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Patients treated with maintenance rituximab had three times longer progression-free survival
Maintenance Rituximab after Cyclophosphamide, Vincristine, and Prednisone Prolongs Progression-Free Survival in Advanced Indolent Lymphoma: Results of the Randomized Phase III ECOG1496 Study
Howard Hochster, Edie Weller, Randy D. Gascoyne, Thomas M. Habermann, Leo I. Gordon, Theresa Ryan, Lijun Zhang, Natalia Colocci, Stanley Frankel, Sandra J. Horning
The researchers in this study wanted to determine if giving rituximab over a long period to patients with advanced-stage, slow-growing (indolent) lymphoma after standard chemotherapy would increase the length of time before the cancer resumed growing (progression-free survival).
Since there is no cure for lymphoma, researchers continue to work on improving current approaches by trying new drugs, new combinations of drugs and, as in this study, adding maintenance therapy. Maintenance therapy is prolonged treatment given after the initial chemotherapy course has taken effect and reduced the cancer. The goal of maintenance therapy is prolonging the amount of time before the cancer returns. Maintenance therapy has been researched and shown to improve outcomes in other cancers such as acute lymphoblastic leukemia, but prior to the development of rituximab, there was limited research involving maintenance therapy for indolent lymphoma. The drug interferon was studied, but this drug can have serious side effects. In recent years, maintenance therapy using rituximab has been used in relapsed lymphoma patients producing longer survival with usually tolerable side effects.
Since this study was designed in 1996 before rituximab was a standard part of initial therapy, the combination of rituximab plus cyclophosphamide, doxorubicin HCl, vincristine and prednisone, more simply referred to as R-CHOP, has become the standard initial therapy for non-Hodgkin lymphoma.
Consequently, it is important to note that this study did not show that adding rituximab as a maintenance therapy to the current standard R-CHOP treatment extends survival. Nevertheless, this study is significant because it demonstrated that adding rituximab in a maintenance dose over time after initial chemotherapy and before relapse is a possible option for prolonging survival and extending the time before disease recurrence without intolerable side effects.
The results showed a significant increase in progression-free survival for those treated with long-term rituximab compared to patients who received no further treatment after chemotherapy.
The results showed a median progression-free survival for the rituximab treated patients that was more than three times longer at 4.3 years compared to 1.3 years. In addition, there was a 60% reduction in risk of progression. The improved progression-free survival was seen in all patients groups receiving rituximab.
Specifically, there was a total of 311 patients who could be evaluated for this study. Of these, 282 had follicular lymphoma, which is a common type of non-Hodgkin Lymphoma (NHL). It is a slow growing lymphoma that arises from B-cells, a type of white blood cell. All had received a combination chemotherapy regimen of cyclophosphamide, vincristine, and prednisone (CVP).
There were 153 randomly assigned to receive maintenance rituximab and 158 were randomly assigned to observation, meaning no further treatment. At 3 years, 68% of the rituximab group survived with no further progression of their cancer compared to 33% of the patients given no further treatment after chemotherapy. Among the subset of patients with follicular lymphoma, 64% of the rituximab patients survived progression free compared to 33% of those given chemotherapy only.
Overall, 92% of the rituximab patients survived 3 years, compared to 86% of the chemotherapy only group. Among the follicular patients, 91% survived 3 years compared to 86% of the chemotherapy only patients. After 3.7 years of follow-up, 21 rituximab patients had died compared to 30 chemotherapy alone patients who died.
Adverse side effects were minimal in both study arms. Toxic side effects during maintenance rituximab involved 1% who experienced a serious (grade 3) loss of infection-fighting white blood cells (neutropenia), and 2% experienced severe (grade 4) neutropenia. That compared to 1% of the chemotherapy alone group that experienced grade 3 neutropenia. Grade 3 infections occurred in 1% in both groups. Other grade 3 toxicities in the rituximab group included lung, heart, allergy, weight gain, and nerve problems, affecting 1% or less.
Patients with stage III and IV non-Hodgkin lymphoma who were older than 18 years, had no prior therapy, and were able to carry on most daily activities (ECOG performance status 0 or 1) were eligible. Non-Hodgkin subtypes of lymphoma included small lymphocytic, follicular small cleaved, and follicular mixed small and large cell lymphomas.
Four weeks after the last combination chemotherapy using cyclophosphamide, vincristine, and prednisone treatments, half the patients who were responding to treatment or whose cancer was not advancing were randomly assigned to rituximab, once per week for 4 weeks every 6 months for four courses. The other half were randomly assigned to an observation group, which would not undergo further treatment.
Indolent lymphomas usually respond to single-agent and combination chemotherapy regimens, meaning the cancer is reduced, or halted for a time following treatment. However, in most cases the cancer comes back, and may or may not be treated again. Over the past 30 years however, no single chemotherapy regimen has been considered to provide a “cure” in terms of providing an extended progression-free period or an overall survival advantage.
Rituximab is a monoclonal antibody drug engineered to specifically attach itself to normal B cells and more than 90% of B-cell lymphomas. It was approved for use in relapsed follicular lymphoma and indolent lymphoma in 1997. In these types of lymphoma, about 48% of patients will respond to treatment, meaning the cancer will decrease or at least stop growing in response to treatment.
Rituximab also is known to rarely cause serious adverse side effects, and these are generally limited to reactions during infusion of the drug (infusional toxicity). Under the approved dose and schedule of once per week for 4 weeks, often results in B-cell depletion that lasts for up to 6 months.
In addition, studies of the drug in the blood stream showed that rituximab remains in the blood stream for 3 to 6 months after 4 infusions. On the basis of these early findings of effectiveness and low occurrence of side effects this study was designed to test whether giving a maintenance dose of rituximab periodically over a longer period of time could extend progression-free time in indolent lymphoma.
A schedule of administration once per week for 4 weeks was repeated every 6 months (four courses) for 2 years. The primary measure of effectiveness for the study was the length of progression-free survival measured from completion of chemotherapy. They compared patients treated with maintenance rituximab to patients who received no further treatment following completion of chemotherapy.
This report shows the results after more than 4 years of following these patients.
This study provides the first large comparison of patients with untreated indolent lymphoma showing that rituximab given as a maintenance therapy after chemotherapy significantly prolongs progression-free survival. The researchers concluded that in untreated indolent lymphoma that maintenance rituximab after chemotherapy significantly prolongs progression-free survival to a far greater extent than achieved by any prior strategy and with minimal adverse side effects.
As is the case with any research, answers lead to more questions.
Since this study was designed in 1996 before rituximab was a standard
part of initial therapy this trial cannot answer questions about the
benefit of rituximab maintenance in patients who were initially treated
with the current standard treatment using chemotherapy plus rituximab.
A new study, however, the International Primary Rituximab and Maintenance
study, was designed to answer the question of whether rituximab added to
the current initial therapy, R-CHOP, as a maintenance therapy extends
progression-free and overall survival. This study has been completed
and initial results are expected to be published in 2009.
As the outlook for survival and improved quality of
life has become better, we can be optimistic that these
questions will eventually lead to answers
that provide even better outcomes and ultimately a cure for lymphoma.