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Numerous Drug Classes Studied for Use in Follicular Lymphoma

Beth Fand Incollingo @fandincollingo
Published: Tuesday, Apr 09, 2013
Dr. Bruce D. Cheson

Bruce D. Cheson, MD

Follicular lymphoma (FL) is characterized by repeated treatment responses and then relapses, and until more effective frontline therapies become available, researchers will need to generate a growing list of drug choices to keep pace with patients’ needs, according to Bruce D. Cheson, MD, of the Lombardi Comprehensive Cancer Center at Georgetown University, Washington, DC, and chair of the Lymphoma Committee of the Alliance for Clinical Trials in Oncology/ Cancer and Leukemia Group B (CALGB).

Cheson, who spoke at the 17th Annual International Congress on Hematologic Malignancies, noted that although there are no new chemotherapy drugs in development for FL, work is being done to bring other classes of agents into the treatment armamentarium— particularly monoclonal antibodies, signaling pathwaytargeting agents, apoptosis-inducing compounds, and immunomodulatory drugs. FL, a typically indolent form of non-Hodgkin lymphoma (iNHL), makes up about 20% of the lymphomas diagnosed in the United States, according to the American Cancer Society.

Rituximab, a monoclonal antibody approved to treat FL, will soon go off patent, but other anti-CD20 antibodies are in development, Cheson said. However, to have value, he noted, such drugs will need to be more effective than rituximab or work in rituximab-resistant disease.

Ofatumumab, a humanized monoclonal anti-CD20 antibody approved under the trade name Arzerra for use in chronic lymphocytic leukemia (CLL), has shown some promise as a single agent in patients with rituximab-resistant FL. In a study of patients with rituximab-refractory FL (N = 116), ofatumumab was well tolerated and modestly active.1 In the study, 27 patients had an overall response rate (ORR) of 22% to the antibody. For all participants, median progression-free survival (PFS) was 5.8 months. PFS jumped to 9.1 months in the 46% of patients who demonstrated tumor reduction three months after the start of therapy.

Cheson said the jury is still out on the antibody obinutuzumab (GA101), which was tested in patients with relapsed FL, and generated response rates and PFS results similar to those associated with rituximab.2,3 “Whether that will go anywhere remains to be demonstrated by the ongoing trial of [alkylating agent] bendamustine with or without GA101 in rituximab-refractory patients,4” he said.

Meanwhile, two antibody drug conjugates that showed promise in phase I trials—DCDT2980S, an anti-CD22 agent, and DCDS4501A, an anti-CD79b agent—are being tested in a randomized phase II study5 Investigators are combining either of the drugs with rituximab in patients with FL and diffuse large B-cell lymphoma, and are allowing crossover at progression to check for non–cross-resistance between the two molecules, Cheson said.

Also on tap is a phase II study of ibrutinib, a specific and irreversible inhibitor of Bruton’s tyrosine kinase that demonstrated an ORR of about 40% in patients with FL in an earlier study, Cheson said. The pill-a-day regimen has been successful for as long as two years in patients with relapsed, refractory FL, he said, and the trial will shed more light on the drug’s toxicity and response rate and duration.6

Selected Novel Agents in Follicular Lymphoma

Drug Description Target
Ofatumumab Monoclonal antibody CD20
Obinutuzumab
(GA101)
Monoclonal antibody CD20
DCDT2980S Antibody–drug conjugate CD22
DCDS4501A Antibody–drug conjugate CD79b
Ibrutinib Kinase inhibitor Bruton's tyrosine kinase
Idelalisib
(GS-1101)
Kinase inhibitor Delta isoform-specific targeter of PI3 kinase
IPI-145 Kinase inhibitor Inhibits PI3K delta and PI3K gamma
ABT-199 BH3-mimetic BCL-2 to induce apoptosis
Lenalidomide Immunomodulatory Angiogenesis
Another promising development is idelalisib (GS- 1101), a delta isoform-specific PI3 kinase inhibitor, Cheson said. In a single-agent, phase I trial, 59% of heavily pretreated patients with iNHL subtypes responded to a dosage of 100 mg or more of the drug twice a day.7 The drug’s tolerability was “exceptional,” Cheson said. Grade 3-4 adverse events occurring in 5% or more of patients and due to any cause were fatigue (6%), neutropenia (8%), diarrhea (8%), pneumonia (10%), anorexia (10%), and ALT/AST elevations (27%). No pattern of drug-related symptomatic adverse events was seen.


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35th Annual Chemotherapy Foundation Symposium: Innovative Cancer Therapy for Tomorrow® Clinical Vignette SeriesJan 31, 20192.0
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