Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

Based on the following published article: Cancer Treat Rev 2007;33(2):161-76

As guideline authors of the Hematology Disease Site Group (DSG) of the Cancer Care Ontario Program in Evidence-Based Care (CCO-EBC) pointed out, research into the use of the CD20 monoclonal antibody rituximab has proliferated since it was first found to be effective in lymphoma in 1997. It has subsequently been evaluated in combination with a variety of first-line chemotherapy regimens, in patients who responded to initial treatment but who subsequently relapsed and, most recently, as maintenance therapy to sustain patients in remission. A systematic summary of the existing evidence would therefore be helpful to facilitate treatment decisions, DSG members explained.

Indolent Histology B-cell and Mantle Cell Lymphomas

Seven randomized controlled trials (RCTs) have evaluated the use of rituximab given in combination with chemotherapy in either first-line or subsequent therapy in indolent B-cell or mantle cell lymphoma. One trial has not yet completed enrolment, but all of the other RCTs have demonstrated improvements in disease control favouring rituximab, DSG members observed. Two of these studies demonstrated a significant improvement in overall survival in favour of rituximab, while a third showed a trend towards a survival benefit with the addition of rituximab.

Another meta-analysis from the Cochrane Haematological Malignancies Group of six RCTs of chemotherapy with or without rituximab in newly diagnosed or relapsed patients with indolent B-cell or mantle cell lymphoma similarly showed an overall survival advantage with additional rituximab vs. chemotherapy alone in five of the trials, supporting the DSG’s interpretation of the data. Two RCTs have been carried out in patients with resistant or relapsed indolent lymphoma who were treated with chemotherapy with or without rituximab. Results from one showed that both progression-free and overall survival were superior in patients treated with chemotherapy plus rituximab, while a trial using a different chemotherapy regimen plus additional rituximab also led to an improvement in progression-free, but not overall, survival. Based on these findings, DSG members made the following recommendations:

• Previously untreated patients with follicular or other indolent B-cell histology lymphoma (e.g. mantle cell lymphoma, marginal zone lymphoma and lymphoplasmacytoid lymphoma) who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab.

• Previously treated patients with follicular or other indolent B-cell histology lymphoma (e.g. mantle cell lymphoma, marginal zone lymphoma and lymphoplasmacytoid lymphoma) who have not previously received rituximab and who are appropriate candidates for chemotherapy should receive this chemotherapy in combination with rituximab.

Maintenance Therapy in Indolent B-cell or Mantle Cell Lymphoma

Maintenance rituximab has been evaluated following rituximab monotherapy, following initial combination chemotherapy and following second-line or subsequent combination chemotherapy. Having reviewed its use in these three main settings, the DSG concluded that five out of the six RCTs of maintenance rituximab demonstrated “clinically important improvements” in disease control, while in two of the studies, maintenance rituximab also prolonged survival.

Members thus decided that there are “clear benefits” in terms of improved disease control and overall survival in patients receiving maintenance rituximab for relapsed follicular lymphoma, and that improved disease control is preserved even in patients who have received combination chemotherapy that included rituximab. Members cautioned that maintenance rituximab has only been studied following initial combination chemotherapy without rituximab. Nevertheless, they concluded that evidence to date supports extending the use of maintenance rituximab to patients who receive initial chemotherapy plus rituximab, citing a “sizable magnitude of benefit” in disease control in this setting plus preservation of the same benefit following rituximab-based chemotherapy in the setting of relapsed disease. Based on this evidence, DSG members made the following recommendation:

• For patients with follicular lymphoma or other indolent B-cell lymphomas who respond to treatment with combination chemotherapy and/or rituximab, this treatment should be followed by the use of maintenance rituximab.

Retreatment Strategy

The role of rituximab given in combination with chemotherapy in patients who had received a prior rituximab-based combination has not been evaluated in any of the randomized trials to date. Because there is no direct evidence supporting its use in this particular setting, the DSG could not offer any definitive recommendations. Nevertheless, both practitioners and provincial policymakers sought some guidelines on this issue and in order to provide them, the group turned to non-RCT data to determine the value of rituximab in this setting.

