EFFICACY AND SAFETY OF CD22-DIRECTED CAR-T CELL THERAPY IN 15 PEDIATRIC REFRACTORY OR RELAPSED B ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS.
Author(s): ,
Jing Pan
Affiliations:
Department of Hematology,Beijing Boren Hospital,Beijing,China
,
Biping Deng
Affiliations:
Department of Immunotherapy,Beijing Boren Hospital,Beijing,China
,
Shuangyou Liu
Affiliations:
Department of Hematology,Beijing Boren Hospital,Beijing,China
,
Jingjing Wang
Affiliations:
Department of Hematology,Beijing Boren Hospital,Beijing,China
,
Tong Wu
Affiliations:
Department of bone marrow transplantation,Beijing Boren Hospital,Beijing,China
,
Zhiyong Gao
Affiliations:
Department of bone marrow transplantation,Beijing Boren Hospital,Beijing,China
,
Yuehui Lin
Affiliations:
Department of Hematology,Beijing Boren Hospital,Beijing,China
,
Yongqiang Zhao
Affiliations:
Department of bone marrow transplantation,Beijing Boren Hospital,Beijing,China
,
Yan Zhang
Affiliations:
Department of bone marrow transplantation,Beijing Boren Hospital,Beijing,China
,
Xiyou Tan
Affiliations:
Department of bone marrow transplantation,Beijing Boren Hospital,Beijing,China
,
Alex Hongsheng Chang
Affiliations:
Clinical Translational Research Center,Shanghai Pulmonary Hospital,Shanghai,China
Chunrong Tong
Affiliations:
Department of Hematology,Beijing Boren Hospital,Beijing,China
(Abstract release date: 05/17/18) EHA Library. Pan J. 06/16/18; 214537; S832
Dr. Jing Pan
Dr. Jing Pan
Contributions
Abstract

Abstract: S832

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 11:30 - 11:45

Location: Room A8

Background
Many patients with refractory or relapsed B cell acute lymphoblastic leukemia (rrB-ALL) have disease progressed again in one year after initial successful CD19-directed chimeric antigen receptors T (19-CAR-T) cell therapy. Most of them are probably refractory to secondary 19-CAR-T therapy. The relapse rate in rrB-ALL is still high even after allogeneic hematopoietic stem cell transplantation (allo-HCT). Therefore, new modalities are needed.

Aims
The efficacy and safety of a novel CD22-directed CAR-T (22-CAR-T) cell therapy in pediatric patients with rrB-ALL were evaluated. 

Methods
Between July 6, 2017 and January 8, 2018, consecutive 15 pediatric patients (pts) with rrB-ALL who received 22-CAR-T cell therapy were enrolled in Beijing Boren Hospital. The median age was 8 (2-18) years old. The median disease course was 21 (5-84) months. 4/15 pts relapsed post- allo-HCT and 11/15 pts relapsed after chemotherapy. 14/15 pts received 19-CAR-T therapy before. One patient had weak CD19 expression on leukemia cells when relapsed. 11/15 pts had hematologic relapse with 42 (5-95.5) % blasts in bone marrow (BM), 2 pts remained minimal residual disease (MRD) positive by flow cytometry (FCM-MRD), and 2 pts developed extramedullary diseases (EMDs) only. All pts had CD22 expression on leukemia cells. A lentiviral vector was used to carry a second-generation CAR including anti-CD22 scFV derived from a humanized CD22 antibody, 4-1BB co-stimulatory and CD3z signaling domains. Manufacture of CAR-T cells from peripheral blood mononuclear cells commenced on day of leukapheresis and was completed in 7-8 days. The median doses of 22-CAR-T cells infused were 8.2 (0.5-34.7) × 105/kg in non-transplant pts, and 0.9 (0.7-5.0) × 105/kg in transplant pts. The 22-CAR-T cell expansion and cytokine releasing syndrome (CRS) were monitored after infusion. The efficacy in BM was evaluated on day 30, and EMDs were examined by imagine tests (ultrasonography, MRI and PET-CT) on day 30 as well. Long term follow-up was carried out and the outcome depended on several factors. 

Results
Peak expansion of CAR-T cells (3.2%—71.7% of CD3+ cells) was detected at day 11±1.8. On day 30, 13/15 (86.7%) pts had response. 10/11 hematologic relapsed pts achieved CR or CR with incomplete count recovery (CRi), and 9 of them became FCM-MRD negative. 1/2 FCM-MRD+ case turned to FCM-MRD-. 1/ 2 EMDs pts achieved CR, but the other patient had only partial response (PR) (mass size: from 10.0×5.3×5.9 cm to 6.2×2.3×3.1 cm). Both 2 pts with no response to 22-CAR-T therapy remained strong CD22 expression on leukemia cells. All pts experienced mild to moderate (grade 0-2) CRS only and 2 pts occurred grade 1 neurotoxicity. There was no significant difference in CRS between pts with and without allo-HCT (P =0.41). With a median follow-up time of 108 (46-199) days, 6 pts had been bridged to allo-HCT after 22-CAR-T cell therapy.11/12 CR/CRi pts achieved progression-free survival (PFS), and 1 of 12 CR/CRi pts had relapsed on day 50. The 6-month PFS rate was 91.7 (91.5-91.9) %. 

