Predictors of Graft Failure Beyond 24 Months Following Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

Background: Hematopoietic stem cell transplant (HCT) is a potentially curative treatment for sickle cell disease (SCD), but it is associated with significant risks including graft failure. While most life-threatening complications of HCT occur within the first few months of transplant, graft failure (GF) can still occur beyond this period. Secondary GF beyond 2 years, when patients are off immunosuppression, may be the result of a different mechanism as opposed to GF before 2 years. Understanding late GF is essential, as it may result from mechanisms different from those affecting early GF, and the risk of late death in transplant recipients remains higher than the general population even several years post-transplantation.

Objective: To determine predictors of late (≥ 24 months) GF in patients who underwent HCT for sickle cell disease.

Methods: This retrospective study analysed data from patients who underwent HCT between 1991 and 2021, using deidentified records submitted to Center for International Blood and Marrow Transplant Research (CIBMTR). We conducted a multivariable logistic regression analysis to evaluate the associations between pre-HCT characteristics and the risk of late GF.

Results: Out of a total of 1858 transplant recipients, 323 patients who experienced GF at a median 4.6 months post-HCT, at a mean age at HCT of 14.46 (±10.58) years, as compared to a mean age of 13.03 (±8.80) years among those without GF (p=0.023), were included in this analysis. GF occurred more frequently in patients with less than 8/8 HLA matching (p<0.001), in patients receiving alternate donor HCT (p<0.001), in patients for whom peripheral blood was the graft source (p<0.001), in whom conditioning regimen was non-myeloablative (p<0.001) and in those with a history of stroke prior to HCT (p=0.011). The risk of GF in patients with a history of intubation prior to HCT did not reach statistical significance ( P=0.07).

We then compared 266 patients who experienced GF <24 months post-HCT with 57 patients who had experienced GF ≥24 months post-HCT. Early GF occurred at a median of 3.7 (0.0-23.9) months as opposed to late graft failure which occurred at a median of 35 ( 24-163.9) months ( P<0.001). Differences in patient demographics, age, sex, donor type, graft type, HLA match, and GVHD prophylaxis did not achieve statistical significance On multivariable logistic regression Non-myeloablative conditioning was significantly associated with higher odds of late GF compared to myeloablative conditioning (OR: 2.327, 95% CI: 1.110-4.887; p=0.025). HLA mismatched (7/8 or ≤6/8) donors compared to 8/8 matched donor was significantly associated with reduced odds of late GF (OR: 0.446, 95% CI: 0.222-0.867; p=0.017) and pre-conditioning mechanical ventilation was associated with lower risk of late GF (OR: 0.250, 95% CI: 0.039-0.890; p=0.03). While GF is more common overall in HLA-mismatched donor HCT, GF appears to be less frequent in patients with HLAmismatched donors at ≥24 months post-HCT.

Conclusion: Use of non-myeloablative conditioning regimen is significantly associated with the risk of late graft failure compared to myeloablative conditioning. These findings thus highlight the importance of a greater understanding of the factors contributing to late GF and the need for focused strategies toward the prevention and management of both early and late graft failures.