Non-RCT data suggested that rituximab-sensitive patients could again respond to retreatment with rituximab as well as they did on initial treatment. DSG members also argued that reuse of previously effective therapies is a “common and effective” tactic in the management of indolent lymphomas and that cumulative toxicity from retreatment with rituximab would not be expected. Based upon these data, the consensus opinion of DSG members indicated the following:

• Patients who have previously received rituximab—including combination rituximab chemotherapy, rituximab monotherapy or maintenance rituximab—and who have achieved a complete or partial response and who have remained treatment-free for at least one year’s duration following the last rituximab administration and who become candidates for chemotherapy should receive chemotherapy in combination with rituximab.

Aggressive Lymphomas

Consensus interpretation of collective results from these trials “strongly” indicate a role for rituximab when added to combination chemotherapy for the initial treatment of adults with diffuse large B-cell lymphoma (DLBCL), DSG members stated. Treatment should also be given at the beginning of each treatment cycle at a dose of 375 mg/m2. As they noted, the DSG did assess the possible role for maintenance rituximab in those who have already received it in combination with upfront chemotherapy. Given that that there has only been a single trial that addressed this question—and which did not show a benefit for maintenance rituximab in this setting—the DSG concluded that there was insufficient evidence to support its use as maintenance therapy in patients who have completed initial chemotherapy that included rituximab.

DSG members also discussed the use of rituximab in patients with AIDS-related aggressive histology B-cell lymphomas, where in a single study evaluating rituximab in this setting, a difference in overall survival was not seen between treatment arms. There was also an increased risk of treatment-related infectious deaths in this particular study, especially among patients with very low CD4 cell counts. These results prompted DSG members to conclude that the evidence supporting the use of rituximab in the setting of AIDS-related lymphoma is insufficient to recommend its use at this time.

DSG members did recommend the use of rituximab in the following setting:

• Previously untreated patients with DLBCL or a variant of DLBCL such as primary mediastinal B-cell lymphoma, T-cell-rich B-cell lymphoma, Burkitt-like lymphoma, transformed lymphoma from an indolent histology or intravascular lymphoma, who are candidates for treatment with curative intent with combination chemotherapy, should receive rituximab with this therapy.

Use in Stem Cell Transplantation

DSG members also reviewed evidence evaluating the use of rituximab in patients who are eligible for high-dose therapy and autologous stem cell transplantation (ASCT). In arriving at their decision, members reviewed two RCTs in which rituximab was used prior to ASCT to help mobilize stem cells prior to transplantation and another trial where it was used after ASCT. The first two studies were underpowered to detect differences in disease control or overall survival between treatment arms, while the third report comparing maintenance rituximab with observation in patients with high-risk DLBCL who had completed high-dose chemotherapy and ASCT similarly detected no difference in event-free survival between treatment arms. Thus, DSG members concluded that evidence is currently insufficient to support the use of rituximab as part of a pre-mobilization strategy prior to, or maintenance therapy following completion of ASCT.

Summary

As the DSG discussed, members made every effort to prioritize evidence used to form the basis of the current guidelines based on the quality of the data. Nevertheless, the group recognized that there is a “hierarchy of outcomes” that influence therapeutic and policy decisions, and that while change in practice should be influenced primarily by evidence supporting prolongation or improvement in quality of life, the group acknowledged that evidence regarding the role of rituximab in lymphoma is “fluid” and “evolving” and would require ongoing evaluation, which will be posted on the CCO-PEBC Web site: www.cancercare.on.ca/index_practiceGuidelinesandEvidencesummaries.htm.

Questions and Answers

The following question-and-answer session was conducted with CCO-PEBC co-author Dr. Kevin Imrie, Department of Hematology, Toronto Sunnybrook Regional Cancer Centre and Associate Professor of Medicine, University of Toronto, Ontario.

Q: You indicated in your introduction that DLBCL may be treated with curative intent but that relapse is still common as it ultimately is in the indolent lymphomas. How has rituximab changed the overall outlook for NHLs?

