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Abstract Background: Acute lymphoblastic leukemia (ALL) exhibits a bimodal age distribution with 60% of cases occurring in children and adolescents (45 y; Howlader SEER Cancer Statistics 2015). Most adults and 15-20% of children will relapse following initial therapy with subsequent poor outcomes. (Bassan, JCO 2012; Locatelli, Blood 2012). Promising results have been observed in studies of anti-CD19 CAR T cells in patients with B cell malignancies, including those treated with KTE-C19, a CD28/CD3ζ anti-CD19 CAR T cell studied in the multicenter ZUMA-1 trial (Neelapu ASCO 2016). However, studies of anti-CD19 CAR T cell therapy in R/R ALL have also observed high incidences of severe CRS in patients with high leukemic burden (Lee, Lancet 2015; Maude NEJM 2014). We present a preliminary analysis of the phase 1 portions of ZUMA-3 and ZUMA-4 which to date have enrolled adult and pediatric patients, respectively with high leukemic burden (M3 marrow). Methods: The primary objective of phase 1 of these multicenter trials is to evaluate the safety of KTE-C19. Eligible patients with R/R ALL are aged ≥18 y (ZUMA-3) or 2-21 y (ZUMA-4) with ≥25% marrow blasts, and adequate renal, hepatic, and cardiac function. Patients are required to have an Eastern Cooperative Oncology Group performance score 0-1 (ZUMA-3) or a Lansky or Karnofsky performance status of >80% (ZUMA-4). Patients with Ph+ ALL and low-burden central nervous system disease are eligible. Patients with Burkitt lymphoma or chronic myeloid leukemia in blast crisis, extramedullary disease only, active graft-versus-host disease, or clinically significant infection are not eligible. KTE-C19 is administered at a target dose of either 1 or 2 × 106 anti-CD19 CAR T cells/kg after low-dose conditioning with fludarabine (25 mg/m2/day for 3 days) and cyclophosphamide (900 mg/m2/day CyFlu; Wayne ASCO 2016; Shah ESMO 2016). Results: As of July 8, 2016, 6 patients have enrolled and 5 patients (3 adult and 2 pediatric) have been treated with KTE-C19. KTE-C19 was successfully manufactured in a centralized, streamlined 6-8-day process for 5 patients with approximately a 2-week turnaround time from the time of apheresis to delivery of KTE-C19 to site for patient infusion (Choi, ASGCT 2016). In one 2-year-old patient with peripheral white blood cells >150,000/μL and >99% leukemic blasts in the apheresis collection, KTE-C19 could not be manufactured. All 5 treated patients had high burden disease with a median 85% of marrow blasts (range, 48%-100%) at screening. All 5 patients received bridging chemotherapy prior to dosing with KTE-C19. No patient experienced a dose-limiting toxicity. Cytokine release syndrome (CRS) was reported in all adult (grade 1, n=1; grade 2, n=2) and pediatric (grade 2, n=2) patients; neurotoxicity (NT) was reported in adults only (grade 3, n=2; grade 4, n=1). CRS and NT were successfully managed to resolution with either tocilizumab, corticosteroids, and/or siltuximab in addition to other supportive care for all 5 patients. MRD- remission has been observed in all 5 patients who received KTE-C19 by day 28, with some remissions occurring as early as day 7. Four of 5 patients have had a CR/CR with partial hematologic recovery to date, and 1 of 5 patients with MRD- remission was showing recovering counts. CAR T cells expanded in blood within 2 weeks after infusion and were also detected in bone marrow and/or cerebrospinal fluid. Additional patients and clinical and correlative biomarker data will be presented. Conclusions: The administered dose of KTE-C19 after low-dose CyFlu conditioning has been tolerable and to date appears safe for further analysis in adult and pediatric patients with high leukemic burden R/R ALL. Initial results demonstrate promising efficacy, and the central manufacturing process is deemed feasible. The phase 1 portions of ZUMA-3 and ZUMA-4 are ongoing with planned expansion to phase 2. Clinical trial information: NCT02614066 (ZUMA-3); NCT02625480 (ZUMA-4). Disclosures Shah: Pfizer: Consultancy, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Plexus Communications: Honoraria; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Honoraria, Speakers Bureau. Lee:Juno: Honoraria. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Schiller:Incyte Corporation: Research Funding. Gökbuget:Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Sabatino:Kite: Employment, Equity Ownership. Bot:Kite Pharma: Employment, Equity Ownership. Rossi:Kite Pharma: Employment, Equity Ownership. Jiang:Kite Pharma: Employment, Equity Ownership. Navale:Kite Pharma: Employment, Equity Ownership. Stout:Kite Pharma: Employment, Equity Ownership. Aycock:Kite Pharma: Employment, Equity Ownership. Wiezorek:Kite Pharma: Employment, Equity Ownership. Jain:Kite Pharma: Employment, Equity Ownership. Wayne:Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Kite Pharma: Honoraria, Other: Travel support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.
Shah et al. (Fri,) studied this question.