Effect of Age, Timing of Thrombotic Microangiopathy and Timing of Acute Graft-Versus-Host Disease on Overall Survival after Hematopoietic Stem Cell Transplantation

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) associated thrombotic microangiopathy (TA-TMA) and acute Graft-Versus-Host-Disease Grades 2-4 (aGVHD) are recognized risk factors for mortality after allo-HSCT. In observational studies (Epperla et al, BJH. 2020), researchers found that not only did TA-TMA have a higher risk of mortality, but also aGVHD had a significantly higher risk of TA-TMA relative to grade I or no acute GVHD. Combined effects of time-dependent risk factors, aGVHD and TA-TMA on overall survival have not been evaluated. Another study (Schoettler et al, BJH. 2024), indicated that aGVHD was a significant risk factor for developing TA-TMA in both children and adults. While age is a significant risk factor for TA-TMA and mortality post-HSCT, it has not been dichotomized with an optimal cutoff. Using the same data from Center for International Blood and Marrow Transplant Research (CIBMTR), we evaluated the association of HSCT recipient age, timing, and order of onset of aGVHD and TA-TMA on overall survival (OS).

Methods: This retrospective secondary analysis of an existing CIBMTR dataset, included all patients with hematological diseases who underwent allo-HSCT between 2008-2016. Patients with missing information on onset of aGVHD and TA-TMA were excluded. Age is a prognostic factor that affects the survival outcomes in patients with TA-TMA as compared to those without TA-TMA. We first evaluated the impact of increasing age as a continuous variable in survival analysis using Cox multivariable model, with all other associated time-independent risk factors (RF) including sex, race, pre-HSCT renal health, donor type, prior autologous transplant, Karnofsky performance score, donor-recipient cytomegalovirus status, conditioning regimens, use of anti-thymocyte globulin/alemtuzumab, graft type and aGVHD prophylaxis. Age cutoff values were determined by restricted cubic spline (RCS) analysis in the same model. OS in patients characterized by the optimal age cutoff was estimated using a Cox proportional hazard stratified regression model with onset of TA-TMA and aGVHD as time-dependent covariates, underlying disease as strata, and other time-independent risk factors. Interactions of aGVHD and TA-TMA by age were also evaluated.

Results: Age as a continuous covariate was a significant RF for mortality. An optimal cutoff at 40 years was estimated based on RCS analysis and patients were categorized into two age groups: <40 years (younger patients) and ≥40 years (older patients). There was significant association (p<0.001) between TA-TMA and aGVHD incidence, controlling for the age groups. In the multivariable Cox regression model for overall survival, interactions aGVHD and TA-TMA with age groups were both significant (p=0.003 and 0.028, respectively). For younger patients, TA-TMA had a hazard ratio (HR) 3.83 (95% CI, 3.24, 4.55), and older patients had a HR 3.00 (95% CI 2.62, 3.45). In regard to the aGVHD, younger patients had a HR of 1.39 (95% CI, 1.30, 1.50) and older patients had a HR 1.59 (95% CI 1.52, 1.67). As expected, in patients without TA-TMA and aGVHD, older patients were at higher adjusted risk for mortality (HR 1.36, 95% CI 1.28, 1.46) than younger patients after allo-HSCT. Older patients with onset of aGVHD, before or after TA-TMA, were at higher adjusted risk for mortality (HR 1.56, 95% CI 1.45, 1.68) than younger patients. There were no significant differences in the adjusted risks for mortality between younger and older patients with onset of TA-TMA alone (in the absence of aGVHD).

Discussion: Acute GVHD grades 2-4 is associated independently with mortality and increased risk for developing TA-TMA, which is also a significant risk factor for mortality. While incidence of TA-TMA was similar, incidence of post-HSCT acute GVHD and all-cause mortality in the patients <40 years were significantly lower than the patients ≥40 years. The adjusted HRs for mortality were higher in patients with the onset of TA-TMA vs no TA-TMA in the patients <40 years relative to patients ≥40 years. Our analysis results demonstrate that order (developing aGVHD or TA-TMA first), their timing, and dichotomizing age by an explicit optimal cut-off are important for meaningful evaluation of the combined effects of these post-HSCT complications.