-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

LBA-4 Reduced Intensity Haploidentical Bone Marrow Transplantation in Adults with Severe Sickle Cell Disease: BMT CTN 1507

Program: General Sessions
Session: Late-Breaking Abstracts Session
Hematology Disease Topics & Pathways:
Research, clinical trials, Sickle Cell Disease, adult, Clinical Research, Hemoglobinopathies, Diseases, Study Population, Human
Tuesday, December 12, 2023, 9:00 AM-10:30 AM

Adetola A. Kassim, MBBS, MS1,2, Mark C. Walters, MD3, Mary Eapen, MBBS, MS4, Nicole Ritzau, RN, BSN5*, Madoc Smith, MSPH5*, Melhem M. Solh, MD6, Christopher McKinney, MD7*, Michael Nieder, MD8*, Maureen Ross, MD, PhD9, Michael Kent, MD, BS10,11, Ghada Abusin, MD12*, Kanwaldeep K. Mallhi, MD13, Jorge Galvez Silva, MD14*, Paul Shaughnessy, MD15,16,17*, Julie Kanter, MD18, Hilary Haines, MD19*, Rafic J Farah, MD20,21, Yasser Khaled, MD22, Allistair Abraham, MD23, Catherine M. Bollard, MD24,25, Kenneth R. Cooke, MD26, Josu de La Fuente, PhD27,28, Rabi Hanna, MD29, Mary M. Horowitz, MD30, Lori C Jordan, MD, PhD31*, Lakshmanan Krishnamurti, MD32, Eric Leifere, PhD33*, Kris Michael Mahadeo, MD34,35*, Shalini Shenoy, MD, MBBS36,37, Nicole M. Ritzau, PhD5*, Michael R. DeBaun, MD, MPH38 and Robert A. Brodsky, MD39,40

1Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN
2Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Nashville, TN
3University of California, San Francisco Benioff Children’s Hospital, Oakland, CA
4Department of Medicine, Medical College of Wisconsin, Milwaukee
5The Emmes Company, Rockville, MD
6Blood and Marrow Transplant Program, Northside Hospital Cancer Institute, Atlanta, GA
7Children’s Hospital Colorado, University of Colorado Anschutz Medical Campus, Aurora, CO
8Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL
9Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
10Atrium Health/Levine Children's Hospital, Charlotte, NC
11Levine Children's Hospital, Charlotte, NC
12Pediatrics Hematology/Oncology, University of Michigan, Pediatrics, Ann Arbor, MI
13Division of Hematology/Oncology and Bone Marrow Transplant, Department of Pediatrics, University of Washington, Seattle, Seattle, WA
1412Pediatric Hematology/Oncology, Pediatric Blood and Marrow Transplantation at Nicklaus Children's Hospital, Miami, FL
15Sarah Cannon Transplant and Cellular Therapy Program, Methodist Hospital, San Antonio, TX
16Sarah Cannon Research Institute, Nashville
17Methodist Hospital, San Antonio, TX
18Division of Hematology and Oncology, University of Alabama At Birmingham, Birmingham, AL
19Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
20Mario Lemieux Center for Blood Cancers, University of Pittsburgh School of Medicine, Pittsburgh, PA
21Lemieux Center For Blood Cancers, Pittsburgh, PA
2216Orlando Health Cancer Institute, Bone Marrow Transplant and Cellular Therapy, Orlando, FL
23Children's National Medical Center, Washington, DC
24Children's National Hospital and The George Washington University, Washington, DC
25Children’s National Hospital, Washington, DC
26The Sidney Kimmel Comp. Cancer Center At Johns Hopkins, Baltimore, MD
27Department of Paediatrics, St Mary’s Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
28Imperial College Healthcare NHS Trust, St Mary's Hospital, London, United Kingdom
29Department of Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic, Cleveland, OH
30Center for International Blood and Marrow Transplant Research, Milwaukee, WI
3121Department of Pediatrics, Division of Pediatric Neurology, Vanderbilt University Medical Center, Nashville, TN
32Section of Pediatric Hematology, Oncology and Bone Marrow Transplant, Yale School of Medicine, Atlanta, GA
3323Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, MD
34MDACC, Houston, TX
35Duke University Hospital, Durham, NC
36Washington University Medical Center, Saint Louis, MO
37Washington University, St. Louis, MO
38Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Vanderbilt University Medical Center, Nashville, TN
39Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
40Division of Hematology, Johns Hopkins Medicine, Baltimore, MD

Background: Allogeneic hematopoietic stem-cell transplantation has curative potential for sickle cell disease (SCD). Event-free survival (EFS) in children with SCD is >90% after a bone marrow transplant (BMT) from a myeloablative matched sibling donor (MSD). Unfortunately, <15% of patients with SCD have MSD, and myeloablative conditioning can be prohibitively toxic in adults with SCD. Reduced intensity HLA-haploidentical BMT with post-transplant cyclophosphamide (PTCy) has been shown in small studies to expand the donor pool with encouraging results. Still, concerns about graft failure and graft-versus-host disease (GVHD) persist. We present the results of a Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1507, multi-center single-arm, phase-II, prospective clinical trial (clinicaltrials.gov #NCT03263559) of haploidentical-BMT with PTCy to estimate EFS at 2-years in adults with severe SCD. Pediatric stratum data is not included in the data presentation and will be available in 2-years.

