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 x 10(9)/L, P = .008; platelet count, 66 vs 128 x 10(9)/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.