Could CAR-T Therapy Be Moving Into Lymphoma? The ASCO Post
Could CAR-T Therapy Be Moving Into Lymphoma?
Could CAR-T Therapy Be Moving Into Lymphoma?
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Stephen J. Schuster, MD
The use of T cells that are genetically engineered to express chimeric antigen receptor (CAR-T) has made headway as an treatment to hematologic malignancies, with the best results achieved in leukemia. At the two thousand fifteen American Society of Hematology (ASH) Annual Meeting and Exposition, a preliminary probe explored the use of CAR-T cells in lymphoma. 1
Durable remissions were observed following a single infusion of CAR-T cells directed against CD19 in very sick, strongly pretreated patients with CD19-positive diffuse large B-cell lymphoma and follicular lymphoma. All patients who achieved finish remission remained in remission at a median follow-up of about one year. Only two patients with mantle cell lymphoma were treated, with one finish remission.
“CAR-T cells targeting CD19 have achieved potent antitumor effects in relapsed/refractory acute lymphoblastic leukemia and chronic lymphocytic leukemia. It is not a spread to hypothesize that CAR-T would be active in non-Hodgkin lymphomas that express CD19,” said lead author Stephen J. Schuster, MD, Director of the Lymphoma Program at the Abramson Cancer Center, University of Pennsylvania, Philadelphia.
“We found durable responses in extensively pretreated patients with active non-Hodgkin lymphoma treated with CAR-T, with less toxicity than is reported with other therapies,” he said.
Patients enrolled in the trial (n = forty three at the time of the ASH meeting) had no available curative therapies and an expected survival of three months or longer. They included patients with diffuse large B-cell lymphoma, either after transplant or transplant-ineligible; patients with follicular lymphoma for whom at least two prior immunotherapy regimens had failed and who had progressive disease within two years of treatment; and patients with mantle cell lymphoma who had relapsed or had persistent disease after first-line rituximab (Rituxan) chemotherapy and were transplant-ineligible or relapsed after transplant.
Once eligibility for the investigate was determined, apheresis and manufacturing of CAR-T cells were initiated. Patients were restaged by computed tomography (CT) scan and bone marrow analysis and then given lymphodepleting chemotherapy on an individualized basis according to histology, past response, and blood counts. Chemotherapy ended one to four days before the CAR-T infusion was administered.
Of the forty three patients enrolled, thirty patients got the protocol-determined dose of CAR-T (15 diffuse large B-cell lymphoma, thirteen follicular lymphoma, two mantle cell lymphoma); six patients failed to produce CAR-T sufficient for infusion.
Diffuse Large B-Cell Lymphoma
Patients with diffuse large B-cell lymphoma were very sick and strenuously pretreated. At the very first response assessment three months after infusion, response rates using anatomic criteria were as goes after: overall response rate of 47%, with finish response in three patients, partial response in four, and progressive disease in eight. Best response was finish remission in six, partial response in one, and progressive disease in eight. Three of the patients with a partial response at three months converted to accomplish remission by six months; one patient with a partial response developed progressive disease.
No patients who achieved a finish remission have relapsed at a median follow-up of 14.Five months, Dr. Schuster told listeners.
“Most of the disease progression [on CAR-T] occurs before three months. You don’t need a CT scan to showcase progressive disease. However, those who achieve finish remission by six months stay in remission. We have one patient in [finish remission] for eighteen months,” he said.
“In [diffuse large B-cell lymphoma], the peak in vivo expansion of T cells doesn’t correlate with response rates,” he added.
Durable responses were observed with a single infusion of CAR-T cells, and persistence of T cells was seen on flow cytometry out to one year. In seven responding patients, the median overall response rate had not been reached at 14.Five months.
“These results in primary refractory [diffuse large B-cell lymphoma] are fairly incredible,” Dr. Schuster said.
Follicular and Mantle Cell Lymphoma
Patients with follicular lymphoma had a median age of fifty nine and had received a median of five prior therapies. One-third had undergone prior stem cell transplant, 71% had enlargened LDH, and 29% had more than one extranodal site.
In eleven evaluable follicular lymphoma patients, the 3-month overall response rate was 73%; there were four patients with accomplish remission, four with partial response, and three patients with progressive disease. Best response rate was 73%, with seven finish remissions, one partial response, and three patients with progressive disease. Three of the patients with a partial response converted to accomplish remission by six months.
The majority of patients who responded have continued to maintain a response at one year. As in the patients with diffuse large B-cell lymphoma, the peak in vivo expansion of CAR-T cells did not correlate with remission. A median follow-up of 14.Three months demonstrated durable responses in those who achieved partial response or accomplish remission, he said.
Looking at overall toxicity, cytokine-release syndrome—mostly grade 2—was reported as ≥ grade three in four patients. Also, reversible central jumpy system toxicity was reported, including agitation and delirium. One case of encephalitis was fatal.
Based on these promising results, investigators conducting a phase II trial called JULIET are planning to enroll adults with diffuse large B-cell lymphoma early in 2016. ■
Disclosure: Dr. Schuster has received consultant fees and/or research funding from Pharmacyclics, Novartis, Janssen, Nordic Nanovector, Celgene, Genentech, and Hoffmann-La Roche.
1. Schuster SJ, Svoboda J, Nasta SD, et al: Sustained remission following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Two thousand fifteen ASH Annual Meeting. Abstract 183. Introduced December 6, 2015.
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Pro Point of View: Marcela Maus, MD
Commenting on the investigate introduced by Schuster et al at the two thousand fifteen ASH Annual Meeting and Exposition, Marcela Maus, MD, Director of the Cellular Immunity Program at Massachusetts General Hospital in Boston, said: “These are amazing results. The probe shows that [chimeric antigen receptor.