Date of Award

January 2025

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Alexa J. Siddon

Abstract

Relapse is the primary cause of mortality for patients with myeloid malignancies post-allogeneic stem cell transplant (aSCT). As early intervention for those deemed high risk for relapse may improve outcomes, identification of residual malignant cell burden is of critical importance. Chimerism testing, the use of DNA sequencing technology to determine the relative percentage of donor to recipient hematopoietic cells post-aSCT, offers a practical metric to monitor for residual leukemic cell burden. The precise value of donor chimerism is influenced by many procedural and contextual factors, and multiple strategies, including the analysis of specific hematopoietic cell subsets, termed lineage-specific chimerism (LSC), may offer more robust associations with prognosis and help guide the use of pre-emptive therapy. The use of donor lymphocyte infusion (DLI) is one such intervention and may mitigate relapse risk, but no widely accepted LSC threshold exists to guide its initiation. The current investigation sought to define an LSC threshold below which relapse is most likely, investigate the threshold’s association with overall survival (OS), and quantify the survival benefit of DLI use within high-risk patients based on this threshold. A retrospective chart review of all patients seen at Yale New Haven Hospital, between 2016-2023, for myeloid malignancies who were treated with aSCT and had available LSC data before the time of relapse or graft failure (N=94) was undertaken. ROC curves were employed to create a threshold based on the difference between one’s T cell (TCC) and myeloid specific (MSC) chimerism. Kaplan-Meier curves and Cox proportional hazards models were used to investigate effects on OS. Having ≥14.5% discrepancy between TCC and MSC was a significant predictor of relapse or graft failure at 1 year (AUC= .831, sensitivity= .796, specificity= .775). Patients with chimerism difference scores above this cutoff point had significantly poorer OS (HR= 2.58, 95% CI= [1.30, 5.13], p= 0.01) despite controlling for covariates. DLI use among this high-risk patient subgroup was shown to significantly improve survival (HR= 0.32, 95% CI= [0.13, 0.79], p= 0.01) with a median OS benefit of 28 months. Our 14.5% chimerism difference threshold may offer promise in triaging high-risk patients for relapse-related work up and serve as one data point on which to support the use of DLI to improve post-aSCT outcomes among high-risk patients.

Comments

This is an Open Access Thesis.

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