MIAMI BEACHLong-term follow-up of the pivotal trial of rituximab(Drug information on rituximab) (Rituxan) in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkins lymphoma (NHL), shows a median duration of response of nearly 1 year (11.6 months), Peter McLaughlin, MD, reported at a poster session of the American Society of Hematology (ASH) meeting.
As previously reported, 80 of 166 patients (48%) responded to rituximab, an anti-CD20 chimeric monoclonal antibody, with 6% complete responses. To date, 20 of the 80 responders (25%) are still in remission, some up to 3 years after treatment, said Dr. McLaughlin, associate professor of medicine, M.D. Anderson Cancer Center.
This study also confirmed that patients treated with rituximab after their first chemotherapy relapse had a higher response rate (57%) than those treated after second (46%) or third relapses from chemotherapy (38%), Dr. McLaughlin said. In refractory patients, the overall response rate was 29% (6 of 21).
Co-author Antonio Grillo-López, MD, chief medical officer of IDEC Pharmaceuticals, said at a press briefing that since treatment of these patients is rarely curative, the therapeutic goal is not necessarily complete response rate but rather overall response rate and longer duration of responses.
Also at ASH, Thomas Davis, MD, of the National Cancer Institute, presented data showing that patients who respond to rituximab can be safely retreated in case of relapse. This phase II study enrolled 58 patients with relapsed or chemotherapy refractory low-grade or follicular B-cell non-Hodgkins lymphoma who had responded to rituximab.
40% Responded a Second Time
Of 57 patients evaluable for efficacy, 23 (40%) responded a second time to rituximab, with 6 (11%) complete re-sponses. To date, the median duration of response is 15+ months (range, 2.5 to 25.1 months), and median time to progression is 16.7+ months (range, 4.6 to 26.6 months).
Dr. Grillo-López said that Rituxan can be used to retreat patients without impairing bone marrow function and at the same time deferring toxic alternative treatments. Adverse events seen with retreatment were similar to those seen with initial treatment.
Of interest, five patients have received a third course of rituximab: Three of these responded, one had stable disease, and one was not evaluable for efficacy. One patient has subsequently received a fourth course of rituximab treatment.
Dr. Grillo-López presented a report on the response criteria used in the rituximab pivotal trial. Presently, he said, there are no standard response criteria for non-Hodgkins lymphoma as there are for solid tumors, chronic lymphocytic leukemia, and Hodgkins disease. Without standard criteria, physicians have no benchmark for evaluating reported response rates of various clinical trials.
He noted that a group of non-Hodgkins lymphoma experts established the stringent response criteria that were applied in the rituximab studies. Subsequently, he said, a panel of international lymphoma experts, along with the National Cancer Institute, have utilized our response criteria as the basis for development of standardized response criteria for measuring tumor sizes and classifying responses in patients with non-Hodgkins lymphoma.
To show how the response criteria used can affect results, the researchers applied three different response criteria to the rituximab database. Using the most stringent criteria for normal lymph node size of 1 cm × 1 cm , the complete response rate for rituximab was 6% (as reported in the pivotal trial). When measured by the less stringent criteria of 1.5 × 1.5 cm, or 2 × 2 cm, the complete response rates climbed to 18% and 28%, respectively.
Thus, without clearly defined or standard response criteria for non-Hodgkins lymphoma, reports in the literature of anticancer agent results must be weighed carefully, he said. A standardized approach will allow physicians to accurately assess new biological agents for non-Hodgkins lymphoma.
Where Does Rituximab Fit?
David Maloney, MD, PhD, of Fred Hutchinson Cancer Research Center, said at the press briefing that antibody-based treatments offer exciting new possibilities for the treatment of patients with lymphoma. However, their exact role remains to be defined.
He noted that with rituximab, there has been no identified cumulative toxicity, the treatment is relatively easy and can be done in the outpatient setting, and responses have been seen in patients with very large tumors, extensive bone marrow involvement, and enlarged spleens.
Radiolabeled antibodies currently under investigation will also add to the treatment choices of patients with lymphoma, Dr. Maloney said. However, he added that these treatments are generally more complicated, have dose-limiting toxicities, and are more difficult to combine with our current chemotherapy regimens.
Dr. Maloney said that in managing patients with low-grade lymphomas, I try to consider not only the current clinical situation of the patient but also the subsequent treatment that the patient will likely require.
For example, he said, damage to the bone marrow or the development of an immune response or HAMA (human anti-murine antibody) may limit future treatment options with other chemotherapy regimens or other monoclonal antibodies.
This appears more likely with current radiolabeled murine antibodies, and I generally reserve their use for patients who have failed treatment with rituximab. However, this issue is very complicated, and we dont yet have any clinical trial data to determine optimal sequencing.
IDEC Pharmaceuticals developed rituximab in collaboration with Genentech, Inc., F. Hoffmann-La Roche, Ltd of Switzerland, and Zenyaku Kogyo Co, Ltd. of Japan. The agent was approved for marketing by the Food and Drug Administration in November 1997, and since then has been used to treat more than 12,000 lymphoma patients worldwide.