What is the efficacy of chimeric antigen receptor (CAR) T-cell therapy in the treatment of acute lymphoblastic leukemia (ALL)?

Updated: Dec 17, 2020
  • Author: Sameh Gaballa, MD, MS; Chief Editor: Emmanuel C Besa, MD  more...
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ALL is the most common pediatric cancer, with approximately 3,100 cases diagnosed in children and adolescents younger than 20 years each year in the United States. Eighty to 85% of pediatric ALL cases originate in B-cells. [7]

Approximately 98% of children with ALL attain complete remission (CR) with standard treatment, and 85% of patients aged 1 to 18 years with newly diagnosed ALL treated with current regimens have long-term event-free survival. [7]  However, R/R ALL carries a poor prognosis: less than 25% of these patients achieve a CR with standard salvage chemotherapy, and responses typically last only 4-9 weeks. [5]

CD19 is uniformly expressed on B-cell precursor ALL cells, making it an attractive target for anti-CD19 CAR T cells. In 2011, researchers at Memorial Sloan Kettering Cancer Center first reported a case in which an adult patient with R/R ALL received anti-CD19 CAR T, and subsequently underwent allogeneic stem cell transplantation (ASCT) after being in remission for 8 weeks following the CAR T infusion. [3]  The same group later published their experience in 53 patients with heavily pre-treated R/R ALL who received autologous T cells modified to express 19-28z, a second-generation CAR specific to CD19. CR was achieved in 83% of patients, with overall survival of 13 months after a median follow-up of 29 months. [8]

Subsequently, in 2014, investigators from the University of Pennsylvania published early results with CTL019 (a CD-19–directed CAR T with a 41BB costimulatory molecule). A total of 30 pediatric and young adult patients (25 years old or younger) with R/R ALL received CTL019 and 90% of them achieved CR. Nineteen patients had sustained remissions beyond 2 to 3 months, suggesting continued function of the infused cells. [5]  Three patients in CR subsequently underwent ASCT. In the patients who did not undergo transplantation, event-free survival at median follow-up of 6 months was 67%. In patients with relapse who received salvage therapy, overall survival at 6 months was 78%. [5]  

Those excellent results led to an open-label, multi-center, global phase II trial (ELIANA), which enrolled pediatric and young adult patients with R/R ALL for treatment with tisagenlecleucel. Among 75 patients who received tisagenlecleucel, the overall response rate was 81% at 3 months, with 60% of patients achieving CR (all patients achieving CR were negative for minimum residual disease [MRD]) and event-free survival of 50% at 12 months. [9]  Median overall survival was not reached, and overall survival at 18 months was 70% in the updated results. [10]  On the basis of this study, in August 2017, the FDA approved tisagenlecleucel (Kymriah) for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. [11]

Currently, there is an unmet clinical need in patients with R/R ALL who are older than 25 years of age. CAR T clinical trials are ongoing in this age group. In the Zuma-3 phase I study, which evaluated KTE-X19 in adult patients with R/R ALL, the CR rate was 68% and all patients were MRD negative. The phase II portion of the study is ongoing. [12]  KTE-X19 is an anti-CD19 CAR T cell that has the same construct of axicabtagene ciloleucel, with a CD28 costimulatory domain. However, it is manufactured differently, by removing circulating CD19-expressing malignant cells from the initial pheresis product prior to the manufacturing process. The removal of these cells reduces manufacturing failures and possible activation and exhaustion of anti-CD19 CAR T cells during the ex vivo manufacturing process.

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