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2nd European Congress on Hematologic Malignancies

Barcelona, Spain / February 24-26, 2006

As stated by Dr. David Linch, Department of Hematology, Royal Free and University College Medical School, London, UK, the monoclonal antibody (MAb) rituximab in combination with chemotherapy is currently used as first-line treatment of advanced-stage indolent lymphomas as exemplified by follicular lymphoma.

Front-line Chemotherapy

Dr. Philippe Solal-Céligny, Chief of Hematology and Medical Oncology, Jean-Bernard Cancer Centre, Le Mans, France, presented median 42-month follow-up data from his randomized phase III study evaluating the addition of the MAb to cyclophosphamide/vincristine/prednisone (CVP) therapy in patients with untreated stage III/IV follicular lymphoma. “There was a very significant difference in overall response rates in favour of rituximab-containing therapy, with complete responses [CRs] being almost four times greater in the 162 patients receiving the rituximab-containing regimen [R-CVP] than among 159 patients randomized to CVP chemotherapy alone (41% vs. 11%; P<0.0001), with a median response duration of 13.5 months in the CVP arm compared with 37.7 months in the rituximab-containing arm.”

About half the study patients had high-risk disease, defined as a Follicular Lymphoma International Prognostic Index (FLIPI) score of 3 to 5. They were given four cycles of CVP with or without the MAb and assigned to a second four cycles if they achieved a response. “The addition of the anti-CD20 MAb more than doubled median time-to-progression compared to chemotherapy alone, from 14.5 months to 33.6 months [P<0.0001] and increased disease-free survival to 44.8 months from 20.5 months [P=0.0005],” Dr. Solal-Céligny reported. The primary end point, median time to treatment failure at 42 months’ follow-up, was seven months and 27 months, respectively, which was a significant difference (P<0.0001) favouring R-CVP, he noted.

Dr. Solal-Céligny added that median time to new lymphoma treatment or death was 12.3 months in the CVP group, but nearly quadrupled to 46.3 months in the R-CVP cohort (P<0.0001). Thirty-five patients in the CVP arm and 23 in the R-CVP arm died during the 42-month follow-up, which is not a statistically significant difference because of the small number of events, but the trend was in favour of R-CVP. On the other hand, significantly more patients in the chemotherapy-alone group than in the R-CVP group died from progression of their lymphoma (25 vs. 12; P=0.02). Kaplan-Meier estimates of three-year overall survival were 81% in the CVP cohort and 89% among patients given R-CVP, which was not a significant difference.

Adverse events were generally mild or moderate, Dr. Solal-Céligny noted. As in most other trials, more grade 3 and 4 neutropenia was associated with the MAb treatment. The incidence of infusion-related syndrome, especially, has fallen markedly since experience with rituximab has been gained. Dr. Solal-Céligny suggested that this long follow-up analysis demonstrates that R-CVP chemotherapy provides extended benefits to patients, including those with high-risk FLIPI scores, who constituted half of the study population. “In our opinion, eight cycles of this combination is a standard first-line regimen for treating patients with advanced previously untreated non-Hodgkin’s lymphoma [NHL],” he concluded.

Immunochemotherapy in Aggressive Disease

A common treatment goal for diffuse large B-cell lymphoma (DLBCL) is cure with first-line therapy consisting of cyclophosphamide/doxorubicin/vincristine/prednisone/bleomycin (CHOP) given every three weeks (CHOP21). To improve on that regimen, researchers have subsequently reduced the dosing interval from three weeks to two weeks (CHOP14). Given the known clinical benefit of adding rituximab to standard CHOP21, investigators have further postulated that adding the MAb to CHOP14 might provide even greater benefit without increasing toxicity.

The RICOVER-60 trial randomized elderly patients aged 61 to 80 years with untreated DLBCL to receive six or eight cycles of CHOP14 with or without eight doses of rituximab. The primary end point was freedom from treatment failure (FFTF), with events defined as additional therapy, failure to achieve complete remission, progressive disease, relapse or death.

As explained by Dr. Jörg Schubert, Saarland University Medical School, Hamburg, Germany, “Interim analysis at 26 months demonstrated a trend for a better FFTF after eight cycles [58%] of CHOP14 compared to six cycles [53%]. However, the trend was neutralized with the addition of rituximab: 70% FFTF for both six and eight cycles of R-CHOP14. Adding eight doses of rituximab increases the efficacy of CHOP14, enabling the number of cycles of CHOP to be reduced and thus limit the toxicity of dose-intense chemotherapy. Response to therapy as measured by CR and unconfirmed CR (CRU) was not different between six cycles and eight cycles of CHOP14 chemotherapy, but there is a highly significant increase in CR when rituximab is included. These data confirm that the addition of rituximab to CHOP14 significantly prolongs failure-free survival and significantly extends overall survival. Once you add rituximab to the mix, there is a dramatic improvement. Importantly, the improved outcomes achieved by adding rituximab were achieved with no compromise in tolerability.”

