Rituximab Helps Patients with Recurrent LymphomasKey Words
Non-Hodgkin’s lymphoma, follicular lymphoma, mantle cell lymphoma, rituximab (Rituxan®), monoclonal antibody, targeted therapy. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Summary
Two studies from Germany showed the targeted therapy rituximab (Rituxan®) to be effective in treating recurrent or refractory follicular and mantle cell lymphomas. In the first study, adding rituximab to a standard chemotherapy regimen improved response rates, progression-free survival, and possibly overall survival - when compared to chemotherapy alone. In the second related study, patients whose recurrent lymphoma had been responsive to the same rituximab combination had their outcomes further improved when they continued to receive rituximab-alone for maintenance.
Source
American Society of Clinical Oncology (ASCO) annual meetings, in Orlando, Florida, May 15, 2005, and Atlanta, Georgia, June 4, 2006.
Background
Follicular lymphoma, one of the most common non-Hodgkin's B-cell lymphomas, is a slow-growing (indolent) cancer that can become more aggressive over time; half of the patients survive eight to 10 years and half longer after diagnosis. These statistics, however, are drawn from the era before rituximab; recent studies suggest that patients will live longer with the use of rituximab. Mantle cell lymphoma is a rare, fairly aggressive form of the disease that is often resistant to chemotherapy; half of these patients will survive three to four years after diagnosis and half longer.
Because standard treatments have been unable to cure either of these diseases, biological and targeted therapies are being actively investigated. One such therapy is rituximab (Rituxan®).
The two coordinated rituximab studies described here were led by Wolfgang Hiddemann, M.D., Ph.D., and Martin H. Dreyling, M.D., Ph.D., from Ludwig Maximilians University in Munich, Germany, researchers with the German Low Grade Lymphoma Study Group. Study 2 followed only those patients who had responded to the rituximab plus chemotherapy combination used in Study 1.
Preliminary results for both studies were presented at the ASCO meeting in 2005 (see the 2005 meeting abstract), and final results for Study 2 on rituximab maintenance were presented at the ASCO meeting in 2006 (see the 2006 meeting abstract).
Study 1
In 1998, researchers with this phase III clinical trial began enrolling patients primarily with advanced follicular (about 50 percent) or mantle-cell lymphoma (about 40 percent) who had relapsed after initial treatment. A few patients had other forms of indolent lymphoma.
The goal was to see if adding rituximab to a standard chemotherapy regimen would increase the likelihood of patients going into full or partial remission (also called complete or partial response). By 2001, more than 300 patients had enrolled.
Initially, patients were randomly assigned to receive either FCM (a chemotherapy regimen including the drugs fludarabine, cyclophosphamide, and mitoxantrone) or FCM plus rituximab (R-FCM). When a statistical analysis showed that patients in the R-FCM group were responding significantly better to their treatment, the FCM-only arm was closed.
Patients who enrolled in the study after this point were assigned to a separate R-FCM group. Final data were collected and analyzed from both the randomized and non-randomized R-FCM groups.
Results of Study 1
By the time the FCM-only arm was closed, 130 patients had been accrued and randomly assigned. The R-FCM group, consisting of 65 evaluable patients, experienced significantly better complete response rates (33 percent vs. 12 percent) as well as better overall response rates (79 percent vs. 58 percent) than those who received FCM-alone. (Overall response rates include patients who experienced either a complete or partial response to treatment.)
Subsequently, the 111 additional patients who were enrolled in the non-randomized R-FCM group showed results comparable to those in the randomized R-FCM group, with a complete response of 27 percent and an overall response rate of 85 percent.
Progression-free and overall survival were also significantly superior in both arms that received rituximab, according to the study’s researchers, compared to patients in the closed arm who had received chemotherapy only.
In all three groups, patients with follicular lymphoma responded slightly better to R-FCM than did those with mantle cell lymphoma.
Study 2
The first study explored whether the addition of rituximab to a standard chemotherapy regimen could improve remission rates in relapsed patients. The second, related study asked a further question: after those same patients achieve a complete or partial remission with an R-FCM regimen, will they stay in remission longer (experience a longer “response duration”) if they continue treatment with rituximab alone (known as maintenance therapy) or if they receive no further treatment and are simply observed?
One hundred and ninety-five patients from Study 1 who had been randomly or directly assigned to receive treatment with R-FCM, and who had experienced a complete or partial remission of their disease, were now randomly assigned to one of two groups for Study 2: they either received rituximab alone (four weekly doses at three months and again at nine months) or no treatment, as researchers followed their progress to see when and if their cancer recurred.
Not as many mantle cell patients responded to R-FCM and thus progressed to Study 2; therefore the ratio of follicular to mantle cell lymphomas changed from about 5-to-4 to about 2-to-1.
Results of Study 2
Of the 195 patients randomly assigned to continue in Study 2, 176 were evaluable in terms of final results. Patients in the watch-and-wait group relapsed at a median of 17 months after they’d completed treatment with R-FCM, while those in the rituximab-maintenance group had so little recurrence that the median time to progression had not been reached more than four years after they received rituximab maintenance.
The advantage was seen in 81 follicular patients and 47 mantle cell patients. At the three-year mark, about 40 percent of mantle cell patients who received rituximab maintenance were still in remission, compared to none in the watch-and-wait group. The results for overall survival showed a non-significant trend in favor of rituximab maintenance: at a median of three years; 22 of 71 watch and wait patients had died, compared to 11 of 67 patients who received rituximab maintenance.
Comments
These studies “clearly show that rituximab improves progression-free survival and prolongs the duration of response,” said Wyndham Wilson, M.D., Ph.D., chief of the lymphoma section at the National Cancer Institute’s Center for Cancer Research. He noted that other standard chemotherapy regimens are used for these diseases as well (for example, CHOP, CVP) and that studies have shown they, too, work better when rituximab is added. Now, he said, doctors can add fludarabine-based chemotherapy to that list.
Hiddeman at the 2006 ASCO meeting called the overall survival data very promising, reaching what he called “borderline significance” at a median of 28 months. He pointed to almost identical survival results from another European study testing rituximab maintenance after initial treatment with CHOP and rituximab.
“Most clinicians will add rituximab to whichever therapy they are using to treat follicular lymphoma,” said John Janik, a physician in the metabolism branch of the Center for Cancer Research at the National Cancer Institute. These data add to other suggestive evidence that adding rituximab may increase overall survival for follicular lymphoma patients.
Limitations
While Wilson agrees that rituximab is effective and does extend response duration and progression-free survival, it is still uncertain if its early use, compared to later use, actually extends patient lives. “What makes data on patients’ overall survival persuasive in any clinical trial is a carefully controlled group of patients,” he said.
In these two trials, however, patients who progressed did not stay in the active study population. Instead they were treated as warranted by their cancer, outside of the study’s limits. In some 30 to 40 percent of cases, said Dreyling, these patients may have received rituximab later. This, said Wilson, potentially confounds the survival results.
Janik does not agree with the advantage the study’s authors claim for rituximab in treating mantle cell lymphoma. “It is always best to separate data on these two very different kinds of lymphoma,” he said. “Persuasive clinical trials in the United States have shown the benefits of rituximab for mantle cell patients are transitory, and there is no good evidence suggesting it helps these patients live longer.
The responses to rituximab maintenance treatment in this trial are predictable, says Janik. “If you are selecting your patients on the basis of a positive response to rituximab, as they did here, there is no reason most of the patients won’t continue to respond. But most trials show that most patients eventually develop rituximab resistance.”
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