Abstract LB044: Tracking clonal hematopoiesis in patients with classical Hodgkin lymphoma
Authors: Marra Andrea , Venanzi Alessandra , Schiavoni Gianluca , Milner Sara Giulia , Limongello Roberto , Santi Alessia , Pettirossi Valentina , Ultimo Simona , Tasselli Luisa , Pucciarini Alessandra , Sciabolacci Sofia , Martelli Maria Paola , Sportoletti Paolo , Ascani Stefano , Falini Brunangelo , Tiacci Enrico 
Published: July 2021

Abstract
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 &gt;70 years and 2/35 &lt;70 years (p-value 0.009). In 3/5 CH cases (aged 30, 45 and 73 years), CH extensively spread through the non-neoplastic tissue microenvironment (32%, 92%, and 60% of cells), being respectively driven by DNMT3AR882H (Case 1), KRASG60D (Case 2) and DNMT3AR882H +TET2Q1274* (Case 5).
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.]
Clonal Hematopoiesis in patients with classical Hodgkin lymphomaPatients with Clonal Hematopoiesis in a 40-cHL case cohortPt.#Age (years)Time of samplingProgressed after 1st line chemotherapyGene mutationVAF in whole bloodVAF in non-neoplastic tissue microenvironmentVAF in tumor cellsCase 145OnsetYESDNMT3AR882H47%16.4%Not detectedCase 2302nd relapseYESKRASG60DNot available45.9%Not detectedCase 383OnsetNot evaluableCBLG375SNot available2.5%Not detectedCase 481OnsetNOTET2N1487lfs843.2%Not detectedNot detectedCase 5731st relapseYESDNMT3AR882HNot available30%43%TET2Q1274Not available8.4%31.1%Clinico-pathological features of cHL cases stratified by clonal hematopoiesis distribution in cHL tissueN=40 patientsClonal Hematopoiesis in cHL tissueP-valueExtensive (n=3)Absent/non-extensive (n=37)AGE&gt;60 years1 (33%)9 (24%)1&lt;60 years2 (67%)28 (76%)EBV STATUSEBV+1 (33%)8 (22%)0.55EBV-2 (67%)29 (78%)HISTOTYPENodular sclerosis1 (33%)21 (57%)0.58Mixed cellularity2 (67%)12 (32%)Other0 (0%)4 (11%)CLINICAL STAGEEarly ≤IIA1 (33%)13 (37%)1Advanced ≥IIB2 (67%)22 (63%)OUTCOME OF FIRST-LINE CHEMOTHERAPYNo progression0 (0%)24 (69%)0.043Progression3 (100%)11 (31%)Follow-up in months0-6-3564 (median)0.0340-149 (range)
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.