Frailty: Evaluation and Effect on Overall Survival and Thrombotic Microangiopathy in Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common treatment modality for acute myeloid leukemia (AML); it is also associated with several adverse outcomes including acute Graft-Versus-Host-Disease (GVHD), chronic GVHD, thrombotic microangiopathy (TMA), and mortality. In recent years, several studies (Matsui et al 2020, Epperla et al 2020, Schoettler et al 2024, Murthy 2023 et al) have reported risk factors linked to these adverse events. The objective of our study is to evaluate the effect of unmeasured risk factors on mortality and incidence of TMA utilizing a joint frailty model. This is a retrospective secondary analysis of an existing CIBMTR dataset that included patients who underwent first allo-HSCT for AML between the years 2008-2016. All known significant risk factors for overall survival after allo-HSCT were included as covariates in the joint frailty mode that allows studying survival processes of correlated time-to event outcomes death and TMA. We included the unobservable variable – frailty as a random effect. We summarized patients’ predicted frailty scores. Analyses were performed using frailtypack, an R package and SAS 9.4. A total of 8135 allo-HSCT AML patients with 4368 deaths and 199 with onset of TMA were included in the analysis. The frailty effect, the combined effect of unobserved covariates, was significant (p<0.0001) along with other previously reported significant risk factors for mortality and TMA. Patients with TMA were classified into three risk groups low/medium, high, and very high, based on the distribution of the predicted frailty scores (Fig 1). One-year estimated OS from HSCT, of low/medium risk N=4141 (51%), high-risk N=2367 (29%), very high- risk N=1627 (20%) patients were 98.8%, 41.1% and 2.3%, respectively, as compared to observed 61.7% for N=8135 patients. Median survival was significantly inferior for the high or very high, risk patients to the patients with low/moderate risk ( Fig 2 ). One-year estimated OS from TMA diagnosis, of low/medium risk (N=104) and high-risk patients (N=56) were 67.6% and 10.1%, respectively, as compared to observed 40.1% for N=199 patients. One-year OS for very-high risk TMA patients was not-estimable. One-year OS for pooled high risk and very-high risk TMA patients (N=95) was 6.7% ( Fig 3 ). This study adds to the growing data of risk factors for TMA and other adverse events following allo-HSCT. These results highlight the importance of considering the latent risk factors in patients. This study can act as a guide for how frailty may be assessed and utilized in determining risk for patients who may undergo allo-HSCT. As TMA is associated with other adverse outcomes including mortality, accounting for frailty allows for a more robust and synergistic assessment of patient risk.