Long-Term Survival and Late Death after Hematopoietic Cell Transplant for Patients with Sickle Cell Disease Surviving for at Least Two-Years after Transplantation
Authors: St. Martin Andrew , Hebert Kyle , Serret-Larmande Arnaud , Jouhet Vianney , Hughes Emily , Stedman Jason Paul , DeSain Thomas , Pillon Danielle , Carpenter Jessica Lyons , Steinert Patricia , Avillach Paul , Eapen Mary 
Published: November 2021

Abstract
Introduction: In 2018, the National Heart Lung and Blood Institute (NHLBI) began work on BioData Catalyst, a shared cloud platform where scientists can access and analyze de-identified data from NHLBI-funded projects. Hematopoietic cell transplant for sickle cell disease is potentially curative but is associated with life threatening complications most of which occur within the first or second year after transplantation. In the current era with increasing interest in gene therapy and/or editing to cure sickle cell disease we felt it timely to report on transplant recipients who have survived beyond 2-years after their transplantation. The aim of the current analysis was: 1) estimate the conditional survival rates after hematopoietic cell transplantation stratified by time survived since transplantation, 2) identify risk factors for death beyond 2-years after transplantation and 3) to compare all-cause mortality risks to those of an age, sex, and race-matched general population in the United States.
Methods: Permission to access de-identified records of 950 patients with sickle cell disease was granted and data were accessed through a BioData Catalyst PIC-SURE portal (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using sex and age-specific US mortality rates. The equality of SMRs was tested and two-sided 95% confidence intervals (CI) were calculated. The incidence of graft failure was calculated using the cumulative incidence estimator to accommodate competing risks.
Results: Patients were transplanted at 94 transplant centers in the United States between 2000 and 2017 with 70% of transplants after 2010. The median follow-up of the cohort was 5 years (range 2 - 20 years). Three hundred patients (32%) were observed for more than 7 years. The median age at transplantation was 11 years and 8% (n=78) were older than 30 years. The predominant donor was an HLA-matched sibling (66%), the predominant graft was bone marrow (70%), and about half the cohort received myeloablative conditioning. The 10-year probability of survival in 2- and 5-year survivors was 96% (95% CI 94-98) and 98% (95% CI 96-99), respectively (Figure 1). The 12-year probability of survival in 7-year survivors was 97% (95% CI 92-99). Risk factors for late death included older age and alternative donors (Table 1). Every 10-year increment in patient age was associated with a 75% increase-risk of mortality. The risk of death is 3.5 times higher after alternative donor (mismatched relative, HLA-matched and mismatched unrelated donor) compared to HLA-matched siblings. Amongst the alternative donors, mortality risks were not different. Compared to an age-, sex- and race-matched US population, the risk for late death was higher in transplant survivors but diminished over time (Table 2). Graft failure (beyond 2-years after transplantation) remains an obstacle; 4% (95% CI 3 - 6) after HLA-matched sibling and 12% (95% CI 8 - 18), (HR 2.59, p&lt;0.0001) after alternative donor transplantation. Mortality risk was higher in those with history of chronic graft-versus-host disease though did not reach level of significance (HR 2.18, p=0.08).
Conclusion: Durable survival is likely in the majority of 2-year survivors. The expected risk for death receded over time but the risk for late death is not negligible even as late as 7-years after transplantation underscoring the need for continued surveillance.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.