Safety and Efficacy of CD19 CAR T-Cells for Pediatric Relapsed Acute Lymphoblastic Leukemia with Active CNS Involvement

Abstract

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>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

Tisagenlecleucel outcomes in relapsed/refractory extramedullary ALL: a Pediatric Real World CAR Consortium Report

“…32 Smaller institutional studies have shown efficacy and tolerability for patients with CNS disease, and commercial use of tisagenlecleucel for these patients continues to expand. 24,26 The data presented here further supports feasibility of treating patients with CNS leukemia with tisagenlecleucel without excess CRS or neurotoxicity. These results are consistent with another report of adult patients with CNS lymphoma who received tisagenlecleucel without evidence of greater than grade 1 neurotoxicity.…”

“…13 Another report of 27 pediatric patients described a higher rate of neurotoxicity in patients with CNS disease prior to lymphodepletion, although this cohort included a combination of patients who received either a 41BB or CD28z based CAR construct. 24 However, a report on the infusion of 7 patients with tisagenlecleucel who had isolated EM disease (negative or BM disease of <1%) demonstrated no increased neurotoxicity and achievement of a complete response (CR) in all patients. 25 Patients receiving either CTL019 and CTL119 for relapsed CNS disease similarly show clearance of CNS disease without increased risk of neurotoxicity and similar survival rates compared to patients without CNS disease at infusion.…”

The Implementation of Chimeric Antigen Receptor (CAR) T-cell Therapy in Pediatric Patients: Where Did We Come From, Where Are We Now, and Where are We Going?

“…Fortunately, subsequent experience has not borne out this concern, and patients with CNS involvement do not appear to have markedly higher rates of neurotoxicity. [56][57][58][59] While the presence of CNS disease does not ipso facto indicate a higher risk of neurotoxicity, a relatively higher burden of it does appear to increase the risk of neurotoxicity, 57,59 and as such, strategies to reduce CNS disease burden are warranted in this population. Moreover, children with CNS disease (either with or without marrow involvement) have been found to have comparable long-term OS and EFS to children with marrow disease only, and are able to achieve remission at comparable rates .…”