STOCKHOLM—Researchers have identified a “highly effective” transplant strategy for pediatric patients with primary immunodeficiencies who lack a suitable HLA-compatible donor, according to a speaker at the 23rd Congress of the European Hematology Association (EHA).
The strategy involves α/β T-cell- and B-cell-depleted haploidentical hematopoietic stem cell transplant (haplo-HSCT) followed by infusion of the T-cell product BPX-501.
Children treated with this strategy in a phase 1/2 trial had disease-free and overall survival rates that compared favorably with rates observed in recipients of matched, unrelated transplants.
In addition, the incidence of severe acute and chronic graft-versus-host disease (GHVD) was low in this trial.
Daria Pagliara, MD, PhD, of Ospedale Pediatrico Bambino Gesu in Rome, Italy, presented these results at the recent EHA Congress as abstract S871.
The research was sponsored by Bellicum Pharmaceuticals, Inc., the company developing BPX-501.
BPX-501 consists of genetically modified donor T cells incorporating the CaspaCIDe safety switch, which is designed to eliminate the T cells in the event of toxicity. Rimiducid is used to activate the CaspaCIDe safety switch, which consists of the CID-binding domain coupled to the signaling domain of caspase-9, an enzyme that is part of the apoptotic pathway.
Dr Pagliara explained that T cells are collected from donors via non-mobilized apheresis, the cells are modified to create the BPX-501 product, and the product is infused in HSCT recipients at day 14 after transplant (+/- 4 days).
The patients do not receive GVHD prophylaxis after transplant but are given rimiducid if they develop GVHD that does not respond to standard therapy.
Patients and transplant characteristics
Dr Pagliara reported results with BPX-501 in 59 patients. They had a median age of 1.85 years (range, 0.21 to 17.55), and 57.6% were male.
Patients had severe combined immune deficiency (32%), Wiskott–Aldrich syndrome (15%), chronic granulomatous disease (12%), hemophagocytic lymphohistiocytosis (10%), combined immunodeficiency disease (7%), major histocompatibility complex class II deficiency (5%), and “other” immunodeficiencies (19%).
The patients received BPX-501 after an α/β T-cell-depleted, B-cell-depleted haplo-HSCT. Most patients had a parent donor (94.9%), and 5.1% had a sibling donor. The median donor age was 34 (range, 21-52).
About half of patients (49.2%) received treosulfan-based conditioning, 39% received busulfan-based conditioning, and 11.9% received other conditioning.
The median CD34 dose was 22.0 x 106/kg, and the median α/β T-cell dose was 0.4 x 105/kg.
The median time to BPX-501 infusion was 15 days (range, 11-56). The median time to discharge was 40 days (range, 18-204).
The median follow-up was 536 days (range, 32-1252).
Engraftment and survival
The median time to neutrophil engraftment was 16 days, and the median time to platelet engraftment was 11 days.
Three patients had primary graft failure (5.1%), but 1 of these patients was successfully re-transplanted from the same donor.
The cumulative incidence of transplant-related mortality was 8.7%.
There were 5 cases of transplant-related mortality, which were due to graft failure/disseminated fungal infection, cytomegalovirus (CMV) encephalitis, worsening juvenile dermatomyositis/macrophage activation syndrome, bronchopulmonary hemorrhage, and CMV/adenovirus.
“I would like to underline that 3 of these 5 patients died of infectious complications that were present before the transplant—1 fungal invasive infection, 1 encephalitis due to CMV reactivation, and 1 pulmonary infection due to the presence of adenovirus and cytomegalovirus,” Dr Pagliara said.
The rate of disease-free survival and overall survival were both 87.6%.
GVHD and adverse events
Dr Pagliara said there were low rates of acute GVHD in the first 100 days.
The rate of grade 2-4 acute GVHD was 8.9%, and the rate of grade 3-4 acute GVHD was 1.8%. There were 4 cases of grade 2 GVHD—three stage 3 skin and one stage 1 upper gastrointestinal. There was a single case of grade 3 GVHD—stage 3 liver.
Of the 19 patients who developed acute GVHD, 7 received at least 1 dose of rimiducid. These patients had visceral involvement or GVHD that was not responsive to standard care.
Four patients had a complete response to rimiducid, and 1 had a partial response. One patient did not respond, and 1 was not evaluable. The non-evaluable patient was on corticosteroids and cyclosporine with controlled GVHD but was unable to be weaned off corticosteroids. Rimiducid was given in an attempt to wean the patient off corticosteroids.
“Most importantly, only 1 patient out of 59 developed chronic GVHD, with only mild involvement of the skin,” Dr Pagliara said. This patient did not receive rimiducid.
Nine patients (15.2%) had at least 1 adverse event (AE).
AEs occurring after BPX-501 administration were grade 1 or 2 in nature. They included diarrhea, vomiting, pyrexia, CMV viremia, rhinovirus infection, hypokalemia, pruritus, and rash.
There were no severe AEs attributed to BPX-501.