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

Abstract

Acute myeloid leukemia (AML) with NPM1 mutation (NPM1mut) 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 NPM1mut AML relapsing with wild-type NPM1 (NPM1wt). We analyzed 104 paired samples of NPM1mut AML patients with relapse and identified 14/104 that relapsed with NPM1wt AML. Blood counts at diagnosis differed significantly between patients with NPM1mut and NPM1wt relapse (median white blood cell count, 30 vs 3 × 109/L, P = .008; platelet count, 66 vs 128 × 109/l, P = .018). NPM1mut relapse occurred significantly earlier than NPM1wt relapse (14 vs 43 months, P = .004). At diagnosis, FLT3-ITD were more frequent in patients with NPM1mut relapse (P = .029), whereas DNMT3A mutations were more frequent in patients with NPM1wt relapse (P = .035). Sequencing analysis of paired samples at diagnosis, molecular remission, and NPM1wt 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 NPM1wt is a distinct disease and that initial leukemia and relapse potentially arise from a premalignant clonal hematopoiesis.

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

“…The most frequently mutated genes, NPM1 , FLT3 , and DNMT3A , show variable evolutionary patterns in different AML cohorts. Mutations in NPM1 are rather stable in all cohorts, lost only in 2/36 CN‐AML patients and 4/21 FLT3 ‐ITD positive patients, which is in line with the reported frequency of NPM1 mutation loss at relapse in general . Similarly, FLT3 ‐ITDs have a rather stable mutation pattern in the CN‐AML cohort, while they are gained at relapse in 6/25 patients, which is in line with the ELN classification that associates FLT3 ‐ITD with poor prognosis .…”

“…Mutations in NPM1 are rather stable in all cohorts, lost only in 2/36 CN-AML patients 41 and 4/21 FLT3-ITD positive patients, 37 which is in line with the reported frequency of NPM1 mutation loss at relapse in general. 42,43,47 Similarly, FLT3-ITDs have a rather stable mutation pattern in the CN-AML cohort, while they are gained at relapse in 6/25 patients, 41 which is in line with the ELN classification that associates FLT3-ITD with poor prognosis. 12 Interestingly in NPM1 + /NPM1 − AML patients, FLT3-ITDs were not detected at relapse although present in 18/61 NPM1 + diagnostic samples, pointing towards the development of an independent AML at relapse.…”

“…12 Interestingly in NPM1 + /NPM1 − AML patients, FLT3-ITDs were not detected at relapse although present in 18/61 NPM1 + diagnostic samples, pointing towards the development of an independent AML at relapse. 42,43 FLT3 point mutations are often lost in the CN-AML cohort 41 and NPM1 + patients, 42,43 while gained in patients of the FLT3-ITD AML cohort. 37 DNMT3A is stably mutated in most of the patients without any loss in the CN-AML cohort, 41 still recurrently lost in 2/18…”

“…FLT3-ITD patients 37 and 6/91 NPM1 + patients. 42,43 Additional examples for stable mutations detected in multiple cohorts include IDH1 and IDH2, although these mutations are also gained in several patients. 37,40,41,43 Genes specifically mutated at diagnosis include NRAS, KIT, and PTPN11.…”

“…42,43 Additional examples for stable mutations detected in multiple cohorts include IDH1 and IDH2, although these mutations are also gained in several patients. 37,40,41,43 Genes specifically mutated at diagnosis include NRAS, KIT, and PTPN11. 38,39,41,43 In contrast, FLT3-ITDs and mutations in WT1, KDM6A, and RUNX1 are often gained at relapse.…”