Efficient Trafficking of Chimeric Antigen Receptor (CAR)-Modified T Cells to CSF and Induction of Durable CNS Remissions in Children with CNS/Combined Relapsed/Refractory ALL

Background Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. This is especially true in children with multiple central nervous system (CNS)/combined relapses that have been through radiation and bone marrow transplant (BMT) with no curative options left. We previously reported complete remissions (CR) and prolonged persistence of engineered T cells in children with ALL treated with CTL019 (CD19 CAR T cells). We now report on outcomes of 12 children with prior CNS relapse, isolated or combined with bone marrow (BM) relapse, treated with CTL019. Objectives Establish the safety and efficacy of CTL019 for children with a history of CNS relapse of CD19+ ALL. In all patients, establish the frequency and magnitude of CTL019 trafficking to CNS. Design We identified ALL pts who had an isolated CNS or combined BM/CNS relapse as their indication for CTL019 therapy. CNS relapse was defined as CNS3 by lumbar puncture (≥ 5 WBC/uL with blasts present on cytospin), or brain/ocular involvement by imaging. Treatment for the CNS relapse prior to CTL019 was determined by the local treating physician. All pts had to be CNS1 (no blasts) or CNS2 ( Results Of 53 pts with CD19+ ALL infused with CTL019, 12 had a CNS3 status 1-12 months prior to infusion (median 4 months). Seven had an isolated CNS relapse and 5 were combined BM/CNS. Three pts with CNS involvement by LP also had ocular involvement and 2 had parenchymal changes on brain MRI. All 12 pts had prior CNS directed radiation and 11/12 had undergone a prior BMT. Patients ranged from a 2 nd to a 6 th relapse pre-CTL019: one 1 st , six 2 nd , three 3 rd and 2 with 4 + CNS relapses. One day prior to infusion, 4 pts (2 with prior CNS, 2 with no prior CNS ALL) had blasts detected in the CSF (CNS2a). All pts were CNS1 on day 28 post infusion, and none have recurred in the CNS. 47 pts (89%) had at least 1 CSF sample evaluated by PCR. 46/47 (98%) of the initial (D28) CSF samples showed high levels of gene marking indicating CTL019 cells, ranging from 1530 to 252,356 copies/ug genomic DNA. Persistence in the CSF was similar to that seen in peripheral blood and bone marrow. Of the 46 pts with CTL019 cells in the CSF, 42 (91%) had cells detected by PCR at their most recent CSF sampling. This included all patients (9/9 pts; 2177 to 15,727 copies by PCR) whose final CSF sample was obtained per protocol at month 12. 8/9 of these pts remain in remission. Encephalopathy, a known side effect of CTL019 therapy, was not increased in pts with a prior CNS relapse. Grade 2-3 encephalopathy was observed in 3/12 (25%) of pts with prior CNS relapse and 12/41 (29%) of non-CNS pts. Grade 2-4 seizure occurred in 4 pts (1 with history of CNS relapse as well as prior seizure). Eight of the 12 CNS pts (67%) remain in a continual CR 3 - 22 months post infusion (median 8 months). Four pts had recurrent BM disease and were CNS negative at subsequent relapse. The patient with the 6 th CNS relapse of Ph+ ALL remains in a CR 22 months post infusion. To date none of the 53 pts, regardless of site of prior relapse, has had a subsequent CNS relapse. Conclusion Single agent CTL019 immunotherapy can induce potent and durable responses in pts with CNS involvement of their relapsed/refractory ALL. Neurotoxicity does not appear to be enhanced in CNS pts, who tolerated therapy equally well. Due to this promising data, a cohort designed for patients who are CNS3 at time of infusion is now enrolling to further assess safety and efficacy in this setting. The unexpected trafficking and durable persistence of CAR T cells to CSF after intravenous infusion may enable treatment of other CNS malignancies. Disclosures Rheingold: Endo: Other: Husband9s employer, has equity interest; Novartis: Consultancy. Off Label Use: CTL019 is not yet FDA approved for therapy for ALL. Maude: Novartis: Consultancy, Research Funding. Aplenc: Sigma Tau: Consultancy. Lacey: Novartis: Research Funding. Levine: Novartis: Patents u0026 Royalties, Research Funding. Melenhorst: Novartis: Research Funding. Shaw: Novartis: Research Funding. Teachey: Novartis: Research Funding. June: University of Pennsylvania: Patents u0026 Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding. Grupp: Novartis: Consultancy, Research Funding.