Gene Therapy for Sickle Cell Disease Is Associated with a Decreased Transplant Length of Stay and Similar Rates of Short-Term Complications Compared to Allogeneic Matched Sibling Stem Cell Transplant: A Single Center Experience

Background: Myeloablative allogeneic hematopoietic cell transplant (alloHCT) with a matched sibling donor (MSD) remains the standard curative treatment approach for young patients with sickle cell disease (SCD). However, adolescent and young adult patients undergoing MSD alloHCT or patients undergoing alterative donor alloHCT experience increased transplant related morbidity/mortality and increased risk for chronic graft-versus-host disease (GVHD). With the 2023 FDA approval of two gene therapy (GT) products for patients ≥12y with a history of vaso-occlusive events (VOEs), patients for whom alloHCT could confer unacceptable risk may now be eligible for transformative therapies. Many of these patients will have known risk factors for transplant-related toxicities including older age, pulmonary disease and other co-morbidities. GT requires the administration of myeloablative busulfan (Bu), and the associated risk in the setting of autologous transplant has not been well described. Here, we report the acute toxicities and resource utilization during the initial transplant admission in a cohort of patients undergoing GT on a clinical trial and compare them to a contemporaneous cohort of MSD alloHCT patients from our institution over the past ten years.

Methods: We retrospectively reviewed all consecutive patients with SCD admitted at Boston Children's Hospital (BCH) for either autologous transplant on a GT clinical trial (NCT03282656) or MSD alloHCT from January 2014 to January 2024. Categorical variables were analyzed using Fisher's exact test and continuous variables were analyzed using a two-tailed unpaired t-test.

Results: Between January 2014-January 2024, 9 consecutive patients underwent GT (NCT03282656), and 12 consecutive patients underwent MSD alloHCT. Eligibility for GT was as stated in the trial, primarily VOEs and acute chest syndrome (ACS). The most common indications for alloHCT were recurrent VOEs and ACS. The median age at transplant was significantly higher in the GT (20.9y) compared to alloHCT (10.3y) cohort (p=0.0045), with the majority of GT patients (66.7%) >16y at time of transplant. Both cohorts had similar comorbidity index (CI) scores (CI score 3-6: 44.5% GT vs 33.3% alloHCT, p=0.67) and all patients in both cohorts had a performance status over 80% at time of transplant. All patients received a pharmacokinetic-adjusted Bu-based regimen; all but one (alloHCT) were myeloablative. All patients in GT cohort received autologous mobilized modified peripheral blood stem cells, while in the alloHCT cohort, 10 (83%) received bone marrow (BM) and 2 (17%) received a combination of BM and umbilical cord blood. GVHD prophylaxis for the alloHCT cohort was a combination of calcineurin inhibitor and short-course methotrexate.

The median follow-up was similar among both cohorts (4.5y GT vs 2.6y alloHCT cohort, p=0.67). There was a trend for shorter median length of hospitalization in the GT compared to alloHCT cohort (34d vs 39.5d, respectively, p=0.054). There was no difference between GT and alloHCT in the median day to neutrophil engraftment (20d vs 23d, p=0.24), platelet engraftment of ≥ 50K/µL (33d vs 30d, p=0.92), number of red blood cell transfusions (3 vs 3.5, p=0.18), number of platelet transfusions (7 vs 13.5, p=0.11), days of intravenous opiate use via patient-controlled analgesia (15d vs 13d, p=0.7) or parenteral nutrition (PN) requirement (44.4% in GT vs 8.3% in alloHCT cohort, p=0.12). No patient in either cohort developed veno-occlusive disease requiring defibrotide or peritoneal drain placement. There was 1 episode of bacteremia in each cohort. One patient in the GT cohort required transfer to the ICU for non-invasive positive pressure ventilation in the setting of a pneumonia. No patient in the GT cohort experienced treatment-related mortality, while 1 patient in the alloHCT cohort died of respiratory failure 1.4y following transplant. There were no cases of grade 3-4 acute GVHD.

Conclusion: Though the long-term efficacy of GT compared to alloHCT remains to be determined, we show that despite the known risk of older age at time of transplant (with most of the GT patients being > 16 years), patients undergoing GT had a similar length of admission and incidence of early post-transplant complications as that experienced by younger patients undergoing MSD alloHCT, the current standard of care when a donor is available.

Williams:Bluebird bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orchard Therapeutics: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees; Skyline Therapeutics (formerly Geneception): Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Verve Therapeutics: Consultancy; Tessera Therapeutics: Consultancy; ExcellThera: Research Funding; Vertex Pharmaceuticals: Consultancy.