Durable Responses With CAR T-Cell Retreatment in Young ALL Patients

A humanized anti-CD19 CAR T-cell therapy (huCART19) led to durable remissions in a majority of children and young adults with B-cell malignancies, including patients previously treated with CAR T-cell therapy, results of a pilot study showed.

The engineered therapy achieved responses in 40 of 41 patients with no prior exposure to CAR T-cell therapy and 21 of 33 patients with disease that had progressed on previous CAR T-cell treatment, reported Shannon L. Maude, MD, PhD, of Children’s Hospital of Philadelphia (CHOP), and co-authors. At 6 months, three fourths of CAR-naive patients and about half of the retreatment group remained in remission. The 1-year relapse-free survival rate was 84% for those with no prior treatment and 74% for those with prior CAR exposure.

As the researchers noted in the study online in the Journal of Clinical Oncology, analysis of B-cell recovery at 6 months suggested better response persistence with huCART19 as compared with a historical patient cohort treated with a murine antibody.

The toxicity profile was similar to that of other CD19-directed CAR T-cell therapies, the team reported.

“This trial included adolescents and young adults up to age 29 years,” Maude told MedPage Today via email. “Responses were seen in adolescents and young adults, but this study did not analyze subgroups by age. The responses and durable remissions seen in patients for whom prior CAR T-cell therapy had failed or not persisted are very encouraging, particularly for this population for which options are limited.”

The study addressed one of the key limitations of CAR T-cell therapy: The treatment has produced “unprecedented” responses in B-cell acute lymphoblastic leukemia (B-ALL), but relapse occurs in more than half of responding patients in some studies, Maude and co-authors noted. In many instances a short duration of CAR T-cell persistence contributes to relapse, emphasizing the need for strategies to improve persistence.

In an effort to overcome loss of persistence, the team developed a humanized CAR T-cell construct as opposed to the murine construct of tisagenlecleucel (Kymriah). The goal was to create an anti-CD19 antibody “more similar to a human protein with the hypothesis that this might decrease the risk of rejection and improve persistence,” the researchers explained.

The first-in-human trial of huCART19 in children and young adults with relapsed or refractory B-ALL or B-lymphoblastic lymphoma (B-LLy) included a total of 74 patients — two with B-LLy. Each patient received a single infusion of huCART19. The study’s primary outcomes were toxicity, response, and persistence of huCART19.

Cytokine release syndrome (CRS) occurred in 62 patients (84%), including eight who had grade 4 CRS. Neurologic toxicities occurred in 29 patients (39%), including grade 3/4 CRS in three patients (4%). All episodes of neurotoxicity fully resolved, the authors reported.

One month after infusion, 98% of the CAR-naive group (including all 39 with B-ALL) had objective responses, as did 64% of previously treated patients. The probability of losing huCART19 persistence at 6 months was 27% in the CAR-naive group and 48% in the retreatment group. Also at 6 months, the incidence of B-cell recovery was 15% and 58%, respectively, in the CAR-naive and -exposed patients.

After a median follow-up of 34.6 months, the 12- and 24-month relapse-free survival (RFS) rates were 84% and 74%, respectively, in patients with no prior exposure to CAR T-cell therapy. The retreatment cohort had a median follow-up of 21.2 months. Among the 21 patients who achieved complete response, the 12- and 24-month RFS rates were 74% and 58%.

Maude noted that huCART19 is currently being studied in a phase II trial at CHOP. “We and others are studying other CAR T-cell therapies in other pediatric malignancies — for example, AML [acute myeloid leukemia]. In addition to humanized CART19, we are exploring combination therapy with immune checkpoint blockade to improve persistence,” she said.