NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse.

Acute myeloid leukemia (AML) with NPM1 mutation (NPM1 mut) defines a World Health Organization entity. Absence of minimal residual disease (MRD) following induction chemotherapy is associated with an excellent prognosis. Data are conflicting on NPM1 mut AML relapsing with wild-type NPM1 (NPM1 wt ). We analyzed 104 paired samples of NPM1 mut AML patients with relapse and identified 14/104 that relapsed with NPM1 wt AML. Blood counts at diagnosis differed significantly between patients with NPM1 mut and NPM1 wt relapse (median white blood cell count, 30 vs 3 × 109/L, P = .008; platelet count, 66 vs 128 × 109/l, P = .018). NPM1 mut relapse occurred significantly earlier than NPM1 wt relapse (14 vs 43 months, P = .004). At diagnosis, FLT3-ITD were more frequent in patients with NPM1 mut relapse (P = .029), whereas DNMT3A mutations were more frequent in patients with NPM1 wt relapse (P = .035). Sequencing analysis of paired samples at diagnosis, molecular remission, and NPM1 wt relapse identified cooccurring mutations that persist from diagnosis throughout remission and at relapse, suggestive of a preexisting clonal hematopoiesis. We provide evidence that AML relapsing with NPM1 wt is a distinct disease and that initial leukemia and relapse potentially arise from a premalignant clonal hematopoiesis.