Nonmyeloablative HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Severe Sickle Cell Phenotype

Abstract

IMPORTANCE Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant. OBJECTIVE To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia. DESIGN, SETTING, AND PARTICIPANTS From July 16, 2004, to October 25, 2013, 30 patients aged 16–65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5–31.7 × 106 cells/kg) from human leukocyte antigen–matched siblings. MAIN OUTCOMES AND MEASURES The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell–thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing. RESULTS Twenty-nine patients survived a median 3.4 years (range, 1–8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%–62%); the myeloid chimerism levels, 86% (95% CI, 70%–100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron. The mean annual hospitalization rate was 3.23 (95%CI, 1.83–4.63) the year before, 0.63 (95% CI, 0.26–1.01) the first year after,0.19 (95% CI, 0–0.45) the second year after, and 0.11 (95%CI, 0.04–0.19) the third year after transplant. For patients taking long-term narcotics, the mean use per week was 639 mg (95%CI, 220–1058) of intravenous morphine–equivalent dose the week of their transplants and 140 mg (95% CI, 56–225) 6 months after transplant. There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects. CONCLUSIONS AND RELEVANCE Among 30 patients with sickle cell phenotype with or without thalassemia who underwent nonmyeloablative allogeneic HSCT, the rate of stable mixed...

Evolution of sickle cell disease from a life‐threatening disease of children to a chronic disease of adults: The last 40 years

“…All 10 patients survived and 9 had long-term stable engraftment. The same group recently extended the series with 30 participants, 87% had long-term stable donor engraftment without graft-vs.-host disease and 1 patient died after engraftment failure from intracranial hemorrhage [141]. These data convincingly demonstrate that non-myeloablative transplants are a reasonable alternative for adults with SCD who have a HLA-matched related donor.…”

Sickle Cell Disease

“…This is becoming potentially more applicable with the development of less toxic conditioning regimens and the use of alternative sources of donor cells, 93 although allogeneic stem-cell donation may be superseded by gene therapy and gene editing approaches (Table S2 in the Supplementary Appendix). 94 A recent case report describing the use of a self-inactivating lentiviral vector to inhibit HbS polymerization as a proof of concept of complete clinical remission with correction of hemolysis and biologic hallmarks of the disease certainly reflects the fast pace of current developments in gene therapy for sickle cell disease.…”

Traffic Light: prognosis-based eligibility for clinical trials of hematopoietic SCT in adults with sickle cell anemia

“…Given that published studies in adults overwhelmingly report non-myeloablative strategies, our model assumes that paradigm for risk estimates. 4,5,7 Weighted Traffic Light eligibility guidelines for clinical trial of HSCT in SCA ( Shown are data from walk-PHaSST for adults with HbSS who had WBC and TRV reported from study entry, including subjects who were dead (black stars) and those who were alive (gray dots) at follow-up. The quadrants are above or below a TRV of 3 m/s (y axis) and above or below a WBC of 13.5 (x axis) at study entry.…”

“…At the National Institutes of Health (NIH), 26/30 SCA adults had long-term donor engraftment following a non-myeloablative preparative regimen and matched sibling donor (MSD) transplant. 4 However, acceptable MSDs are available in o20% of patients, 5,6 whereas haploidentical donors may be available in 475% of adults with SCA. 7 Bolaños-Meade et al 7 at Johns Hopkins University reported on 14 adults who underwent a reduced intensity preparative regimen, followed by a haploidentical graft.…”