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564 Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Severe Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Clinical Allogeneic Transplantation Results II
Hematology Disease Topics & Pathways:
sickle cell disease, HSCs, Adult, Diseases, Non-Biological, Therapies, chemotherapy, Pediatric, Hemoglobinopathies, Young Adult, Cell Lineage, Study Population, Clinically relevant
Monday, December 7, 2020: 8:15 AM

Adetola A. Kassim, MD, MS1,2,3, Josu de la Fuente4, Ali Debsan Alahmari, MBBS, MD, MNAMS5*, Michael J. Eckrich, MD, MPH6, Rabi Hanna, MD7, Nathalie Dhedin, MD8*, Biljana N. Horn, MD9, Vandy Black, MD, MSc10,11, Roseane V Gouveia12*, Adriana Seber, MD, MS13, Belinda Pinto Simões, MD, PhD14,15*, Thalita Cristina de Mello Costa, MD16*, Renato Guerino-Cunha17*, Carmem M. S. Bonfim, MD PhD18,19*, Roberto Luiz da Silva20*, Nelson Hamerschlak, MD, PhD21,22, Juliana Folloni Fernandes, MD23*, Michael Kent, MD, BS24, Satya Prakash Yadav, MBBS, MD25,26, Erfan Nur, MD, PhD27,28, Mohsen Alzahrani29,30*, Ben Carpenter, PhD31*, William Tse, MD32,33*, Maria Isabel34*, Hemalatha G Rangarajan, MD35,36,37, Ibrahim Ahmed, MD38, Adeseye Michael Akinsete, MBBS39*, Courtney D. Fitzhugh, MD40, Kathryn A. Culos, PharmD41*, Leena Karnik, FRCPath, MRCP42*, James Connelly, MD43*, Carrie Kitko, MD44,45, Jennifer Andrews, MD, MSc46, Karina L Wilkerson, NP, MSN47*, Robert Brodsky48,49*, Tatsuki Koyama50* and Michael R. DeBaun, MD, MPH51

1Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Nashville, TN
2Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
3Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
4Department of Paediatrics, St. Mary's Hospital/Imperial College London, London, United Kingdom
5King Faisal Hospital & Research Ctr., Riyadh, SAU
6Pediatric Blood and Marrow Transplantation Program, Texas Transplant Institute at Medical City Dallas, San Antonio, TX
7Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
8St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
9UF Shand's Children Hospital, University of Florida, Gainesville, FL
10University of Florida College of Medicine, Newberry, FL
11Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Florida College of Medicine, Gainesville, FL
12Hospital Sao Camilo Pompeia, Pediatric Oncology and Hematopoietic Cell Transplantation, São Paulo, Brazil
13Hospital Samaritano, Sao Paulo, SP, Brazil
14Department of Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Ribeirão Preto, Brazil
15Center for Cell-Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil., Ribeirão Preto, Brazil
16School of Medicine of Ribeirão Preto, University of São Paulo, São José Do Rio Preto, Brazil
17Ribeirão Preto Medical School, University of São Paulo, Departments of Medical Imaging and Hematology /Clinical Oncology, São Paulo, Brazil
18Federal University of Parana, Curitiba, PR, Brazil
19Hospital Nossa Senhora das Graças, Curitiba, Brazil
20IBCC Oncologia (Instituto Brasileiro de Controle do Câncer), São Paulo, Brazil
21Hematology, Hospital Israelita Albert Einstein, São Paulo, Brazil
22Hospital Israelita Albert Einstein, Sao Paulo, Brazil
23Department of Hematology and Bone Marrow Transplantation, Hospital Israelita Albert Einstein, Hematology unit, São Paulo, Brazil
24Atrium Health/Levine Children's Hospital, Charlotte, NC
25Pediatric Hemato-Oncology & BMT, Medanta The Medicity, Gurgaon, India
26Pediatric Hemato-Oncology & BMT, Fortis Memorial Research Institute, Gurgaon, Haryana, India
27Department of Clinical Hematology, Slotervaart Hospital, Amsterdam, Netherlands
28Department of Clinical Hematology, Amsterdam University Medical Centers, Academic Medical Center, Amsterdam, Netherlands
29Saudi Society of Blood & Marrow Transplantation (SSBMT), Riyadh, Saudi Arabia
30Division of Adult Hematology and SCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
31University College London Hospital, London, United Kingdom
32Bone Marrow Transplant, University of Louisville, Louisville, KY
33University of Louisville, Louisville, KY
34Vall d' Hebron Hospital, Department of Hematology / Oncology, Barcelona, Spain
35Hem/Onc/BMT, Nationwide Children’s Hospital, Columbus, OH
36Division of Pediatric Hematology, Oncology, Blood and Marrow Transplant, Nationwide Childrens Hospital, Columbus, OH
37Nationwide Childrens Hospital, Columbus, OH
38Division of Pediatric Hematology, Oncology, Blood and Marrow Transplant, Children's Mercy Hospital, Kansas City, MO
39College of Medicine, Division of Pediatric Hematology & Oncology, Lagos University Teaching Hospital, Lagos, Nigeria
40Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
41Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN
42Department of Paediatrics, St. Mary's Hospital, London, United Kingdom
43Department of Pediatrics, Division of Pediatric Hematology Oncology, Vanderbilt University Medical Center, Nashville, TN
44Pediatric Hematology/Oncology Division, Vanderbilt-Ingram Cancer Center, Nashville, TN
45Vanderbilt University Medical Center, Franklin, TN
46Vanderbilt University Medical Center, Nashville, TN
47Hematology/Oncology Department Sickle Cell Disease Center of Excellence, Vanderbilt University Medical Center, Nashville, TN
48Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
49Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD
50Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN
51Vanderbilt-Meharry Center for Excellence in Sickle Cell Disease, Vanderbilt University School of Medicine, Nashville, TN

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to > 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants.

Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules.

Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as <5% donor myeloid chimerism or < 5% donor cells by whole blood chimerism by day +42 posttransplant. Secondary graft rejection was defined <5% donor myeloid chimerism or < 5% donor cells by whole blood chimerism with prior documentation of > 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD.

Results: We enrolled 41 consecutive participants from 8/14/2014 – 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were <18 years of age. Donors included siblings (14/41, 34%), parents (27/41, 61%), and 88% (36/41) had sickle cell trait. Median TNC dose was 5.8 x 108 /kg (4.2, 8.0), and median CD34+ and CD3+ cell doses were 3.9 x 106/kg (2.6, 6.1) and 32.3 x 108/kg (27.1, 50.8), respectively. A total of 93% of participants engrafted. Median times to neutrophil (> 500/mcL) and platelet (>50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants <18 years of age, and all had autologous reconstitution (Table).

Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (< 18 years), and all older participants (> 18 years) engrafted. The trial will add new stopping rules by age strata (<18, > or = to 18 years) and will modify the conditioning regimen in pediatric stratum.

Disclosures: Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun: Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

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