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541 Hematopoietic Stem Cell Transplantation from HLA Identical Sibling Forsickle Cell Disease an International Survey on Behalf of Eurocord-Monacord, EBMT Paediatric Disease Working Party and CIBMTR

Hemoglobinopathies, Excluding Thalassemia – Clinical
Program: Oral and Poster Abstracts
Type: Oral
Session: 114. Hemoglobinopathies, Excluding Thalassemia – Clinical: Promising Therapies in Sickle Cell Disease
Monday, December 7, 2015: 10:30 AM
W340, Level 3 (Orange County Convention Center)

Barbara Cappelli, MD1,2*, Francoise Bernaudin, MD3, Annalisa Ruggeri, MD, PhD4,5*, Myriam Labopin, MD6*, Fernanda Volt, MT1*, Belinda Pinto Simoes, M.D., Ph.D.7,8, Alina Ferster, MD, PhD9, Sophie Dupont, MD10*, Josu de la Fuente, PhD, FRCP, FRCPI, FRCPCH, FRCPath11, Jean-Hugues Dalle, MD, PhD12, Marco Zecca, MD13*, Marie Robin, MD, PhD14, Mark C. Walters, MD15, Nathalie Dhedin, MD16*, Gerard Michel, MD17*, Patrick Lutz18*, Benedicte Neven, MD, PhD19*, Yves Bertrand, MD, PhD20*, Jean Pierre Vannier, MD, PhD21*, Mouhab Ayas, MD22, Susanne Matthes, MD23*, Hanadi Elayoubi, MD1*, Agnes Devergie, MD1*, Chantal Kenzey, CRA1*, Franco Locatelli, MD24, Christina Peters, MD, PhD25*, Vanderson Rocha, MD, PhD26,27, Mary Eapen, MBBS28 and Eliane Gluckman, MD1

1Eurocord International Registry, Paris, France
2Monacord, Centre Scientifique de Monaco, Monaco, Monaco
3Dept. Pediatrie, Hopital Intercommunal de Creteil, Creteil, France
4Eurocord, Hôpital Saint Louis APHP, University Paris-Diderot, Paris, France
5Service d’Hématologie et Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France
6Department of Hematology and Cell Therapy, Saint Antoine Hospital, Paris, France
7University of São Paulo,, São Paulo, Brazil
8Ribeirão Preto Medical School, Ribeirao Preto, Brazil
9Dept. of Hémato-oncologie pédiatrique, Children's University Hospital Reine Fabiola, Brussels, Belgium
10Cliniques Universitaires Saint Luc, Hemato-Oncology Unit, Brussels, Belgium
11Centre for Haematology, Imperial College London, London, United Kingdom
12Hematology, Hopital Robert Debre, Paris, France
13Pediatric Hematology/Oncology, IRCCS Policlinico San Matteo, Pavia, Italy
14Hematology - Bone Marrow Transplantation, Saint-Louis Hospital, Paris, France
15UCSF Benioff Children's Hospital, Oakland, CA
16Department of Hematology, Adolescents and young adults unit, Saint-Louis Hospital, Paris, France
17Timone Enfants Hospital and Aix-Marseille University, Department of Pediatric Hematology and Oncology, Marseille, France
18CHRU Strasbourg, Strasbourg, France
19Pediatric Hematology-Immunology and Rheumatology Unit, Assistance Publique-Hôpitaux de Paris, Necker-Enfants Malades University Hospital, Paris, France
20Pediatric Hematology and Oncology Unit, IHOP, Lyon, France
21Paediatric Oncology and Haematology Unit, Charles Nicolle Rouen University Hospital, Rouen, France
22Department of Pediatric Hematology/Oncology, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
23St Anna Children's Hospital, Vienna, Austria
24Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
25Stem Cell Transplantation Unit, St. Anna Children's Hospital, Vienna, Austria
26Churchill Hospital, Oxford University, Oxford, United Kingdom
27Eurocord - Monacord, Hôpital Saint Louis, Paris, France
28Medical College of Wisconsin, Milwaukee, WI

Introduction:

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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