Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin

Exp Mol Pathol. 2018 Aug;105(1):139-143. doi: 10.1016/j.yexmp.2018.07.002. Epub 2018 Jul 11.

Abstract

Background: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT).

Case presentation: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period.

Discussion and conclusion: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic-stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion.

Keywords: Allogeneic transplantation; Chemotherapy; DNMT3A mutation; Molecular monitoring; Therapy-related acute myeloid leukemia.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Bone Marrow Transplantation / adverse effects*
  • DNA (Cytosine-5-)-Methyltransferases / genetics*
  • DNA Methyltransferase 3A
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mutation, Missense*
  • Nucleophosmin
  • Transplantation, Homologous

Substances

  • DNMT3A protein, human
  • NPM1 protein, human
  • Nucleophosmin
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methyltransferase 3A