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

Iván Martín; Blanca Navarro; Eva Villamón; Carlos Solano; Alicia Serrano; Marisa Calabuig; Paula Amat; Fernando Domingo; Rosario Abellán; Francisca García; María Dolores Olivares; Francisco Javier Chaves; Mar Tormo; Juan Carlos Hernández-Boluda

doi:10.1016/j.yexmp.2018.07.002

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.

Authors

Affiliations

¹ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: marcasi@alumni.uv.es.
² Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: nacublan@ext.uv.es.
³ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: eva.villamon@uv.es.
⁴ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain; Department of Medicine, School of Medicine, University of Valencia, Valencia, Spain. Electronic address: carlos.solano@uv.es.
⁵ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain.
⁶ Genomic and Genotyping Unit, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: m.rosario.abellan@uv.es.
⁷ Genomic and Genotyping Unit, INCLIVA Research Institute, University of Valencia, Valencia, Spain.
⁸ Genomic and Genotyping Unit, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: felipe.chaves@uv.es.
⁹ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: tormo_mar@gva.es.
¹⁰ Hematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, University of Valencia, Valencia, Spain. Electronic address: hernandez_jca@gva.es.

PMID: 30017658
DOI: 10.1016/j.yexmp.2018.07.002

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