Program: Oral and Poster Abstracts
Type: Oral
Session: 114. Hemoglobinopathies, Excluding Thalassemia – Clinical: Promising Therapies in Sickle Cell Disease
Hematopoietic stem cell transplantation (HSCT) is, to date, the only curative therapy for sickle cell disease (SCD). However, HSCT is offered to relatively few patients with SCD for a number of reasons including lack of a suitable HLA-matched donor, lack of consensus on indications for HSCT, the potential for trading one chronic condition (i.e., SCD) for another, such as chronic graft-versus-host disease (GVHD), and the mortality associated with the procedure. To-date, most HSCTs for SCD have utilized matched siblings as donors and are performed in children and adolescents. We report outcomes after HLA-matched sibling HSCT of patients reported to the Eurocord-Monacord/European Group for Blood and Marrow Transplantation (EBMT) and Center for International Blood and Marrow Transplant Research (CIBMTR).
Material and methods:
One thousand patients with SCD received HLA identical sibling HSCT between 1991 and 2013; n=439 from CIBMTR and n=561 from EBMT centers. HSCTs were performed in 90 centers in 23 countries.
Results:
Median age at HSCT was 9 years (range 1-54y); 85% of patients were aged <16 years. Approximately half of patients were female and 53% of HSCTs were performed after 2007. Most patients (94%) were homozygotes for hemoglobin S (HBS). The most common indication for HSCT was stroke. Other indications included: central nervous system event lasting longer than 24 hours, elevated cerebral arterial velocity, acute chest syndrome or vaso-occlusive crisis requiring hospitalization. Red blood cell transfusions were given before HSCT to 93% and hydroxyurea to 56% of the evaluable patients (N=510). Most HSCTs (n=872; 87%) used myeloablative-conditioning regimens, mainly based on the combination of busulfan with cyclophosphamide (n=719; 82%) or fludarabine (n=82; 9%). One hundred and twenty six patients (13%) received reduced intensity conditioning regimens; fludarabine with cyclophosphamide was the predominant regimen (n=48; 38%). Most regimens included in vivo T-cell depletion (71%) with anti-thymocyte globulin (n=630) or alemtuzumab (n=76). The predominant GVHD prophylaxis regimens were cyclosporine alone (19%), or combined with methotrexate (56%). The predominant stem cell source was bone marrow (84%); peripheral blood and cord blood were employed in 7% and 9% of patients, respectively. The median follow-up was 45 (1.1-324.6) months.
The cumulative incidence (CI) of neutrophil engraftment at day+60 was 98% (96.6% for CB, 98.3% for BM and 95.2% for PB) with a median time to recovery of 19 days, while that for platelet engraftment was 98 % (96±2% for CB, 99±1% for BM and 98±9% for PBSC) with a median time to recovery of 25 days. Twenty-six patients experienced primary and 47 patients secondary graft failure; 67 patients died mainly due to GVH or infection. The 3-year probabilities of overall (OS) and event-free survival (EFS, alive with engraftment) were 94% (95% CI 92-95) and 90% (95% CI 68-82), respectively. According to stem cell source, 3-year OS was 99% after CB, 94% after BM and 80% after PBS (p<0.0001). In multivariate analysis, every year in age increment (HR 1.1, 95% CI 1.07-1.14, p<0.001) and use of peripheral blood (HR 3.43, 95% CI 1.49-7.88, p=0.004) were associated with higher mortality. In univariate analysis, EFS was better in patients receiving myeloablative compared to reduced intensity conditioning (91±1% vs 82 ±1%, respectively; p<0.001). In multivariate analysis, EFS was lower with every year in age increment (HR 1.05, 95% CI 1.02-1.07, p<0.001), peripheral blood grafts (HR 1.83, 95% CI 1.07-3.15, p=0.03) and HSCTs prior to 2000 (HR 0.77, 95% CI 0.64-0.92, p=0.005). CI of acute GVHD grade 2-4 was 14.4% (12.2-16.7) of chronic GVH 13.3 (11-15.8). Risks of acute GVHD were higher with increasing age (HR1.04 95% CI 1.01-1.07, p=0.008). None of the variables tested were associated with chronic GVHD.
Conclusion:
This large registry based international study shows that HLA identical sibling transplant is successful more than 90% of the patients with severe SCD with limited transplant related complications (rejection, GVHD). Strategies aimed at lowering graft failure and GVHD are desirable to further optimize the observed 3-year event-free survival. Importantly, these data should increase awareness to early referral to HSCT of patients with severe SCD.
Disclosures: Walters: ViaCord and AllCells, Inc: Other: Medical director . Bertrand: ERYTECH Pharma: Consultancy . Peters: Medac: Research Funding ; Fresenius: Research Funding ; Amgen: Research Funding ; Jazz: Research Funding ; Novartis: Research Funding ; Pfizer: Research Funding ; Sanovi: Research Funding ; Pierre-Fabre: Research Funding .
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