Using Risk Factors to Guide CAR T Approach Before, After Infusion in B-ALL

Researchers of a new paper are offering their approach to management of younger patients with B-cell acute lymphoblastic leukemia (B-ALL) receiving chimeric antigen receptor (CAR) T-cell therapy.

The paper, published in Blood, focuses on the case of a young patient with relapsed B-ALL, following the 10-year remission mark for the first child treated with CD19-targeted CAR T-cell therapy, adding promise to the notion that the technology can provide long-term durable remissions in patients who are highly refractory to chemotherapy.

“While CD19 CAR T cells have transformed treatment of pediatric relapsed/refractory (R/R) B-ALL, applying risk factors associated with success or failure of this therapy to optimize outcomes is a crucial next step. Although we use a single case to illustrate these important considerations, unique populations (eg, infants, those with early CNS [central nervous system] relapse, etc.) warrant unique considerations,” wrote the researchers.

They outlined limitations with the 2 currently approved CAR T-cell therapies for R/R B-ALL—tisagenlecleucel (Kymriah) and brexucabtagene autoleucel (Tacartus)—that younger patients face, including the absence of data comparing long-term outcomes for the 2 treatments and their insufficiency in patients who have relapsed less than 36 months after diagnosis or have a late first relapse and are positive for minimal residual disease after reinduction therapy. Notably, event-free-survival was 25% at 24 months among patients with high-risk first relapse in a recent phase 3 Children’s Oncology Group trial.

In their paper, the researchers followed the case of a 19-year-old male patient who relapsed 6 months after completing treatment for B-ALL. Following relapse, the patient received reinduction therapy and subsequent blinatumomab treatment but had persistent CD19-positive disease.

Recent data from an analysis of over 400 patients from multiple pediatric centers found that no response to blinatumomab was associated with lower complete response (CR) rates of CD19 CAR T-cell therapy, suggesting that being refractory to the immunotherapy could help identify patients with inherent resistance to CD19-targeting, T-cell dysfunction, or other high-risk factors. However, the researchers noted that the data should not be used as a contraindication to CAR T-cell therapy, as the majority of patients refractory to blinatumomab do achieve CRs with the treatment approach.

Without head-to-head data comparing long-term outcomes for the 2 approved treatments in younger patients, CAR T-cell treatment for the patient was made based on treatment preferences, which included a desire to avoid allogeneic hematopoietic stem cell transplantation (HSCT).

“While tisgenlecleucel has established persistence and demonstrated the potential for durable remission without HSCT, the shorter persistence of CD28-containing CD19 CAR T-cell

constructs (brexucabtagene autoleucel and its predecessor axicabtagene autoleucel) and poor long-term survival without consolidative HSCT are critical considerations,” wrote the researchers. “We recommend consolidative HSCT for those in remission after receiving a CD28 CAR T-cell construct, particularly in HSCT-naïve patients. Thus, for families wishing to avoid or who are ineligible for HSCT, tisagenlecleucel would be preferable.”

Prior to CAR T-cell infusion, bone marrow disease burden was 30%, which the researchers recognized as a risk factor for toxicity and worse long-term relapse-free survival. While there is a lack of agreement on what is deemed “high-disease burden,” the researchers cited a report of 185 patients that showed patients with over 5% bone marrow blasts had significantly inferior 12-month event-free survival (31% vs 70%) and overall survival rates (70% vs 85%) compared with patients with low-disease burden. The data suggest a subset of patients who may not achieve long-term remissions with CAR T-cell treatment and who may be considered for post–CAR T-cell consolidative HSCT.

Reference

Myers R, Shah N, Pulsipher M. How we use risk factors for success or failure of CD19 CAR T-cells to guide management of children/AYA with B-cell ALL. Blood. Published online November 24, 2022. doi:10.1182/blood.2022016937