New therapy for B cell NHL

ASH 2008: Novel Therapy Shows Promise in B Cell Non-Hodgkin's Lymphoma

Roxanne Nelson
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December 7, 2008 (San Francisco, California) — An investigational drug with a novel mechanism of action has shown promising activity in leukemia and lymphoma patients who were resistant to other therapies in a phase 2 study highlighted here at the American Society of Hematology (ASH) 50th Annual Meeting and Exposition. Fostamatinib disodium is the first drug to target the protein spleen tyrosine kinase (SYK), and is under development by Rigel Pharmaceuticals, Inc.

Fostamatinib produced significant responses in patients who had failed standard therapies for diffuse B cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma (CLL/SLL). It also prolonged stable disease in patients with follicular lymphoma, Jonathan W. Friedberg, MD, from the James P. Wilmot Cancer Center, University of Rochester, in New York, reported at a packed plenary session.

These results look promising, J. Evan Sadler, MD, PhD, from the Division of Hematology at Washington University, in St. Louis, Missouri, commented to Medscape Oncology, and this drug offers hope of very specific targeted therapy. One of the great success stories in recent years has been imatinib (Gleevec), which is a "beautiful example of a targeted therapy that is terribly effective, and now we are all looking for the next one," he said

"What is most exciting about this type of targeted therapy is that it confirms the laboratory findings about this B cell receptor and that inhibition of this signal does result in tumor responses and disease stability in a large number of patients," he said.

The future of this drug is going to be 2-fold, he said. "First, we are going to confirm our results in additional trials and, equally important, we are going to be doing laboratory investigations to see if we can predict which tumors are the most sensitive to this drug."

Certain normal and malignant B cells rely on "tonic" B cell receptor (BCR)-mediated survival signals, which induce the phosphorylation of the associated Ig alpha and beta proteins. It also induces the recruitment and activation of SYK, which then initiate downstream events and amplify the original BCR signal. A subgroup of diffuse large B cell lymphomas exhibits the overexpression of BCR pathway components, including SYK, and also relies on tonic BCR signaling.

Fostamatinib disodium inhibits SYK, is currently being developed for the treatment of rheumatoid arthritis, and has demonstrated significant in vitro activity against BCR-dependent non-Hodgkin's lymphomas. A phase 1 trial of 13 patients evaluated the efficacy of 2 dose levels (200 and 250 mg twice daily) and, based on those results, the 200 mg dose was selected for the current phase 2 trial.

"We tested 2 doses based on prior experience with rheumatoid arthritis patients, and we agreed the safe dose was 200 mg," said Dr. Friedberg. "The phase 2 component was the more important part of the trial."

Dr. Friedberg and colleagues assessed the efficacy of fostamatinib in 68 patients with relapsed or refractory non-Hodgkin's lymphoma in 3 separate disease cohorts: diffuse large B cell lymphoma (n = 23), follicular lymphoma (n = 21), and other B cell non-Hodgkin's lymphoma (n = 24), including SLL/CLL (n = 11), mantle cell lymphoma (n = 9), marginal zone/mucosa-associated lymphoid tissue (MALT) (n = 3), and lymphoplasmacytic non-Hodgkin's lymphoma (n = 1). The median age of patients was 61 years, and they had received a median of 5 previous therapies, including autologous stem-cell transplantation (n = 16) and radioimmunotherapy (n = 8).

Treatment with fostamatinib produced a complete or partial response in 22% of patients with diffuse B cell lymphoma (4 partial responses and 1 complete response) and in 55% of patients with CLL/SLL (6 partial responses and 0 complete responses). Among patients with follicular lymphoma, 10% of patients (n = 2) achieved a partial response, and there was 1 partial response observed in the MALT subgroup.

Stable disease was observed in an additional 23 patients, including 12 with follicular lymphoma, 4 with diffuse B cell lymphoma, 4 with mantle cell lymphoma, 2 with CLL/SLL, and 1 with MALT. The median progression-free survival among all patients was 4.5 months, but 16 patients received treatment for more than 200 days, and 14 remain in the study. Of the cohort, 4 patients with diffuse B cell lymphoma succumbed to their disease, and 1 patient with CLL died of infection after treatment.

The researchers found that, overall, fostamatinib was very well tolerated. "The patients were heavily pretreated, and they had few other therapeutic options," said Dr. Friedberg. "We have to put side effects into the perspective of patients who have had a lot of prior therapies and other chemotherapies. Very few patients experienced the typical chemotherapy side effects, such as nausea and fatigue."

There were 4 reported cases of febrile neutropenia and 8 patients requiring a dose modification because of neutropenia, hypertension, mucositis, or liver-function-test abnormalities.

This agent, Dr. Friedberg concluded, represents a safe and novel therapeutic approach that should be further developed for the treatment of B cell non-Hodgkin's lymphoma.

"The next 10 years in cancer research are going to be important," said Owen A. O'Connor, MD, PhD, associate professor of medicine at Columbia University Medical Center, in New York City. "New technology is going to be able to help us understand cancer — not just genes turned on and genes turned off, but complex signaling networks."

"It's the next wave of understanding cancer biology, so we can develop new targeted drugs," said Dr. Owen, who introduced the study when it was presented at the plenary session. "This is a nice example of how we can actually [transfer] laboratory-based work into the clinic relatively quickly."

Dr. Friedberg and most of the coauthors have received research funding from Rigel.

American Society of Hematology (ASH) 50th Annual Meeting and Exposition: Abstract 3. Presented December 7, 2008