DNMT3A,   TET2,  General AML

ASH 2017 | Clonal hematopoiesis in AML patients receiving allo-HSCT in CR 

Clonal Hematopoiesis of Intermediate Potential (CHIP) is the presence of hematologic malignancy-associated somatic mutations such as DNMT3A, TET2, ASXL1 in the peripheral blood or bone marrow but absence of diagnostic criteria for hematologic neoplasm and it is a common phenomenon in healthy individuals.

Persistent Clonal Hematopoiesis-Associated Mutations (CH-mutations) in Acute Myeloid Leukemia (AML) patients in Complete Remission (CR) is associated with an increased risk of relapse. The prognostic impact of CH-mutations in AML patients in CR particularly in the setting of Allogenic Hematopoietic Stem Cell transplantation (allo-HSCT) is not fully understood. 

At the 59th Annual Meeting & Exposition of the American Society of Hematology (ASH), Juliane Grimm from the University Leipzig, Leipzig, Germany, on behalf of colleagues presented, data from a study which aimed to analyze the biologic implications and prognostic impact of CH-mutations present in AML patients in CR or in CR with incomplete peripheral recovery (CRi) prior to allo-HSCT.

Peripheral blood samples collected within 29 days pre-HSCT from 113 AML patients (median age = 63.6 years) who received HSCT after non-myeloablative conditioning in CR (CR1 61.9%, CR2 14.2%) or CRi (23.9%) were analyzed. CH‑mutations were identified by targeted amplicon sequencing (mean amplicon coverage per sample 7205x). 

The key findings of the study were:
  • Seventy CH-mutations were identified in 48 AML patients (42.5%) in CR/CRi with a mean VAF of 19.1% (58.6% of mutations with VAF>10%)
  • Most frequent mutations include DNMT3A (31.4%), TET2 (28.6%) and ASXL1 (14.3%)
  • Presence of ≥ 1 CH-mutation in CR/CRi did not impact Leukemia Free Survival (LFS), P = 0.95 or Overall Survival (OS), P = 0.37
  • Patients with ≥ 2 CH‑mutations had longer LFS (P = 0.02) and OS (P = 0.007) compared to patients with no or 1 CH‑mutation
  • In CR/CRi, DNMT3A mutations did not influence LFS (P = 0.73) or OS (P = 0.71)
  • TET2 mutations in CR/CRi did not impact LFS (P = 0.25) but significantly associated with longer OS (P = 0.06)
  • ASXL1 mutations associated with longer LFS, P = 0.11 and OS P =0.13
  • Presence of CH-mutations at diagnosis: 83 CH-mutations were found in 55/76 patients (29 persistent, 9 new, 45 lost)
  • After cytarabine therapy, 35% of diagnostic CH‑mutations persisted and 11% CH-mutations were newly detected

The presenter concluded that in AML, CH-mutations are frequently present (42.5%) in CR/CRi and show high VAFs (mean 19.1%) thus suggesting the presence of clonal hematopoiesis. The presence of more than one CH-mutation does not impact prognosis. Additionally, patients with ≥ 2 CH‑mutations had longer LFS & OS, which suggests that there is an “increased immunogenic potential with higher number of CH‑mutations leading to potent graft vs leukemia effects in the HSCT context”.

References
  1. Grimm J. et al. Prognostic Impact of Clonal Hematopoiesis in Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission. Oral Abstract 406. ASH 59th Annual Meeting and Exposition, Atlanta, GA.
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