Clinical outcome and immune recovery aft er adopti ve ... · Bertaina A, Merli P, Pagliara D, Li...
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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). Bertaina et al (Blood, 2014) have previously shown that α/β TCR T cell depleted haplo-transplantation in children with multiple types of non-malignant disorders was feasible. An ongoing Phase I/ II trial evaluates the safety and efficacy of post-transplant infusion of donor T-cells transduced with the iC9 suicide gene (BPX-501 cells) in order to further optimize the recovery of adaptive immunity, (ClinicalTrials.gov identifier: NCT02065869). The iC9 gene contains sequence for the CD19 marker, so that the BPX-501 cells (CD3+/CD19+) can be easily tracked in peripheral blood. We report on 12 children with hemoglobinopathies, sickle cell disease and Diamond Blackfan Anemia treated at OPBG. Methods and Technology All patients were transplanted from a carrier parent. Median number of CD34+ and αβ+ T-cells infused was 22.5 x 10 6 /kg and 0.3 x 10 5 /kg, respectively. In all patients, conditioning regimen included i.v. busulfan (dose adjusted according to weight), thiotepa (10 mg/Kg) and fludarabine (160 mg/m 2 ). 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/m 2 on day -1) was administered to prevent EBV-related lymphoproliferative disorders. No post- transplantation pharmacological 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. Demographics Demographics ■ Five patients were males and 7 were females. ■ Median age at HSCT was 7.9 years (range 2.5-11.9). ■ 2 patients had DBA and 1 had SCD. ■ All 9 TM patients were β0/β0. ■ All 12 patients were transfusion-dependent and receiving iron-chelation therapy before haplo-HSCT. BPX-501 Technology ■ GMP BPX-501 T cells are derived from non-mobilized donor leukapheresis and are expanded, transduced and selected for the iC9 gene, cryopreserved and shipped back to the clinical site. Haplo-Transplant Outcome ■ 11/12 patients maintained full donor chimerism. The patient with secondary graft failure was re-transplanted from the same donor, attaining full donor chimerism. ■ No TRM – all patients alive and well. ■ Initial discharge at median of 21 days (14-55) and there were no re- hospitalizations. ■ Grade I/II skin acute GvHD occurred in 2 patients (31 & 59 days after HSCT, respectively, which was successfully treated with steroids) and no chronic GVHD occurred. Hematopoietic Recovery ■ Median time to neutrophil recovery was 14 days (range 11-32 days). ■ Median time to platelet recovery was 11 days (range 9-12 days). ■ Median time to last RBC transfusion was 6.5 days (4 – 33 days). Hemoglobin Levels Immune Reconstitution ■ Median time of infusion of 1x10 6 BPX-501 T cells/kg was 14 days after HSCT (range 10-26). ■ BPX-501 cells expanded after infusion and still persist in all patients. ■ Immune reconstitution with normal cellular and humoral immunity at 180 days. Conclusions Children with hemoglobinopathies, sickle cell disease 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 the overall immune reconstitution and transplant outcomes. Clinical outcome and immune recovery aſter adopve 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-haploidencal stem cell transplantaon (HSCT) Bertaina A, Merli P, Pagliara D, Li Pira G, De Angelis B, Brescia LP, Strocchio L, Del Bufalo F, Montanari M, Lucarelli B, Algeri M, Moseley A, Locatelli F. 1250 Time from HSCT (days) cells/mcl 1000 750 500 250 0 30 90 180 270 360 30 90 180 270 360 30 90 180 270 360 CD3+ 1000 Time from HSCT (days) 500 -250 CD3+ Subsets 50 Time from HSCT (days) cells/mcl 20 -10 CD3+ CD19+ CD4+ CD8+ cells/mcl 40 30 0 10 750 0 250 IgA Ig Level (mg/dL) 0 200 400 600 800 IgG IgM IgA IgG IgM IgA IgG IgM 35 35 35 500 500 500 6 Month 9 Month 12 Month Time Point Median HgB (g/dL) Range At Discharge 9.1 (7.0 - 11.4) 100 days 10.5 (9.8 - 13.9) 180 days 11 (10.1 - 13.4) Bertaina A, Merli P, Pagliara D, Li Pira G, De Angelis B, Brescia LP, Strocchio L, Del Bufalo F, Montanari M, Lucarelli B, Algeri M, Locatelli F. (Ospedale Pediatricio Bambino Gesu) There are no relevant conflicts of interest to disclose. Moseley A –Bellicum Pharmaceucals All patients who have reached 6 month follow-up remain transfusion free with median hemoglobin of 11 g/dL (range 10-13). Patient 016 Patient 032 Patient 047 Patient 061 Patient 025 Patient 034 Patient 051 Patient 066 Patient 026 Patient 036 Patient 058 16 Time from HSCT (days) g/dL 14 10 8 4 10 30 60 90 100 12 6 0 2 180 270 360 Patient 075 Subject Age (Yrs) Diagnosis 016 11 THALASSEMIA MAJOR 025 10 THALASSEMIA MAJOR 026 10 THALASSEMIA MAJOR 032 3 SICKLE CELL DISEASE 034 3 THALASSEMIA MAJOR 036 9 DIAMOND BLACKFAN ANEMIA 047 8 THALASSEMIA MAJOR 051 5 THALASSEMIA MAJOR 058 9 THALASSEMIA MAJOR 061 4 DIAMOND BLACKFAN ANEMIA 066 2 THALASSEMIA MAJOR 075 5 THALASSEMIA MAJOR
Transcript of Clinical outcome and immune recovery aft er adopti ve ... · Bertaina A, Merli P, Pagliara D, Li...
