flow plots demonstrate >50% CSF blasts with loss of CD34 consistent with posttreatment changes observed in the marrow). CNS involvement occurred without circulating blasts or leukocytosis. CNS-directed therapy included dexamethasone, intrathecal cytarabine/hydrocortisone, and craniospinal irradiation resulting in blast clearance.

Although KMT2A-rearranged AML carries an inherent predisposition to CNS involvement, this case highlights isolated CNS relapse during menin inhibitor therapy and raises the hypothesis that menin inhibition–associated differentiation may alter disease distribution. This case underscores the importance of vigilance for CNS monitoring as these agents enter broader clinical use.

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