Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA-Haploidentical HSCT (haplo-HSCT) in Children with Malignant or Non-Malignant Disorders
Authors: Algeri Mattia , Merli Pietro , Qasim Waseem , Slatter Mary , Kuhn Melissa , Locatelli Franco 
Published: October 2019

Abstract
Background
Allogeneic hematopoietic stem cell transplantation (HSCT) is an established treatment for children with leukemia or life-threatening non-malignant disorders. Approximately 25% of patients have a HLA-matched sibling and ~50% have a suitable matched unrelated donor, leaving ~25% of patients who require an alternative donor. HLA-partially matched (haploidentical, haplo) donors represent a suitable alternative for these children; extensive T-cell depletion of the graft is largely employed to minimize the risk of graft-versus-host disease (GvHD).
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 CD3+ CD19+ T-cells following transplant. The polyclonal nature of the BPX-501 T cells 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.
Aims
To evaluate the safety and efficacy of BPX-501 T cells administered after a T-cell receptor αβ and B-cell-depleted haplo-HSCT in pediatric patients with malignant or non-malignant disorders. The primary endpoint is event-free survival at 180 days (events include TRM (or NRM for malignant patients), severe GVHD (acute Grade 2-4 organ or extensive chronic GVHD) and life-threatening infections (Grade 4).
Methods
This multicenter EU (NCT02065869), prospective trial utilizes αβ-T and B-cell-depleted haplo-HSCT followed by infusion of donor lymphocytes genetically modified with iC9 (BPX-501). BPX-501 cells were planned to be infused on day14±4 after the allograft. No post-transplant pharmacological GvHD prophylaxis was employed. Patients who develop GvHD resistant to conventional steroid therapy could receive ≥1 dose of dimerizing rimiducid activating iC9.
The efficacy evaluable population (EEP) was defined as any patient who received HSCT, BPX-501 infusion and at least one follow-up assessment.
Results
At the time of clinical cut-off (June 30, 2018) 166 patients met the EEP definition. All patients were from EU sites. Key baseline and transplant characteristics are shown in Table 1.
In patients who obtained sustained engraftment of donor cells, the median time for neutrophil and platelet engraftment was 16 (15-17) and 11 (11-12) days, respectively. No patients experienced graft failure. Thirty-one patients developed Grade I-IV aGvHD (18.7% [95% CI;12.8 - 24.7%]). Three patients developed Grade III-IV aGvHD (1.8% [95% CI; 5.2 - 14.1%]). Of 132 evaluable patients, 9 developed cGvHD (7.2% [95% CI; 2.6 - 11.7%]) with only 2 patients experiencing moderate - severe cGvHD (95% CI: 0.0 - 3.1). Rimiducid was administered to 11 patients. Ten patients had ≥ 1 response assessment following administration of rimiducid. The best overall response rate (CR/PR) was 100% with 9 patients (90%) achieving complete response.
At the time of clinical cut off, EFS at 180 days was 92.7% (95% CI: 88.7 - 96.7%). An interim analysis with approximately 100 patients from a concurrent Matched Unrelated Donor (MUD) HSCT comparator trial and previously published data is planned for the time of the congress.
At a median follow-up of 17.6 mos (1.5 - 43.7 mos) 5 patients experienced transplant related mortality (TRM) (3.3% [95% CI: 0.4 - 6.2%]). DFS was 89.4% (95% CI: 84.7 - 94.2%). Overall survival (OS) was 94.2% (95% CI: 90.5 - 97.9%).
CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by day 100. IgA and IgM levels achieved normal values by day 180. The percentage of circulating and median absolute BPX-501 T-cells at Day 100 were 9.06% ± 10.52% (0 - 54.9%) and 109.49 ± 213.99 cells/ml (0 - 1001 cells/ml), respectively.
Conclusion
Preliminary evaluation of the primary endpoint and additional time-dependent efficacy outcomes, shows that the adoptive transfer of BPX-501 T cells following αβ-T and B-cell depleted haplo-HSCT followed by infusion of BPX-501 represents a novel and highly effective transplantation strategy for pediatric patients with malignant or non-malignant disorders. Despite the addition of BPX-501, overall rates of GvHD were low with few cases of high-grade aGvHD or cGvHD. Rimiducid was shown to be an effective treatment for patients who developed steroid-refractory GvHD.

Disclosures
Qasim: Bellicum: Research Funding; Autolus: Equity Ownership; Servier: Research Funding; Orchard: Equity Ownership. Slatter:Medac: Other: Travel assistance. Locatelli:bluebird bio: Consultancy; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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.