Unrelated Donor Cord Blood Transplantation for Children with Severe Sickle Cell Disease: Results of a Phase II Study from the Blood and Marrow Transplant Clinical Trials Network
Biology of Blood and Marrow Transplantation
Most children with sickle cell disease (SCD) who might otherwise be considered for curative hematopoietic cell transplantation (HCT) lack a healthy matched related donor. Barriers to alternative donor HCT for SCD include graft rejection, graft-versus-host disease(GVHD) and regimen-related toxicities. To address these problems, we initiated a phase II trial of unrelated bone marrow or cord blood transplantation (CBT) using a novel, alemtuzumabbased, reduced intensity conditioning (RIC) regimen
... ing (RIC) regimen in children with severe SCD. Here we report the results for the 8 children who received unrelated CBT on this study. Patients were prepared for HCT following alemtuzumab(10, 15 and 20 mg on day -21, -20 and -19 respectively), fludarabine(30 mg/m 2 day -8 to -4) and melphalan(140 mg/m 2 day -3). Cyclosporine or tacrolimus and mycophenolate were administered for GVHD prophylaxis. Donor/recipient HLA match status was 5/6 in all patients based on low/ intermediate resolution molecular typing at HLA -A, -B, and high resolution typing at -DRB1. Median recipient age was 13.7 years (range 7.4 to 16.2 years). The median pre-cryopreservation total nucleated cell dose was 6.4x10 7 /kg (range 3.1 to 7.6) and the median post-thaw infused CD34 cell dose was 1.5x10 5 /kg (range 0.2 to 2.3). The conditioning regimen demonstrated a favorable safety profile. All patients achieved an absolute neutrophil count.500/mm 3 by day 33 (median 22 days). Six of eight patients had a platelet recovery to . 50,000/mm 3 by day 100. Five patients had autologous hematopoietic recovery and three patients had sustained full donor engraftment. Two of 3 engrafted patients developed grade II acute GVHD. Of these, one developed extensive chronic GVHD that was fatal 14 months post-transplant. With a median follow up of 1.8 years (range 1 -2.6), 7 patients are alive with a 1-year survival of 100% and 2 are alive without graft failure or disease recurrence. Total nucleated or CD 34+ cell dose, HLA mismatch or ABO mismatch were not correlated with graft rejection in this small series. Conclusion: This RIC regimen was associated with a high rate of graft rejection after unrelated CBT. The CBT arm has been closed, but the trial remains open to enrollment for eligible patients with 8/8 HLA allele matched unrelated bone marrow donors. Novel approaches aimed at reducing graft rejection while minimizing toxicity will be needed before RIC unrelated donor CBT can be widely adopted for transplanting children with severe SCD.