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 59^th 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”.