NEJM Evid. 2023 May;2(5):
Lachelle D Weeks,
Abhishek Niroula,
Donna Neuberg,
Waihay Wong,
R Coleman Lindsley,
Marlise Luskin,
Nancy Berliner,
Richard M Stone,
Daniel J DeAngelo,
Robert Soiffer,
Md Mesbah Uddin,
Gabriel Griffin,
Caitlyn Vlasschaert,
Christopher J Gibson,
Siddhartha Jaiswal,
Alexander G Bick,
Luca Malcovati,
Pradeep Natarajan,
Benjamin L Ebert.
Background: Clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) are defined by somatic mutations in genes associated with myeloid neoplasms (MN) at a variant allele fraction (VAF) ≥ 0.02, in the absence and presence of cytopenia, respectively. CHIP/CCUS is highly prevalent in adults and defining predictors of MN risk would aid clinical management and research.Methods: We analyzed sequenced exomes of healthy UK Biobank (UKB) participants (n = 438,890) in separate derivation and validation cohorts. Genetic mutations, laboratory values, and MN outcomes were used in conditional probability-based recursive partitioning and Cox regression to determine predictors of incident MN. Combined statistical weights defined a clonal hematopoiesis risk score (CHRS). Independent CHIP/CCUS patient cohorts were used to test prognostic capability of the CHRS in the clinical setting.
Results: Recursive partitioning distinguished CHIP/CCUS cases with 10-year probabilities of MN ranging from 0.0078 - 0.85. Multivariable analysis validated partitioning variables as predictors of MN. Key features, including single DNMT3A mutations, high risk mutations, ≥ 2 mutations, VAF ≥ 0.2, age ≥ 65 years, CCUS vs CHIP and red blood cell indices, influenced MN risk in variable direction. The CHRS defined low risk (n = 10018, 88.4%), intermediate risk (n = 1196, 10.5%), and high risk (n = 123, 1.1%) groups. In clinical cohorts, most MN events occurred in high risk CHIP/CCUS patients.
Conclusions: The CHRS provides simple prognostic framework for CHIP/CCUS, distinguishing a high risk minority from the majority of CHIP/CCUS which has minimal risk for progression to MN.