Prevalence of Clonal Hematopoiesis in Patients with Monoclonal Gammopathy of Undetermined Significance

INTRODUCTION:

Clonal hematopoiesis of indeterminate potential (CHIP) is defined by the expansion of progeny derived from hematopoietic stem cells (HSCs) that have acquired somatic mutations at a VAF greater that 2%. CHIP manifests in 10% of patients older than 65 and is associated with an increased risk of progression to hematologic malignancies such as the myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although the risk factors for developing CHIP remain incompletely defined, they include prior exposure to chemotherapy and a history of smoking. Monoclonal gammopathy of undetermined significance (MGUS) is characterized by the abnormal growth of clonal plasma cells in the bone marrow and carries a risk of 1% for progression to multiple myeloma (MM) per year. Like CHIP, it becomes more prevalent with age and has been associated with smoking. Additionally, patients with MM have been demonstrated to have an increased risk for myeloid malignancies. Thus, an examination for a correlation between CHIP and MGUS promises to reveal a link between these two pre-malignant conditions. However, a recent study did not demonstrate such an association, but this study was performed in a very elderly population and may not be applicable to younger patients. In this study, we aim to assess the relationship between CHIP and MGUS in a population-based cohort of MGUS patients seen at UT Southwestern Medical Center.

METHODS:

To evaluate an association between CHIP and MGUS, we collected bone marrow samples from 37 patients diagnosed with MGUS at UT Southwestern Medical Center. We employed a hybridization capture-based next generation sequencing assay in order to detect CHIP. We identified 24 genes known to cause CHIP in adults. We also evaluated patients' risk for developing Multiple Myeloma after having been diagnosed with CHIP.

RESULTS:

The mean age of MGUS patients was 68, ranging between 26-92. 17 patients had IgG, 10 had IgA, five had IgM, and five had light-chain MGUS. We identified 18 mutations to validate the presence of CHIP in 10 (27%) patients, with the most frequent being in DNMT3A and TET2 (Fig. 1). Three out of the 10 patients harbored two mutations and one patient harbored four mutations. History of chemotherapy (n=6) and smoking (n=14) was taken into consideration to determine the relative risk of patients with MGUS developing CHIP. We found that those who had a prior history of smoking and chemotherapy displayed a higher risk of acquiring CHIP (Fig. 2). 54% of patients displayed high levels of serum kappa free light chains at the time of diagnosis.

CONCLUSION:

There was no significant association between CHIP and MM progression. Our analysis showed one patient with CHIP progression, and two patients without CHIP progression. Because the rates of CHIP and MGUS are positively correlated with characteristics like aging and a history of smoking, we expected to see relatively high rates of CHIP in patients within our cohort. However, our data suggests that CHIP is frequent (27%) in MGUS patients, but larger future cohorts need to be evaluated to validate this association.

Kroger:Takeda: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; DKMS: Research Funding; Riemser: Research Funding; Neovii: Honoraria, Research Funding; Amgen: Honoraria; Kite: Honoraria; Jazz: Honoraria; Sanofi: Honoraria. Madanat:Sierra Oncology, Stemline Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees; BluePrint Medicines, GERON, OncLiv: Consultancy, Honoraria. Awan:Genentech: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Pharmacyclics: Consultancy, Research Funding; Gilead Sciences: Consultancy; Kite Pharma: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; MEI Pharma: Consultancy; Verastem: Consultancy; Incyte: Consultancy; BeiGene: Consultancy; Johnson and Johnson: Consultancy; Dava Oncology: Consultancy; BMS: Consultancy; Merck: Consultancy; Cardinal Health: Consultancy; ADCT Therapeutics: Consultancy; Epizyme: Consultancy; Caribou Biosciences: Consultancy; Cellecter Bisosciences: Consultancy. Ramakrishnan:Kite: Consultancy; BMS: Consultancy; Rafael Pharma: Consultancy; Pharmacyclics LLC: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cellectar Biosciences: Membership on an entity's Board of Directors or advisory committees. Anderson:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.