Safety and Efficacy of CD19 CAR T-Cells for Pediatric Relapsed Acute Lymphoblastic Leukemia with Active CNS Involvement
Authors: Jacoby Elad , Ghorashian Sara , Vormoor Britta Julia , De Moerloose Barbara , Bodmer Nicole , Maschan Michael , Yanir Asaf David , Bielorai Bella , Rogosic Srdan , Molostova Olga , Rossig Claudia , Toren Amos , von Stackelberg Arend , Bourquin Jean-Pierre 
Published: November 2020

Background: CAR T cells targeting CD19 are approved for patients with relapsed or refractory acute lymphoblastic leukemia (ALL), failing two or more prior therapies. The central nervous system (CNS) is a known sanctuary site of ALL. Despite observations of CAR T-cells trafficking to the CNS in patients, most clinical trials excluded patients with active CNS leukemia, partially for concerns of neurotoxicity.
Methods: We conducted an international retrospective study of patients who were referred to CAR T-cell therapy for relapsed ALL with CNS involvement.
Results: We reviewed data of 27 patients (16 males and 11 females) from 8 centers who were treated with CD19 CAR T-cells for ALL relapse involving the CNS. Fifteen patients had a prior bone marrow transplantation, and in seven total body irradiation was given. Four additional patients received previous cranial radiation. At time of CAR T-cell order or clinical trial inclusion, ten patients had an isolated CNS relapse, and 17 had a combined CNS and marrow relapse. The median number of cells in the CSF of patients at enrollment was 65 (range 0-5670), and 16 of 21 patients who had imaging performed showed leukemia-associated changes in brain MRI.
All patients received bridging chemotherapy between enrolment and lymphodepletion, including intrathecal chemotherapy alone or in combination with systemic chemotherapy and/or radiation. At lymphodepletion, 15 patients had cleared CNS disease while 12 had active CNS blasts or imaging lesions.
Following lymphodepletion with fludarabine and cyclophosphamide, patients received 2nd-generation CAR T cells: 15 patients treated with a CD19-4-1BB CAR and 12 with a CD19-CD28 CAR. Cytokine release syndrome (CRS) occurred in 20 patients: 12 patients (100%) treated with CD19-CD28 CARs and 8 with CD19-4-1BB CARs (53%, p=0.006). Immune-effector cell neurotoxicity (ICANS) was diagnosed in 11 patients, 9 of 12 following CD28-based CARs, and 3 of 15 following 41BB-based CARs (p=0.004). Patients with active CNS-disease prior to lymphodepletion also had a higher rate of ICANS (75% vs 20%, p=0.004) but not of CRS. One patient died of grade 5 ICANS on day +7 following CD28-based CARs for an isolated CNS relapse.
Twenty-four of 26 evaluable patients (92%) had a complete remission following CAR T-cells. Nine patients were further referred to an allogeneic transplant, all following CD28-based CARs. Overall, six patients had relapsed - in four relapse involved bone marrow, and in two the CNS.
Conclusions: In this cohort of patients with active CNS disease treated with CD19 CAR T-cells, we report a high remission rate in previously heavily pre-treated patients. Toxicities are significant, and associated mostly with the costimulatory domain of the CAR (CD28&gt;41BB) and the presence of active CNS disease at lymphodepletion. This may be informative when designing future clinical studies of CAR T cell therapy for patients with CNS manifestations of ALL.

Disclosures
Jacoby: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lonza: Membership on an entity's Board of Directors or advisory committees. Ghorashian:Novartis: Honoraria; UCLB: Patents & Royalties; Amgen: Honoraria. De Moerloose:Novartis: Consultancy. Rossig:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. von Stackelberg:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, advisory committees and speakers bureau, Speakers Bureau. Bourquin:Servier: Other: Travel Support.

OffLabel Disclosure:
We describe the use of commercial and investigational CAR T-cell products