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970 Allogeneic Hematopoietic Stem Cell Transplantation in Children and Adults with Chronic Granulomatous Disease (CGD): A Study of the Inborn Errors Working Party (IEWP) of the EBMT

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Clinical Allogeneic Transplantation: Results I
Hematology Disease Topics & Pathways:
Diseases, Biological, Adult, Therapies, bone marrow, Pediatric, immunodeficiency, Immune Disorders, Young Adult, Study Population, Clinically relevant, transplantation, stem cells
Monday, December 3, 2018: 5:15 PM
Seaport Ballroom A (Manchester Grand Hyatt San Diego)

Robert Chiesa1,2*, Junfeng Wang3,4*, Henric-Jan Blok4,5*, Benedicte Neven, MD6*, Despina Moshous, MD7*, Ansgar Schulz, MD8*, Manfred Hoenig, MD9*, Michael H. Albert, MD10,11*, Fabian Hauck, MD12*, Amal Al-Seraihy, MD13,14*, Jolanta Gozdzik, MD, PhD15, Per Ljungman, MD, PhD16, Caroline A. Lindemans, MD17*, Krzysztof Kalwak, MD18*, Brigitte Strahm, PD Dr.19*, Urs Schanz, MD20, Petr Sedlacek, MD21*, Karl-Walter Sykora, MD22*, Serap Aksoylar, MD23*, Franco Locatelli24, Polina Stepensky, MD25*, Robert Wynn, MD26, Su Han Lum, MD27*, Marco Zecca, MD28*, Paul Veys, MD, PhD2*, Andrew Gennery, MD29*, Matthias Felber, MD30*, Arjan Lankester, MD, PHD4*, Tayfun Guengoer, MD31* and Mary Slatter, MD32*

1Bone Marrow Transplantation Department, Great Ormond Street hospital NHS Trust, London, ENG, United Kingdom
2Bone Marrow Transplantation Department, Great Ormond Street hospital NHS trust, London, United Kingdom
3EBMT Statistical Unit, Leiden, Netherlands
4Leiden University Medical Center, Leiden, Netherlands
5EBMT Data Office Leiden, Leiden, Netherlands
6Necker Children's Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
7Necker Children’s Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
8Department of Pediatrics, University Medical Center, Ulm, Germany
9Pediatrics, University Medical Center Ulm, Ulm, Germany
10Pediatric Infection/Immunity and Hematology/Oncology, Munich, DEU
11Dr. von Hauner University Children's Hospital, Ludwig Maximilian University, Munich, Germany
12Ludwig-Maximilians-Universität, Hauner University Children’s Hospital, Munich, Germany
13King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
14Paediatric SCT Program, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
15Jagiellonian University, Cracow, Poland
16Departments of Hematology and Cellular Therapy/Allogeneic Stem Cell Transplantation, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
17Wilhelmina Children's Hospital, Pediatric Blood and Bone Marrow Transplantation Program, Utrecht, Netherlands
18Medical University, Wroclaw, Poland
19Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany
20Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland, Zurich, Switzerland
21Department of Pediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic
22University Children's Hospital, Hannover, Germany
23Paediatric BMT Centre, Izmir, Turkey
24Department of Hematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
25Hadassah University Hospital, Dept. of Bone Marrow Transplantation, Jerusalem, Israel
26Dept. of Blood and Marrow Transplantation, Royal Manchester Children's Hospital, Manchester, United Kingdom
27Newcastle Children Hospital, Pediatric Bone Marrow Transplantation Department, Newcastle, United Kingdom
28Pediatric Hematology/Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
29Great North Children's Hospital, Newcaslte, United Kingdom
30Universitäts-Kinderspital Zürich, Zurich, Switzerland
31University Children's Hospital, Zurich, Switzerland
32Great North Children`s Hospital, Newcastle, United Kingdom

Introduction: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disease characterized by impairment of the phagocyte NADPH-oxidase complex, resulting in deficient microbial killing and life-threatening bacterial and fungal infections. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative approach, but it can be complicated by graft failure, graft versus-host disease (GvHD) and transplant-related mortality (TRM). In order to define prognostic risk factors in this setting, the IEWP of the EBMT performed a large retrospective registry study on 600 pediatric and adult patients with CGD undergoing allo-HSCT.

