Fludarabine may improve outcomes in pediatric B-cell acute lymphoblastic leukemia
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Fludarabine exposure appeared associated with improved clinical outcomes among pediatric patients undergoing chimeric antigen receptor T-cell therapy for refractory or relapsed B-cell acute lymphoblastic leukemia, study results showed.
Linde Dekker, a PhD student at Princess Máxima Center for Pediatric Oncology in the Netherlands, presented the findings at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR.
Rationale and methods
“Fifteen percent of [patients with B-cell ALL] are primary refractory or relapse after initial treatment, but there are novel therapies for these patients,” Dekker said during her presentation. “In the past, these patients had limited treatment options. We now know that there is a 40% to 50% event-free survival rate after CD19 CAR T-cell therapy for B-cell ALL in children and young adults. However, 50% still relapse; therefore, there is room for improvement.”
Investigators assessed the effect of fludarabine exposure on clinical outcomes after CD19 CAR-T.
The analysis included 26 children and young adults (median age, 14.4 years; 57.6% male) with relapsed or refractory B-cell ALL undergoing treatment with tisagenlecleucel (Kymriah, Novartis).
Before CAR T-cell infusion, patients received fludarabine for 4 consecutive days at a daily dose of 30 mg/m² and cyclophosphamide for 2 consecutive days at a daily dose of 500 mg/m².
Leukemia-free survival served as the primary outcome. Secondary outcomes included CD19+ relapse and B-cell aplasia. Median follow-up was 389 days.
Key findings
Researchers reported a variable area under the curve (AUC) with fludarabine (range, 8.7 mg*h/L to 21.8 mg*h/L).
Investigators observed minimal event probability at a cumulative fludarabine exposure of 14 mg*h/L or greater, and they defined underexposure as AUC of less than 14 mg*h/L.
Patients in the underexposed group experienced shorter leukemia-free survival (P < .001), higher CD19+ relapse (P < .0001) and shorter duration of B-cell aplasia (P = .009).
Researchers observed no differences in baseline characteristics between the two groups.
Dekker noted study limitations, including the fact that the small number of patients did not allow for inclusion of potential covariates that may influence clinical outcomes.
Implications
“Optimal fludarabine exposure needs to be validated in a prospective cohort, and a dosing regimen needs to be improved,” Dekker said. “Outcome of CD19 CAR T-cell therapy might be improved by increasing the fludarabine dose in the lymphodepleting regimen.”
A prospective trial that includes children and young adults with B-cell ALL is underway, Dekker added.
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Dekker L, et al. Abstract 127. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR; April 23-26, 2022; Salt Lake City.
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