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

Abstract

BackgroundAlthough 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 ResultsWe 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.ConclusionThere 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 1Patient 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 IrradiationPatient 1Patient 2Patient 3Age, Gender14 yo Male3 ½ yo Male14 yo MaleDiagnosisHemoglobin SSβ-Thalassemia majorHemoglobin SSIndication for TransplantSubarachnoid Hemorrhage Veno-occlusive crisesAlternative to life-long transfusions and iron chelation therapyMultiple Cerebral infarcts Acute Chest Syndrome Veno-occlusive crisesTransplant #1 Conditioning RegimenBusulfan Thiotepa Cyclophosphamide Rabbit ATGBusulfan Thiotepa Fludarabine Rabbit ATGBusulfan Fludarabine Rabbit ATGTransplant #1 Cell SourceBM, 9/10 HLA mismatch at A locusSingle 6/6 HLA matched UCBBM, 10/10 HLA matched siblingGVHD Prophylaxis for Transplant #1Cyclosporine MMFCyclosporine MethotrexateType of Graft FailureSecondaryPrimarySecondaryRescue Transplant Conditioning RegimenFludarabine 30mg/m2 on days -4 through -2; TBI 400cGy on day 0Fludarabine 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,+4Recue Transplant Cell SourceSame donor, Mobilized PBSCHaploidentical motherHaploidentical fatherRescue GVHD ProphylaxisTacrolimus MMFTime to Neutrophil Engraftment (days)141415Time to Platelet Engraftment (days)182522Day 28 Percent Donor Cells98%100%99%Acute GVHDNoneSkinNoneChronic GVHDNoneOral and Integument (resolved)Pericardial effusion (resolved)Duration of Post-Rescue Transplant Immune Suppression17 months37 months16 months DisclosuresNo relevant conflicts of interest to declare.