Research ArticleCancer

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

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Science Translational Medicine  16 Sep 2020:
Vol. 12, Issue 561, eabb7661
DOI: 10.1126/scitranslmed.abb7661

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A tale of two relapses

Allogeneic hematopoietic stem cell transplantation can offer a cure for patients with otherwise incurable hematologic cancers. It is a form of cancer immunotherapy, as the transplanted blood cells from a healthy donor help destroy remaining leukemic cells, a phenomenon called the graft-versus-leukemia effect. Unfortunately, patients can still relapse. To understand the mechanisms involved in such posttransplant relapses, Bachireddy et al. performed detailed genetic analysis of cancer cells from 10 patients with chronic lymphocytic leukemia who relapsed after transplant. The authors found two distinct patterns among these patients: early relapse, caused by preexisting treatment resistance, and late relapse, driven by immune-mediated evolutionary pressure.

Abstract

Leukemic relapse remains a major barrier to successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) for aggressive hematologic malignancies. The basis for relapse of advanced lymphoid malignancies remains incompletely understood and may involve escape from the graft-versus-leukemia (GvL) effect. We hypothesized that for patients with chronic lymphocytic leukemia (CLL) treated with allo-HSCT, leukemic cell–intrinsic features influence transplant 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. Early relapses after allo-HSCT exhibited notable genetic stability; single CLL cell transcriptional analysis demonstrated a cellular heterogeneity that was static over time. In contrast, CLL cells relapsing late after allo-HSCT displayed notable genetic evolution and evidence of neoantigen depletion, consistent with marked single-cell transcriptional shifts that were unique to each patient. We observed a greater rate of epigenetic change for late relapses not seen in early relapses or relapses after chemotherapy alone, suggesting that the selection pressures of the GvL bottleneck are unlike those imposed by chemotherapy. No selective advantage for human leukocyte antigen (HLA) loss was observed, even when present in pretransplant subpopulations. Gain of stem cell modules was a common signature associated with leukemia relapse regardless of posttransplant relapse kinetics. These data elucidate the biological pathways that underlie GvL resistance and posttransplant relapse.

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