Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia

Abstract

Some patients with acute myeloid leukemia (AML) who are in complete remission after induction chemotherapy harbor persisting pre-leukemic clones, carrying a subset of leukemia-associated somatic mutations. There is conflicting evidence on the prognostic relevance of these clones for AML relapse. Here, we characterized paired pre-treatment and remission samples from 126 AML patients for mutations in 68 leukemia-associated genes. Fifty patients (40%) retained ≥1 mutation during remission at a VAF of ≥2%. Mutation persistence was most frequent in DNMT3A (65% of patients with mutations at diagnosis), SRSF2 (64%), TET2 (55%), and ASXL1 (46%), and significantly associated with older age (p < 0.0001) and, in multivariate analyses adjusting for age, genetic risk, and allogeneic transplantation, with inferior relapse-free survival (hazard ratio (HR), 2.34; p = 0.0039) and overall survival (HR, 2.14; p = 0.036). Patients with persisting mutations had a higher cumulative incidence of relapse before, but not after allogeneic stem cell transplantation. Our work underlines the relevance of mutation persistence during first remission as a novel risk factor in AML. Persistence of pre-leukemic clones may contribute to the inferior outcome of elderly AML patients. Allogeneic transplantation abrogated the increased relapse risk associated with persisting pre-leukemic clones, suggesting that mutation persistence may guide post-remission treatment.

Prognostic significance of mutation profile at diagnosis and mutation persistence during disease remission in adult acute myeloid leukaemia patients

“…The general persistence of mutations in remission was associated with worse prognosis in our study, irrespective of VAFs or the number of mutations, which is in agreement with previous reports (Jongen‐Lavrencic et al , ; Rothenberg‐Thurley et al , ). Although DNMT3A mutations are the most frequently persisting mutations in AML, we and others have showed that their persistence does not seem to further impact prognosis of the DNMT3A mutated patients (Gaidzik et al , ; Jongen‐Lavrencic et al , ; Sun et al , ).…”

“…While previous studies identified persistent mutations in AML remission in 40–52% patients, we identified persistent mutations in a lower fraction of patients (33%), despite an identical spectrum of affected genes ( DNMT3A, TET2, IDH1/2, RUNX1, ASXL1, and SRSF2 ) and identical detection thresholds (2% VAF) (Klco et al , ; Morita et al , ; Rothenberg‐Thurley et al , ). This lower proportion of persistent mutations in our cohort is likely explained by the preferential selection of samples from the deepest (molecular) remission while other studies analysed post‐induction samples possibly including residual low‐level leukemic mutations representing minimal residual disease (MRD) (Jongen‐Lavrencic et al , ; Klco et al , ; Rothenberg‐Thurley et al , ). This assumption is supported by Parkin et al who analysed remission samples with a sensitivity as low as 0·002% VAF and confirmed that remission samples harbour a mixture of low‐level VAF mutations representing residual leukaemia clones that reappear at relapse, and high‐level mutations probably representing ancestral pre‐leukemic clones (Parkin et al , ).…”

Clonal evolution of acute myeloid leukemia from diagnosis to relapse

“…If residual leukemia cells are not able to gain the mutation quickly enough, they may be eradicated by the therapy. Thus, mutation clearance is directly correlated to the risk of AML relapse and its dynamics . On the other hand, as the subclonal diversity of AML at diagnosis is commonly high, individual cells capable of giving rise to relapse may already exist at diagnosis .…”

Clonal hematopoiesis and preleukemia—Genetics, biology, and clinical implications

“…86 In a larger cohort of 126 patients who reached CR after induction chemotherapy, 40% had at least one persisting mutation (VAF >2%) in a CR blood or marrow specimen. 87 In most of these patients, only a subset of the AML-associated mutations remained detectable and had allele frequencies of ≥10%, indicating persistence of preleukemic clones that substantially contributed to remission hematopoiesis, as opposed to a few residual leukemia cells. Patients with persisting mutations were older than those with complete mutation clearance, and mutation persistence was most common in DNMT3A, SRSF2, TET2, and ASXL1, suggesting that at least some of these patients may have had age-associated CH preceding their AML.…”