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3774 Chimeric Antigen Receptor 4SCAR19-Modified T Cells in Acute Lymphoid Leukemia: a Phase II Multi-Center Clinical Trial in ChinaClinically Relevant Abstract

Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation
Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemia: Therapy, excluding Transplantation: Poster III
Monday, December 7, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Lujia Dong, M.D.1,2, Lung-Ji Chang, PhD3,4, Zhiyong Gao, MD1*, Dao-Pei Lu, MD5, Jian-Ping Zhang, MD5*, Jing-Bo Wang, MD6*, Le-Ping Zhang, MD7*, Yu-Hong Chen, MD8*, Hu-Yong Zheng, MD9*, Ting Liu10, Ting Niu, MD, PhD10, He Huang, MD, PhD11, Rong Liu, MD12*, Heng-Xiang Wang, MD13*, Li Gao, MD14*, Tong-Hua Yang, MD15* and Xun Lai, MD15*

1BMT Center, Fu Dan University, Shanghai Dao-Pei Hospital, Shanghai, China
2America Yuva Biomed, Beijing, China
3Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, FL
4Shenzhen Genoimmune Medical Institute (GIMI), Shenzhen, China
5Ludaopei Hematology Oncology Center, Beijing, China
6Department of Hematology, Beijing Aerospace General Hospital, Beijing, China
7Department of Pediatric Hematology, Peking University, People’s Hospital, Beijing, China
8Institute of Hematology, BMT Center, Peking University, People’s Hospita, Beijing, China
9Hematology Oncology Center, Beijing Children’s Hospital, Capital Medical University, Beijing, China
10Department of Hematology, West China Hospital, Sichuan University, Chengdu, China
11Bone Marrow Transplantation Center, the First Affiliated Hospital of Zhejiang University, Hangzhou, China
12Department of Hematology, Capital Institute of Pediatrics, Beijing, China
13Department of Hematology, Air Force General Hospital, PLA, Beijing, China
14Departmen of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
15Department of Hematology, First People’s Hospital of Yunnan Province, Kunming, China

Background: Relapsed/refractory leukaemia is associated with poor prognosis. T cells genetically modified to express CD19-specific chimeric antigen receptor (CD19CAR) in patients  (pts) with chronic lymphoblastic leukemia (CLL) and acute lymphoblastic leukemia (ALL) have shown a remarkable ant-cancer activity. However, many questions remain related to the predictive indicators of long-term response and the management of cytokine release syndrome (CRS) after CAR-T cell  infusion. In this phase II  multi-center clinical trial,  we evaluated the safety and efficacy of a fourth generation, safety-improved CD19-CAR (4SCAR19) in B-ALL pts.

Patients and Methods:  Fifty evaluable B-ALL patients (pts), with demonstrated persistent disease following salvage chemotherapy  from 14 hospitals in China between July 2013 and June 2015 have been enrolled. The mean age is 14 (from 3 to 65) including 26 children and 24 adults. Leukemic genotypes include 16 Bcr-Abl (13 pT315I), 11 WT-1, 3 MLL-AF4, 3 E2A-PBX-1, 1 TEL/AML1, 1 IKZF1, 1 K-ras and the remaining 14 pts have undetectable genotype. Their disease characteristics include: 4 hypercritical acute leukemia, 10 extramedullary leukemia (7 CNSL, 3 multiple sites), with associated co-morbidity: 12 Aspergillus pneumonia, 4 cGVHD, 2 pleura /pericardial cavity effusion, 2 hepatitis B, 2 diabetes mellitus, 1 gastrointestinal hemorrhage, and 1 liver/spleen abscess. Twenty-one (42%) pts received allo-HSCT including 15 haplo-identical, 5 matched related donor (MRD) and 1 unrelated cord blood (URD-CB). These pts who relapsed after transplantation have received chemotherapy (chemo), combined with Tyrosine Kinase Inhibitors (TKIs, 10), donor leukocyte infusion (DLI, 19), or dendritic cells-cytokine induced killer cell (DC-CIK)/NK cell infusions (7). CAR-T cells were prepared from autologous (37), transplant donor (12) or non-transplant donor mother (1). T cells. Peripheral lymphocytes were collected from leukapheresis, and T cells were transduced with a 4th generation, safety-engineered, CD19scFv/CD28/CD137/CD27/CD3ζ-iCasp9 (4SCAR-19) lentivector.  Pre-CAR-T lymphodepleting chemotherapy includes individualized chemo in 17 pts, and the others received Fludarabine (Flu) + Cyclophosphamide (Cy)(FC), or either Flu or Cy regimen: (1) FC: Cy 250mg/m2/d x3d and Flu 30mg/m2/d x3d ,or (2) either Flu x3 days,  or (3) Cy x3 days, followed by CAR-T infusions at a dose of 2.13 (range from 0.42 - 5.9) x106 CAR-T cells per kg body weight per infusion. 

Results: For statistical analysis, 50 patients were divided into 2 cohorts: Cohort 1: B-ALL with morphological blast <50%, 35; and Cohort 2: Blast ≥50%, 15 pts before CAR-T  treatment. The end points are: 1. early response (1-3 mon. after CAR-T infusion), and 2. leukemia-free survival (LFS) and overall survival (OS). LFS is defined as survival without recurrent malignancy and MRD (-). Early response evaluation is summarized below:

B-ALL Pts.

BM Blast % 

Days reached the best response

Best response duration (day)

CR % (CR/PR/NR)

35

<50 

13~30

44~210

94.3% (33/0/2)

15

≥50

17~70

15~120

66.7% (10/1/5)

Toxicities: CRS occurred in most pts within the first 10 days of CAR-T cell infusion. 47/50 (94%) pts developed fever with elevated IL-2, IL-6, IL-10, and interferon gamma.  Eight (16%) pts required either 12.5 mg Etanercept or 8 mg/kg tocilizumab, and three pts were treated with both drugs. Four pts developed hypotension and fully recovered after receiving dopamine. Four pts were treated once by methylprednisolone (1 mg/kg/day). The median follow-up was 4 months(range from 3~24 month), with 16 pts followed up for more than 6 months. Clinical outcomes: 1. LFS: The 120 days LFS for pts in cohort 1 and cohort 2 were 86% (CI,80%~93%) and 44.4% (CI,  31%~58%, P=0.0030), respectively.  2. OS (10 month) probabilities for patients in cohort 1 and cohort 2 were 82% (73%~91%) and 36% (19%~52%) (P= 0.0029), respectively.  

Conclusion: Our results indicate the potential of rapid leukemia eradication kinetics of 4SCAR19 therapy in treating chemo-resistant B-ALL. This therapy dramatically improves the prognosis of B-ALL pts by either providing a bridging approach to allo-HSCT or a better remission induction with longer period of CR than the routine treatment. Moreover, pts with morphological blasts <50% have demonstrated significantly better outcomes than pts with blasts ≥50%.

Disclosures: Dong: America Yuva Biotech: Consultancy , Other: clinical consultation .

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