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.

11th Congress of the European Hematology Association

Amsterdam, The Netherlands / June 15-18, 2006

According to Dr. Richard Klasa, British Columbia Cancer Research Centre, Vancouver, “The idea of maintenance is not only to keep patients in remission but also to increase response rates, perhaps even lift a patient with a minor response or stable disease into the partial remission category, or an individual with a partial remission into complete remission.” There are good reasons to use the anti-CD20 monoclonal antibody rituximab, he told delegates. CD20 antigen persists on residual or recurrent lymphoma cells in those who have had four-week courses of the antibody, so the CD20 target is still present. Its limited toxicity over a long course is also appealing and its long half-life permits dosing on a patient-friendly schedule. Studies have also shown that treatment levels correlate with response, so there is a rationale for increasing the levels or maintaining them for an extended period of time.

EORTC 20981 Trial

Dr. Klasa’s group participated in the pivotal EORTC (European Organization for Research and Treatment of Cancer) 20981 phase III trial. The induction phase was designed to compare the effect of standard cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP) chemotherapy to CHOP with added rituximab (R-CHOP) in 465 relapsed or resistant follicular lymphoma patients. The 334 patients who demonstrated either a complete or partial response to induction therapy were then randomized to maintenance therapy with rituximab or observation. The induction dose of rituximab was 375 mg/m2 on day 1 of each chemotherapy cycle, while the maintenance-phase patients received an infusion of 375 mg/m2 every three months for a period of two years or until relapse. The primary end point of the maintenance analysis was progression-free survival (PFS) and the secondary end points were overall survival (OS) and toxicity, as per NCIC common toxicity criteria.

“Inclusion criteria satisfied the condition that these were the kind of patients seen in clinical practice,” Dr. Klasa noted. “It was important that they had a maximum of two prior treatments and fully 80% had only one. Half of those were given a single agent only, so they were relatively early in the treated history of their disease and none had anthracycline as part of their previous treatment.”

Following the induction phase, the patients who were given R-CHOP achieved a significantly higher rate of complete remission than did those who received CHOP chemotherapy alone (29% vs. 16%, P<0.0001), he reported. R-CHOP also increased PFS significantly compared with CHOP alone (median 33 months and 20 months, respectively [P=0.0003]).

The first full analysis of the EORTC study demonstrated a significant OS benefit for patients treated with rituximab maintenance therapy. At a median follow-up of nearly three years, the OS rate was 85.1% for rituximab maintenance in contrast to 77.1% in the untreated cohort (P=0.011). Patients who received R-CHOP induction followed by maintenance therapy achieved a reduction in the risk of death by approximately half. Additionally, median PFS was significantly increased almost 3.5-fold with rituximab maintenance compared with the group randomized to observation (51.6 months vs. 15 months, P<0.0001). Dr. Klasa explained that maintenance therapy increased PFS for both induction arms but the best results were obtained with R-CHOP followed by rituximab maintenance.

“Results from the maintenance phase of the trial reveal that a similar number of adverse events occur following maintenance with the active drug or observation, suggesting that maintenance therapy with the immunotherapy is well tolerated,” Dr. Klasa reported. “There was a bit more neutropenia and granulocytopenia in the R-CHOP group, but it did not seem to translate into any important changes in terms of major events. Seven cases of grade 3-4 neutropenia were recorded in the observation arm compared to 11 with rituximab and the incidence of severe granulocytopenia was nine and 18 cases, respectively. Infections, mainly respiratory tract, were more prevalent among immunotherapy patients than untreated ones; 15 vs. four.” Cardiac and cutaneous events were minimal, he noted.

He concluded that the benefits of rituximab maintenance therapy have been demonstrated in at least five randomized trials for both untreated and relapsed follicular lymphoma and the type of chemotherapeutic induction does not matter very much. The pattern of improved PFS and OS is consistent when maintenance therapy is administered.

