Follicular Lymphoma (2005)

A meta-analysis of 10 Phase III studies has found that interferon-α2 prolonged survival and the duration of remission in patients with follicular lymphoma when given initially along with relatively intense chemotherapy and at a dose of at least 5 million units a month (for a cumulative monthly dose of at least 36 million units). Still, notes lymphoma expert James O. Armitage, MD, it may be too late to incorporate interferon into current regimens for a number of reasons, including its toxicity and its being superceded by newer, better tolerated chemotherapies, immunotherapy, and radioimmunotherapy, such as rituximab, ibritumomab tiuxetain (Zevalin), and I-131tositumomab (Bexxar). Interferon-α2 has been widely used to treat follicular lymphoma in Europe, but not in the United States, and according to Dr. Armitage, this is partly due to a negative attitude toward the drug on the part of US oncologists. “Interferon-α2 is an active drug in follicular lymphoma, but it has never been a popular drug in the US, partly because it is difficult to administer. It has always amazed me that hepatologists who use it for chronic hepatitis can get their patients to take interferon, but oncologists say they can't,” said Dr. Armitage, who is Joe Shapiro Professor of Medicine and Distinguished Chair of Oncology at the University of Nebraska Medical Center and a member of OT's Editorial Board.Figure: James O. Armitage, MD: “Interferon alpha-2 is an active drug in follicular lymphoma, but it has never been a popular drug in the US, partly because it is difficult to administer. It has always amazed me that hepatologists who use it for chronic hepatitis can get their patients to take interferon, but oncologists say they can't.”Dr. Armitage noted that the amount of benefit derived from the use of interferon-α2 in patients with follicular lymphoma, as demonstrated in the meta-analysis, was as good or better than therapy for patients with breast cancer, yet the negative attitude toward this agent persists. “There appears to be a subgroup of patients whose survival is improved by interferon-α2. Maybe this meta-analysis will make oncologists re-think using this drug,“ Dr. Armitage commented. He added that although interferon-α2 was approved for melanoma in the US in the late 1980s, it did not gain approval for follicular lymphoma until a decade later and then became reimbursable. By that time, rituximab was being used and was easier to use and thus more attractive to oncologists. Author's Perspective The lead author of the meta-analysis (published in the April 1 issue of the Journal of Clinical Oncology [2005; 23:2215–2223] and supported in part by a grant from the drug's manufacturer, Schering-Plough), Ama Z. S. Rohatiner, MD, Professor of Hemato-oncology at St. Bartholomew's Hospital in London, said that the results need to be viewed in the context of the current situation for oncologists and patients: “It is a sad situation. Interferon-α2 could prolong survival, but it is quite toxic and difficult for patients to take. With initial treatment, patients get flu-like symptoms that resolve, but they suffer severe fatigue over a long period of time. “The fact is that we have new and better treatments now, such as chemotherapy combinations, antibodies, and radiolabeled antibodies that are easier to take. Although these treatments have not been shown to improve survival, they are devoid of the toxicity of interferon.” Study Details The meta-analysis was conducted partly because previous randomized controlled trials of interferon-α2 included patients with a variety of histologic subtypes and any type of low-grade lymphoma, as well as differences regarding use of radiotherapy, she and her coauthors noted. The meta-analysis was confined to a total of 1,922 newly diagnosed patients with follicular lymphoma, and the goal was to determine whether interferon-α2 given at any point increased response rate, remission duration, and survival. The difference in survival with initial interferon-α2 as part of intensive chemotherapy increased over time, and it is likely that the curves will widen further with longer follow-up, Dr. Rohatiner said. “The meta-analysis supports the use of interferon-α2 as part of treatment for follicular lymphoma, at least when given in the context of some of the chemotherapy regimens that have been used in the last 20 years.” The studies included in the meta-analysis were conducted at a time when the standard therapy for follicular lymphoma was chlorambucil in the UK; CVP (cyclophosphamide, vincristine, and prednisone) in Europe; and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) in the US. It is difficult to know how to incorporate interferon into the present algorithms of therapy, she said. Pegylated interferon-α2 has less toxicity than interferon-α2 when studied in chronic myelogenous leukemia, and may hold promise as an alternative to interferon-α2. ‘3 Phenotypes’ Dr. Armitage said, “In the US, oncologists fit into what I jokingly call ‘three phenotypes’ for treating follicular lymphoma. Today, all the regimens are used along with rituximab. There is the Stanford approach with CVP + rituximab; the SWOG approach with CHOP plus rituximab; and the M. D. Anderson approach with fludarabine and mitoxantrone plus rituximab.” A Phase II trial is currently being conducted under the auspices of the Southwest Oncology Group (SWOG) to determine the effect of interferon-α2 on a contemporary regimen. The study will evaluate the combination of CHOP + rituximab + interferon-α2. Entry to the study is nearly completed. “We are doing this study to determine what interferon-α2 does to CHOP-like regimens,” he said.