Effect of ABO Mismatch and RBC Alloimmunization on the Outcomes of Patients with Sickle Cell Disease Undergoing Hematopoietic Stem Cell Transplantation

Background: Hematopoietic stem cell transplantation (HSCT) remains the only well-established curative option for sickle cell disease (SCD) patients. Non-myeloablative (NMA) conditioning has been used to improve the outcomes and reduce toxicities in adult SCD patients. However, Recipient/Donor (R/D) ABO incompatibility and alloimmunization could be significant impediments to successful outcomes when transplanting SCD patients due to risks of hemolysis, delayed engraftment, poor graft function and graft failure (GF). Herein, we report our experience with allogeneic HSCT for SCD and the effects of RBC groups mismatch and alloimmunization on the outcome of transplanted patients.

Methods: We conducted a retrospective analysis of all adolescents and adult SCD patients (age >14 year) that underwent HSCT from January 2015 to February 2022 at our center. All patients received Intravenous alemtuzumab (1 mg/kg divided over 5 days on days -7 to -3) and 300 cGy TBI on day -2 or -1 for conditioning. Pre-transplant preparation consisted of hydroxyurea at maximum tolerated dose for 2-3 months and one session of exchange transfusion. Peripherally mobilized stem cells targeting 10x10⁶ /kg of CD34 cells were used. For graft versus host disease (GVHD) prophylaxis sirolimus was started on day -1 and continued for one year with tapering if lymphoid chimerism was > 50%. For Patients with major ABO incompatibility, we administered 2 doses of rituximab (375 mg/m²) and 3 sessions of plasmapheresis before starting the conditioning regimen targeting an isoheamagglutinin titer < 1/32.

The primary objective was to determine the impact of RBC groups mismatch and alloimmunization on the outcome of transplanted patients. The secondary objective was to assess the impact of GF on overall survival (OS). Logistic regression was done to evaluate predictors for GF. Kaplan-Meier method was used for survival analysis.

Results: A total of 194 patients were included with a median age of 26 years and 55.6% being males. The median baseline Hgb and HbS were 93 g/L and 71.3%, respectively. Indications of stem cell transplantations were most commonly due to recurrent vaso-occlusive crisis in 52.57% of patients, CNS disease in 19.58%, and acute chest syndrome in 17.01%. Other indications included sickle nephropathy, sickle hepatopathy, priapism and AVN in 10.82% of patients collectively. Around 59% of donors were sickle cell disease carriers, and 41% were healthy donors.

After a median follow up of 28.8 months (5-83), sixteen patients (8%) experienced graft failure (3 with primary GF and 13 with secondary GF). On univariate analysis (table 1a), ABO minor incompatibility (odds ratio (OR), 3.63; 95% confidence interval (CI), 1.13 -11.65, P=0.029, and RBC alloantibodies against donor non-ABO antigens (OR, 4.22; 95% CI, 1.17 -15.14, P=0.039) were predictive for GF. However, on multivariate analysis (table 2a), only RBC alloantibodies against donor non-ABO antigens (OR, 8.29; 95% CI, 2.01 to 34.05, P=0.0033) was predictive of GF.

None of the 16 patients with major ABO incompatibility developed GF. Two-years OS for all patients was 95%. The median OS for patients with GF was 98% compared to 74% patients without GF, P<0.0001) (Figure 1).

Conclusion: In our SCD transplanted patients, RBC alloantibodies against donor non-ABO antigens was an independent risk factor for GF. Patients with GF had an inferior survival and strategies for decreasing the risks are needed.

Al Saleh:Bio pharma: Other: Financial support to attend medical conference; Roche: Other: Financial support to attend medical conference; Janssen: Other: Financial support to attend medical conference; Sanofi: Other: Financial support to attend medical conference; Amgen: Other: Financial support to attend medical conference; Takeda: Other: Financial support to attend medical conference; Novartis: Other: Payment for an educational presentation.