Abstract LB044: Tracking clonal hematopoiesis in patients with classical Hodgkin lymphoma

Background: Clonal hematopoiesis (CH) is frequent in the elderly and predisposes to blood cancers, mostly of myeloid and T-cell origin. CH incidence and trajectories are not well characterized in classical Hodgkin lymphoma (cHL), a B-cell neoplasm frequent in the young and uniquely featuring rare tumor cells embedded in a supportive microenvironment of hematopoietic origin. Methods: We analyzed for CH 40 cHL cases by subjecting to whole-exome and/or targeted sequencing (mean unique coverage ~150X and ~1000X, respectively) tumor cells microdissected from a tissue biopsy and matched non-neoplastic cells circulating in the blood (n=27 cases) and/or microdissected from the lymph node microenvironment (n=14 cases). Results: 5 cases (12.5%) had blood and/or tissue CH (Table 1), including 3/5 with >70 years and 2/35 Notably, in Case 5 CH originated also the tumor cell clone, which was infected by the Epstein-Barr virus and had almost no other somatic mutations exome-wide. This is the first description, in a human B-cell lymphoma clone, of mutant DNMT3AR882, a hotspot in myeloid and T-cell neoplasms. In Case 1, the same mutation determined a massive blood CH (DNMT3AR882H in 94% leukocytes and in 96% B cells), which was surprisingly absent from the tumor cell clone (instead carrying STAT6 and SOCS1 mutations, typical of cHL) and that 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). Thus, CH trajectories must be carefully disentangled to correctly interpret the histogenesis and pathogenesis of multiple blood cancers arising in patients with CH. Finally, all 3 cases with extensive CH spreading in the cHL tissue progressed after first-line chemotherapy, versus 11/35 (31%; p-value 0.043) evaluable cases with absent or non-extensive tissue CH, who otherwise had similar clinical features (Table 1) and received a no less intense first-line therapy. Conclusion: Our results expand to cHL the spectrum of hematologic malignancies associated with CH, with potential implications for the pathogenesis and prognosis of this cancer. [A. Marra and A. Venanzi are co-first authors of this work.] Citation Format: Andrea Marra, Alessandra Venanzi, Gianluca Schiavoni, Sara Giulia Milner, Roberto Limongello, Alessia Santi, Valentina Pettirossi, Simona Ultimo, Luisa Tasselli, Alessandra Pucciarini, Sofia Sciabolacci, Maria Paola Martelli, Paolo Sportoletti, Stefano Ascani, Brunangelo Falini, Enrico Tiacci. Tracking clonal hematopoiesis in patients with classical Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB044.