Higher CAR T-cell dose linked to improved outcomes for younger patients with leukemia
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Younger patients who received higher doses of tisagenlecleucel for advanced B-cell acute lymphoblastic leukemia achieved better outcomes, according to results of a retrospective study.
Patients who received cell doses at the higher end of the FDA-approved range survived longer and experienced no additional treatment-related toxicity, findings published in Blood Advances showed.
Background
Tisagenlecleucel (Kymriah, Novartis) — a CD19-directed chimeric antigen recptor T-cell therapy — is approved in the United States for patients aged 26 years or younger with relapsed or refractory B-cell ALL.
The FDA approved use of the single-dose therapy at a range of dose levels. These include 0.2 to 5 × 106 CAR T cells/kg body weight for patients who way 50 kg or less, and 0.1 to 2.5 × 108 CAR T cells/kg for patients who weigh more than 50 kg.
“CAR T-cell therapy is a living drug, with the expectation that CAR T cells expand in vivo following clinical infusion,” Liora Schultz, MD, pediatric oncologist at Stanford Children's Health | Lucile Packard Children's Hospital, told Healio.
“It was unclear what role the upfront dose played, [because] CAR T cells have the capacity to expand in the patient,” she added. “This motivated a formal study of the role of CAR T cell dose on post-CAR outcomes and survival.”
Methodology
Schultz and colleagues used retrospective data from the Pediatric Real World CAR Consortium (PRWCC), a group of 15 institutions that perform CAR-T for younger recipients and collect data on patient outcomes.
The analysis included 180 patients who underwent apheresis for the manufacturing of commercial tisagenleculeucel for relapsed or refractory B-cell ALL at one of the PRWCC institutions between Aug. 30, 2017, and March 6, 2020.
The researchers divided the cohort into dose level quartiles to determine the effect of cell dose on treatment outcomes. The groups included:
Median dose of CAR T cells was 1.7 × 106 CAR T cells/kg.
Efficacy outcomes — including OS, PFS and EFS — served as the study’s primary endpoints. Researchers also assessed treatment-related toxicity and safety.
Key findings
Researchers reported significantly longer OS (P = .031), EFS (P = .0079) and RFS (P = .0045) among patients who received higher doses of tisagenlecleucel.
The magnitude of dose effect on OS increased with higher dose levels (dose level 2 vs. dose level 1, HR = 0.68;95% CI, 0.33-0.1.38; dose level 4 vs. dose level 1, HR = 0.26; 95% CI, 0.1-0.69).
Univariate analysis showed those who received dose level 4 achieved longer EFS than those in dose level 1 (HR = 0.33; 95% CI, 0.17-0.65].
Safety results showed no association between higher CAR T-cell dose levels and increased treatment related cytokine release syndrome, neurotoxicity, or grade 3 or higher adverse events.
Clinical implications
Schultz said that clinicians sometimes face the decision of whether to give multiple infusion bags when the original manufacturing results in prepared treatments that are on the lower end of the approved dosing range. The results of her group’s study should leave clinicians more confident about providing a second bag of cells to achieve an overall higher cell dose.
“When clinically available, this study’s [results] support the use of higher CAR T-cell dosing, within the approved dose range,” she told Healio. “This study demonstrated that higher dosing … was associated with improved survival, without statistically significant increases in key CAR-related toxicities."
References:
- American Society of Hematology. Higher doses of CAR-T therapy bring survival advantage for young patients with hard-to-treat B-ALL (press release). Available at: https://www.hematology.org/newsroom/press-releases/2022/higher-doses-of-car-t-therapy-bring-survival-advantage.
- Stefanski H, et al. Blood Adv. 2022;doi:10.1182/bloodadvances.2022007246.
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