Reports

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42nd Annual Meeting of the American Society of Clinical Oncology

Atlanta, Georgia / June 2-6, 2006

According to Dr. Martin Dreyling, Malignant Lymphoma Group, University of Munich-Grosshadern Hospital, Munich, Germany, final results of a prospective, randomized trial of the German Low Grade Lymphoma Study Group (GLSG) confirmed that maintenance therapy with rituximab following combined chemoimmunotherapy is both safe and highly effective in patients with relapsed or refractory follicular lymphoma and, to a lesser extent, relapsed or refractory mantle cell lymphoma. The study involved patients with follicular and mantle cell lymphoma, all of whom had either relapsed or proven refractory to previous chemotherapy. Other entry criteria included the presence of symptoms requiring treatment, a large tumour burden or rapid disease progression. “Performance status had to be fairly good and there were two sequential randomizations,” Dr. Dreyling indicated.

The initial randomization was to chemotherapy consisting of four courses of fludarabine 25 mg/m2/day on days 1 to 3; cyclophosphamide 200 mg/m2/day on days 1 to 3; and mitoxantrone 8 mg/m2/day on day 1, given either alone or with rituximab 375 mg/m2/day on day 0. “Results from the first randomization confirmed that overall survival [OS] is improved by the addition of the antibody in combination with chemotherapy,” Dr. Dreyling stated.

Approximately 200 patients who had responded to chemotherapy±rituximab with either a complete response (CR) or a partial response (PR) were subsequently randomized to either a watchful waiting arm or maintenance rituximab 375 mg/m2/week for four weeks, given at three and nine months after completion of salvage therapy. Approximately two-thirds of patients included in the second randomization had follicular lymphoma and one-third had mantle cell lymphoma.

Eighty per cent of patients in both study arms of the second randomization had received combination chemotherapy/rituximab during the induction phase. There was a significant increase in progression-free survival (PFS) in the maintenance treatment arm over the three-year follow-up. Overall, 50% of patients in the maintenance arm did not progress over the course of follow-up vs. 20% in the observation arm. In the follicular lymphoma patient subgroup, 70% did not progress over follow-up compared with 40% in the watchful waiting arm.

Mantle cell lymphoma tends to be far more aggressive than follicular lymphoma and according to other investigators, patients do not appear to benefit from additional rituximab maintenance therapy. However, noted Dr. Dreyling, “We found that these patients derived at least some benefit from maintenance rituximab, with some achieving ongoing remissions such that after three years, PFS rates were 40% in the maintenance arm.” Very few patients in the observation arm were similarly free of disease progression at three years, he added.

At the same study end point, there was a trend towards improved OS that achieved borderline significance in favour of the maintenance arm, with 82% in this cohort still alive at three years compared with 55% of the observation arm (P=0.056). The rate of infection was not different between the two study arms. Leukocyte and lymphocyte counts were not significantly lower in the maintenance arm.

Follicular Lymphoma Results Confirmed

Dr. Dreyling and colleagues carried out a parallel study, again in relapsed follicular lymphoma. Patients received an initial induction regimen of rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP). Patients who responded to the induction phase were again randomized to maintenance rituximab—“eight applications but given just once every three months,” Dr. Dreyling remarked—or to observation alone. “Results were almost superimposable,” he told delegates, “and for OS, there was again a borderline significant benefit for patients treated with maintenance rituximab (P=0.059).”