Patients and Methods: We analyzed the outcome of patients with CGD who received allo-HSCT in EBMT centers between 1993 and 2017. The main end-points of the study were overall survival (OS) and event-free survival (EFS; events were death and primary or secondary engraftment failure) according to patient’s age, donor type, stem cell source and conditioning regimen. One patient died before allo-HSCT and was excluded from analysis.

Results: We studied 536 children (aged < 18 years) and 63 adults (aged ≥ 18 years) affected by CGD. The median follow-up was 45.37 months (IQR 15.8-81.8). Genetic results were available for 307 patients: inheritance was X-linked (75%) or autosomal recessive (25%). Median age at transplant was 7.2 years (range: 0.12-48.56). Conditioning regimen was Busulfan/Fludarabine (n=244; 41%), Busulfan/Cyclophosphamide (n=104; 17%), Treosulfan/Fludarabine (n=76; 13%), Treosulfan/Fludarabine/Thiotepa (n=52; 9%) or other drug combinations (n=123; 20%). Donors were human leukocyte antigen (HLA) matched related (MFD, 10/10; n=211, 40%), matched unrelated (MUD, 10/10 or 6/6 in UCB; n=201; 38%), mismatched related (MMFD, ≥ 9/10; n= 27; 5%) or mismatched unrelated (MMUD, ≥ 9/10 or 5/6 in UCB; n= 83; 16%). Stem cell source was bone marrow (BM; n=408; 69%), peripheral blood (PB; n=153; 26%) or umbilical cord blood (UCB; n=27; 5%). Donor engraftment occurred in 516 evaluable patients (88%), while primary or secondary engraftment failure occurred in 68 patients (12%). Seventy-nine patients (13%) died after allo-HSCT.

The 2 year Kaplan-Meier estimate of OS and EFS were 87.1% (95% CI, 84.2-89.9) and 77.8% (95% CI, 74.2-81.4), respectively (Fig A). The 2-year cumulative incidence of grade II-IV acute GvHD, chronic GvHD and extensive chronic GvHD was 18.6% (95%, 15.1-22.2), 16.2 % (95%, 18.8-19.7) and 5.5% (95%, 3.4-7.7), respectively. A univariate cox model with spline term demonstrated that older age at transplant was associated with an increased risk of death (p=0.002). Children undergoing allo-HSCT had a superior 2y OS (88.1%; 95% CI 85.2-91.0), compared to adults (78.2%; 95% CI, 67.7-88.7), p=0.03 (Fig B). Patients undergoing allo-HSCT from a MFD had a superior EFS (86.5%; 95% CI 81.5-91.4) compared to MUD (73.3%; 95% CI 66.7-79.9), MMUD (78.2%; 95% CI 69-87.5) and MMFD (59.7; 95% CI 40.4-79.1), p< 0.001 (Fig C). Patients receiving BM grafts had superior 2y EFS (81.0%; 95% CI 76.9-85.1) compared to PB (72.5%; 95% CI 64.7-80.4) and UCB (66.7%; 95% CI 48.9-84.4), p=0.04. The pattern of disease inheritance and the choice of conditioning regimen didn’t have an impact on outcome (Fig D). Fifty-three patients with graft failure underwent a second allo-HSCT and the 2y OS in this group was 82.1% (95% CI, 71.5-92.7). Year of transplantation didn’t have an influence on outcome.

Conclusion: This is the largest study describing the outcome of allo-HSCT in children and adults affected by CGD. We demonstrate an excellent outcome, with a low incidence of graft failure, TRM and GvHD. Older patients with CGD have reduced survival after allo-HSCT, indicating that transplant should be considered at a younger age. The use of a MMFD is associated with poorer outcome; indication to transplant in this setting should be carefully evaluated by the treating physicians.

Disclosures: Chiesa: Bluebird Bio: Consultancy; Gilead: Consultancy. Kalwak: medac: Other: travel grants; Sanofi: Other: travel grants. Sykora: Aventis-Behring: Research Funding; medac: Research Funding. Wynn: Orchard SAB: Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Equity Ownership; Chimerix: Research Funding; Genzyme: Honoraria; Bluebird Bio: Consultancy; Orchard Therapeutics: Consultancy; Chimerix: Consultancy. Zecca: Chimerix: Honoraria. Veys: Pfizer: Honoraria; Servier: Research Funding; Novartis: Honoraria. Slatter: Medac: Other: Travel assistance.

*signifies non-member of ASH