Can Emergency Hematopoiesis Due to Sepsis Lead to Clonal Hematopoiesis? Implications for Understanding the Pathogenesis of Clonal Evolution

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.2691-2691
• Main Authors: Ogbue, Olisaemeka, Kewan, Tariq, Mehkri, Omar, Fadell, Francois, Nautiyal, Ishani, Reynold, Megan, Durmaz, Arda, VanOudenhove, Jennifer, Awada, Hussein, Unlu, Serhan, Singh, Abhay, Visconte, Valeria, Mendez, Lourdes, Bosler, David S., Duggal, Abhijit, Halene, Stephanie, Maciejewski, Jaroslaw P., Al-Jaghbeer, Mohammed J, Gurnari, Carmelo
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-187424

O.O & T.K are co-first authors. Clonal (myelo) hematopoiesis of indeterminate potential (CHIP) arises from somatic mutations in myeloid genes, providing a proliferative and survival advantage to the affected “CHIP-initiating” early hematopoietic precursor cells. Understanding the conditions that lead to the emergence of detectable clones (early seeding of myeloid neoplasia-MN) is of great interest due to its clinical implications. Among CH facilitating states, aging has been extensively studied, but a clear distinction between the impact of chronological versus biological aging remains challenging. Additionally, other factors contributing to CHIP development may include chemotherapy, genetic predisposition, bone marrow failure states, or immunodeficiency. However, not all CHIP-promoting factors have been identified because they are subtle, pathophysiologically complex, and thus remain cryptic. We hypothesized that episodes of emergency hematopoiesis (EH), such as those caused by acute infections, could potentially result in acquisition of CHIP with repeated episodes of EH resulting in clonal expansion. If this hypothesis is confirmed, one could envision that both instances of significant hematopoietic expansion (high leukocytosis) and repeated cycles of EH could be at play in conjunction with chronological factors. For instance, the older an individual is, the greater is the number of EH episodes possible. To examine our theory, we prospectively collected blood samples from patients admitted at the intensive care unit (ICU) of Cleveland Clinic and Yale University. Inclusion criteria required a white blood cell (WBC) count ≥ 15K/uL. Patients with known or prior malignancies and those exposed to chemotherapy were excluded. For relevant comparisons, we assessed CH incidence in our cohort against a group of patients with solid tumors screened for CH (n=107) but without acute infections, along with historical CHIP cohorts. CH screening employed a targeted NGS myeloid gene panel with a reported VAF cut-off of 2%. A total of 78 individuals admitted to the ICU with possible infections and leukocytosis were enrolled in this study. The median age was 70 years (IQR: 61-77), with a M:F ratio of 1.7 (Table 1). Time from leukocytosis onset to sampling was 3 days (IQR: 1-5), the median WBC at ICU admission was 18 K/uL (IQR: 16-21), and the median absolute neutrophil count (ANC) was 16 K/uL (IQR: 12-20). Overall, 94 variants were identified including 16 (median VAF 50.1)