The use of bridging therapy before treatment with axicabtagene ciloleucel was associated with worse overall survival in univariate, multivariate, and propensity score–matched analyses performed on data from the U.S. Lymphoma CAR T Consortium, investigators reported at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition.1
“No type of bridging therapy was associated with a different outcome in this analysis,” said lead author Michael Jain, MD, PhD, of Moffitt Cancer Center, Tampa, Florida. “It’s not clear why, but just getting another line of therapy [while awaiting CAR T-cell manufacturing] is not beneficial. Hopefully, we can tease out any differences over time, to see if there is an optimal means of bridging.”
Michael Jain, MD, PhD
As background, Dr. Jain noted that the pivotal chimeric antigen receptor (CAR) T-cell therapy trials took different approaches to bridging therapy. Bridging was not allowed in the ZUMA-1 trial of axicabtagene ciloleucel, and the median time from apheresis to CAR T-cell delivery was 17 days. The JULIET trial of tisagenlecleucel had delays in the process of manufacturing CAR T cells, with 92% of patients receiving bridging therapy, and a median time to CAR T-cell infusion of 54 days. In the TRANSCEND study of lisocabtagene maraleucel, 59% of patients received bridging therapy, and the median time to delivery was 24 days in the optimized subset.
U.S. Lymphoma CAR T Consortium Population
The U.S. Lymphoma CAR T Consortium includes 17 academic centers that contribute data from patients with lymphoma treated with standard-of-care CAR T-cell therapy. As of September 30, 2018, the registry included 298 patients who underwent apheresis with the intent to manufacture axicabtagene ciloleucel for large B-cell lymphoma, of whom 53% received bridging therapy and were followed for a median of 14 months after leukapheresis. Bridging therapy, defined as lymphoma therapy given between apheresis and the start of lymphodepleting chemotherapy, consisted of steroids alone (23%), chemotherapy (54%), radiation therapy (12%), or targeted therapies (10%).
KEY POINTS
- The use of bridging therapy before treatment with axicabtagene ciloleucel was associated with worse overall survival in univariate, multivariate, and propensity score–matched analyses performed on data from the U.S. Lymphoma CAR T Consortium.
- In the multivariate analysis, controlling for numerous confounding factors, bridging therapy vs no bridging was associated with a hazard ratio of 1.8 (P = .03).
- In the propensity score–matched analysis, the hazard ratio for survival was 1.7 (P = .02).
- Although the study was not powered by subgroup, it showed no obvious differences according to type of bridging therapy.
- Bridging therapy during the CAR T-cell manufacturing process should be individualized.
Of note, at baseline, a higher proportion of patients in the bridging group had a poor performance status, high International Prognostic Index (IPI) scores, bulky disease greater than 10 cm, and genetic double translocations of MYC and BCL2 and would not have met all the eligibility criteria for ZUMA-1 for reasons other than bridging therapy. “Patients who were chosen for bridging had more high-risk features, which makes sense, but our propensity analysis matched for various features that are important to outcomes, and we made the high-risk features similar between the groups. Even after doing this, overall survival remained worse for patients receiving bridging therapy,” Dr. Jain said.
Outcomes Worse After Bridging Therapy
In the univariate analysis, bridging therapy was associated with worse progression-free and overall survival. In the multivariate analysis correcting for confounding features, there was no statistically significant difference in overall response rate, complete response rate, and progression-free survival between bridging and no bridging groups, but bridging therapy was associated with significantly worse overall survival (hazard ratio [HR] = 1.8; P = .03), Dr. Jain reported.
In the univariate analysis of patients who underwent leukapheresis (n = 298), the hazard ratios were 1.6 (P = .002) for progression-free survival and 2.5 (P < .001) for overall survival, favoring patients who did not receive bridging therapy. At 12 months, progression-free survival rates were 55% for patients who did not receive bridging therapy and 39% for patients who did. Overall survival rates were 81% and 56%, respectively. “The efficacy of axicabtagene ciloleucel was not different across the bridging strategies,” noted Dr. Jain.
In the propensity score–matched outcomes, the difference in progression-free survival was no longer statistically significant (HR = 1.2; P = .3), but a statistically significant difference remained for overall survival (HR = 1.7; P = .02), Dr. Jain reported.
Deaths due to lymphoma were higher in the bridging group (37% vs 17%), as was nonrelapse mortality (7.1% vs 1.5%), grade ≥ 3 neurotoxicity (34% vs 28%), and grade ≥ 3 cytokine-release syndrome (9% vs 5%).
Conclusions and Recommendations
“Not every patient needs bridging therapy, so in our practice, if we can avoid it, we will.”— Michael Jain, MD, PhD
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Dr. Jain acknowledged that a limitation of the study is its retrospective nature. “In retrospective studies, you can only match for covariates you think are important. There may be ones we don’t know about or haven’t measured that could be impacting these findings. It may be that the selection of bridging is a powerful expression of a physician’s concern about the patient being at a high risk of death,” he said in an interview with The ASCO Post.
“However, the other possibility is that, by giving bridging therapy, we are doing something that’s affecting the CAR T-cell therapy,” offered Dr. Jain. “We did see more patients dying of infection if they underwent bridging, but the main driver was that, if patients relapsed after CAR T-cell therapy, they did not do as well if they had bridging. They had a shorter overall survival from the time of relapse.”
Bridging therapy obviously helps many patients, Dr. Jain emphasized. “Some patients may have died or not received CAR T-cell therapy without it,” he said. “Prospective evaluation of different bridging strategies is warranted to determine whether any can improve outcomes after axicabtagene ciloleucel, and/or whether they should be utilized only for patients requiring emergent disease control during the manufacturing period. At this point, our overall recommendation is for clinicians to carefully consider how to manage patients during the bridging period. Not every patient needs bridging therapy, so in our practice, if we can avoid it, we will.”
DISCLOSURE: Dr. Jain has served in a consulting or advisory role for Kite/Gilead; and has been reimbursed for travel, accommodations, or other expenses by Kite/Gilead.
REFERENCE
1. Jain MD, Jacobs MT, Nastoupil LJ, et al: Characteristics and outcomes of patients receiving bridging therapy while awaiting manufacture of standard of care axicabtagene ciloleucel CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B-cell lymphoma: Results from the U.S. Lymphoma CAR-T Consortium. 2019 ASH Annual Meeting and Exposition. Abstract 245. Presented December 7, 2019.
