CD19-Directed CAR T-Cells Yielded High CR Rates in Relapsed, Refractory Follicular Lymphoma

Patients with relapsed or refractory follicular lymphoma with or without transformation had high rates of complete response and durable remission after undergoing CD19-directed CAR T-cell therapy, according to a small study published in the medical journal Blood.

Patients with relapsed or refractory follicular lymphoma or histologic transformation have limited survival with current treatment options. This phase I/II study tested CD19-directed CAR T-cell therapy in adults with relapsed or refractory CD19-positive B-cell malignancies.

Twenty-one patients with follicular lymphoma (n=8) or histologic transformation (n=13) were treated with lymphodepletion with cyclophosphamide and fludarabine-containing regimen and then 2x10⁶ CD19 CAR-T cells/kg with a 1:1 CD4+:CD8+ CAR T-cell ratio.

Among the patients with follicular lymphoma, 88% achieved complete remission (CR) with a median time to response of 29 days. With a median follow-up of 2 years, all patients who achieved complete remission remained in remission.

“These data demonstrate a high rate of durable CR in high-risk follicular lymphoma patients treated with CD19 CAR T-cells,” researchers led by Alexandre Hirayama, of Fred Hutchinson Cancer Researcher Center, wrote.

Among the 13 patients with follicular lymphoma with transformation, the best overall response rate was 46%. All patients who responded achieved complete remission. Among patients with a complete remission, at a median follow-up of 38 months, the median duration of response was 10.2 months and the median progression-free survival was 11.2 months. Durable remissions were observed for up to 39 months after infusion.  

“The serum IL-8 concentration on day 0 before CAR T-cell infusion was higher in histologic transformation compared to follicular lymphoma patients (median, 9.6 vs 2.5 pg/mL, P=.01),” the researchers wrote. “IL-8 has been described to mediate the recruitment of tumor-associated neutrophils and promote DLBCL progression and can contribute to local immune suppression. Patients with histologic transformation had also higher pre-treatment LDH, which could reflect more aggressive disease and a more immunosuppressive tumor microenvironment.”

CAR T-cell therapy was relatively well tolerated, according to the researchers. No severe cytokine release syndrome or neurotoxicity were reported. Half of patients with follicular lymphoma and 39% of those with transformation had grade 1 or worse CRS; similarly, half of patients with follicular lymphoma and 23% of those with transformation had neurotoxicity of grade 1 or worse.

Stephen J. Schuster, MD, of the University of Pennsylvania’s Abramson Cancer Center, called the results “very significant” because they independently confirm Schuster and colleagues’ previous report of durable efficacy with CAR T-cell therapy in 14 patients with relapsed or refractory follicular lymphoma.

“We reported that 89% of follicular lymphoma patients who had a response to CAR T (10 complete and 1 partial response), maintained that response at a median follow-up of 28.6 months, with all patients achieving a complete response remaining in remission at the time of our first report,” Schuster told Cancer Network.  “This is very similar to [Hirayama’s] report of 7 of 8 patients (88%) achieving complete responses and maintaining their remissions at 24 months median follow-up.  Clearly, CAR T is effective therapy for relapsed or refractory follicular lymphoma and I am sure that the ongoing multicenter trials will also confirm this.”

In addition, the results reported for CAR T therapy of follicular lymphoma transformed to large cell lymphoma (46% complete responses with some durable out to 39 months) are similar to outcomes reported by Schuster and colleagues, as well as others, for DBLCL.

“This highlights the different biology of transformed follicular lymphoma and, although still a success relative to other therapies for these patients, indicates the need to improve outcomes for patients with large B-cell lymphomas,” Schuster said.