Distinct evolutionary paths in chronic lymphocytic leukemia during resistance to graft-versus-leukemia

Abstract

One Sentence Summary:We find that the clinical kinetics of chronic lymphocytic leukemia relapse after stem cell transplant are underwritten by distinct genetic and epigenetic evolutionary trajectories and suggest that the selection pressures of the post-transplant, immunologic bottleneck are unlike those imposed by chemotherapy.Abstract: Resistance to the graft-versus-leukemia (GvL) effect remains the major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis of GvL resistance for advanced lymphoid malignancies remains incompletely understood. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell-intrinsic features shape GvL outcomes by directing the evolutionary trajectories of CLL cells. Integrated genetic, transcriptomic and epigenetic analyses of CLL cells from 10 patients revealed that the clinical kinetics of post-HSCT relapse are shaped by distinct molecular dynamics and suggest that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for HLA loss was observed, even when present in pre-transplant subpopulations. Regardless of posttransplant relapse kinetics, gain of stem cell modules was a common signature associated with leukemia relapse. These data elucidate the biological pathways that underlie GvL resistance and post-transplant relapse. IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the earliest forms of successful cancer immunotherapy whose study has elucidated critical insights into tumorimmune interactions (1, 2). As the only curative option for aggressive and advanced hematologic malignancies, allo-HSCT derives its potency from the underlying, donor-derived graft-versusleukemia (GvL) effect wherein donor immune cells recognize and eradicate recipient leukemic cells. Reduced-intensity conditioning regimens (RIC) for allo-HSCT are increasingly used to reduce treatment-related morbidity and preserve the curative GvL effect (3, 4), but posttransplant disease recurrence limits their efficacy. Therefore, elucidating the mechanisms underpinning GvL resistance is vital to improve transplant outcomes.Multiple studies have identified various pathways of GvL resistance associated with relapse of myeloid malignancies, including loss of HLA class I and II genes, upregulation of inhibitory immune checkpoint molecules, and oncogene-driven immune evasion (5-9). For lymphoid malignancies however, less is known about potential mechanisms of GvL evasion. In particular, how underlying genetic and epigenetic features inform the clinical kinetics of post-transplant relapse or whether dysregulation of HLA class I and II genes influences GvL resistance remains unclear.To address these questions, we assembled a cohort of 10 patients with chronic lymphocytic leukemia (CLL), the majority of whom were treated with RIC allo-HSCT. We hypothesized that leukemic-intrinsic features primarily shape...