Impressive response with CAR T cells directed against CD19 for refractory B-cell lymphoma

Chimeric antigen receptor (CAR) T cells directed against CD19 (CTL019) induced durable remissions in patients with refractory B-cell lymphomas, according to a study in the New England Journal of Medicine.

In a study of 28 patients with lymphoma who received CTL019 cells, about 65% had a response—43% of patients with diffuse large B-cell lymphoma (DLBCL) and 71% of patients with follicular lymphoma (FL) achieved complete remission. One in three patients developed transient encephalopathy, and one in five developed severe cytokine release syndrome (CRS).

“As of May 2017, no patient who had a complete response had a relapse or required additional therapy,” wrote the authors, led by Stephen J. Schuster, MD, from the Lymphoma Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.

Only 20% to 30% of patients with progressive or unresponsive DLBCL respond to currently available therapies. The 2-year survival rate is only 22% in patients with FL who are refractory to treatment with rituximab and alkylating agents and have progressive disease despite idelalisib treatment, the investigators noted.

“Thus, our observed complete response rates of 43% for patients with DLBCL and 71% for those with FL, with sustained remissions lasting up to 3 years after a single dose of CTL019 cells, support further development of this approach,” they wrote.

They added: “It is noteworthy that our patients received personalized lymphodepleting regimens that were based on their response history, blood counts, and organ function, and that the rate of complete response in our study is similar to the rates reported in studies that used cyclophosphamide-fludarabine, a less disease-specific and potentially more toxic lymphodepleting regimen.”

Patients were eligible for the study if they had CD19-positive DLBCL or FL with no curative treatment options,

After leukapheresis, patients underwent staging followed by chemotherapy to deplete T lymphocytes. Patients could receive bridging therapy while CTL019 cells were manufactured. CTL019 cells were infused 1 to 4 days after the completion of lymphodepleting chemotherapy. The dose was 1.00×10⁸ to 5.00×10⁸ CTL019 cells.

The overall response rate at 3 months was the primary objective. Response rates were 50% (7 of 14) among patients with DLBCL and 79% (11 of 14) among those with FL. Sixteen of 28 patients overall (57%) had a complete response (43% of those with DLBCL and 71% of patients with FL).

“All patients in complete remission by 6 months remained in remission at 7.7 to 37.9 months (median, 29.3 months) after induction,” the investigators wrote.

Among patients with DLBCL, median progression-free survival (PFS) was 3.2 months (95% CI, 0.9-not reached), and 43% of these patients were progression-free at median follow-up (95% CI, 18-66) of 28.6 months. Among patients with FL, median PFS was not reached, and 70% (95% CI, 38-88) were progression-free at the median follow-up.

The median duration of response was not reached. At median follow-up, 86% of patients with DLBCL who had a response and 89% of patients with FL who had a response had maintained their response.

Severe cytokine-release syndrome occurred in five patients. One patient was treated with tocilizumab and had a rapid reversal of symptoms and a complete response to CTL019 therapy. There were no deaths from cytokine-release syndrome.

Eleven patients experienced neurologic toxicity related to administration of CTL019 cells. Three patients had grade ≥ 3 encephalopathy. Neurologic symptoms were self-limiting, and fully resolved within 1 week, with the exception of one patient. The patient had a history of optic atrophy and developed encephalopathy with progressive neurologic deterioration that resulted in death.

This report follows one presented in December 2017 at the American Society of Hematology meeting, where Dr. Schuster reported data from the global phase 2 JULIET study of 81 adults with DLBCL who were treated with the CD19-directed CART cell therapy tisagenlecleucel. The overall response rate at 3 months in JULIET was 53.1%, with a rate of complete response of 39.5%.

Based on the results from the JULIET trial, a supplemental biologics license application was filed with the US Food and Drug Administration (FDA) to expand the indication for tisagenlecleucel to include adults with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplant. The FDA had already approved tisagenlecleucel in August 2017 for the treatment of children and adults up to age 25 with B-cell precursor acute lymphoblastic leukemia.

To read more about this study, click here.