Study Design and Methods:

Eligibility: SCD patients aged 15.00-45.99 years with prior stroke, recurrent ACS or pain, chronic transfusion regimen, or tricuspid valve regurgitant jet velocity (TRJV) ≥2.7 m/sec were eligible. Participants were required to have an HLA-haploidentical first-degree relative donor, willing and able to donate bone marrow. The primary objective was EFS (survival without primary or secondary graft failure or second infusion of stem cells) at 2 years after haploidentical-BMT. Secondary objectives included determining the impact on clinical and laboratory manifestations of SCD and other transplant outcomes at 2 years post haploidentical-BMT. The protocol was opened for enrollment on 10/5/2017, completed accrual on 01/6/2021, and data are current as of 8/2023. Preconditioning with hydroxyurea (HU) 30mg/kg/day (Day-70 to Day-10); Conditioning regimen included Thymoglobulin (rATG), Thiotepa, Fludarabine, Cyclophosphamide, and Total Body Irradiation (TBI). GVHD prophylaxis included PTCy, sirolimus, and mycophenolate mofetil, figure.

Results: A total of 54 eligible participants enrolled from 19 sites; 42 (78%) proceeded to transplant. Amongst enrolled participants, 59.3% are male, 92.6% are Black, and 3.7% are Hispanic. 10 participants started HU but did not proceed to BMT, and 2 did not start HU or proceed to BMT. Reasons included donor issues (n=4), withdrawal of consent (n=2), insurance coverage (n=2), death (n=1), and other (n=3). 38/42 (90%) participants completed the study as planned; 2 participants withdrew consent, and 2 were lost to follow-up. The median age was 22.8 years at enrollment; 47/54 (87%) of enrolled participants had Hemoglobin SS disease, 40/54 (74.1%) had a Lansky/Karnofsky score of 90-100 at baseline, and 41/54 (75.9%) had an HLA match score of 4/8. Recurrent vaso-occlusive pain episodes (38.9%), acute chest syndrome (16.8%), and overt stroke (16.7%) were the most common indications for transplant. Only 13 (31%) participants achieved the intended 30 mg/kg/day dosing of HU preconditioning.

Estimated 2-year EFS is 88% (95% CI: 73.5%, 94.8%); all except one qualifying event occurred within 12 months. The 2-year overall survival (OS) post-HU was 93.0% (95% CI: 79.8%, 97.7%), and the 2-year OS post-transplant was 95.0% (95% CI: 81.5%, 98.7%); 2 (4.8%) participants had primary graft failure, and 1 (2.4%) had secondary graft failure before day +100. The cumulative incidence of grades II-IV acute GVHD at day 100 was 26.2% (95% CI: 14.0%, 40.2%), and grades III-IV acute GVHD at day 100 was 4.8% (95% CI: 0.9%, 14.4%). There were two deaths in the first year post-BMT (1 -organ failure; 1-ARDS), none in the second year; 33 (78.6%) participants reported at least one re-admission post-BMT, mainly due to either bacterial infection (n=41) or viral reactivation (n=36), table.

Conclusion: This multi-center phase-II trial of a reduced intensity haploidentical-BMT in adults with SCD shows durable donor engraftment at 2-years with low mortality. The 2-year EFS and OS are comparable to that reported after MSD myeloablative BMT. These results support haploidentical BMT with PTCy as a suitable and tolerable curative therapy for adults with SCD and severe end-organ toxicity such as stroke and pulmonary hypertension, a population typically excluded from participating in myeloablative gene therapy and gene editing trials.

Disclosures: Walters: AllCells, Inc: Consultancy, Other: Medical Director; BioChip Labs: Consultancy, Other: Medical Director; Vertex Pharmaceuticals: Consultancy; Ensoma, Inc: Consultancy. Solh: Bristol-Myers Squibb: Speakers Bureau. McKinney: Bluebird Bio: Other: Advisory Board; Horizon Therapeutics: Other: Advisory Board. Shaughnessy: Autolus Therapeutics, BMS: Honoraria; BMS, Sanofi: Speakers Bureau. Kanter: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; OptumRx: Consultancy; Beam: Consultancy, Honoraria; ECOR1: Consultancy; Fulcrum: Consultancy; Guidepoint Global: Consultancy; Watkins, Lourie, Roll&Chance: Consultancy; Bausch: Honoraria; Austin Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chiesi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Consultancy; GLG: Consultancy; Cowen: Consultancy. Bollard: Cabaletta Bio, Catamaran Bio: Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Patent applications in CAR-NKs; Roche: Consultancy. Cooke: Jazz Pharmaceuticals: Consultancy. Hanna: Sanofi: Speakers Bureau; SOBI: Speakers Bureau; Vertex: Honoraria; EDITAS: Research Funding. Mahadeo: Jazz: Honoraria, Research Funding. DeBaun: Novartis, Forma, Vertex: Consultancy, Other: Consulting. Brodsky: Alexion, AstraZeneca Rare Disease: Research Funding.