The results with six cycles of R-CHOP14 in this largest randomized trial of DLBCL are the most promising reported for elderly patients to date. Six cycles of R-CHOP14 should be considered the reference standard, Dr. Schubert concluded.

Maintenance Therapy

According to Dr. Linch, “Clearly, if you start with your most potent therapies up front, they will undoubtedly result in the best disease-free survival from the time of diagnosis, but it will not necessarily result in better overall survival, if by using those agents early in the course of the disease, the response to them is reduced at later stages.”

Recent data from a landmark European Organisation for Research and Treatment of Cancer (EORTC) trial, however, suggest that maintenance therapy with the MAb is highly beneficial for all indolent lymphoma patients, regardless of the induction regimen used. The lead investigator of that trial remarked that he had not seen such improvement in progression-free survival (PFS) and overall survival in the past 30 years and indicated that maintenance therapy with rituximab might well become the new standard of care for these patients.

Dr. Eva Kimby, Associate Professor of Hematology, Karolinska University Hospital, Stockholm, Sweden, reported that the two main objectives of the EORTC trial were to establish the effect of adding rituximab to CHOP on day 1 of each cycle for six cycles in relapsed or resistant stage III or IV follicular lymphoma and, more importantly to her presentation, study the effect of the MAb on PFS in long-term maintenance of patients in remission who had responded to R-CHOP or CHOP induction treatment. They were followed for a median of 39 months after induction therapy and 33 months after randomization to standard observation (132 patients) or maintenance therapy with rituximab (375 mg/m2) every three months for two years or until relapse (136 patients).

“Adding rituximab to induction therapy almost doubled the number of patients who achieved CR, from 16% to 29%, and significantly extended the duration of disease-free survival by more than 50%, from 20 to 33 months [P=0.0003] at a median 39 months of follow-up. Both treatment arms yielded similar partial response rates, 52.5% and 53.7%,” Dr. Kimby reported. “A highly significant advantage was observed in PFS, which was our primary end point, among patients randomized to rituximab maintenance when compared with the observation arm, 38 and 15 months, respectively [P<0.0001],” she told delegates. This represents a 60% decrease in the risk of disease progression for patients who were given MAb maintenance therapy.

Dr. Kimby reported that the latest analysis of this EORTC trial data demonstrates that maintenance therapy with rituximab can deliver significantly improved overall survival in patients with relapsed follicular lymphoma. She noted that after three years, maintenance patients achieved an 85% overall survival rate compared to 77% of those assigned to the observation arm (P=0.011). At 33 months, rituximab reduced the risk of death by 48%.

Moreover, subgroup analysis showed little difference in improvement of overall survival among individuals in the maintenance arm, whether they underwent induction with R-CHOP or CHOP. The reduction in risk for death was 50% for those who had received R-CHOP and 48% for those who were given CHOP alone. Similarly, Dr. Kimby added, there was no significant difference in overall survival in the maintenance group between patients who had achieved partial or CRs at induction. PFS was also significantly prolonged in the MAb maintenance arm by almost 30 months in both subgroups. The R-CHOP induction subgroup given active maintenance treatment achieved 52 months of PFS, in contrast to the observation arm which reached only 23 months (P=0.0043). PFS in the maintenance group given CHOP induction was 42 months vs. 12 months for the patients in the watch-and-wait cohort (P<0.0001).

Dr. Kimby also pointed out that toxicity of CHOP and R-CHOP induction was similar and rituximab maintenance was associated with minimal toxicity. Grade 3 and 4 leukopenia was, as expected, somewhat higher during active maintenance treatment, as was granulocytopenia, and there were some pulmonary events. However, the incidence of cardiotoxicity was no greater among patients maintained on the MAb than among those undergoing watchful waiting. Grade 3 and 4 infections in the maintenance arm were 7.2% and 1.8%, respectively, compared with 1.8% and 0.6% in the observation arm and none were fatal.

The Role of New Biologics

As the first of the proteasome inhibitors to be entered into clinical trials, bortezomib is a potent and selective inhibitor of the proteasome, which is the primary component of the protein degradation pathway of a cell. It inhibits proliferation and induces apoptosis of human myeloma cell lines and also inhibits nuclear factor Kappa B activation, thereby overcoming treatment resistance and adding to the myeloma activity of dexamethasone, melphalan and doxorubicin. Targeting the ubiquitin proteasome pathway has been shown to be a valid and effective approach to treating hematologic malignancies, including selected NHL subtypes.

