Graft Failure after Hematopoietic Cell Transplantation for Hemoglobin Disorders: Successful Application of a Rescue Regimen

Abstract Background Although patients with clinically significant hemoglobinopathies can be supported with blood transfusions and iron chelation therapy, the only curative option is allogeneic hematopoietic stem cell transplantation (HCT). Unfortunately, there is a risk of graft rejection as a consequence of donor sensitization and alloimmunization related to transfusion exposures and a hyperproliferative marrow niche. Typically, graft rejection after HCT for hemoglobinopathies is accompanied by autologous hematopoietic recovery, but there is also a risk of graft failure and marrow aplasia which can cause a fatal outcome. To accommodate individuals who lack a suitable sibling donor, transplant options are being expanded to include alternative sources of hematopoietic donors which carry higher risks of graft rejection, graft-versus-host disease and transplant-related mortality. Given the significant risk of graft failure after alternative donor HCT, it is important to develop a plan for stem cell rescue when these complications occur. Methods and Results We reviewed 3 patients with hemoglobin disorders who were successfully rescued by alternative transplantation regimens following primary or secondary graft failures. Two patients with sickle cell disease and one with β-thalassemia major were treated at our institution with a reduced-intensity regimen. All 3 patients had graft rejection accompanied by marrow aplasia within 2 months after HCT. Patient 1 was successfully rescued with mobilized peripheral blood stem cells from the same HLA mismatched sibling donor after a minimal toxicity preparative regimen. Patients 2 and 3 were successfully rescued from HLA-haploidentical donors after a minimal toxicity preparative regimen that included in vivo T-cell depletion by post-grafting high dose cyclophosphamide. Refer to Table 1 for patient and transplant characteristics. Conclusion There are 3 methods to rescue patients from graft rejection: donor lymphocyte infusions, the intensification of immunosuppression or a rescue allogeneic transplant. Here we report our local experience with graft failure and its successful management in 3 patients with hemoglobin disorders. Although graft rejection remains a major obstacle to successful transplantation for hemoglobinopathies, better donor selection and screening by lymphocyte cross matching, optimized conditioning regimens and improved supportive care should improve outcomes after alternate donor HCT. We speculate that it is also possible now to rescue from graft failure in most cases and that an allogeneic HCT rescue might be utilized for a curative outcome. Table 1 . Patient characteristics, rescue transplant regimen, engraftment, graft-versus-host-disease (GVHD), and duration of immune suppression post-rescue HCT. BM, Bone Marrow; UCB, Umbilical Cord Blood; ATG, Anti-thymocyte Globulin; HLA, Human Leukocyte Antigen; MMF, Mycophenolate Mofetil; TBI, Total Body Irradiation Patient 1 Patient 2 Patient 3 Age, Gender 14 yo Male 3 ½ yo Male 14 yo Male Diagnosis Hemoglobin SS β-Thalassemia major Hemoglobin SS Indication for Transplant Subarachnoid Hemorrhage Veno-occlusive crises Alternative to life-long transfusions and iron chelation therapy Multiple Cerebral infarcts Acute Chest Syndrome Veno-occlusive crises Transplant #1 Conditioning Regimen Busulfan Thiotepa Cyclophosphamide Rabbit ATG Busulfan Thiotepa Fludarabine Rabbit ATG Busulfan Fludarabine Rabbit ATG Transplant #1 Cell Source BM, 9/10 HLA mismatch at A locus Single 6/6 HLA matched UCB BM, 10/10 HLA matched sibling GVHD Prophylaxis for Transplant #1 Cyclosporine MMF Cyclosporine Methotrexate Type of Graft Failure Secondary Primary Secondary Rescue Transplant Conditioning Regimen Fludarabine 30mg/m2 on days -4 through -2; TBI 400cGy on day 0 Fludarabine 30 mg/m2 on days -6 through -2; TBI 400cGy on day 0; Cyclophosphamide 14.5 mg/kg/day on days -6, -5; and 50 mg/kg/day on days +3,+4 Recue Transplant Cell Source Same donor, Mobilized PBSC Haploidentical mother Haploidentical father Rescue GVHD Prophylaxis Tacrolimus MMF Time to Neutrophil Engraftment (days) 14 14 15 Time to Platelet Engraftment (days) 18 25 22 Day 28 Percent Donor Cells 98% 100% 99% Acute GVHD None Skin None Chronic GVHD None Oral and Integument (resolved) Pericardial effusion (resolved) Duration of Post-Rescue Transplant Immune Suppression 17 months 37 months 16 months Disclosures No relevant conflicts of interest to declare.