A single infusion of a new chimeric antigen receptor (CAR) T-cell therapy has showed durable remissions in patients with relapsed or refractory mantle cell lymphoma who had stopped responding to Bruton's tyrosine kinase (BTK) inhibitor therapy.
These patients "have a very poor prognosis," note the authors, led by Michael Wang, MD, professor of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center in Houston. They represent a therapeutic challenge, the authors add, and retrospective studies evaluating salvage therapy have shown low response rates and a median overall survival of 6 to 10 months.
In contrast, the results they now report with the investigational anti-CD19 CAR T-cell therapy, KTE-X19 (Kite Pharma, now part of Gilead), show that 63 (85%) of 74 patients in the intention-to-treat analysis had an objective response, and 59% of patients achieved a complete response (CR).
These results come from the ZUMA-2 phase 2 multicenter trial and were published in the April 2 issue of the New England Journal of Medicine.
"Our reported results, including a manageable safety profile, point to this therapy as an effective and viable option for patients with relapsed or refractory mantle cell lymphoma," Wang said in a statement.
KTE-X19 is awaiting approval in the United States for use in mantle cell lymphoma, with a decision expected in August. It could be the third CAR T cell to reach the market, but the first for this indication.
Heavily Pretreated Patients
The ZUMA-2 trial involved 74 patients with relapsed or refractory mantle cell lymphoma. They had received up to five previous lines of therapy, including BTK inhibitor therapy with either ibrutinib (Imbruvica, Pharmacyclics/Janssen) or acalabrutinib (Calquence,AstraZeneca).
"All the patients underwent leukapheresis to obtain cells for KTE-X19 manufacturing," the authors note.
KTE-X19 was successfully manufactured for 96% of patients and 92% of patients actually received the single infusion.
"The median time from leukapheresis to the delivery of KTE-X19…was 16 days," the authors note.
Before receiving the CAR T cell, patients received a conditioning chemotherapy consisting of fludarabine and cyclophosphamide, given on days -5, -4, and -3 prior to receiving a single intravenous infusion of KTE-X19, at a dose of 2x106 CAR T cells/kg of body weight on day 0.
For the primary efficacy analysis, the median follow-up was 12.3 months.
Among all 74 enrolled patients who made up the intention-to-treat analysis, 85% had an objective response — the primary endpoint of the study — with 59% of patients achieving a complete response (CR).
"The median time to an initial response was 1.0 month…and the median time to a complete response was 3.0 months," Wang and colleagues report.
Of those who achieved either a partial response or whose disease stabilized following the infusion, 57% achieved a CR after a median of 2.2 months.
Moreover, among protocol-specified patients (n = 60), a single infusion of KTE-X19 led to an objective response in 93% of patients and a CR of 67%.
At 12 months, estimated progression-free survival (PFS) was 61% and overall survival was 83%. PFS rates at 6 months were equivalent among patients with poor prognostic features as well, as investigators pointed out.
Some 57% of patients in the primary efficacy analysis and 78% of patients who achieved a CR continued to respond to treatment after a median follow-up of 12.3 months.
As has been seen with other CAR T-cell therapies, this product also had serious and life-threatening toxic events, the authors note, but they add that in this trial no patient died as a result.
Adverse events (AEs) of grade 3 or higher occurred in virtually all patients, Wang and colleagues note. Most commonly, these involved cytopenias (94% of patients) and infections (32%).
Further, cytokine release syndrome (CRS), a well-recognized AE of all CAR T-cell therapy, occurred in 91% of patients; however, no patient died of CRS and most episodes were grades 1 and 2.
When CRS occurred, 59% of patients received treatment with the interleukin-6 inhibitor tocilizumab (Actemra, Genentech) and all events resolved within a median of 11 days.
A total of 63% of patients also developed a neurologic event. None were fatal, but grade 3 or higher neurologic events were seen in 31% of patients. Grade 3 or higher infections also occurred in about one third of patients, the most common being pneumonia.
The study was funded by Kite Pharma, a Gilead company. Wang reports he has received research support and has served on the advisory board and as a consultant for Kite Pharma.
N Eng J Med. Published online April 2, 2020. Abstract
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Cite this: New CAR T-Cell Therapy Finds Niche in R/R Mantle Cell Lymphoma - Medscape - Apr 07, 2020.