CAR T-cell therapy may serve as bridge to transplantation for ALL
SALT LAKE CITY — Chimeric antigen receptor T-cell therapy may have a synergistic role with hematopoietic stem cell transplantation to improve leukemia-free survival without an increased risk for severe graft-versus-host disease among patients with acute lymphoblastic leukemia, according to study results presented at the BMT Tandem Meetings.
Although chimeric antigen receptor (CAR) T-cell therapy has shown great promise for hematologic malignancies, its responses are not durable for all patients, and antigen-negative escape has been increasingly recognized as a concern.
HSCT may be curative for patients with relapsed/refractory ALL, particularly for patients in minimal residual disease-negative remission.
Haneen Shalabi, DO, physician in the Pediatric Oncology Branch of the NCI/NIH, and colleagues previously demonstrated CAR T-cell therapy induced minimal residual disease-negative remission among patients, with high leukemia-free survival post-HSCT.
“This study differs from other research that has been presented, because we have a large proportion of patients who received CAR T therapy who went on to receive a consolidative stem cell transplant” Shalabi told HemOnc Today. “The data in this area are limited, so this is relevant and new information.”
In the current analysis, Shalabi and colleagues analyzed the depth of remission, CAR T-cell persistence and posttransplant toxicities to better understand the role of CAR T-cell therapy in the peri-HSCT setting.
The analysis included children and young adults with relapsed/refractory CD19-positive or CD22-positive ALL treated in a phase 1 trial of anti-CD19 CAR T-cell therapy (n = 55) or anti-CD22 CAR T-cell therapy (n = 36).
Fifty-four patients achieved a complete response. Forty-five of these patients — including 28 treated on anti-CD19 CAR T and 17 on anti-CD22 CAR T — achieved minimal residual disease negativity by flow cytometry, and 25 went on to receive a stem cell transplant.
Of the 20 patients who did not go on to transplant, 19 (95%) had prior HSCT, and 16 (80%) relapsed post-CAR T infusion.
Twenty-five patients went on to receive HSCT. Median time to HSCT was 57 days (range, 44-126) post-CAR T-cell therapy. This represented a first HSCT in 19 patients and a second HSCT or higher for six.
Using a competing-risk analysis that compared risk for relapse vs. risk for transplant-related mortality, 24-month cumulative incidence of post-HSCT relapse was 13.5% (95% CI, 3.2-32.1) among all patients who underwent HSCT and 11.3% (95% CI, 1.7-31.1) among patients undergoing their first HSCT.
All patients received transplants at their home institutions and preparative regimens and stem cell sources varied per institutional guidelines.
Ten patients (40%) developed acute GVHD, including 12% who had grade 3 to grade 4 GVHD, which is comparable to expected rates of GVHD post-HSCT.
Six patients died of transplant-related mortality, two of whom were undergoing a second HSCT. Researchers noted these rates also are comparable to historical controls.
Next-generation sequencing (NGS)-based minimal residual disease analysis was available for eight patients on the CD22 protocol. All eight patients were minimal residual disease negative by flow cytometry and, concurrently, NGS negativity occurred among six of eight patients. For the other two patients, NGS-based negativity was achieved over time.
Regarding CAR persistence, because 67% of patients who received the CD19 protocol did not have detectable CAR T at the time of the initiation of the preparative regimen, CAR persistence may not impact post-HSCT outcomes, and shorter-acting CARs may be preferred when HSCT is a readily available option, Shalabi said.
“All CARs are created differently,” she said. “With shorter-acting CAR T cells, the persistence is not there. In this high-risk patient population, some of whom have never achieved remission, taking them to transplant would be the optimal treatment after CAR T.”
Although researchers detected no CAR T cells in the posttransplant bone marrow of patients with minimal residual disease-negative response who went on to myeloablative transplant, “that’s not the point,” study author Daniel W. Lee, MD, director of pediatric stem cell transplantation and assistant professor of pediatric hematology oncology at University of Virginia Children’s Hospital, told HemOnc Today.
Relapse without a post-CAR T transplant occurs either because of antigen escape — in as many as 50% of patients receiving CAR T cells in some series, meaning persistence of CAR T cells pre- or posttransplant may not matter — or the CAR T cells don’t persist, Lee added.
“Researchers have suggested CAR T-cell persistence or B-cell aplasia for at least 6 months after CAR T may correlate with a better long-term outcome without a transplant,” he added. “The problem is we can’t predict who is and isn’t going to lose their B-cell aplasia during that 6 months.
“Standard of care, at least for a refractory ALL patient in minimal residual disease-negative remission who has not had a transplant before, is to undergo transplant if they are otherwise eligible,” Lee added. “Why should an investigational therapy — even one as promising as CAR T cells, which is still in early stages — change decades worth of dogma, just because the cells persist in a fraction of patients? We might get there one day, but we have to do a better job being able to predict which patients are going to fall into that category and which ones won’t.”
Undergoing HSCT following CAR T-cell therapy requires additional hospital stay and costs, but the long-term effects of CAR T-cell therapy may not be as pronounced as with other therapies, Shalabi said.
“Although the side effects of CAR T-cell therapy could be significant, they are mostly short term and usually resolve by day 28,” she said. “Our patients have excellent quality of life once they are discharged from the hospital.”
Researchers postulate whether CAR T-cell therapy, by leading to NGS negativity, can allow for deintensification of HSCT conditioning, potentially reducing the risk for transplant-related mortality and long-term comorbidities
“Also, because of the predictive power for relapse the NGS provides over flow cytometric minimal residual disease testing, we plan to look at NGS-based minimal residual disease results for all our CAR patients,” Nirali N. Shah, MD, MHSc, associate research physician in the Pediatric Oncology Branch of the NCI, told HemOnc Today. – by Alexandra Todak
Shalabi H, et al. Abstract 6. Presented at: BMT Tandem Meetings; Feb. 21-25, 2018; Salt Lake City.
Disclosures: The study authors report no relevant financial disclosures.