Clonal Hematopoiesis and COVID-19 Severity in Cancer Patients
Authors: Bolton Kelly L. , Foote Michael , Jee Justin , Safonov Anton , Ptashkin Ryan , Devlin Sean , Gedvilaite Erika , Gao Teng , Papaemmanuil Elli , Pessin Melissa S. , Kamboj Mini , Vijai Joseph , Offit Kenneth , Awadalla Phillip , Nataranjan Pradeep , Berger Michael F. , Norton Larry , Levine Ross L. , Zehir Ahmet 
Published: February 2021

Background: Advanced age, medical co-morbidities and a pro-inflammatory immunologic profile are associated with severe COVID-19. Acquired somatic mutations in hematopoietic stem cells (clonal hematopoiesis or CH) are common in elderly individuals. Previous studies have shown CH is associated with alterations in immunologic repertoire and function. Here, we investigate whether CH predisposes to severe COVID-19 or other infections.
Methods: We performed a retrospective cohort study of 39,291 adult cancer patients with non-hematologic malignancies who had their tumor and blood sequenced using a panel of 468 known cancer driver genes. We identified individuals who tested positive for SARS-CoV-2 between March 8, 2020 and June 9, 2020. We determined the association between CH and severe COVID-19 (hypoxic event, hospitalization or death) using multivariable logistic regression models. We used an established aggregation schema for ICD-CM codes to identify distinct infection subtypes. The relationship between CH and risk of incident infections was determined using multivariable Cox regression.
Results: In the study cohort, 436 patients were positive for SARS-CoV-2 and 165 developed severe COVID-19. COVID-19 patients with CH were more likely to develop severe disease compared to non-severe (OR=1.8; 95% CI: 1.1-2.9; p=0.01). CH was also more common among patients with severe COVID-19 compared to COVID-19 negative individuals (OR=1.6, 95% CI: 1.2-2.4, p=0.01). In 62,891 person-years of follow-up, 4,059 individuals developed an infection. CH was associated with risk of sepsis (HR=1.13; 95% CI 1.01-1.25, p=0.04) and bacterial enteritis (HR=1.8, 95% CI 1.1-2.8, p=0.01).
Conclusions: CH is associated with severe COVID-19 and an increased risk of other infections in cancer patients.

Disclosures
Bolton: GRAIL: Research Funding. Jee:MDSeq Inc.: Patents & Royalties. Papaemmanuil:Celgene: Consultancy, Honoraria, Research Funding; Prime Oncology: Consultancy, Honoraria; Illumina: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSKCC: Patents & Royalties; Kyowa Hakko Kirin: Consultancy, Honoraria; Isabl: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Berger:Illumina: Research Funding; Grail: Research Funding; Roche: Consultancy. Levine:Prelude Therapeutics: Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Lilly: Consultancy, Honoraria; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Amgen: Honoraria; Gilead: Honoraria. Zehir:Illumina: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment.