1. Fuerst, Mark L.

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ATLANTA-Responses to chimeric antigen receptor (CAR) T-cell therapy are still strong after 1 year in patients with refractory non-Hodgkin lymphoma (NHL), according to a new study presented at the 2017 American Society of Hematology Annual Meeting.

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Long-term follow-up of ZUMA-1, a pivotal trial of the autologous anti-CD19 CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in patients with refractory, aggressive NHL (Abstract 578), also sheds light on why therapy fails in some patients.


Initial results of ZUMA-1, the first, multicenter trial of anti-CD19 CAR T cells in refractory NHL, reported positive results of an overall response rate of 82 percent and complete response rate of 54 percent (J Clin Oncol 2017;35(15 Suppl):7512-7512). Based on data from ZUMA-1, the FDA granted a priority review to axi-cel in May 2017 for transplant-ineligible patients with relapsed or refractory NHL. The 101 patients in ZUMA-1 received the target dose of axi-cel 2 x 106 cells per kg after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The median survival follow-up was 8.7 months.


Recent ZUMA-1 Findings

The latest analysis of ZUMA-1, which combines phase I and II trial data, assessed the rate and durability of responses and survival among these patients after a median follow-up of 15.4 months. Among 108 patients with fast-growing and refractory aggressive NHL, more than half were still alive at least 1 year after receiving a single infusion of the CAR T-cell therapy. More than 1 year later, 42 percent of patients remain in remission and 40 percent of patients exhibit no evidence of cancer.


"Long-term follow-up of ZUMA-1 confirms that these responses can be durable and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission," said lead author Sattva S. Neelapu, MD, Professor, Department of Lymphoma/Myeloma, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, Houston. "With existing therapy, the median survival for people with this disease is only 6 months. Here, we see more than half of patients-59 percent-are still alive over a year after treatment."


Neelapu said the durability findings are also consistent with observations from earlier, single-institution trials of axi-cel in this patient population. The study, which is being conducted at 22 sites, is the largest study of a CAR T-cell therapy's efficacy to date, he noted.


No new deaths related to the therapy occurred. Early in the study, four patients died within 2 months of treatment-two attributable to the CAR T-cell therapy and two to unrelated adverse side effects that are typical of disease progression. Common adverse events consisted of cytokine release syndrome (CRS), neurologic toxicities, neutropenia, anemia, and thrombocytopenia. Ten patients experienced a serious adverse event 6 months after the primary analysis, including infections in eight patients. The researchers observed no new onset CRS or neurologic events related to axi-cel in the updated analysis.


Unlike standard therapies, axi-cel is a one-time infusion. The side effects experienced are usually only for 1-2 weeks as opposed to traditional chemotherapies when the side effects occur for 1-2 weeks after each cycle of chemotherapy, he said.


The study also provides clues as to why some patients relapse or do not respond to CAR T-cell therapy. After analyzing tumor tissue from before and after treatment in patients who relapsed, the researchers found that in one-third of patients the CD19 protein was no longer present on cancer cells. More than two-thirds of tumors showed evidence of another protein, PD-L1, which likely helped the cancer cells survive by inhibiting the function of the infused T cells. Follow-up studies are now underway to identify possible approaches to overcoming these problems.


A randomized trial to compare the efficacy of this therapy with second-line standard of care, which includes autologous stem cell transplantation for relapse after first-line therapy, is planned in patients with aggressive B-cell NHL.


FDA Approval

"Axi-cel is markedly superior to standard therapy. More importantly, it appears to induce durable remissions that last years in a significant proportion of patients, suggesting the possibility of achieving cures in these patients who typically do not survive beyond 6 months. This is the first therapy that has been ever approved by the FDA for relapsed or refractory large B-cell lymphoma and is likely to save the lives of many patients," said Neelapu.


The FDA approved axi-cel for adult patients with relapsed or refractory large B-cell lymphoma who have failed at least two lines of systemic therapies. The lymphoma subtypes included in this indication are diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma (transformed follicular lymphoma).


The researchers noted that about half of the patients who initially responded to axi-cel then relapsed. "We need to understand the mechanisms of resistance to this therapy so that we can further improve efficacy," said Neelapu. The therapy also needs to be tested in large B-cell lymphoma patients relapsing after first-line therapy to see whether it is more effective than the current standard of care, autologous stem cell transplantation. He suggested that CAR T-cell therapy should also be tested in other B-cell lymphomas, such as follicular lymphoma and mantle cell lymphoma.


Neelapu cautioned that all providers involved in the care of patients receiving CAR T-cell therapy should be well-versed in the grading and management of the toxicities associated with this therapy, which can be fatal if not recognized and managed promptly. In a recent publication, the researchers provided step-by-step instructions for the management of toxicities associated with CAR T-cell therapy (Nat Rev Clin Oncol 2018;15:47-62). "These guidelines are easy to follow even for physicians not previously experienced in administering this therapy," he stated.


Mark L. Fuerst is a contributing writer.