1. Fuerst, Mark L.

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Chimeric antigen receptor (CAR) T-cell therapy has the potential to cure the most diffuse large B-cell lymphoma (DLBCL) patients who have recurrent disease.

CAR T Cell Therapy. ... - Click to enlarge in new windowCAR T Cell Therapy. CAR T Cell Therapy

In a debate on which approaches will impact the largest number of recurrent DLBCL patients in the future, Frederick Locke, MD, Co-Leader of the Immuno-Oncology Program and Vice Chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center, emphatically said the answer is CAR T-cell therapy at the 2021 Great Debates & Updates in Hematologic Malignancies virtual meeting.


Refractory DLBCL carries a poor prognosis. Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the United States, causing about 10,000 deaths each year. Outcomes in refractory, aggressive NHL are poor, with overall response rates (ORR) around 26 percent, including complete response (CR) of less than 10 percent, and median overall survival of about 6 months.


"These are not just refractory, but relapsed, patients as well. That's where CAR T-cell therapy comes in," Locke noted.


ZUMA-1, a multicenter trial of axicabtagene ciloleucel (axi-cel) in refractory aggressive large B-cell lymphoma (LBCL), met its primary endpoint of ORR in a Phase II cohort of 101 patients. The ORR was 82 percent, including 54 percent CRs.


"The response rate was great, but what was most striking is the duration of response," said Locke. At a median follow-up of 27.1 months, the median duration of response was 11.1 months. "This is a remarkable result in patients without any other treatment options," he noted.


Overall survival (OS) is another measure of the durability of response, Locke stated. After a median follow-up of 51.1 months, median OS was 25.8 months and the 4-year OS rate was 44 percent.


"The real question to ask is, What approach will cure the largest number of patients? CAR T-cell therapy provides an opportunity for prolonged disease-free survival. Patients live with lymphoma, and possibly never come back for treatment. That should be the goal," he said. "Once patients relapse, the chance of cure goes down significantly."


Currently, second-line therapy consists of chemoimmunotherapy. If patients respond, they have consolidation with an autologous transplant, but the chance of response after second-line therapy and autologous transplant is at best 25 percent, Locke explained.


"CARs are a possible cure for refractory DLBCL and are headed in the right direction," he said. Studies from the National Cancer Institute show about 40 percent of patients with LBCL treated with CD19 CAR-T cells remain in ongoing remission 4-8 years after therapy.


Do novel therapies provide long-term durable responses? asked Locke. A combination of polatuzumab plus bendamustine and rituximab represents a promising new treatment for patients with transplant-ineligible relapsed/refractory DLBCL. Data presented at the 2020 ASH Annual Meeting from a randomized, Phase III trial shows improvement when polatuzumab was added in as triplet therapy, with a 20 percent durable response. But there is no evidence of cure, he said, and about half of the patients (47%) were not eligible for transplant because of age and almost another half (42%) had only one prior line of therapy.


"This is not the same population as that tested in the pivotal trials of CAR T-cell therapy," he said. "The definition of refractory disease is more liberal than defined in SCHOLAR-1." SCHOLAR-1 was a patient level meta-analysis of refractory aggressive NHL.


Age is not a contraindication for CAR T-cell therapy in LBCL. "Data from ZUMA-1 clearly demonstrates durable responses in older patients. Real-world data suggest better efficacy in older patients, as compared to younger ones," said Locke. "Real-world data is lacking with novel agents."


Patients with co-morbidities can benefit from CAR T-cell therapy in LBCL. The U.S. Lymphoma CAR T Consortium studied 275 patients from 17 centers who were treated with axi-cel as a standard of care.


"Co-morbidities at apheresis that would have met ZUMA-1 exclusion criteria did not preclude durable progression-free survival. Patients with relapsed, rather than refractory, disease had better efficacy outcomes on univariate and multivariate analysis," said Locke, who added that CAR-T cells allow for treatment of relapsed patients.


ZUMA-12 examined CD19 CAR T-cell therapy for high-risk LBCL patients as part of frontline therapy. An interim analysis found a 74 percent CR rate. In comparison, ZUMA-1 for third-line LBCL patients had a CR rate of 49 percent.


"Ongoing randomized Phase III trials are testing CD19 CAR-T therapy as compared to second-line therapy with consolidation," said Locke. "Compared to CAR T-cell therapy, recent pivotal trials for novel agent combinations targeted patients that were older; patients who had fewer prior lines of therapy; and more patients with relapsed, rather than refractory, disease. Long-term remissions in refractory patient populations are not proven."


Intriguing data on bi-specific T-cell engagers (BiTEs) were presented at the 2020 ASH Annual Meeting, however, "patient populations are heterogeneous and follow-up is short," said Locke. He suggested using BiTE responses in follicular lymphoma as a marker for how well they may do in DLBCL. The BiTE mosunetuzumab in relapsed/refractory NHL led to about a 50 percent response rate, with median duration of CR of 21 months. In contrast, in ZUMA-5, a trial of CD19 CAR T-cell therapy for relapsed/refractory follicular lymphoma, data show a 76 percent CR and median duration CR has not been reached.


Locke suggested a more appropriate question to debate would be: Which approaches will cure the largest number of patients with recurrent DLBCL in the future? His answer: "CAR T-cell therapy really approaches a cure."


Mark L. Fuerst is a contributing writer.