Internal Medicine Resident St Elizabeth's Medical Center Boston, Massachusetts, United States
Introduction: The hallmark of AL Amyloidosis is the production, aggregation, and deposition of immunoglobulin free light chains in target organs. Cardiac events are the major cause of mortality in AL amyloidosis. Clonal hematopoiesis of unknown potential (CHIP) is associated with increased cardiovascular risk in the general population and decreased overall survival in multiple myeloma patients receiving autologous stem cell transplant. Large studies looking at incidence and outcome of patients with concurrent CHIP and AL amyloidosis are missing. We performed a single center, retrospective analysis to evaluate the prevalence of CHIP in AL amyloidosis and associated disease characteristics and outcomes, including major organ dysfunction progression free survival (MOD-PFS).
Methods: Demographics and clinical characteristics of patients diagnosed with AL amyloidosis at DFCI from January 2018 to April 2023 who received a bone marrow aspirate/biopsy with a rapid heme panel (RHP) were collected. Variables of interest included age, ethnicity, Mayo stage, Palladini renal stage, involved organs, FISH abnormalities, left ventricular ejection fraction, and anginal symptoms. MOD-PFS was defined based on Kastritis et al. Variant alle fraction (VAF) to define CHIP was set at 2%. Two samples independent t-test, Wilcoxon rank sum test, Fisher exact test were used for comparison between groups. We used the Cox proportional hazard regression model to estimate the association between CHIP status and MOD-PFS. All analyses were carried out with the STATA statistical package. This study was approved by the institutional review board.
Results: Seventy-six patients were identified meeting criteria. Of these, 16 (21%) were found to meet diagnostic criteria for CHIP. DNMT3A was the most frequently involved gene (7/16, 44%), followed by GNB1, TET2, ATM (each 2/16, 12.5%), and SF3B1, ZRSR2, EZH2, BRCC3, PPM1D, ASXL1 (6%). Among the variables of interest, patients with CHIP had a higher prevalence of t(11;14) (11/13, 85%, versus 15/41, 37%, p=0.004) and a lower Palladini renal stage (p=0.001). Median follow-up time for the entire cohort was 25 months (range 1 – 175 months). In a univariate analysis model, CHIP presence was not associated with an increased hazard for lower MOD-PFS (hazard ratio 0.998, 95% CI 0.38 – 2.64), although a limited number of events was recorded given short duration of follow up.
Conclusions: This is the first, large series describing the prevalence and clinical implications of CHIP in patients with AL amyloidosis. In our study, CHIP was associated with presence of t(11;14), the most frequent cytogenetics in AL amyloidosis and a negative prognostic factor. A lower Palladini renal risk score was noted in patients with CHIP. Because of the limited number of events, no multi-variate Cox regression analysis was performed. Future studies will help confirm our findings and clarify the impact of CHIP in AL amyloidosis patients’ outcome.
