The Impact of Age-Related Clonal Hematopoiesis on Outcomes of Adults With Acute Lymphoblastic Leukemia

Age-related clonal hematopoiesis (ARCH) denotes accumulation of DNA mutations in hematopoietic stem cells as a result of aging, inflammation, and other environmental factors. The role of ARCH in lymphoid leukemogenesis is unknown. We hypothesize that ARCH is a precursor lesion for acute lymphoblastic leukemia (ALL) in older adults, and ARCH-associated ALL is a unique entity with different molecular and clinical characteristics. We retrospectively studied 345 patients with ALL (83% B-ALL, 14% T-ALL, 3% ETP-ALL). The median age at diagnosis was 47 years (18-88 years), and 45% were women. Cytogenetic groups were as follows: 24% had Ph+ ALL, 13% had Ph-like ALL, and 3% had ALL with KMT2A rearrangement. The most frequent mutation was the loss of the CDKN2A gene (32%), followed by mutations in the TP53 (17%) and IKZF1 (16%) genes. Mutations involving the recurrently mutated genes in ARCH were seen in 32% of patients, with the following order of frequency: TP53 (17%), DNMT3A (5%), TET2 (4%), RUNX1 (3.5%), ASXL1 (3%), IDH1/2 (2%), and U2AF1 (1%). ARCH-associated mutations were more common in older adults (≥40 years) than in young adults (41% vs. 17%, P<0.0001). The high variant allelic frequencies for ARCH-associated mutations at diagnosis suggested that these might be founder clones. We performed single-cell multiomics (DNA+protein) analysis of ARCH-associated ALL samples to gain insights into the distribution of ARCH mutations in immunophenotypically-defined clusters. ARCH mutations were found in ALL cells as well as myeloid cells but were not found in nonmalignant mature lymphoid cells. Analysis of serial samples revealed that ARCH clones persist at the time of remission and re-emerge at relapse. The overall survival for patients with ARCH-associated ALL was shorter than for patients without ARCH (median, 32 vs. 84 months, P=0.02). In conclusion, ARCH is an ancestral event in older adults with ALL and constitutes fertile soil for acute lymphoblastic leukemogenesis leading to inferior clinical outcomes.