Clonal Hematopoiesis Is Associated with Non-Myeloid Subsequent Malignant Neoplasms after Autologous Hematopoietic Cell Transplantation

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with multiple myeloma or relapsed/refractory lymphoma, resulting in a growing number of survivors. However, these HCT survivors are at higher risk of developing subsequent malignant neoplasms (SMNs) compared to the general population, attributed in part to pre-HCT therapeutic exposures as well as the procedure of HCT itself. Clonal hematopoiesis of indeterminate potential (CHIP) has been recognized as an aging phenomenon, associated with increased risk of chronic disease and all-cause mortality in the general population. In patients undergoing HCT, CHIP is common (prevalence 20-40%) and is an established risk factor for myeloid SMNs. The role of CHIP in non-myeloid SMNs, which represent the most common group of SMNs in long-term HCT survivors, has not been well-characterized. We addressed this knowledge gap by evaluating the association between CHIP and non-myeloid SMNs in a large cohort of HCT survivors.

Methods: This was a retrospective cohort study of 1931 consecutive patients who underwent a first autologous HCT for lymphoma or myeloma between 2010 and 2016 at a single center, with available pre-HCT DNA obtained from peripheral blood stem cells (99% of the overall cohort). We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP variants (variant allele frequency [VAF] ≥2%). The primary outcome was eight-year (y) cumulative incidence of non-myeloid SMN (non-dermatologic solid malignancy, melanoma, or de novo lymphoma). Cumulative incidence of non-myeloid SMNs was calculated, taking into consideration competing risk of death. Multivariable logistic regression was used to identify variables associated with risk (odds ratio [OR]) of having CHIP, and Fine–Gray multivariable regression was used to evaluate the association between CHIP and non-myeloid SMNs, adjusting for relevant sociodemographic and clinical variables and accounting for death as competing risk.

Results: Median age at HCT was 58.8y (range 18.4-78.1y); 59.1% were male; race/ethnicity: non-Hispanic White (51.5%), Hispanic (25.4%), Asian (10.9%), Black (10.8%); 53.2% had lymphoma and 46.8% had myeloma; 36.7% had Karnofsky Performance Scale (KPS) ≤80 at HCT and 47.1% had high (≥3) HCT-comorbidity index (CI). The cohort provided 8,730 person-years of follow-up. CHIP: Overall, 389 patients (20.1% of the cohort) had at least one CHIP variant and 94 (4.9%) had ≥2 variants. Among the identified CHIP variants, 78.1% had calculated VAFs 2-<10% and 21.9% had VAFs ≥10%. DNMT3A was the most frequently mutated gene (36.6%), followed by TET2 (15.2%), PPM1D (13.1%), ASXL1 (6.7%), and TP53 (6.3%). In the multivariable model, factors independently associated with odds of having CHIP were older (≥60y) age at HCT (adjusted OR [aOR]=2.8; 95%CI, 2.2-3.5) and a higher HCT-CI score (aOR=1.1; 95%CI, 1.1-1.2). Non-myeloid SMNs: In total, 115 patients developed non-myeloid SMNs after HCT. The 8-year cumulative incidence of non-myeloid SMNs was significantly higher in patients with CHIP, compared to those without CHIP (15.0% vs 7.2%, p<0.001); the incidence increased by VAF: 0-2% (7.2%), 2-<10% (14.0%), and ≥10% (19.4%), p=0.001. The presence of a TP53 CHIP mutation was associated with a particularly higher incidence of non-myeloid SMNs, compared to no CHIP (23.9% vs 7.2%, p=0.03). In the adjusted (age, sex, race/ethnicity, and KPS) multivariable model, CHIP was significantly and independently associated with risk of developing a non-myeloid SMN (adjusted hazard ratio [aHR]=1.7, 95%CI=1.1-2.3; reference: no CHIP).

Conclusions: In this well-characterized and demographically diverse cohort of patients undergoing HCT, CHIP was associated with a significant and independent risk of non-myeloid SMNs after HCT. Notably, patients with high VAF CHIP or TP53 CHIP mutations had an exceptionally elevated risk of non-myeloid SMNs. These findings may provide new insights into the pathobiology of non-myeloid SMNs after HCT, and further underscore the potential for CHIP as a novel biomarker for risk-based monitoring of subsequent cancers in HCT survivors.