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2286 Clinical Outcome and Immune Recovery after Adoptive Infusion of BPX-501 Cells (donor T cells transduced with iC9 suicide gene) in Children with Hemoglobinopathies and Diamond-Blackfan Anemia Given α/β T-Cell Depleted HLA-Haploidentical Stem Cell Transplantation (HSCT)

Clinical Allogeneic Transplantation: Results
Program: Oral and Poster Abstracts
Session: 732. Clinical Allogeneic Transplantation: Results: Poster I
Saturday, December 3, 2016, 5:30 PM-7:30 PM
Hall GH (San Diego Convention Center)

Alice Bertaina, MD, PhD1, Pietro Merli, MD1*, Daria Pagliara, MD1*, Giuseppina Li Pira, PhD1*, Biagio De Angelis, PhD1*, Letizia Pomponia Brescia, MD1*, Luisa Strocchio, MD1*, Francesca Del Bufalo, MD2*, Mauro Montanari, MD3*, Barbarella Lucarelli, MD1*, Mattia Algeri, MD1*, Martha French, PhD4*, Annemarie Moseley, MD, PhD4* and Franco Locatelli, MD1,5*

1Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy
2Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico bambino Gesù, Rome, Italy
3Department of Hematology, Ospedale Pediatrico Bambino Gesù, Rome, Italy
4Bellicum Pharmaceuticals, Houston, TX
5University of Pavia, Pavia, Italy


Background: Allogeneic HSCT from either an HLA-identical sibling or an unrelated donor is a potentially curative treatment for patients with hemoglobinopathies and erythroid disorders (ED), such as Thalassemia Major (TM), Sickle Cell Disease (SCD) and Diamond-Blackfan Anemia (DBA). The limited historical experience with HLA-haploidentical HSCT in this setting has reported a disease-free survival probability lower than that reported using HLA-matched donors. In the last few years, we have developed a novel method of graft manipulation, based on the selective depletion of α/β+ T-cells and CD19+ B-cells (ClinicalTrial.gov identifier: NCT01810120), which was shown to be safe and effective in children with multiple types of non-malignant disorders (Bertaina el al, Blood 2014). To further optimize this approach through the acceleration of the recovery of adaptive immunity, we designed an ongoing phase I/II trial aimed to test the safety and efficacy of post-transplant infusion of donor T-cells transduced with the iC9 suicide gene (BPX-501 cells) in children with either malignant or non-malignant disorders (ClinicalTrials.gov identifier: NCT02065869). As the transduced gene contains sequences for the CD19 marker, BPX-501 cells (CD3+/CD19+) can be easily tracked in peripheral blood. We report on 10 children with hemoglobinopathies and ED who were enrolled in the phase II portion of the study. 

Patients and methods: Five patients were males and 5 were females, and median age at diagnosis and at HSCT was 5.34 and 9.52 years (range 2.33-11.71), respectively. Seven patients had TM (all bo/bo), 2 DBA and 1 SCD. All 10 patients were transfusion-dependent and receiving iron-chelation therapy before haplo-HSCT. Among the thalassemia patients, 4 patients belonged to class I and 3 to class II of the Pesaro classification. All patients were transplanted from a parent. Median number of CD34+ and αβ+ T-cells infused was 22.5 x 106/kg and 0.3 x 105/kg, respectively. In all patients, conditioning regimen included busulfan (16 mg/Kg), thiotepa (10 mg/Kg) and fludarabine (160 mg/m2). Rabbit ATG (12 mg/Kg over 3 days, from day -4 to day -2) was administered to prevent graft-versus-host disease (GvHD) and graft failure and Rituximab (200 mg/ m2 on day -1) was administered to prevent EBV-related lymphoproliferative disorders. No post-transplantation GvHD prophylaxis was given.  Median follow-up is 301 days (range 41-420 days). Basic phenotyping of circulating lymphocytes was assessed by flow cytometry on fresh heparinized peripheral blood samples at 10, 20, 30, 60, 90, 120 and 150 days post haplo-HSCT.

Results: After haplo-HSCT, the median time to reach neutrophil and platelet recovery was 14 days (range 11-28) and 10 days (range 8-12), respectively. After engraftment of the allograft, BPX-501 cells were infused (dose: 1x106 cells/kg) at a median time of 13.5 days after HSCT (range 10-26). Nine of the 10 patients maintained sustained donor engraftment, reaching full chimerism. The patient who experienced secondary graft failure was successfully re-transplanted from the same parent and he is full donor chimeric with transfusion-independence. Grade I/II skin acute GvHD occurred in 2 patients (at 31 and 59 days after HSCT, respectively). There was no occurrence of chronic GVHD. Remarkably, no patient has died and none of the patients have been re-hospitalized after initial discharge. The last erythrocyte transfusion was administered on day +7 post-transplant (range 4-33 days). At last follow-up, the median hemoglobin value of these patients was 11.35 gr/dL (range 10.2-13.4). BPX-501 cells expanded after infusion and still persist in all patients at last follow-up. All children are alive and transfusion-independent. Details on T cell, NK cell and B cell recovery are shown in Figure 1 (Panel A-D).

Conclusions: Children with hemoglobinopathies and DBA can benefit from curative haplo-HSCT after depletion of α/β T-cells followed by infusion of BPX-501 cells, which, expanding and persisting over time, contribute to speed immune recovery of adaptive T-cell immunity, thus rendering the procedure safer.

Figure 1.


Disclosures: French: Bellicum Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees. Moseley: Bellicum Pharmaceuticals: Employment, Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH