Second Tisa-cel Infusion Demonstrates Short MRD-Negative Responses in Pediatric B-ALL


Tisagenlecleucel reinfusion shows promise as as an effective bridge to hematopoietic stem cell transplantation in pediatric B-cell acute lymphoblastic leukemia.

Christa Krupski, DO, MPH

Christa Krupski, DO, MPH

In a retrospective analysis, reinfusion of tisagenlecleucel (tisa-cel; Kymriah) led to short durations of minimal residual disease (MRD)–negative responses in children and young adults with B-cell acute lymphoblastic leukemia (B-ALL), according findings presented at the 2023 Transplantation & Cellular Therapy Meetings.1

In total, 18 patients reinfused because of B-cell aplasia loss while in remission from first tisa-cel infusion (n = 24) had MRD negativity and 6 had detectable disease 28 days after reinfusion. In those reinfused for disease treatment (n = 17), 6 had MRD negativity and 11 had detectable disease at day 28.

“For the majority of patients, our data indicate that if second infusion is used, a plan for definitive therapy, such as stem cell transplant, should be made early, as response and remissions were not durable,” said Christa Krupski, DO, MPH, of the University of Cincinnati in Ohio, in a presentation of the data.

Treatment options are limited for children and young adults with B-ALL who do not respond to or relapse after first CAR T-cell infusion. Previously, a retrospective analysis investigated the efficacy of CAR T-cell therapy reinfusion in children and young adults with B-ALL who participated in 1 of 3 phase 1 clinical trials (NCT01593696, NCT02315612, and NCT03448393) between July 2012 and January 2021. This analysis revealed that 38.9% (n = 7) of patients who received reinfusion because of persistent or relapsed antigen-positive disease following their first infusion responded to reinfusion, 5 of whom achieved MRD negativity.2

Krupski presented findings from a retrospective review of tisa-cel reinfusion in pediatric B-ALL that included patients from 13 Pediatric Real World CAR Consortium sites who all received 2 tisa-cel infusions. Patients received second infusions from the time of tisa-cel commercialization, with a data cutoff of November 2021.1

The primary end point of this study was day 28 complete remission rate after tisa-cel reinfusion. Secondary end points included B-cell aplasia reestablishment rates, as well as overall survival (OS) and event-free survival (EFS) after reinfusion. Exploratory analyses evaluated tisa-cel reinfusion–associated toxicities and the feasibility of tisa-cel reinfusion as an effective bridge to hematopoietic stem cell transplantation (HSCT).

This study included 42 patients initially diagnosed with B-ALL. Patients had a median age of 8 years (range, 0-25) at diagnosis and a median age of 12.5 years (range, 0-26) at their first tisa-cel infusion.

This population was heavily pretreated, as 33% (n = 14) of patients had experienced 2 prior relapses and 24% (n = 10) of patients had experienced 3 or more prior relapses. Additionally, 43% (n = 18), 9% (n = 4), and 19% (n = 8) had received 3, 4, and 5 or more therapies prior to their second tisa-cel infusion, respectively. In total, 83% (n = 35) of patients had not received prior HSCT. All 17% (n = 7) of patients who did undergo prior HSCT did so prior to their second tisa-cel infusion. Reinfusions occurred at a median of 173 days (range, 52-521) after first infusion.

In total, 81% (n = 34) of patients received the standard lymphodepleting chemotherapy regimen fludarabine and cyclophosphamide. Additionally, most patients received the same tisa-cel dose for both infusions, at 69% (n = 29) vs 19% (n = 8), 7% (n = 3), and 5% (n = 2) who received second doses that were higher, lower, or unknown relative to their first doses, respectively.

Overall, 41% and 57% of patients received second reinfusion for detectable disease or loss of B-cell aplasia while in ongoing remission, respectively. In addition, 1 patient received reinfusion because they did not respond to their first tisa-cel infusion; the investigators excluded this patient from subsequent analyses.

In all evaluable patients (n = 41), the 1-year OS rate after reinfusion was 84%. The 1-year EFS rate was 41%, with events including relapse and death.

Patients reinfused for B-cell aplasia loss while in remission were analyzed to determine whether reinfusion led to B-cell aplasia reestablishment and remission maintenance. At day 28, of the 18 patients in this subgroup with MRD negativity, 6 had reestablished B-cell aplasia. The median duration of B-cell aplasia in these patients was 67 days, and all lost B-cell aplasia by 3 months. Four of these patients relapsed and required multiple lines of salvage therapy, including transplant. “Reinfusion for loss of B-cell aplasia while in remission may be of more benefit in initial response vs reinfusion during active disease,” Krupski noted.

Of the 12 patients reinfused for B-cell aplasia loss who achieved MRD negativity at day 28 but did not reestablish B-cell aplasia, 6 received consolidation with HSCT, and 4 maintained remissions without additional therapy. Three of these 12 patients relapsed, including 1 who relapsed post-HSCT. Of these 12 patients, 1 each died of disease and HSCT complications. Overall, second reinfusion was definitive therapy for 5 of the 24 patients reinfused while in remission.

Of the 6 patients reinfused while in remission who did not achieve MRD negativity and instead had disease progression at day 28, 3 died, 2 from disease and 1 from HSCT complications.

Patients reinfused for disease treatment were analyzed to determine the role of reinfusion in reestablishing remission. Of these 17 patients, 6 achieved MRD negativity at day 28, of whom 5 relapsed. Four of those patients had early relapse at a median of 115 days and required multiple lines of salvage therapy, and 1 patient relapsed after consolidative HSCT. Of the 6 patients in this group who achieved MRD negativity, 1 died of HSCT complications.

A total of 65% (n = 11) of patients reinfused for disease had detectable disease at day 28. After additional salvage attempts, 7 of these patients died, 5 from disease and 1 each from HSCT complications and infection.

The investigators also evaluated the role of tisa-cel as a bridge to transplant. In total, 71% (n = 29) of all studied patients underwent HSCT at any time after reinfusion. Of these patients, 52% (n = 15) were reinfused for disease, 9 of whom were alive at the last follow-up, and 48% (n = 14) were reinfused for B-cell aplasia loss, 11 of whom were alive at the last follow-up. These patients were transplanted for various indications, including consolidative transplant or transplant after relapse.

Of the 24 patients across both reinfusion indication groups who achieved reinfusion-induced MRD-negative remission, 9 received early HSCT, at a median of 64 days (range, 49-99) post-reinfusion. Of these patients, 2 relapsed post-transplant, and 2 died of transplant-related complications. At a median of 474 days (range, 385-686) post-reinfusion, 5 of the 9 patients were alive in remission and did not require additional therapy.

In addition, 15 patients in MRD-negative remission did not undergo HSCT, 10 of whom experienced early relapse at a median of 138 days (range, 79-641) post-reinfusion. “This group highlights a missed opportunity where patients could have gone to transplant in a window of remission,” Krupski said. At a median of 849 days (range, 284-1270) post-reinfusion, 5 of the 15 patients in MRD-negative remission were alive and did not require additional therapy.

Regarding reinfusion-associated toxicities, 24% of patients experienced any-grade cytokine release syndrome (CRS), and 2% of patients had grade 3 or higher CRS. Additionally, 7% of patients had any-grade neurotoxicity, and 2% of patients experienced grade 3 neurotoxicity. No reinfusion-related deaths occurred.

“Tisa-cel reinfusion is well tolerated. It may be a good option for some patients, such as those who cannot tolerate transplant or who have limited other therapeutic options,” Krupski concluded. “Based on these data, we recommend tisa-cel reinfusion be used as a bridge to transplant in patients who are eligible.”

1. Krupski C, Baggott C, John S, et al. Outcomes following tisagenlecleucel reinfusion in children and young adults with B-cell acute lymphocytic leukemia. Presented at: 2023 Transplantation & Cellular Therapy Meetings; February 15-19, 2023; Orlando, FL. Abstract LBA4.
2. Holland EM, Molina JC, Dede K, et al. Efficacy of second CAR-T (CART2) infusion limited by poor CART expansion and antigen modulation. J Immunother Cancer. 2022;10(5):e004483. doi:10.1136/jitc-2021-004483
Recent Videos
Related Content