Conclusion

Our results indicate that CD22-directed CAR-T cell therapy is quite effective and safe for treating pediatric rrB-ALL, and could be valuable especially for those who have failed to previous 19-CAR-T therapy. Extended observation period will be required to determine the long-term outcome and whether subsequent allo-HCT could further reduce the relapse rate after CAR-T cell therapy.

Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): B cell acute lymphoblastic leukemia, Immune therapy, Pediatric

Abstract: S832

Type: Oral Presentation

Presentation during EHA23: On Saturday, June 16, 2018 from 11:30 - 11:45

Location: Room A8

Background
Many patients with refractory or relapsed B cell acute lymphoblastic leukemia (rrB-ALL) have disease progressed again in one year after initial successful CD19-directed chimeric antigen receptors T (19-CAR-T) cell therapy. Most of them are probably refractory to secondary 19-CAR-T therapy. The relapse rate in rrB-ALL is still high even after allogeneic hematopoietic stem cell transplantation (allo-HCT). Therefore, new modalities are needed.

Aims
The efficacy and safety of a novel CD22-directed CAR-T (22-CAR-T) cell therapy in pediatric patients with rrB-ALL were evaluated. 

Methods
Between July 6, 2017 and January 8, 2018, consecutive 15 pediatric patients (pts) with rrB-ALL who received 22-CAR-T cell therapy were enrolled in Beijing Boren Hospital. The median age was 8 (2-18) years old. The median disease course was 21 (5-84) months. 4/15 pts relapsed post- allo-HCT and 11/15 pts relapsed after chemotherapy. 14/15 pts received 19-CAR-T therapy before. One patient had weak CD19 expression on leukemia cells when relapsed. 11/15 pts had hematologic relapse with 42 (5-95.5) % blasts in bone marrow (BM), 2 pts remained minimal residual disease (MRD) positive by flow cytometry (FCM-MRD), and 2 pts developed extramedullary diseases (EMDs) only. All pts had CD22 expression on leukemia cells. A lentiviral vector was used to carry a second-generation CAR including anti-CD22 scFV derived from a humanized CD22 antibody, 4-1BB co-stimulatory and CD3z signaling domains. Manufacture of CAR-T cells from peripheral blood mononuclear cells commenced on day of leukapheresis and was completed in 7-8 days. The median doses of 22-CAR-T cells infused were 8.2 (0.5-34.7) × 105/kg in non-transplant pts, and 0.9 (0.7-5.0) × 105/kg in transplant pts. The 22-CAR-T cell expansion and cytokine releasing syndrome (CRS) were monitored after infusion. The efficacy in BM was evaluated on day 30, and EMDs were examined by imagine tests (ultrasonography, MRI and PET-CT) on day 30 as well. Long term follow-up was carried out and the outcome depended on several factors. 

Results
Peak expansion of CAR-T cells (3.2%—71.7% of CD3+ cells) was detected at day 11±1.8. On day 30, 13/15 (86.7%) pts had response. 10/11 hematologic relapsed pts achieved CR or CR with incomplete count recovery (CRi), and 9 of them became FCM-MRD negative. 1/2 FCM-MRD+ case turned to FCM-MRD-. 1/ 2 EMDs pts achieved CR, but the other patient had only partial response (PR) (mass size: from 10.0×5.3×5.9 cm to 6.2×2.3×3.1 cm). Both 2 pts with no response to 22-CAR-T therapy remained strong CD22 expression on leukemia cells. All pts experienced mild to moderate (grade 0-2) CRS only and 2 pts occurred grade 1 neurotoxicity. There was no significant difference in CRS between pts with and without allo-HCT (P =0.41). With a median follow-up time of 108 (46-199) days, 6 pts had been bridged to allo-HCT after 22-CAR-T cell therapy.11/12 CR/CRi pts achieved progression-free survival (PFS), and 1 of 12 CR/CRi pts had relapsed on day 50. The 6-month PFS rate was 91.7 (91.5-91.9) %. 

Conclusion

Our results indicate that CD22-directed CAR-T cell therapy is quite effective and safe for treating pediatric rrB-ALL, and could be valuable especially for those who have failed to previous 19-CAR-T therapy. Extended observation period will be required to determine the long-term outcome and whether subsequent allo-HCT could further reduce the relapse rate after CAR-T cell therapy.

Session topic: 26. Gene therapy, cellular immunotherapy and vaccination - Clinical

Keyword(s): B cell acute lymphoblastic leukemia, Immune therapy, Pediatric

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