Endothelial Complications of Hematopoietic Cell Transplantation for Sickle Cell Disease

Introduction Hematopoietic cell transplantation (HCT) is a curative therapy for sickle cell disease (SCD), with especially favorable outcomes in young patients from HLA-identical donors. Unfortunately, HCT is associated with endothelial injury syndromes (EIS), including veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), transplant-associated thrombotic microangiopathy (TA-TMA), and also acute graft-versus-host disease (GVHD), that increase transplant risk. This is further complicated by hemolysis-mediated endothelial dysfunction in patients with SCD. The impact of EIS in this population is not certain. We thus sought to better evaluate endothelial complications of HCT for SCD in a large, international registry.

Methods We examined de-identified records of HCT for SCD that were retrieved from data on patients transplanted between 1991 and 2020 in the United States submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR) obtained through curesickle.org. Patients were followed longitudinally until death, loss to follow-up, or last contact through June 2021 at 3, 6, 12, and 24 months after HCT, and then every 2 years. Donors included HLA-matched siblings, haploidentical relatives, and HLA-matched and HLA-mismatched unrelated donors. We examined overall survival, event-free survival, and acute and chronic GVHD. Cox regression models were used to examine for risk factors associated with TMA and VOD. In addition, one-factor (univariate) analysis was used to identify factors associated with higher risk complications.

Results A total of 1641 unique patients underwent a first allogeneic HCT between 1991 and 2020, with a median year of HCT of 2014. Of HCT recipients, 67.7% were below the age of 18 years at HCT and 74.7% had Karnofsky performance score ≥ 90. Acute GVHD grades II-IV developed in 18.3% and 22.3% developed chronic GVHD. Graft failure was reported in 17.6% following HCT, which was from an HLA-identical sibling in 61.5%, mismatched relative in 17.6%, matched unrelated donor in 10.2%, and mismatched unrelated donor in 10.7%. Conditioning regimen was myeloablative (50.8%), reduced intensity (23%), or non-myeloablative (22.3%). Patients were followed for a median of 47.8 months (0.3 - 312.9), with 3-year overall survival 91.2% and 3-year event-free survival 85.2%. Median time to death was 9.6 months for 152 patients. Estimated hazard ratio (HR) of death in 7/8 vs. 8/8 HLA matching was 1.5 (95% CI: 0.752, 2.445), which was not statistically significant. However, HR of death for ≤ 6/8 vs. 8/8 HLA matching was 1.7 (95% CI: 1.215, 2.445), indicating a statistically significant increased risk of death.

TA-TMA was reported in 27 patients at a median of 2.8 months post-HCT. Univariate analysis of risk factors for TA-TMA indicated increasing incidence with the year of HCT. Age at HCT, HLA matching, and conditioning regimen intensity were not significantly associated. VOD was reported in 24 cases; Cox proportional hazards analysis indicated decreasing incidence with year of HCT. Estimated HR for VOD of patients who developed grade II-IV AGVHD group was 2.965, (95% C.I. 1.089, 8.074). Age at HCT, conditioning intensity, and donor type were not significant. Acute and chronic GVHD were associated with recipient age > 10 years and donors other than HLA-matched siblings; non-myeloablative conditioning was protective against GHVD development.

Conclusion Incidence of endothelial complications following HCT for SCD is low, although TA-TMA has been increasingly recognized in recent years. VOD has been observed less frequently over time and correlates with acute GVHD. Donor type, recipient age, and conditioning intensity have the greatest impact on GVHD development.

No relevant conflicts of interest to declare.