Tisa-cel CAR-T reinfusion lacks durability for younger patients with B-cell ALL
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A small percentage of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia who received a second infusion of tisagenlecleucel had clinically meaningful responses, data from a retrospective study showed.
Despite the drug appearing to be safe and well-tolerated, findings presented at Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR revealed only transient responses to repeat therapy with the CD19-directed chimeric antigen receptor T-cell therapy, including mostly nondurable remissions.
“We have shown that reinfusion with [tisagenlecleucel] is not a definitive therapy,” Christa Krupski, DO, MPH, professor in the department of pediatrics at University of Cincinnati and pediatric bone marrow transplant physician at Cincinnati Children's Hospital Medical Center, told Healio. “The remissions it produces are unlikely to be long lasting, so physicians who treat these patients will need to have something else in mind before moving forward.”
Background
Tisagenlecleucel (Kymriah, Novartis)— also known as tisa-cel — has historically produced initial complete responses among approximately 80% of younger patients with B-cell ALL, Krupski said.
Those who experience disease progression after CAR-T have few treatment options, one of which is a second tisa-cel infusion. Prognosis is poor after this treatment, with the limited data available showing response rates to reinfusion ranging from 28% to 52%, Krupski said during a presentation.
Additionally, previous research suggested that patients with a short duration of B-cell aplasia after CAR-T infusion are susceptible to disease relapse.
Typically, the manufacturer has enough cells and produces a second dose of the agent that is kept in reserve, but little data exist regarding the effectiveness of reinfusion for patients who relapse after CAR-T, Krupski said.
A few patients at Krupski’s center experienced loss of B-cell aplasia early after CAR-T infusion and received reinfusions with a second dose of tisa-cel.
“We were unable ... to get them back into remission, or even get them to a point of B-cell aplasia again,” she said, adding that her group was unsure if the poor results were attributable to the patients they treated or a lack of robustness with the overall approach of tisa-cel reinfusion.
“This is what sparked our interest, and we have used our membership in the Pediatric Real World CAR Consortium to harness data from many centers and get some meaningful results,” Krupski said.
Methodology
Krupski used the Pediatric Real World CAR Consortium — a group of 15 institutions that perform CAR-T for younger patients and collect data on patient outcomes — to collect data on 42 younger patients (median age at first CAR-T infusion, 12.5 years; range, 0-26) with B-cell ALL who received reinfusion of tisa-cel at one of 13 participating sites.
Twenty-four patients (57%) received tisa-cel infusion for B-cell aplasia loss while having an ongoing complete response during their first CAR-T infusion. Seventeen patients (41%) received reinfusion for having detectable disease at day 28 after infusion. The remaining patient received reinfusion for having no response to the first infusion.
Median time between tisa-cel infusions was 173 days (range, 52-521).
The complete response rate 28 days after tisa-cel reinfusion served as the study’s primary outcome measurement. Secondary outcome measurements included rates of reestablishing B-cell aplasia, OS and EFS after tisa-cel reinfusion.
Median follow-up was 496 days (range, 150-1,335).
Key findings
Researchers reported a 1-year OS rate of 84% after reinfusion with tisa-cel for the entire study group.
Reinfusion with tisa-cel conferred a 41% EFS rate at 1 year.
Treatment-related toxicities appeared manageable overall, according to investigators. Twenty-four percent of patients developed cytokine release syndrome, with only 2% of cases being grade 3 or higher.
Investigators reported limited neurotoxicity after tisa-cel reinfusion (overall incidence, 7%; grade 3 or higher, 2%).
Reinfusion served as definitive therapy requiring no further treatment for five of the 24 patients who received tisa-cel reinfusion for B-cell aplasia loss while in complete remission.
Eleven of 17 patients who received a second infusion for treatment of disease progression had detectable disease 28 days after treatment, compared with six patients reported as minimal residual disease (MRD)-negative 28 days after infusion. Four of the patients with MRD-negative disease eventually experienced disease relapse.
Clinical implications
The results confirm what Krupski and colleagues expected based on limited available data and their own experience: The use of tisa-cel reinfusion has limited effectiveness and should be given as a bridge toward another definitive therapy or with a strategy regarding next steps in mind.
This is especially true for patients who can tolerate hematopoietic stem cell transplantation, because delaying providing a second infusion of tisa-cel instead could “miss a window of opportunity to provide a curative option,” Krupski said.
“[Physicians] don’t want to falsely put our hope in something that is ultimately not going to be of benefit to the patient,” she told Healio.
Krupski said the study’s findings will change the way she approaches management of patients who have early relapse or loss of B-cell aplasia after tisa-cel infusion.
“The main takeaway is that if you're going to consider a second infusion ... then it should not be looked at as definitive therapy,” Krupski said. “It needs to be a bridge to something, and that something, in my opinion, is a transplant for definitive therapy.”
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Krupski C, et al. Abstract LBA4. Presented at: Tandem Meetings | Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, Feb. 15-19, 2023; Orlando.
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