Improving Overall Survival

“The rationale for meta-analysis in the indolent lymphoma setting is the ability of rituximab to sensitize tumour cells to chemotherapy and that the combination is already known to enhance response to therapy, PFS and event-free survival,” he said. “It is of special interest because when published individually, most trials have reported non-significant trends, or borderline significance, for improvements in OS associated with immunochemotherapy. But when you put the data from all the trials together, the differences become significant,” he told delegates.

Six high-quality, prospective randomized trials involving 1478 patients with untreated, histologically confirmed indolent and mantle cell lymphoma were assessed. These trials included a rituximab component with any one of several chemotherapy protocols, including CHOP, CNOP, CVP, FCM or MCP, in this Cochrane meta-analysis. The main objective was to measure the impact of rituximab on OS, but time to progression, overall response and toxicity were also reviewed. “The Cochrane meta-analysis revealed that OS was significantly improved following treatment with immunochemotherapy compared with chemotherapy alone,” Dr. Engert reported. “This effect is very strong for indolent lymphoma, with about a 40% improvement in OS in this very short follow-up period. Significance in mantle cell lymphoma was borderline, but that was attributed to the small number of patients.”

Estimating how many deaths immunochemotherapy may prevent, he said that assuming an OS rate among follicular lymphoma patients of 90% at two years, 28 patients will need to be treated to save one life. If the risk of dying is greater, such as in the case of 70% two-year survival with mantle cell disease, then 11 will have to be treated with the antibody-chemotherapy combination to spare one life.

Cochrane reviews are important systematic assessments of health care interventions based on reliable evidence, Dr. Engert concluded. This meta-analysis demonstrates that the addition of rituximab to chemotherapy improves OS in NHL patients, particularly those with follicular lymphoma, compared to chemotherapy alone.

Immunochemotherapy Trials

Dr. Robert Marcus, Department of Haematology, Addenbrookes Hospital, Cambridge, UK, noted that there was no proven long-term benefit in PFS or OS from treatment of follicular lymphoma with anthracyclines or stem cell transplantation in the pre-monoclonal-antibody era. In fact, until the advent of rituximab, maintenance therapy had generally been considered impractical. Interferon was suggested to confer benefit by increasing tumour sensitivity to second-line chemotherapy but it has not entered general clinical practice, possibly because of its poor adverse effects and tolerability profile. In the antibody era, on the other hand, he said large randomized trials confirm that rituximab added to initial chemotherapy yields major improvements in clinical parameters, such as overall response rate, complete response rate, PFS, time to treatment failure and duration of response in untreated patients with indolent NHL.

Dr. Marcus reported on a study of 321 untreated patients with stages III to IV follicular lymphoma (Marcus et al. Blood 2005;105(4):1417-23). Cyclophosphamide/vincristine/prednisone (CVP) was given alone every 21 days for eight cycles or with rituximab (R-CVP) added on day 1 of each cycle. The latter protocol more than doubled median time to progression, relapse or death from 14 months to 33 months (P<0.0001) at a median follow-up of 30 months compared to CVP alone. Median time to treatment failure quadrupled from seven to 27 months across most patient subgroups regardless of age, bone marrow involvement, LDH levels and FLIPI status.

Significantly more patients in the immunochemotherapy arm than the CVP arm responded to treatment (81% vs. 57%, P<0.0001) and significantly more of those achieved complete remission (41% vs. 10%, P<0.0001). “In this study, the addition of rituximab to CVP demonstrated major improvements in all clinical end points with minimal additional side effects,” he concluded. “R-CVP is a highly effective, short duration and very low toxicity regimen that may now be considered as a new standard regimen for the treatment of previously untreated patients with follicular NHL.”

