Analysis of clonal hematopoiesis in classical Hodgkin lymphoma patients by targeted deep sequencing.

Clonal hematopoiesis (CH) is prevalent in the elderly and predisposes to hematological malignancies, mostly of myeloid and T-cell origin. CH incidence and, even more, tissue distribution are not well characterized in classical Hodgkin lymphoma (cHL), a B-cell neoplasm frequent in the young and unique for its rich microenvironment of hematopoietic derivation. We analyzed for CH 40 cHL cases by sequencing microdissected tumor cells and matched normal cells from blood and/or lymph nodes. Five patients had blood and/or tissue CH, including 3/5 with >70 years and 2/35 below this age. CH spread through the tissue microenvironment extensively in 3 patients (aged 45, 30 and 73 years), all failing first-line therapy and respectively featuring mutant DNMT3AR882H, KRASG60D and DNMT3AR882H+TET2Q1274* in 33%, 92% and 60% of non-neoplastic cells. In the latter case, DNMT3A/TET2-mutant CH originated also the neoplastic clone, which was infected by the Epstein-Barr virus and had almost no other somatic mutations exome-wide. Surprisingly, in the former DNMT3A-mutant case, CH did not originate the lymphoma clone despite massively involving the blood and the B-cell lineage (~94% leukocytes; ~96% mature blood B-cells) and instead led, 6 years after therapy for cHL, to a possibly therapy-unrelated NPM1-mutated acute myeloid leukemia (with normal karyotype, wild-type TP53 and PPM1D). Our results expand to cHL the spectrum of hematologic malignancies associated with CH, with potential implications for the pathogenesis and prognosis of this mature B-cell neoplasm.