Clinical outcomes of Japanese patients treated with out-of-specification tisagenlecleucel in a phase 3b trial

The final manufactured tisagenlecleucel product should meet the commercial product release specifications to ensure the quality in terms of safety, purity, identity, and potency. However, it may occasionally fail to meet these specifications due to the nature of patient-derived cells with variable properties as starting material and the complex manufacturing process. The final product that does not meet at least one of the commercial release specifications is referred to as "out-of-specification" (OOS). However, the benefit-risk profile of OOS tisagenlecleucel has not yet been fully elucidated.

To evaluate the safety and efficacy of OOS tisagenlecleucel in Japanese patients with relapsed or refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and B-cell acute lymphoblastic leukemia (B-ALL).

This is a single-arm, open-label, multicenter phase 3b study (NCT04094311). Patients consistent with label indication were enrolled and followed-up for 3 months.

Of the 29 patients enrolled between December 2019 and May 2022 across 13 qualified sites in Japan, 28 received tisagenlecleucel, and of these, 23 had r/r DLBCL and 5 had r/r B-ALL. The primary reasons for OOS were low cell viability (15 of 24 batches) and low dose (8 of 23 batches) tisagenlecleucel in the r/r DLBCL group, and high dose (4 of 5 batches) in the r/r B-ALL group. In patients with r/r DLBCL, the grade 3 or 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome occurred in 3 and 1 patients, respectively. Response assessments were performed for 15 of 23 patients with r/r DLBCL: 6 achieved a complete response, and 1 achieved a partial response as the best response within 3 months.

Despite the limited patient sample size, our findings affirm that the infusion of OOS tisagenlecleucel is a viable option, with no observed increase in toxicity and outcomes comparable to those of in-specification products in clinical and real-world studies.