According to Dr. André Goy, Chief, Lymphoma Division, Hackensack University Medical Center, New Jersey, the biology of bortezomib supports combination studies with biologicals, including rituximab. His group designed a randomized, multicentre, dose-defining phase II study of combination bortezomib/rituximab for safety, response rate and duration among a population of 81 relapsed/refractory follicular or marginal zone lymphoma (MZL) patients treated once weekly with 1.6 mg/m2 bortezomib plus rituximab 375 mg/m2 or 1.3 mg/m2 plus rituximab twice weekly. The groups were well balanced in terms of prognostic indicators.

Dr. Goy reported that results showed no difference between the treatment arms in terms of CR, CRU or partial response, with an overall response rate of about 52% in the biweekly arm (41 patients) and 54% in the weekly arm (40 patients), when stable disease is included. Although few in number, patients with MZL were responders in both arms and among individuals who had received prior rituximab, response rates were 46% and 56% and included some CRs.

“The most important take-home message from the study in terms of toxicity is that when you compare arm A [bi-weekly] vs. arm B [weekly], grade 3 to 4 toxicity was 54% with the biweekly regimen in contrast to 18% with the weekly regimen,” Dr. Goy told delegates. “There was no grade 4 toxicity in the weekly arm vs. 15% in arm A, including metabolic acidosis, sepsis and thrombocytopenia. Moreover, there were no neutropenic or opportunistic infections, although four herpes zoster reactivations were observed in each arm. I think it is important that there was a difference in the amount of bortezomib received as a percentage of maximum cumulative dose: 61% in arm A [twice-weekly] and 98% in arm B [weekly]. Clearly, fewer patients were able to continue on full treatment in the twice-weekly arm. Patients received more of the expected cumulative dose in the weekly schedule,” he noted.

Dr. Goy concluded that bortezomib/rituximab therapy is feasible with much less toxicity when given once-weekly, even when a higher percentage of intended dose is actually delivered, and the activity in relapsed/refractory follicular lymphoma and MZL patients in both arms was greater than 50%. “We need more follow-up for survival and duration of response and a phase III trial is to be starting soon,” he stated.

Questions and Answers

The following question-and-answer section was conducted with Dr. Eva Kimby, Associate Professor of Hematology, Karolinska University Hospital, Stockholm, Sweden; Dr. Philippe Solal-Céligny, Chief of Hematology and Medical Oncology, Jean-Bernard Cancer Centre, Le Mans, France; and Dr. David Linch, Department of Hematology, Royal Free and University College Medical School, London, UK.

Q: In the EORTC study, did patients who had prior R-CHOP and were then assigned to rituximab maintenance treatment derive as much benefit as the ones who previously had just CHOP?

Dr. Kimby: We did not think of that when we made the first analysis, but the patients were stratified, so we think that conclusion can be drawn. There was a significant improvement in those patients.

Q: If a combination regimen is to be used up front, should it be with an anthracycline-containing regimen?

Dr. Solal-Céligny: There are pros and cons. In the era before anti-CD20 MAbs, doxorubicin up front did not improve follicular lymphoma prognosis and we do not yet know if rituximab will change that, even though some results suggest that R-CHOP yields better results than R-CVP. There is the problem of cardiac toxicity because these patients will now live 15 years or longer. An anthracycline will hamper salvage treatment. In case of histologic transformation, it will be very difficult to treat them again with an anthracycline.

Q: Do you intend to give anthracyclines to a patient up front, out of trial?

Dr. Solal-Céligny: After 65 years of age, no. Before 65, depending on the FLIPI risk, I may treat him with an anthracycline-containing regimen. In patients with a disseminated low or intermediate risk, I will first try a non-anthracycline-containing combination.

Dr. Kimby: No anthracyclines. I think transformations are very common and I want to save anthracyclines for the occasions when they appear.

Q: Was there a correlation between lymphocyte counts and infections on maintenance with rituximab?

Dr. Kimby: There were some grades III and IV toxicity regarding neutropenia and lymphopenia compared to the non-maintenance arm, but they were not related to infections.

Q: Is follicular lymphoma a curable disease or is rituximab just a way to postpone classic chemotherapy?

Dr. Linch: There is no evidence yet that rituximab in combination with chemotherapy is leading to cure. But even if there were just a relatively small cure rate, say 20%, that would be incredibly important.