CAR-Modified T-Cell Therapy Shows Durable Response in Non-Hodgkin Lymphoma

Infusions of CTL019, a CAR-modified T-cell therapy against CD19, achieved durable responses and showed an acceptable safety profile in heavily pretreated patients with CD19-positive DLBCL, MCL, and FL.

Stephen J. Schuster, MD

Infusions of CTL019, a chimeric antigen receptor (CAR)-modified T-cell therapy against CD19, achieved durable responses and showed an acceptable safety profile in heavily pretreated patients with CD19-positive diffuse large B-cell lymphoma (DLBCL), mantle cell (MCL), and follicular lymphoma (FL), according to findings presented at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland.

In 19 patients evaluable at three months, the overall response rate (ORR) was 68%. In 13 patients with DLBCL, the ORR was 46%, which consisted of two complete responses (CR) and four partial responses (PR). At the time of the analysis, the median progression-free survival (PFS) was 90 days (range, 7-400). For seven patients in the FL cohort, the ORR was 100%, with three patients achieving a CR and four with a PR. Of two patients with mantle cell lymphoma (MCL), the ORR was 50% and remained ongoing at 50 days.

“The response is very rapid, and we can tell very quickly during the first weeks if the cells are working,” said Stephen J. Schuster, MD, lymphoma program, Abramson Cancer Center, University of Pennsylvania. “CTL019 chimeric antigen receptor modified T cells directed against CD19 can achieve durable responses in patients with relapsed or refractory CD19-positive diffuse large B-cell and follicular lymphomas; it is too early to make a conclusion regarding the patients with mantle cell lymphoma.”

Patients enrolled in the trial were required to have CD19-positive B-cell lymphomas with no available curative treatments options. Patients had an expected survival of 12 weeks or more and measurable disease. Patients with DLBCL had relapsed/refractory disease after autologous stem cell transplantation (ASCT) and FL patients had been treated with two or more prior therapies.

The study enrolled 30 patients total, 19 with DLBCL, eight with FL, and three with MCL. Eight patients, seven with DLBCL and one with FL, were not evaluable for response. Three of these patients were removed from study prior to T-cell infusion due to progressive disease, one patient withdrew consent, three patients had inadequate in vitro T-cell expansion, and the dose in one patient was less than protocol specified.

A total of 13 patients with DLBCL, seven with FL, and two with MCL received the CTL019 protocol-specified cell dose. Preinfusion chemotherapy regimens included EPOCH in two patients, cyclophosphamide in nine, radiation plus cyclophosphamide in two, bendamustine in six, and one patient received cyclophosphamide-fludarabine.

“Most of these patients come to us already immunodepleted; the need for the chemotherapy immune-depletion step is debatable,” Schuster remarked. “A low dose is used but most cases of neutropenia seen in this study were attributed to the chemotherapy used for the lymphocyte depletion step.”

The median age of patients with DLBCL was 58 years (range, 25-77), and 68% of patients were male. In the FL cohort, the median age was 60.5 years (range, 43-71), 38% of patients were male and patients had received a median of 5.5 prior therapies (range, 4-8), including two prior transplants. 86% of patients had stage III or IV disease and LDH was increased in 63% of patients. The three patients with MCL arm were younger, with a median age of 56 and 52% were male. All MCL patients had received a median of four prior therapies and all had stage III or IV disease.

Overall, six patients in the FL cohort experienced a CR as their best response, with one PR. Three patients with a PR at three months by computed tomography converted to a CR at a six-month analysis. One patient with PR at three months maintained this response at 6 and 12 months before experiencing disease progression at approximately 12 months. PFS was a median 250 days (range 150-400).

Grades 3/4 adverse events (AEs) included hypophosphademia in four patients, leukopenia in five patients, neutropenia in nine patients, and lymphopenia in 18 patients. AEs possibly related to treatment included two cases of acute kidney injury, one acidosis, two cytokine release syndrome, one fever, two hypotension, one hypertension, one delirium, and one case of encephalopathy, which resulted in death.

“The toxicity of this approach appears acceptable, given the overall condition of these patients,” Schuster suggested.

CTL019 is comprised of autologous T cells that express a chimeric antigen receptor (CAR) with specificity for CD19 along with activation and costimulatory signaling via CD3-zeta and CD137 (4-1BB) signaling domains. This mechanism has been shown to potentiate antitumor effects in patients with relapsed/refractory CD19-positive leukemia. The logical next step was to evaluate these CAR cells in CD19-positive lymphoma, Schuster suggested.

CTL019, which is being developed through collaboration between the University of Pennsylvania and Novartis, was one of the first CAR-modified T cell therapies to receive a breakthrough therapy designation. This designation, which the therapy received in July 2014, was for the agent’s efficacy in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia. The treatment continues to be explored across a variety of hematologic malignancies.

Schuster SJ, Svoboda J, Nasta SD, et al. Phase II trial of chimeric antigen receptor modified T cells directed against CD19 in relapsed/refractory diffuse large B cell, follicular, and mantle cell lymphomas. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 139.