A co-operative trial carried out in Spain further demonstrated that induction with fludarabine/cyclophosphamide/rituximab (FCR) followed by rituximab maintenance is highly effective front-line treatment for follicular lymphoma. Focusing on clinical and molecular response rates with that combination in 75 newly diagnosed stage I and II follicular lymphoma patients who completed six induction cycles, Dr. José Tomás, M.D. Anderson International España, Madrid, said all patients responded to the induction course, with 86% obtaining a complete response, 6% an unconfirmed complete response and 8% a partial response. “A total of 45 patients [60%] were identified as having a monoclonal population at diagnosis by molecular techniques,” Dr. Tomás noted. “Only one had minimal residual disease [MRD] positive for bcl-2 cells; the others were MRD-negative. We found the FCR regimen to have very potent anti-tumour activity in newly diagnosed follicular lymphoma patients, with 95% molecular responses in a patient population in which 78% of patients had intermediate to high FLIPI scores. However, profound immunosuppression was sometimes observed, resulting in opportunistic infections and toxicity. Neutropenia increased progressively from 6% in the first cycle to 40% in the sixth cycle, and a significant reduction in lymphocyte count persisted for at least six months in nearly all patients after treatment ended.”

Questioning Established Practice

Commenting on the results of the various monoclonal antibody trials, Dr. Michele Ghielmini, Instituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland, said that, “Despite advances, follicular lymphoma remains an incurable disease. Patients achieve remission but remission is not synonymous with longer survival or better quality of life. Sooner or later, [patients] relapse. So, since rituximab maintenance after rituximab induction is effective in prolonging remission and almost without side effects, should not all indolent lymphoma patients receive rituximab maintenance therapy? Secondly, if patients receiving CHOP chemotherapy can expect to have an event-free survival of only one year, but four to five years if they receive rituximab on top of that, is the CHOP regimen really necessary? If the beneficial effect is mainly due to rituximab, why do we need CHOP at all?” he mused. “That leads to the last question: if maintenance works so well, do patients really need induction? With single-agent rituximab, do we really need concentrated weekly rituximab before going on to maintenance? Could we not just start with one infusion every two months and being an indolent disease, maybe remission will come along as time passes. And in the same vein, if rituximab works so well, do we need chemotherapy at all?”

Dr. Rien van Oers, Head, Department of Clinical Hematology, Academic Medical Center, Amsterdam, The Netherlands, said there are still three questions to be fully addressed before rituximab finds common use in clinical practice. First, what is the optimal type of induction therapy to use prior to maintenance? Recent data from the EORTC 20981 study reveal that optimal results are obtained when immunochemotherapy precedes rituximab maintenance therapy, suggesting that R-CHOP is the best choice for induction therapy in relapsed/refractory patients at the present time.

Second, what is the best way to predict and manage adverse events in patients treated with rituximab maintenance? According to Dr. van Oers, immunochemotherapy adds little to the adverse-event profile associated with chemotherapy. Rituximab is generally well tolerated and adverse events are manageable. There is no cumulative toxicity from such maintenance therapy.

Third, what is the optimal schedule for rituximab maintenance? Different maintenance schedules have been investigated, with patients receiving one dose of rituximab every two to three months or four weekly doses at six-month intervals for up to two years; each regimen has achieved significant clinical benefit. Several groups are investigating rapid infusion of rituximab as a means of reducing resource utilization and the amount of time patients spend receiving their treatment, Dr. van Oers concluded.

Questions & Answers

The following section is based on discussions with Dr. Richard Klasa, British Columbia Cancer Research Centre, Vancouver, and Dr. Max Wolf, Peter MacCallum Cancer Centre, Melbourne, Australia, during the scientific sessions.

Q: What should be done following relapse from maintenance rituximab?

Dr. Klasa: There are two categories of patients, early relapsers and those 10 years out on the progression-free end. I think the idea is to switch to another combination of drugs or a different agent for the early relapsers, but re-treat the second group with the same regimen again.

Q: How serious is the threat of infections, considering the increased neutropenia associated with rituximab?

Dr. Wolf: The majority were upper respiratory tract and lower respiratory tract, as well as some increase of skin infections. However, the number of septicemias was very small in all study arms and we did not see fatal infections during maintenance therapy. Almost twice as many patients came off study because of aggressive disease than toxicity.