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4693 Early Donor T-Cell Engraftment Is Critical for Immune Tolerance in Reduced Intensity Haploidentical Bone Marrow Transplant with Post-Transplant Cyclophosphamide for Sickle Cell Disease: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Sickle Cell Disease, Biological therapies, Clinical Research, Hemoglobinopathies, Diseases, Therapies, Adverse Events, Transplantation
Monday, December 12, 2022, 6:00 PM-8:00 PM

Jim A. Connelly, MD1, Eden Biltibo, MD, MS1, Karina Wilkerson, MSN, NP2,3*, Adriana Seber, MD, MS4, Roseane V Gouveia5*, Carmem Bonfim, MD, PhD6*, Belinda Pinto Simões, MD, PhD7*, Erfan Nur, MD, PhD8, Biljana N. Horn, MD9, Michael Eckrich, MD, MPH10, Rabi Hanna, MD11, Nathalie Dhedin, MD12*, Fahed Almhareb, MBBS, FACP13, Mahmoud Aljurf, MD13, Hemalatha G. Rangarajan, MD14, Katie S. Gatwood, PharmD15*, Lindsay Orton, PharmD1*, Carrie Lynn Kitko, MD16, Mohsen Alzahrani17*, Ali Debsan Alahmari, MBBS, MD, MNAMS18*, Josu De La Fuente, MD, PhD19* and Adetola A. Kassim, MBBS, MS20,21

1Vanderbilt University Medical Center, Nashville, TN
2Department of Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN
3Vanderbilt-Meharry Sickle Cell Disease Center of Excellence, Vanderbilt University School of Medicine, Nashville, TN
4Hospital Samaritano, Sao Paulo, SP, Brazil
5Hospital Sao Camilo Pompeia, Pediatric Oncology and Hematopoietic Cell Transplantation, São Paulo, Brazil
6Bone Marrow Transplantation unit, Federal University of Parana, Curitiba, PR, Brazil
7Center for Cell-Based Therapy, Hemotherapy Center of Ribeirão Preto, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
8Department of Clinical Hematology, Slotervaart Hospital, Amsterdam, Netherlands
9Department of Pediatrics, University of Florida, Gainesville, FL
10Levine Children's Hospital At Carolinas Medical Center, Charlotte, NC
11Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Cleveland Clinic Foundation, Cleveland, OH
12St-Louis Hospital, APHP, Adolescents and Young Adults Hematology Department, Paris, France
13Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
14Division of Hematology, Oncology, Blood and Marrow Transplant, Nationwide Childrens Hospital, Columbus, OH
15Department of Pharmacy, Vanderbilt University Medical Center, Nashville, TN
16Division of Pediatric Hematology/Oncology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN
17Division of Adult Hematology and SCT, Department of Oncology, King Abdulaziz Medical City, Riyadh, Saudi Arabia
18King Faisal Hospital & Research Ctr., Riyadh, SAU
19Department of Paediatrics, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
20Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN
21Vanderbilt-Meharry Center of Excellence in Sickle Cell Disease, Nashville, TN

Introduction: Global application of bone marrow transplant (BMT) for sickle cell disease (SCD) requires a protocol that addresses the core limitations of this approach - namely donor availability, graft-versus-host disease (GVHD) and engraftment. To meet these demands, we developed the Vanderbilt Haploidentical Learning Collaborative across 10 countries and 22 sites with a common related HLA-haploidentical (haploBMT) reduced intensity platform. Our phase II trial (ClinicalTrials.gov identifier NCT01850108) was successfully employed with a probability of overall survival of 96.7% (95% CI 87.1- 99.2%) at one year, but a high rate of graft failure (GF) in pediatric patients (<18 years), prompting us to perform an in-depth analysis of engraftment kinetics.

Methods: Seven Institutional Review Board approved sites enrolled patients undergoing a haploBMT for SCD from 8/14/2014-2/28/2022. Common conditioning included: thymoglobulin 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included post-transplant cyclophosphamide 100 mg/kg, mycophenolate mofetil, and sirolimus (de la Fuente et al. BBMT 2019). Hydroxyurea and hypertransfusion to lower the percentage hemoglobin S <30% for at least 60 days pre-conditioning was variably employed. Primary GF was defined as <5% donor myeloid/lymphoid or whole blood (WB) chimerism at one-month (M1) post-haploBMT. Secondary GF was defined <5% donor myeloid/lymphoid or WB chimerism with prior documentation of >5% donor cells at M1. Categorical variables were compared using Fisher’s exact test. Continuous variables were compared using Wilcoxon rank sum test.

Results: A total of 41 pediatric and 39 adult subjects were enrolled for data analysis. GF was only noted in the pediatric cohort with 4 (10%) and 6 (15%) developing primary and secondary GF, respectively. Primary GF was associated with lack of a hypertransfusion pre-conditioning (0% vs 54%) and CMV reactivation (75% vs 21%) compared to engrafted patients.

For secondary GF, we evaluated the mechanisms of prolonged tolerance including early donor T-cell engraftment. Although our data was limited by only 28% (n=22) having lymphocyte subsets at M1, pediatric patients had lower T-cell counts (median 45.0 cells/µL, IQR: 6.50-118) compared to adults (median 723 cells/µL, IQR 618-1325) (Figure). Older recipient age and positive recipient CMV status were the only variables significantly associated with both CD4+ plus CD8+ count >100 cells/µL and donor CD3+ chimerism >90% (Table). Pediatric T-cell engraftment matched adult values at later time points except in patients with secondary GF and improvement in T-cell counts above 500 cells/µL at M2 was associated with a higher TNC dose (median 4.57x108 cells/µL, IQR 2.86-5.75 vs 1.74x108 cells/µL, IQR 1.55-2.24).

We next evaluated the impact of low donor T-cell engraftment at M1. Patients with low donor T-cell engraftment had significantly higher rates of immune-mediated complications including secondary GF (CD3+ chimerism ­<90%: 42.9% vs 0%, p=0.001) and chronic GVHD (CD4+ plus CD8+ <100 cells/µL: 63.6% vs 9.1%, p=0.024). Incidence of viral reactivation was not different between cohorts. Disease and GVHD-free survival positively trended with donor T-cell engraftment (Table), and patients with both CD4+ plus CD8+ count <100 cells/µL and donor CD3+ chimerism <90% at M1 had severe immune-mediated complications, implicating an association of inadequate immune control with poor early donor T-cell engraftment.

Conclusions: This analysis illustrates the importance of early T-cell engraftment in developing bi-directional immune tolerance following haploBMT. Although our study identified recipient age and CMV status as important factors in T-cell engraftment, the mechanism behind these factors, such as age-associated differences in drug metabolism and the role of CMV in promoting donor T-cell expansion, and how donor T cells promote tolerance require additional investigation. Our study demonstrates the importance of monitoring T-cell counts and sorted chimerism early post haploBMT and raises the question of how best to intervene in patients with low donor T-cell engraftment at M1. Our consortium plans to prospectively evaluate immune tolerance, including regulatory T-cell dynamics and impact of immune interventions at M1, to answer these important questions.

Disclosures: Connelly: X4: Consultancy, Current Employment; Horizon: Consultancy, Ended employment in the past 24 months; Sobi: Consultancy, Ended employment in the past 24 months. Nur: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gatwood: Jazz Pharmaceuticals: Speakers Bureau; Kite Pharma: Speakers Bureau; sanofi: Speakers Bureau; AstraZeneca: Research Funding. Kitko: Horizon Therapeutics: Consultancy.

*signifies non-member of ASH