Leukapheresis and Tisagenlecleucel Manufacturing Outcomes in Patients Age <3 Years with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Tisagenlecleucel is approved for the treatment of relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) in patients up to age 25 years based on the results of a pivotal trial (ELIANA) in pediatric and young adult patients. However, that trial did not include patients age <3 years because of the challenges posed by leukapheresis of very young and low-weight patients. Data on leukapheresis material and manufacturing outcomes among patients age <3 years have been collected since the time of global regulatory approval. Here we report leukapheresis characteristics and manufacturing outcomes for tisagenlecleucel produced for patients age <3 years in US and non-US commercial settings. Qualified patients with r/r B-ALL were age <3 years at the time of request for commercial tisagenlecleucel, with manufacturing data starting after August 30, 2017 (date of first US Food and Drug Administration approval). Leukapheresis and manufacturing outcomes data were stratified by age and weight. CD3+ cell count and CD3+/total nucleated cell (TNC) percentages were obtained from the leukapheresis material; leukocyte subpopulations were obtained via quality control vials. Of the 146 tisagenlecleucel quality control batches analyzed for CD3+ cell count and CD3+/TNC%, 86 batches (84 patients) were from US sites and 60 batches were from non-US sites. The median patient age and weight were 1.2 years and 10.4 kg at US sites and 1.5 years and 10.5 kg at non-US sites. Globally, 137 of 146 batches (94%) were manufactured within specifications across 16 countries. Among tisagenlecleucel batches manufactured in the United States between 2017 and 2021, there was a trend toward increasing CD3+ counts, CD3+/TNC%, and manufactured dose of chimeric antigen receptor (CAR) T cells; there was no difference in median days of collection by patient age or weight. Globally, a trend toward 1 or more potential additional collection days was observed for patients weighing ≤10 kg. Leukapheresis and tisagenlecleucel manufacturing in pediatric patients with r/r B-ALL age <3 years, including infants (<1 year), and low weight are feasible. As global experience with leukapheresis and patient identification for CAR-T cell therapy increased over time, a corresponding improvement in tisagenlecleucel manufacturing success has been observed. Clinical outcome data for these patients are currently being explored.

Leukapheresis guidance and best practices for optimal chimeric antigen receptor T-cell manufacturing.

Chimeric antigen receptor (CAR) T-cell therapy is an individualized immunotherapy that genetically reprograms a patient's T cells to target and eliminate cancer cells. Tisagenlecleucel is a US Food and Drug Administration-approved CD19-directed CAR T-cell therapy for patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia and r/r diffuse large B-cell lymphoma. Manufacturing CAR T cells is an intricate process that begins with leukapheresis to obtain T cells from the patient's peripheral blood. An optimal leukapheresis product is essential to the success of CAR T-cell therapy; therefore, understanding factors that may affect the quality or T-cell content is imperative. CAR T-cell therapy requires detailed organization throughout the entire multistep process, including appropriate training of a multidisciplinary team in leukapheresis collection, cell processing, timing and coordination with manufacturing and administration to achieve suitable patient care. Consideration of logistical parameters, including leukapheresis timing, location and patient availability, when clinically evaluating the patient and the trajectory of their disease progression must be reflected in the overall collection strategy. Challenges of obtaining optimal leukapheresis product for CAR T-cell manufacturing include vascular access for smaller patients, achieving sufficient T-cell yield, eliminating contaminating cell types in the leukapheresis product, determining appropriate washout periods for medication and managing adverse events at collection. In this review, the authors provide recommendations on navigating CAR T-cell therapy and leukapheresis based on experience and data from tisagenlecleucel manufacturing in clinical trials and the real-world setting.