CAR T-cell therapy effective for refractory large B-cell lymphomas
medwireNews: The results of two studies published in The New England Journal of Medicine support the use of autologous chimeric antigen receptor (CAR) T cells directed against CD19 in patients with relapsed or refractory B-cell lymphomas.
The first of these – a multicenter phase II trial that was reported simultaneously at the 2017 American Society of Hematology Annual Meeting in Atlanta, Georgia, USA – enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma that had not responded to prior treatment. The majority (69%) had received at least three previous lines of therapy.
The personalized CAR T-cell product axicabtagene ciloleucel (axi-cel) was successfully manufactured and delivered at a target dose of 2x106 cells/kg to 101 (91%) participants after administration of a conditioning regimen comprising low-dose cyclophosphamide and fludarabine.
Axi-cel treatment led to an objective response in 82% of patients at a median of 1.0 month, with 54% achieving a complete response. Just under half (42%) of the responses, including complete responses in 40% of patients, were ongoing at a median follow-up of 15.4 months.
“These findings compare favorably with the results of the recent SCHOLAR-1 study of existing therapies for this disease, which showed an objective response rate of 26% and a complete response rate of 7%,” say Sattva Neelapu (The University of Texas MD Anderson Cancer Center, Houston, USA) and fellow ZUMA-1 investigators.
They report that the most frequent toxicities of at least grade 3 were neutropenia, anemia, and thrombocytopenia, observed in a respective 78%, 43%, and 38% of study participants. And grade 3 or worse cytokine release syndrome and neurologic events (including encephalopathy and confusion) occurred in 13% and 28% of patients, respectively. Three patients died during the course of the study, of which two deaths were attributed to the cytokine release syndrome induced by axi-cel.
In light of the “substantial clinical benefit for patients with refractory disease,” Neelapu et al conclude that their results “support the use of axi-cel as an effective therapeutic option in adult patients with relapsed or refractory large B-cell lymphoma after at least two prior systemic therapies.”
In the second study, 28 patients with relapsed or refractory diffuse large B-cell or follicular lymphoma were treated with the anti-CD19 CAR T-cell therapy CTL019 (tisagenlecleucel) at doses ranging from 1x108 to 5x108 cells after receiving a lymphodepleting regimen chosen by the investigator on the basis of the patient’s treatment history, blood counts, and organ function.
At the 3-month mark, an objective response was achieved by 68% of patients, with rates of 50% and 79% in the diffuse large B-cell and follicular lymphoma groups, respectively.
The corresponding rates of complete response at 6 months were 57%, 43%, and 71%, reports the team led by Stephen Schuster, from the University of Pennsylvania in Philadelphia, USA. Of note, all participants who achieved complete remission at this timepoint remained in remission for a median of 29.3 months (range 7.7–37.9 months) from induction.
Grade 3–5 cytokine release syndrome occurred in 18% of patients, while 11% experienced encephalopathy of at least grade 3, which in two cases was self-limiting but was fatal in one follicular lymphoma patient.
Noting that their study included “patients with a poor prognosis and no available curative treatment options,” Schuster and colleagues urge the further development of CAR T-cell therapy in this setting.
In a linked editorial, Walter Urba (Providence Portland Medical Center, Oregon, USA) and co-authors point out that “[d]espite the impressive clinical results, approximately half the patients with refractory or relapsed large B-cell lymphomas will not have a durable response after anti-CD19 CAR T-cell therapy.”
They highlight the necessity of devising methods to boost the efficacy of CAR T-cell therapy, but caution that “because the mechanisms of the toxic effects associated with this therapy are not completely understood, strategies that enhance the potency of these products run the risk of inadvertently worsening the already daunting toxic effects.”
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