Clonal hematopoiesis in diffuse large B-cell lymphoma: clinical impact and genetic relatedness to lymphoma and therapy-related myeloid neoplasm

Clonal hematopoiesis in diffuse large B-cell lymphoma: clinical impact and genetic relatedness to lymphoma and therapy-related myeloid neoplasm Clonal hematopoiesis (CH) is an age-related phenomenon characterized by the overrepresentation of blood cells derived from a single clone, conferring an increased risk of myeloid neoplasms (MN), cardiovascular disease, and death from non-hematological malignancies.1,2 Recent work demonstrated a high prevalence of CH that divergently evolves to lymphoma and MN in patients with angioimmunoblastic T-cell lymphoma (AITL).3 Several studies have shown CH occurs in 10-30% of patients with B-cell lymphoma (BCL).4,5 Whether CH impacts the outcome of BCL remains controversial.4,5 Moreover, whether CH clones divergently evolve to BCL and MN is unclear.Herein, we evaluated a cohort of patients with diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma (HGBCL) who were analyzed for mutations using a targeted next-generation sequencing (NGS) panel covering 400 genes (MSK-IMPACT).6 We aimed to investigate: i) the prevalence of CH and its impact on outcome; ii) the risk of t-MN in patients harboring CH mutations; iii) the possibility of divergent clonal evolution from CH to BCL and MN.NGS data on diagnostic tissue between January 2015 and September 2021 were available for 362 (94%) DLBCL and 23 (6%) HGBCL patients.Among DLBCL, 187 (48.5%) were of germinal center B-cell (GCB) subtype and 173 (45%) of non-GCB subtype and two (0.5%) without an available immunophenotype.Median age was 64 years (range, 19-95) at the time of lymphoma diagnosis and 65 years (range, 20-95) at the time of CH detection.Time points for CH detection were variable due to the retrospective nature of the study: 206 and 179 patients were tested after and before chemotherapy, respectively.One hundred and twentyseven patients had paired MSK-IMPACT performed on uninvolved bone marrow (BM) or peripheral blood (PB) (Online Supplementary Figure S1).For cases with paired analysis, a 0.01 variant allele frequency (VAF) cutoff in BM/PB was used for CH calling.5,7,8 In this subgroup, CH was present in 37 of 127 (29%) patients and absent in 90 of 127 (71%) (referred to as CH+ and CH-cohorts, respectively).For the 258 cases without paired analysis, CH calling was performed using NGS data from lymphoma tissue and/or saliva samples based on the following criteria suggesting tissue infiltration by blood: i) variants were reported as common in CH genes in the literature; 9 and ii) variants had a VAF <1/10 of the highest VAF of any DLBCL-associated mutation in lymphoma tissue.As a result, 17 (7%) and 241 (93%) patients were classified as CH+ and CH-, respectively.Overall, the CH prevalence was 14% (54/385).