UPDATED RESULTS FROM ZUMA-4: A PHASE1/2 STUDY OF KTE-C19 CHIMERIC ANTIGEN RECEPTOR (CAR) T CELL THERAPY IN PEDIATRICAND ADOLESCENT PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA
Author(s): ,
Daniel W. Lee
Affiliations:
Division of Pediatric Hematology/Oncology, Department of Pediatrics,University of Virginia,Charlottesville,United States
,
Alan S. Wayne
Affiliations:
Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood and Marrow Transplantation,Children's Hospital Los Angeles, USC-Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California,Los Angeles,United States
,
Van Huynh
Affiliations:
Division of Oncology, Blood and Marrow Program,CHOC Children's Hospital,Orange,United States
,
Rupert Handgretinger
Affiliations:
Department of Pediatric Hematology and Oncology, University Children's Hospital, Eberhard Karls University,Tuebingen,Germany
,
Patrick A. Brown
Affiliations:
Pediatric Leukemia Program, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine,Baltimore,United States
,
Rob Pieters
Affiliations:
Princess Maxima Center for Pediatric Oncology,Utrecht,Netherlands
,
Andrew C. Dietz
Affiliations:
Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood and Marrow Transplantation,Children's Hospital Los Angeles, USC-Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California,Los Angeles,United States
,
Michael A. Pulsipher
Affiliations:
Children's Center for Cancer and Blood Diseases, Division of Hematology, Oncology and Blood and Marrow Transplantation,Children's Hospital Los Angeles, USC-Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California,Los Angeles,United States
,
John Rossi
Affiliations:
Kite Pharma,Santa Monica,United States
,
Armen Mardiros
Affiliations:
Kite Pharma,Santa Monica,United States
,
Yizhou Jiang
Affiliations:
Kite Pharma,Santa Monica,United States
,
Lynn Navale
Affiliations:
Kite Pharma,Santa Monica,United States
,
Jeff Aycock
Affiliations:
Kite Pharma,Santa Monica,United States
,
Shanna Stout
Affiliations:
Kite Pharma,Santa Monica,United States
,
Jeff Wiezorek
Affiliations:
Kite Pharma,Santa Monica,United States
Rajul Jain
Affiliations:
Kite Pharma,Santa Monica,United States
(Abstract release date: May 18, 2017) EHA Learning Center. W. Lee D. May 18, 2017; 180616
Daniel W. Lee
Daniel W. Lee

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Abstract
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Abstract: E840

Type: Eposter Presentation

Background
Acute lymphoblastic leukemia (ALL) exhibits a bimodal age distribution with 60% of cases occurring in children and adolescents (<20 y) and 25% in older adults (>45 y; http://seer.cancer.gov/csr/1975_2013/) and is the most common childhood malignancy (Hematol Rep 2014;6:5554; Front Oncol 2014;4:63). ALL has an incidence of 1.2 to 1.4 per 100,000 per year in Europe (BMC Cancer 2015;15:771). As many as 20% of children relapse after initial therapy, with subsequent poor clinical outcomes (Front Oncol 2014;4:63). Promising results were observed with KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in B cell malignancies, including refractory, aggressive non-Hodgkin’s lymphoma in the ZUMA-1 trial (Blood 2016;128:LBA-6). Here, we present updated results from the phase 1 portion of ZUMA-4, a phase 1/2 trial of KTE-C19 in pediatric and adolescent patients with relapsed/refractory (R/R) ALL.

Aims
The aim of the phase 1 study is to evaluate the safety of KTE-C19 in pediatric and adolescent patients with R/R ALL.

Methods
Pediatric and adolescent patients (aged 2-21 y) with high burden R/R ALL (>25% marrow blasts), adequate renal, hepatic, pulmonary and cardiac function received 2 × 106 CAR T cells/kg after low-dose conditioning chemotherapy consisting of cyclophosphamide (900 mg/m2 once) and fludarabine (25 mg/m2/d for 3 days) (CyFlu). The primary endpoint of phase 1 is the incidence of dose-limiting toxicities. Secondary endpoints include efficacy outcomes and biomarker assessments.

Results
As of 19 Jan 2017, 5 patients have enrolled and 4 have been treated with KTE-C19 at 2 × 106 CAR T cells/kg. KTE-C19 was successfully manufactured in a centralized, streamlined 6–8-day process for all patients across a range of baseline absolute lymphocyte counts (0.21–1.0 × 109/L) except in 1 patient who had disease progression with white blood cells 150,000/µL at apheresis and <0.2% T cells in the apheresis collection. All 4 treated patients had high disease burden with a median marrow lymphoblast content of 57% (range, 41–99%). All 4 patients received bridging chemotherapy during the manufacturing period before conditioning chemotherapy and KTE-C19. No patient experienced a dose-limiting toxicity. One patient had a grade 5 adverse event of disseminated mucormycosis which was not related to KTE-C19. Cytokine release syndrome was reported in all 4 patients (all ≤ grade 3); neurologic events were reported in 1 patient (grade 3). All cytokine release syndrome events resolved with tocilizumab, corticosteroids, and/or siltuximab plus other supportive care with a median duration of 8.5 (range, 4–16) days. Minimal residual disease-negative remission was observed in all 4 patients. One patient received stem cell transplant post-remission, which is allowed per protocol at investigator discretion. Peak expansion of CAR T cells occurred 1-2 weeks post-KTE-C19 infusion. Updated data with additional patients, different dose of KTE-C19, earlier tocilizumb use, and biomarkers will be presented.

Conclusion
KTE-C19 after low-dose CyFlu has been tolerable and appears safe for further analysis in pediatric and adolescent patients with R/R ALL. No dose-limiting toxicities were observed with KTE-C19 at the 2 × 106 cells/kg dose in patients despite high leukemic burden. All patients receiving KTE-C19 achieved a minimal residual disease-negative remission. Based on these results, ZUMA-4 continues to enroll (NCT02625480).

Session topic: 2. Acute lymphoblastic leukemia - Clinical

Keyword(s): Immunotherapy, Cellular therapy, Antigen-specific T cells, Relapsed acute lymphoblastic leukemia

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