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

Introduction: Related reduced-intensity HLA-Haploidentical bone marrow transplant (haplo-BMT) expands the donor pool to approximately 90% of children and adults with sickle cell disease (SCD). In 2013, we developed the multi-institutional Vanderbilt Global Haploidentical Learning Collaborative to optimize haplo-BMT for SCD. In a Phase II clinical trial, we developed a protocol focused on improving engraftment rates by augmenting the original Hopkins haplo-BMT approach (Bolaños-Meade et al. Blood 2012) with thiotepa. We initially demonstrated 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 the results of our phase-II trial (ClinicalTrials.gov identifier NCT01850108).

Material and methods: The trial opened in October 2013, and each site has a standalone Institutional Review Board-approved protocol with institutional-specific eligibility criteria and a data-sharing agreement with Vanderbilt University Medical Center. A DSMB assessed the aggregate results for participant safety and clinical trial futility. Collaborators met via videoconferencing initially weekly and then bi-weekly to discuss best practices. The common conditioning regimen included: thymoglobulin 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m², cyclophosphamide 29 mg/kg and TBI 2Gy. Graft-versus-host disease (GVHD) prophylaxis included post-transplant cyclophosphamide 100 mg/kg, mycophenolate mofetil, and sirolimus. Bone marrow was the donor source and was primed with filgrastim (5-10 μg/kg/d x5 days) in 11% (9/80) of haploidentical donors. Primary and secondary graft failure was defined as <5% donor myeloid/lymphoid whole blood chimerism at Day>28 and >Day+28 (after initial engraftment), respectively. Primary endpoints were 1-year and 2-year EFS. Primary or secondary graft failure and death were considered events. Safety stopping rules were implemented, independent of age, based on graft failure, death, grade III or IV acute GVHD, or moderate or severe chronic GVHD. Local treating physicians classified the severity of chronic GVHD.

Results: At the interim analysis of May 1, 2022, we report results from patients enrolled from 8/14/2014 - 2/28/2022. Final enrollment is a total of 80 participants from 7 sites, 45% were male. Donors were siblings (42.5%), parents (53.8%), daughters (2.5%) and cousins (1.3%); 83.8% (n=67) had sickle cell trait. Participants clinical and laboratory data are listed in table 1. Graft failure occurred in 12.5% (10/80) of the participants, with 4 primary and 6 secondary graft failures, table 2. All graft failures were in participants <18 years of age, and all had autologous reconstitution. For engrafted participants, the median whole blood chimerism values for D+180 and D+365 post-transplant was 100% (n=67; IQR: 99.8 - 100; Range 30.0 - 100) and 100% (n=50; IQR: 100 - 100; Range 95.0 - 100), respectively. Among engrafted participants, 97.7% (43/44) were off immunosuppression at D+365 post-transplant. The incidence of grades III-IV acute and moderate/severe chronic GVHD were 8.8% (7/80) each. The median follow-up time was 1.4 years, based on the time of graft failure, death, or May 1, 2022. Mortality was 5.0% (4/80), Table 2. A Kaplan-Meier analysis for survival found no difference by age group <18 years or >18 years of age (p=0.760). Kaplan-Meier based probability of overall survival was 96.7% (95% CI 87.1% - 99.2%) at one year and 94.3% (95% CI 83.0% - 98.2%) at two years. Results of the final analysis of primary and secondary endpoints (1- and 2-year EFS) will be submitted for publication after all participants have been followed for a minimum of one year (anticipated 2/23).

Conclusion: Our Vanderbilt Global Haploidentical learning collaborative is a successful and efficient approach to sharing best practices and implementing curative therapy for SCD. After 8 years, we have shown low mortality rate and 100% engraftment in adults using our haplo-BMT regimen. Three new research questions have emerged in the consortium: 1. What strategies can we develop to address the high graft failure in children? 2. How can we optimize supportive care practices and minimize severe infectious complications in adults? 3. What are the heart, lung, kidney, and other late-health effects after curative therapy?

de la Fuente:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. 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. Connelly:X4: Consultancy; Horizon: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. DeBaun:Novartis, GBT, Vertex, and Forma Pharmaceutical: Consultancy, Research Funding.