Delayed Immune Reconstitution and Increased Viral Infections Following Haploidentical BMT with Post-Transplant Cyclophosphamide for Sickle Cell Disease: Results of a Haploidentical Transplant Consortium for Hemoglobinopathies (ICHH)

Abstract

Introduction Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) has increased curative options for patients with sickle cell disease (SCD), with near universal donor availability. However, this approach is associated with increased risk of graft failure, delayed engraftment, and early viral reactivation. Limited knowledge exists regarding immune reconstitution (IR) following haplo-BMT. We hypothesized that the immunomodulatory properties of the pre-transplant conditioning and PTCy contribute to increased early infectious risk and late effects. Objective To characterize IR and impact on infection and late effects post haplo-BMT for SCD. Methods We examined clinical outcomes and IR in 23 patients with severe SCD who received haplo-BMT in the context of a collaborative consortium involving three centers (France, London, U.S.). Common conditioning included fludarabine 150 mg/m2 total, cyclophosphamide 14.5 mg/kg x2, thiotepa 10 mg/kg x1, and thymoglobulin 4.5 mg/kg total, and total body irradiation 200 cGy x1. 18/23 received pre-conditioning with azathioprine 3 mg/kg/day, hydroxyurea 30 mg/kg/day, and hyper-transfusion. Graft source was bone marrow, and 20/23 donors were mobilized with filgrastim 10 mcg/kg/day x 5 days. PTCy (50 mg/kg/day x2), MMF, and sirolimus were given for GvHD prophylaxis. Cellular subsets analyzed included CD4, CD8, NK, and B cells. Patients deceased or without IR data were excluded. Results Table 1 shows patient and donor characteristics. Median total nucleated and CD34 cell doses were 4.9 × 10(9)/kg and 4.69 × 10(6)/kg, respectively. Among engrafted patients, those who received preconditioning had delayed platelet recovery (mean 35 days vs 27, p = 0.002), but higher median CD4 absolute cell count (cells/mL) at D+30 (43 vs 41), D+60 (190 vs 98), D+90 (229 vs 191), D+180 (304 vs 308), D+360 (1255 vs 394) compared to those without, respectively. While not statistically significant either, similar patterns were seen for CD8 and CD19 cells. Post-transplant infections were mostly viral, and occurred in the majority of patients 69.6% (16/23), Figure 2. Conclusion Delayed early IR and viral reactivation/infections were observed following haplo-BMT with PTCy for SCD. Further prospective studies are needed to better characterize IR following this approach to optimize immune-prophylaxis.