Association between pre-transplant biological aging markers and clinical outcomes in allogeneic hematopoietic cell transplant recipients.

Abstract

6562 Background: Cancer and its treatments can accelerate the aging process, placing survivors at increased risk for poor outcomes. Hematopoietic cell transplant (HCT) recipients may show variations in biological aging before HCT due to previous treatment exposures; however, pre-transplant transcriptomic markers of biological aging have not yet been investigated as predictors of clinical outcomes. We used data from the Center for International Blood and Marrow Transplant Research (CIBMTR) to examine the hypothesis that recipients with greater pre-transplant expression of molecular processes in the cellular senescence pathway—a fundamental mechanism of aging—would have worse clinical outcomes. Methods: Participants included 261 adults ( M age =41.3 years) that received an HLA-matched unrelated donor myeloablative HCT between 1995–2005 for acute myelogenous leukemia (AML) in complete remission and had pre-transplant blood samples available in the CIBMTR Repository. Whole-genome RNA sequencing of recipient peripheral blood mononuclear cells (PBMCs) was used to derive molecular senescence markers, including the DNA damage response (DDR; 29-gene composite), cellular senescence signals p16 INK4a and p21 ( CDKN2A and CDKN1A , respectively), the pro-inflammatory senescence-associated secretory phenotype (SASP; 60-gene composite) and the SenMayo senescence gene set (125-gene composite). We examined acute and chronic graft-versus-host disease (GVHD), transplant-related mortality (TRM), relapse, leukemia-free survival (LFS), and overall survival (OS) as clinical outcomes. Results: Transcriptomic composites were examined as continuous variables. Cox proportional hazard models adjusting for patient, disease, and transplant characteristics and major cell subsets in the PBMC pool revealed that elevated SASP and SenMayo expression were associated with increased risk of TRM ( HR =3.56, p =.005 and HR =6.88, p =.002, respectively) and OS ( HR =2.31, p =.03 and HR =4.50, p =.004, respectively). However, enhanced expression of senescence signal p21 was associated with decreased risk of relapse ( HR =0.52, p =.01) and LFS ( HR =0.70, p =.03). The DDR and senescence signal p16 INK4a did not significantly relate to clinical outcomes. Conclusions: Transcriptomic markers of biological aging assessed in allogeneic HCT recipients before transplant are predictive of relapse and survival outcomes. Specifically, findings suggest that enhanced expression of pro-inflammatory SASP and SenMayo genes may represent a pre-transplant molecular risk profile, whereas elevated expression of p21 may serve as a protective prognostic indicator in the HCT setting. Given the heterogeneous nature of senescent cells, research that examines these transcriptomic markers following HCT as well as how recipient and donor profiles may interact to influence outcomes is warranted.