Mantle cell lymphoma (MCL), a subtype of non-Hodgkin lymphoma (NHL), is diagnosed in about 4200 people per year in the United States.1 MCL often progresses quickly and most patients require immediate treatment. But MCL is incurable with current therapeutic options, which means effective approaches for relapsed/refractory disease are in demand.

Treatment with ibrutinib, a bruton tyrosine kinase (BTK) inhibitor, is the current standard approach for relapsed/refractory MCL. But patients who progress following this treatment have an overall survival rate of just 6 to 10 months.2-4 Very few of these patients are candidates for stem cell transplantation. “There are no good treatment options for MCL after failing BTK inhibitors,” said Julio Chavez, MD, who researches and treats lymphoma at Moffitt Cancer Center, Tampa, Florida.  

Enter chimeric antigen receptor T-cell (CAR-T) immunotherapy — or clinical investigations of it in MCL, at least. This approach is being increasingly explored to treat aggressive subtypes of NHL. Given the poor prognosis of patients with relapsed/refractory MCL, investigating whether CAR-T therapy could improve survival times is logical.

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The phase 2 ZUMA-2 study sought to do just that. And, interestingly, there was no phase 1 study of ZUMA-1 — the dose of KTE-X19 being investigated in the phase 2 trial was determined on the basis of studies of axicabtagene ciloleucel in patients with large B-cell lymphoma and of KTE-X19 in patients with acute lymphoblastic leukemia.

KTE-X19 is a CAR-T that targets CD19 cells.5 A multicenter group of researchers, led by Michael Wang, MD, from the MD Anderson Cancer Center, Houston, Texas, enrolled patients with relapsed/refractory MCL whose disease had progressed after treatment with BTK inhibitors.

After undergoing leukapheresis and treatment with conditioning therapy, patients received a single infusion of KTE-X19 at a dose of 2×106 CAR T cells per kilogram of body weight. The protocol also allowed for bridging therapy with dexamethasone, ibrutinib, or acalabrutinib. The median time from leukapheresis to the delivery of KTE-X19 at the trial site was 16 days.

As of May 30, 2018, 28 patients had received KTE-X19 and there were follow-up data available of at least 1 year for that small group (median follow-up, 13.2 months), according to information presented at the Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy and Center for International Blood and Marrow Transplant Research. These data were presented in February 2020 at that meeting.

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Since then, updated data and trial details were presented in an article published in the New England Journal of Medicine on April 2, 2020.6 For that update, enrolled patients had to have received 5 or fewer prior therapies, 1 of which was required to be a BTK inhibitor (BTKi) — but the BTKi (either ibrutinib or acalabrutinib) was not required to be the last line of therapy before trial entry, and patients were not required to have disease that was refractory to BTK inhibition (it was determined that 88% of the treated patients had disease that was considered to be refractory to BTK inhibitor therapy). Other previous therapies still must have included anthracycline- or bendamustine-containing chemotherapy and an anti-CD20 monoclonal antibody.

Objective response rate (which includes both complete and partial response) was the focus of the preliminary studies, and the study update. Would CAR-T therapy renew the body’s fight against cancer, even at this late stage of the disease? For most patients who had at least 7 months of follow-up, the answer was: likely yes. The authors wrote in NEJM that “among the protocol-specified 60 patients with relapsed or refractory mantle-cell lymphoma, KTE-X19 resulted in an objective response in 93% of the patients and in a complete response in 67%.”6

Based on this complete response rate, the US Food and Drug Administration awarded KTE-X19 Priority Review in February 2020.7 It had already received a Breakthrough Therapy Designation from the agency. The Prescription Drug User Fee Act (PDUFA), or target action date for a final decision by the FDA, is anticipated to be on or before August 10, 2020.