Another prospective, randomized trial similarly supports the benefit of combining the monoclonal antibody with chemotherapy during the induction phase followed by maintenance interferon (IFN). Dr. Charles Foussard, Hematology Department, CHU-Hôtel Dieu, Angers, France, presented findings on behalf of GELA-GOELAMS (Groupe d’Etude des Lymphomes de l’Adulte-Groupe Ouest-est d’étude des Leucémies Aiguës et autres Maladies du Sang) investigators. The study compared the impact of administering 12 cycles of CHVP (cyclophosphamide 600 mg/m2, doxorubicin 25 mg/m2, etoposide 100 mg/m2 and prednisone 40 mg/m2) plus 18 months of IFNa-2b 4.5 MU administered t.i.d. (reduced to 3 MU in patients aged >70 years) (CHVP-IFN) to that of six courses of the same chemotherapy regimen plus six infusions of rituximab 375mg/m2 followed by 18 months of maintenance IFNa-2b (R-CHVP-IFN). The primary end point was event-free survival (EFS). Inclusion criteria consisted of previously untreated stage II to IV follicular lymphoma patients requiring treatment due to a high tumour burden. A total of 183 patients received CHVP-IFN and 175 patients received R-CHVP-IFN. The regimen consisted of CHV given on day 1, and P on days 1 to 5. Arm A received CHVP monthly for six months followed by another six courses every two months along with IFNa-2b. Arm B received six monthly courses of CHVP, the same 18 months of maintenance IFNa-2b plus six infusions of rituximab on days 1 and 8 of course 3 and 4, and on day 1 of courses 5 and 6.

As the group originally reported at the American Society of Hematology meeting in 2004, their first analysis of all 358 patients demonstrated a significant improvement in response to therapy in the rituximab-containing arm at both six and 18 months. Indeed, at a median follow-up of 30 months, the median EFS rate had not been reached in either arm but the estimated rate at 2.5 years was 78% in the rituximab-containing arm vs. 62% in the arm without.

In their second analysis, the median follow-up was 42 months and the median EFS for the whole population has not yet been reached, investigators reported. However, outcomes are still highly promising in the rituximab-containing arm.

At 42 months, CRs were observed in 75% of the rituximab-maintenance arm (arm B) vs. 60% for arm A. PRs were seen in 6% of arm B vs. 12% of arm A, while disease stabilized or progressed in 19% of arm B vs. 28% of arm A. EFS rates were 81% in the R-CHVP-IFN arm vs. 62% in the CHVP-IFN arm again at 42 months, while OS rates at the same study end point were 91% and 84% (P=0.029) for arms B and A, respectively. Improvement was also seen in patients with low, intermediate and high Follicular Lymphoma International Prognostic Index (FLIPI) scores, Dr. Foussard added. He concluded that, “In this phase II trial, rituximab combined with CHVP and IFNa-2b induces a high response rate in follicular lymphoma patients with a high tumour burden. It also allows you to reduce the duration of chemotherapy and improves OS in these patients and it reduces the risk of death by [a factor of] 2.”

In discussing these and related studies, Dr. Andrew Zelenetz, Chief, Lymphoma Service, Memorial Sloan-Kettering Cancer Center, New York, noted that this study and several others in which rituximab was combined with CHOP all show the same benefit. For example, a phase III trial from the European Organization for Research and Treatment of Cancer, as presented by Dr. Marinus Van Oers, Academic Medical Centre, University of Amsterdam, The Netherlands, and colleagues at ASH 2005, provides additional evidence supporting the use of rituximab maintenance therapy in relapsed, low-grade non-Hodgkin’s lymphoma.

In this study, investigators used an induction regimen consisting of CHOP or rituximab/CHOP (R-CHOP), followed by a second randomization to extended-dose monoclonal antibody or observation. Results showed that the use of rituximab maintenance significantly improved median PFS and at three years, the OS rate was 83% vs. 72% for those who were not on maintenance therapy.

Of note, no evidence has materialized in any of the maintenance trials with rituximab to support concerns that long-term use of the monoclonal antibody might impair humoral immunity and lead to excessive infections or reactivation of latent viral infections.

Diffuse Large B-cell Lymphoma

Results from a study involving elderly patients with diffuse large B-cell lymphoma (DLBCL) suggest that a modified course of rituximab plus chemotherapy provides a positive clinical benefit.