A: Low-grade lymphomas are really managed as chronic diseases as the disease comes back in the majority of patients. But for aggressive lymphomas, we treat very much with curative intent and many, if not most, of our patients with DLBCL are cured now. Before the introduction of rituximab five to seven years ago, we were still aiming for a cure but it was a 50-50 sort of thing, and often the disease came back. Rituximab has significantly decreased the likelihood of recurrence [in aggressive lymphomas] and it also improves overall survival, which is not always the case with a new treatment because some treatments may decrease recurrence risk but they do not improve survival. This is one of those circumstances where survival is also improved.

Q: How did your group decide to perform this systematic review of the use of rituximab in lymphoma and issue practical guidelines based on this review?

A: Our group first looked at rituximab in lymphoma in about 1998 or 1999, when it first came out, and we have actually done several updates and even a complete rewrite of these guidelines as evidence emerged. We are now dealing with over 22 RCTs in multiple types of lymphomas so this is the most recent and most complete look at the evidence, but it is still our third or fourth look at the literature and we will probably have to review the document once again before too long. This review is new in that 1) the evidence in adding rituximab to chemotherapy for indolent lymphoma to improve survival is now compelling and 2) we also have evidence to support rituximab maintenance in indolent lymphoma after chemotherapy.

Q: Do you personally favour any one particular chemotherapy regimen to which you prefer to add rituximab? If so, what are the advantages of this particular combination regimen from your perspective?

A: One of the complexities in dealing with lymphoma is that it is not one disease, it is a group of different diseases. In the aggressive lymphomas, where evidence is most mature, treatment is fairly standardized throughout North America and in most cases, it is CHOP combined with rituximab. In the more indolent or low-grade lymphomas, there have been a series of RCTs looking at rituximab use with different chemotherapy regimens. My interpretation of the data is that it does not really matter what regimen you use, the addition of rituximab improves outcomes with all of them. However, prior to the introduction of rituximab, CVP was the standard regimen and because many of us participated in this large important trial, there was a comfort level in using CVP and we knew it was well tolerated. In addition, many Canadian physicians and patients prefer to start with less toxic therapy and to leave options open for more intensive therapy later in the disease course. This will obviously change if we get evidence to suggest one regimen is superior but right now, in most Canadian centres, we are aggressively adding rituximab to regimens for pretty much everybody, but we tend to want to use less intensive chemotherapy first. My own personal bias is to use CVP combined with rituximab first-line, primarily because we still believe low-grade lymphomas are somewhat of a chronic disease and we want to leave our options open for the next time when we will need to treat it. CHOP, in contrast, can only be given once and then you have used that option up.

Q: Rituximab does not appear to influence outcomes in patients with mantle cell lymphoma to the same extent as it does those with follicular lymphoma, yet it is still recommended for patients with mantle cell lymphoma in the treated and untreated setting. Was there a reason why the group decided rituximab is useful in this patient group?

A: Mantle cell lymphoma is a group of lymphomas that share the worst features of both aggressive and indolent lymphoma, so it is aggressive but not curable, and standard chemotherapy for this lymphoma is not really ideal. We have some real evidence of benefit for rituximab in this setting but it is somewhat less compelling than its use in aggressive lymphoma as it does improve duration of response in mantle cell lymphoma, but there is less consistent evidence that it improves survival. On the other hand, no study has shown that rituximab is harmful, so when your options are poor and patient survival is quite short, it was the group’s opinion that rituximab should be recommended in mantle cell lymphoma even if it is not completely clear what it does to survival.

Q: You indicate that the role of rituximab is fluid and evolving. Are there emerging areas where its use may be extended in the near future?

A: I would say that its use has been expanded as maintenance therapy after [initial treatment of] indolent lymphoma where survival has been improved by giving rituximab for two years [after initial treatment]; this has become standard practice throughout Canada now. In the future, I think the one significant area where we are still waiting to see its benefit is in chronic lymphocytic leukemia, the most common form of leukemia in the Western world, and because ALL expresses the CD-20 antigen against which rituximab works, it may be beneficial here as well. At the moment, we do not have compelling RCT data that rituximab is helpful in ALL, as the studies are just being done, but we anticipate that we will get an answer one way or the other in the near future. We also do not know how many times you can use rituximab as these are hard studies to do, but it was our strong consensus view that it would be silly not to make rituximab available again to patients who have a good, long-lasting response to rituximab the first time. If it has worked in the past, it should be made available and used again in combination with future chemotherapy.