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

Alexander Höllein1, Manja Meggendorfer1, Frank Dicker1

  • 1MLL Munich Leukemia Laboratory, Munich, Germany.

Blood Advances
|November 21, 2018
PubMed

Insights

Acute myeloid leukemia (AML) with NPM1 mutation that relapses with wild-type NPM1 is a distinct disease. This suggests a pre-existing clonal hematopoiesis may drive both initial leukemia and relapse in NPM1-mutated AML.

Area of Science:

  • Hematology
  • Molecular Oncology
  • Genetics

Background:

  • Acute myeloid leukemia (AML) with NPM1 mutation (NPM1mut) is a distinct WHO entity.
  • Absence of minimal residual disease (MRD) post-chemotherapy indicates a good prognosis.
  • Conflicting data exist regarding NPM1mut AML relapsing with wild-type NPM1 (NPM1wt).

Purpose of the Study:

  • To investigate the characteristics of NPM1mut AML relapsing with NPM1wt.
  • To determine if NPM1wt relapse represents a distinct clinical and molecular entity.
  • To explore the potential role of pre-existing clonal hematopoiesis.

Main Methods:

  • Analysis of 104 paired samples from NPM1mut AML patients with relapse.
  • Comparison of clinical and molecular features between NPM1mut and NPM1wt relapse groups.
  • Sequencing of paired samples at diagnosis, remission, and relapse.

Main Results:

  • 14 out of 104 patients relapsed with NPM1wt AML.
  • Significant differences in blood counts (WBC, platelets) and relapse timing between NPM1mut and NPM1wt relapse.
  • FLT3-ITD mutations were more frequent in NPM1mut relapse, while DNMT3A mutations were more frequent in NPM1wt relapse.
  • Co-occurring mutations persisted from diagnosis through remission to relapse, suggesting clonal hematopoiesis.

Conclusions:

  • AML relapsing with NPM1wt is a distinct disease entity.
  • Initial leukemia and relapse may originate from pre-malignant clonal hematopoiesis.
  • Understanding these distinct relapse patterns can inform future therapeutic strategies.

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