As pointed out by lead author Dr. Eric Raefsky, Sarah Cannon Research Institute, Nashville, Tennessee, treatment with R-CHOP has been shown to improve survival in this patient population. In fact, R-CHOP is considered the standard of care for DLBCL. However, as investigators noted, the administration of six to eight courses of R-CHOP is very difficult in certain patient groups. For example, anthracyclines are contraindicated in patients with decreased ejection fractions. Patients over the age of 70 years with DLBCL also often have poor performance status or other medical illnesses that complicate treatment.

Previous attempts to develop a well-tolerated but still active regimen for such patients have so far been unsuccessful. Thus, in this phase II trial, investigators tried to develop a regimen that was both effective and tolerable for DLBCL patients unable to receive the standard six to eight cycles of R-CHOP. To that end, they reduced the duration of chemotherapy to three courses and substituted mitoxantrone for doxorubicin.

They also used maintenance rituximab in those patients who responded to three courses of the regimen. A total of 35 patients with previously untreated CD20+ DLBCL who were either over the age of 70 years or were poor CHOP candidates because of comorbidities, ECOG 2 performance status or a reduced ejection fraction, were enrolled in the trial. Cyclophosphamide was delivered at a dose of 500 mg/m2 together with mitoxantrone 10 mg/m2 and vincristine 1 mg/m2 on day 1. Oral prednisone was given at a dose of 80 mg on days 1 through 5 and pegfilgrastim was given at a dose of 6 mg on day 2. Cycles were repeated every 21 days, at which point responders were treated with maintenance rituximab 375 mg/m2 for four doses. The first course of maintenance rituximab was initiated at week 12 and then treatment courses were repeated every six months for a total of four courses.

At the time of their presentation, 91% or 32 patients in the study had completed three courses of R-chemotherapy, and all of them had either an objective response to treatment or stable disease. Twenty-four of these patients had received maintenance rituximab and at the time of publication, two patients had completed treatment.

Ten patients (31%) achieved a CR to initial therapy, while 12 patients (38%) achieved a PR. Disease stabilized in the final ten patients (31%). At a median follow-up of 12 months, the PFS rate is estimated to be 92%, with a projected two-year PFS rate remaining at 92%.

Grades 3 and 4 neutropenia occurred in roughly one-third of patients. There was some grade 3 thrombocytopenia, but most grade 3 non-hematologic toxicities occurred in <10% of the patient group, and there were no grade 4 non-hematologic toxicities.

The PFS rate of 92% at two years is surprisingly high, suggesting a role for maintenance rituximab following abbreviated chemotherapy. Investigators cautioned, however, that further evaluation is required.

Summary

A common theme from studies presented at this year’s ASCO meeting is that the use of rituximab during both the induction phase and as maintenance therapy significantly improves outcomes for patients with relapsed or refractory follicular lymphoma and, to a somewhat more limited extent, mantle cell lymphoma.

It is noteworthy that the addition of rituximab does not increase the toxicity profile of chemoimmunotherapy regimens, and it is not associated with an increased risk of infection when used on its own. Questions and Answers

This question-and-answer section is based on an interview with Dr. Martin Dreyling, University Hospital Grosshadern, Munich, Germany.

Q: Was there any difference in OS if you broke the cohort up into patients with follicular lymphomas vs. those with mantle cell lymphoma?

A: At this point in time, we did not see a major difference in OS but it is rather an early time point for OS so we can only conclude that right now there was no major difference between the two groups.

Q: Do you think this study is sufficient to confirm the benefit of using rituximab in both the induction phase with chemotherapy plus as maintenance therapy?

A: One study does not tell you the whole story. We also carried out a parallel study, again in relapsed follicular lymphoma, and in this study, patients received an initial induction regimen of R-CHOP. Following induction, those who responded were again randomized to either maintenance rituximab, eight applications given just once every three months, or to observation alone. Results were almost superimposable on our results. As for OS, there was a borderline significant benefit for patients treated with maintenance rituximab (P=0.059).