High Marks for CAR T-Cell Therapy in MCL

More than 90% of patients with advanced mantle cell lymphoma (MCL) responded to the CD19-targeted chimeric antigen receptor (CAR) T-cell therapy KTE-X19, and a majority had no disease progression at 12 months, a multicenter trial showed.

Results in 60 evaluable patients showed that 57 (93%) had objective responses, including 40 complete responses. After a median follow-up of 12.3 months, the estimated 12-month progression-free survival rate was 61% and estimated overall survival was 83%.

Severe, potentially life-threatening adverse events known to be associated with CAR T-cell therapy occurred in 15-30% of the patients, as reported in the New England Journal of Medicine.

"[CAR T-cell therapy] offers an option for a very difficult patient population," said the study's lead author, Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston. "Relapsed and refractory mantle cell lymphoma is not curable at all, and the reported survival of these patients is 6 to 10 months. Nearly half of the patients in this study are doing fine at 2 years. This is really a life-saving therapy for a very desperate, heavily treated, noncurable population."

"I have been treating mantle cell lymphoma for 20 years, and after the BTK [Bruton's tyrosine kinase] inhibitors, this is one of the most exciting and promising new therapies for our patients," he told MedPage Today.

MCL generally has an aggressive clinical course, which has been improved by the availability of BTK inhibitors. Patients who have disease progression during or after BTK therapy have a poor prognosis and limited remaining options. Allogeneic stem-cell transplantation is an option for some patients but is associated with a high risk of nonrelapse mortality, even with reduced-intensity conditioning, Wang and co-authors noted in their introduction.

CAR T-cell therapy has substantially improved the outlook for many patients with relapsed/refractory aggressive B-cell lymphomas. In one study of axicabtagene ciloleucel (Yescarta) for large B-cell lymphoma (LBCL), almost half of the patients were alive after 39 months of follow-up, and median survival was 25.8 months. In another study, CAR T-cell therapy led to durable clinical responses in relapsed/refractory MCL.

Development of KTE-X19 followed recognition that patients with a high concentration of leukemic blasts in peripheral blood might have relatively few T cells in the starting material for CAR T-cell production. The KTE-X19 production process involves removal of CD19-expressing malignant cells, reducing the possibility of activation and exhaustion of anti-CD19 CAR T cells during ex vivo manufacturing processes, the authors wrote.

Investigators at 20 sites in the U.S. and Europe conducted a phase II trial of KTE-X19 in adults with MCL that had relapsed or was refractory to as many as five prior regimens, including a BTK inhibitor and an anti-CD20 monoclonal antibody. Patients underwent leukapheresis and standard conditioning therapy, and those with a high disease burden could receive bridging therapy prior to conditioning, at the treating physician's discretion.

Each patient received a single infusion of KTE-X19 at a dose based on studies of axicabtagene ciloleucel in LBCL and prior studies of KTE-X19 in acute lymphoblastic leukemia. The trial's primary endpoint was objective response, as determined by an independent radiology review committee. The study involved a total of 74 patients, and the primary analysis included 60 patients who had received treatment and were evaluated for response 6 months after the required week-4 disease assessment.

In addition to the primary efficacy analysis, which showed an overall response rate of 93% and complete response rate of 67%, an intention-to-treat analysis that included all 74 patients yielded an 85% overall response rate, including complete responses in 59%. With a median follow-up exceeding a year, the data showed that 57% of the 60 patients in the primary efficacy analysis remained in remission.

With respect to the safety of KTE-X19, 94% of patients had grade ≥3 cytopenias and 32% had infections. Grade ≥3 cytokine release syndrome occurred in 15% of patients and grade ≥3 neurologic events in 31%. Two fatal infectious adverse events occurred during the study.

"Once this is approved, we immediately want to move it to the front line," said Wang. "We know who some of the high-risk patients are with newly diagnosed mantle cell lymphoma: blastoid or pleomorphic, Ki-67 more than 50%, p53 mutations, and complex karyotype. For these patients, nothing is curative, including stem-cell transplant, chemotherapy, or targeted therapies."

"Nothing, aside from this cellular therapy, can cause long-term remissions in these types of patients," he continued. "Since we know these patients are going to relapse very soon, we should give CAR T-cell therapy in the front line."

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