Administration of BPX-501 Cells Following Αβ- T and B-Cell-Depleted HLA-Haploidentical HSCT in Children with Fanconi Anemia
Authors: Naik Swati , Baumeister Susanne H.C. , Aquino Victor , Ruggeri Annalisa , Pagliara Daria , Aldinger Melissa , Locatelli Franco 
Published: October 2019

Abstract
Background
Allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to rescue trilineage cytopenias and to prevent occurrence of myeloid malignancies in patients with Fanconi Anemia (FA). HLA-identical family donor HSCT is a recommended treatment strategy with an ≥80% cure rate, and outcomes of HSCT from unrelated donors have progressively improved over time. However, HLA-partially matched (haplo) HSCTs have been historically associated with inferior results. Innovative approaches of graft manipulation, such as selective depletion of αβ-T and B cells, have recently been reported to improve the outcomes of haplo-HSCT in children with non-malignant disorders, however obstacles remain, such as delayed recovery of adaptive immunity with a risk of life-threatening infections. Novel strategies aimed at accelerating immune reconstitution are warranted to optimize the outcomes of patients transplanted from a HLA-haploidentical family donor.
BPX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. The polyclonal nature of the BPX-501 provides broad virus and tumor-specific immunity, while the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid which induces dimerization and activation of iC9, inducing apoptosis of BPX-501.
Aims
To evaluate the safety and efficacy (acceleration of immune recovery and prevention of transplant-related mortality while maintaining low rates of acute and chronic GvHD) of BPX-501 administered after a αβ T and B-cell depleted haplo-HSCT in pediatric patients with FA.
Methods
This is a multicenter US (NCT03301168) and EU (NCT02065869), prospective trial utilizing αβ-T- and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified to express iC9 (BPX-501 T cells). BPX-501 cells were planned to be infused on day14±4 after the allograft per protocol. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy were eligible to receive ≥1 dose of dimerizing rimiducid activating iC9.
The efficacy-evaluable population (EEP) was defined as any patient with FA who received HSCT, BPX-501 infusion and had at least one follow-up assessment.
Results
At the time of clinical cut-off (June 30th, 2018), 14 patients met the EEP definition. Nine and 5 patients were transplanted in the EU and US, respectively. The median follow-up was 23.5 mos (0.75 - 42 mos). Key baseline and transplant characteristics are detailed in Table 1.
The median time for neutrophil and platelet engraftment was 14 (11-15) and 10 (8 - 11) days, respectively. One patient experienced primary graft failure (7.7% [95% CI: 0-22.2%]). Only one patient developed Grade I aGvHD (7.7% [95% CI: 0-22.2%]). Two patients developed cGvHD (19.2% [95% CI: 4-43.2%]), both cases being moderate. Rimiducid was not administered to any patient.
One patient died after transplantation due to brain hemorrhage 25 days post HSCT. The event was unrelated to BPX-501 (TRM 7.1% [95% CI: 0-20.6%]). No patients died of infectious complications. The probability of both overall survival (OS) and disease-free survival (DFS) was 92.9% (95% CI: 79.4-100%). The median time from last red blood cell (RBC) transfusion was 23.6 mos (0.2 - 41.9 mos).
CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 360 days, respectively. IgA and IgM levels achieved normal values by 30 and 180 days, respectively. The percentage of circulating and median absolute BPX-501 cells at Day 100 were 3.35% ± 2.94% (0 - 8.4%) and 29.09 ± 39.56 cells/ml (0 - 135 cells/ml), respectively.
Conclusion
These data indicate that the adoptive transfer of BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a novel and highly effective transplantation strategy for pediatric patients with FA. Further, despite the addition of BPX-501, low rates and severity of both acute and chronic GvHD was observed, a finding that could translate into significant long-term benefit, in terms of reduction of squamous cell carcinoma a well-known complication occurring in FA patients after HSCT.

Disclosures
Aldinger: Bellicum Pharmaceuticals, Inc.: Employment. Locatelli:Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.