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The FDA has granted a priority review designation to tisagenlecleucel-T as a treamtnet for pediatric and young adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia, making it the first CAR T-cell therapy to enter regulatory review.
Stephan Grupp, MD, PhD
The FDA has granted a priority review designation to tisagenlecleucel-T (CTL019) as a treatment for pediatric and young adult patients with relapsed and refractory B-cell acute lymphoblastic leukemia (ALL), making it the first CAR T-cell therapy to enter regulatory review.
The biologics license application (BLA) for tisagenlecleucel-T is based primarily on findings from the global, phase II ELIANA study along with a multicenter trial conducted in the United States and a single institution trial. In findings presented at the 2016 ASH Annual Meeting for the first 50 patients enrolled in the ELIANA trial, the complete remission (CR) or CR with incomplete blood count recovery (CRi) rate was 82% with tisagenlecleucel-T, the 6-month overall survival rate was 89% (95% CI, 76-95), and the disease-free survival rate was 60%.
Under the priority review program, the FDA will decide on the BLA for tisagenlecleucel-T within 6 months compared with the standard 10-month review. The accelerated review timeline follows a breakthrough therapy designation from the FDA for tisagenlecleucel-T in ALL.
“Even if a patient has difficult-to-treat relapsed/refractory leukemia, we have seen treatment with CTL019 in clinical trials put cancer into remission,” ELIANA lead investigator Stephan Grupp, MD, PhD, director of the Cancer Immunotherapy Frontier Program and director of Translational Research for the Center for Childhood Cancer Research at CHOP, said in a statement. “This could be a first-of-its-kind treatment with exciting potential to help pediatric and young adult relapsed and refractory B-cell ALL patients.”
The ELIANA study enrolled patients at 25 centers in the United States, Europe, Asia, and Australia. At the time of the assessment, there were 81 participants in the study, of which 5 were awaiting infusion and 14 discontinued prior to infusion due to deaths (n = 5), manufacturing failures (n = 5), and adverse events (n = 3). The primary efficacy analysis was conducted after a median of 4.3 months of follow-up for the first 50 patients treated with tisagenlecleucel-T.
All patients received lymphodepleting chemotherapy prior to infusion of tisagenlecleucel-T. Fludarabine was administered at 30 mg/m2 daily for 4 doses and cyclophosphamide was given at 500 mg/m2 daily for 2 doses. The targeted dose of each tisagenlecleucel-T infusion was 2.0 to 5.0 x 106 kg for patients ≤50 kg and 1.0 to 2.5 x 108 for those >50 kg.
All doses of tisagenlecleucel-T were manufactured in the United States by Novartis, the company developing the autologous T-cell therapy in conjunction with the University of Pennsylvania. The longest wait time from enrollment to infusion was 41 days.
The median age of patients was 12 years (range, 3-23), and 55% were male. More than half (56%) had received a prior stem cell transplant, and the median number of prior lines of therapy was 3 (range, 1-8). Patients had primary refractory (10%), chemo refractory (11%), and relapsed ALL (79%).
The CR rate was 68% with tisagenlecleucel-T, and 14% of patients had a CRi. All patients with a CR/CRi also tested negative for minimal residual disease (95% CI, 69-91; P <.0001).
Forty-four patients continue to be followed in the study at the time of the assessment. Eighteen discontinued follow-up due to deaths (n = 6), relapse (n = 5), starting a new therapy while in CR (n = 5), and patient or guardian decision (n = 2). There were 2 deaths within 30 days of treatment (1 from ALL and 1 from cerebral hemorrhage). There were no deaths related to cytokine release syndrome (CRS) and no cases of cerebral edema were reported.
Seventy-nine percent of patients experienced CRS, of which 21% was grade 3 and 27% was grade 4. CRS occurred within 3 days of treatment (range, 1-22) and lasted for a median of 8 days (range, 1-36). Fifty-nine percent of patients with CRS were admitted to the intensive care unit for a median of 8 days (range, 1-34). To resolve CRS, patients required treatment with anti-cytokine therapy (51%), high dose vasopressors (33%), invasive ventilation (20%), and dialysis (12%).
Other AEs of interest included cytopenias that did not resolve by day 28 (all-grades, 37%; grade 3, 11%; grade 4, 19%), infections (all-grades, 40%; grade 3, 23%; grade 4, 3%), transient neuropsychiatric events (all-grades, 45%; grade 3, 15%; grade 4, 0%), and tumor lysis syndrome (all-grades, 5%; grade 3, 5%; grade 4, 0%).
“The past 5 years have seen tremendous progress in the development and application of cellular engineering in an effort to personalize the treatment of cancer,” Carl June, MD, director of the Center for Cellular Immunotherapies in the Perelman School of Medicine at the University of Pennsylvania, said in a statement. “We now know that it is possible to treat patients in clinical trials across the world using this approach, and the results we have observed mark a potential new paradigm in the treatment of blood cancers that have not responded to standard therapies.”
Novartis announced plans to also file for potential approval for tisagenlecleucel-T as a treatment for patients with relapsed/refractory diffuse large B-cell lymphoma. This application is anticipated later this year. Additionally, the company plans to submit applications in Europe.
“The priority review and file acceptance of CTL019 by the FDA brings us one step closer to delivering this novel treatment option to children and young adults with relapsed/refractory B-cell ALL in the United States,” Vas Narasimhan, global head of Drug Development and chief medical officer, Novartis, commented in a statement.
Grupp SA, Laetsch TW, Buechner J, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia. 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 221.
Most adverse events (AEs) occurred during the first 8 weeks of treatment. Seventy-one percent of patients experienced AEs with tisagenlecleucel-T within the first 8 weeks of treatment, of which 68% were suspected to be related to treatment. After 8 weeks, the serious AE rate dropped to 17%, of which 2% were related to tisagenlecleucel-T. The rate of treatment-related grade 3/4 AEs dropped from 74% to 10%, before and after the 8-week mark, respectively.