BackgroundAllogeneic 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). Bertaina et al (Blood, 2014) have previously shown that α/β TCR T cell depleted haplo-transplantation in children with multiple types of non-malignant disorders was feasible. An ongoing Phase I/II trial evaluates the safety and effi cacy of post-transplant infusion of donor T-cells transduced with the iC9 suicide gene (BPX-501 cells) in order to further optimize the recovery of adaptive immunity, (ClinicalTrials.gov identifi er: NCT02065869). The iC9 gene contains sequence for the CD19 marker, so that the BPX-501 cells (CD3+/CD19+) can be easily tracked in peripheral blood. We report on 12 children with hemoglobinopathies, sickle cell disease and Diamond Blackfan Anemia treated at OPBG.
Methods and TechnologyAll patients were transplanted from a carrier 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 i.v. busulfan (dose adjusted according to weight), thiotepa (10 mg/Kg) and fl udarabine (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 pharmacological GvHD prophylaxis was given. Median follow-up is 301 days (range 41-420 days). Basic phenotyping of circulating lymphocytes was assessed by fl ow cytometry on fresh heparinized peripheral blood samples at 10, 20, 30, 60, 90, 120 and 150 days post haplo-HSCT.
Demographics
Demographics■ Five patients were males and 7 were females.■ Median age at HSCT was 7.9 years (range 2.5-11.9). ■ 2 patients had DBA and 1 had SCD. ■ All 9 TM patients were β0/β0. ■ All 12 patients were transfusion-dependent and receiving iron-chelation
therapy before haplo-HSCT.
BPX-501 Technology■ GMP BPX-501 T cells are derived from non-mobilized donor leukapheresis and
are expanded, transduced and selected for the iC9 gene, cryopreserved and shipped back to the clinical site.
Haplo-Transplant Outcome■ 11/12 patients maintained full donor chimerism. The patient with secondary graft
failure was re-transplanted from the same donor, attaining full donor chimerism. ■ No TRM – all patients alive and well.■ Initial discharge at median of 21 days (14-55) and there were no re-
hospitalizations.■ Grade I/II skin acute GvHD occurred in 2 patients (31 & 59 days after HSCT,
respectively, which was successfully treated with steroids) and no chronic GVHD occurred.
Hematopoietic Recovery■ Median time to neutrophil recovery was 14 days (range 11-32 days). ■ Median time to platelet recovery was 11 days (range 9-12 days). ■ Median time to last RBC transfusion was 6.5 days (4 – 33 days).
Hemoglobin Levels
Immune Reconstitution■ Median time of infusion of 1x106 BPX-501 T cells/kg was 14 days after HSCT
(range 10-26). ■ BPX-501 cells expanded after infusion and still persist in all patients.■ Immune reconstitution with normal cellular and humoral immunity at
180 days.
ConclusionsChildren with hemoglobinopathies, sickle cell disease and DBA can benefi t 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 the overall immune reconstitution and transplant outcomes.
Clinical outcome and immune recovery aft er adopti ve 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-haploidenti cal stem cell transplantati on (HSCT)Bertaina A, Merli P, Pagliara D, Li Pira G, De Angelis B, Brescia LP, Strocchio L, Del Bufalo F, Montanari M, Lucarelli B, Algeri M, Moseley A, Locatelli F.
1250
Time from HSCT (days)
cell
s/m
cl
1000
750
500
250
030 90 180 270 360
30 90 180 270 360
30 90 180 270 360
CD3+
1000
Time from HSCT (days)
500
-250
CD3+ Subsets
50
Time from HSCT (days)
cell
s/m
cl
20
-10
CD3+ CD19+
CD4+CD8+
cell
s/m
cl
40
30
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750
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IgA
Ig Level (mg/dL)0 200 400 600 800
IgGIgMIgAIgGIgM
IgAIgGIgM
35
35
35
500
500
500
6 M
on
th9
Mo
nth
12 M
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th
Time Point Median HgB (g/dL) Range
At Discharge 9.1 (7.0 - 11.4)
100 days 10.5 (9.8 - 13.9)
180 days 11 (10.1 - 13.4)
Bertaina A, Merli P, Pagliara D, Li Pira G, De Angelis B, Brescia LP, Strocchio L, Del Bufalo F, Montanari M, Lucarelli B, Algeri M, Locatelli F. (Ospedale Pediatricio Bambino Gesu)There are no relevant confl icts of interest to disclose.Moseley A –Bellicum Pharmaceuti cals
All patients who have reached 6 month follow-up remain transfusion free with median hemoglobin of 11 g/dL (range 10-13).
Patient 016Patient 032Patient 047Patient 061Patient 025Patient 034Patient 051Patient 066Patient 026Patient 036Patient 058
16
Time from HSCT (days)
g/dL
14
10
8
4
10 30 60 90 100
12
6
0
2
180 270 360
Patient 075
Subject Age (Yrs) Diagnosis
016 11 THALASSEMIA MAJOR
025 10 THALASSEMIA MAJOR
026 10 THALASSEMIA MAJOR
032 3 SICKLE CELL DISEASE
034 3 THALASSEMIA MAJOR
036 9 DIAMOND BLACKFAN ANEMIA
047 8 THALASSEMIA MAJOR
051 5 THALASSEMIA MAJOR
058 9 THALASSEMIA MAJOR
061 4 DIAMOND BLACKFAN ANEMIA
066 2 THALASSEMIA MAJOR
075 5 THALASSEMIA MAJOR
