Enhancement of survival parameters in follicular lymphoma
This report is based on medical data presented at a medical convention recognized or published in a journal with a reading committee or in a commentary signed by a recognized health professional. The subject matter discussed in this report is only for recognized health professionals in Canada.
2nd European Congress on malignant hemic
BARCELONA, Spain/24-26 February 2006
As Dr. David Linch, Department of Hematology, Royal Free and University College Medical School, London, UK, says, the Association of Rituximab (monoclonal antibody) with chemotherapy is currently the first-line treatment Advanced indolent lymphomas, of which follicular lymphoma is an example.
First Instance chemotherapy
Dr. Philippe Solal-Céligny, chief, Hematology and Medical oncology, Jean-Bernard cancer Centre, le Mans, France, presented data from a median follow-up of 42 months from his randomized phase III trial on the addition of monoclonal antibody to CVP (cyclophosphamide/vincristine/prednisone) scheme in patients with stage III or IV follicular lymphoma never treated. There was a very significant difference in the overall response rate for rituximab-based treatment, with the number of complete [RC] responses being almost four times higher in the 162 patients in the rituximab group [R-CVP] than in the 159 CVP group patients alone (41% vs. 11%; p < 0.0001). The median duration of the response was 13.5 months in the CVP group, compared to 37.7 months in the rituximab group.
About half of the patients in the trial were afflicted with high-risk lymphoma, according to the International Prognostic Index (IPI) for follicular lymphoma (score 3 – 5). They received four cycles of the CVP scheme with or without monoclonal antibodies. Patients receiving a response received four more cycles. "The addition of the monoclonal anti-CD20 antibody has more than doubled the median progression time, compared to chemotherapy alone, from 14.5 months to 33.6 months [P < 0.0001] and had cancer-free survival from 20.5 months to 44.8 months [P = 0,0005], says Dr. Solal - Céligny . The primary endpoint – the median period of therapeutic failure after 42 months of follow-up – was seven months and 27 months, respectively, which represents a significant difference (P < 0.0001) in favour of the R-CVP scheme.
The median interval before a new treatment or death was 12.3 months in the CVP group, but was nearly four times higher (46.3 months) in the R-CVP group (p < 0.0001). Thirty-five patients from the CVP group and 23 from the R-CVP group died during the 42 months of follow-up, which does not represent a statistically significant difference due to the small number of events. That said, there is a trend in favour of R-CVP. In contrast, a significantly higher number of patients in the CVP group died from a progression of their lymphoma (25 vs. 12 in the R-CVP Group; p = 0.02). According to the Kaplan-Meyer estimation method, overall survival at three years was 81% in the CVP group and 89% in the R-CVP group, the difference being not significant.
The side effects were generally mild or moderate, says Dr. Solal-Céligny. As occurred in most other trials, more cases of Class 3 and 4 neutropenia were recorded in the monoclonal antibody group. The incidence of perfusion-related syndrome, in particular, has been significantly reduced by the experience gained from the administration of rituximab. This analysis of a long-term follow-up, says Dr. Solal-Céligny, proves that R-CVP has pronounced benefits, including in patients with an IPI score that indicates a high risk, half of the patients in the trial. "In our opinion, the administration of eight cycles of this association represents a standard first-line treatment of advanced non-Hodgkin's lymphoma [NHL] ever treated," he concludes.
Immunochimiothérapie of aggressive lymphoma
One of the usual objectives for the treatment of diffuse large cell lymphoma B (LDGCB) is the healing obtained by the first-line CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone/bleomycin) scheme administered all Three weeks (CHOP21). To improve this pattern, researchers subsequently reduced the dosage interval from three weeks to two weeks (CHOP14). Given the recognized beneficial effects of adding rituximab to the standard CHOP21 scheme, investigators hypothesized that the addition of monoclonal antibody to the CHOP14 scheme could further enhance beneficial effects without aggravating Toxic effects.
In the randomized trial RICOVER-60, patients aged 61 to 80 years with untreated LDGCB received six or eight cycles of the CHOP14 regimen, with or without the eight doses of rituximab. The primary endpoint was the absence of therapeutic failure (AET), the events being defined as the administration of an additional treatment, the absence of complete remission, the progression or recurrence of lymphoma or death.
As explained by Dr. Jörg Schubert, Faculty of Medicine, University of Saarland, Hamburg, Germany, the 26-month interim analysis showed a trend towards a better rate of AET after eight cycles [58%] of the CHOP14 scheme, Compared to six cycles [53%]. In contrast, the trend was disappearing in patients who received rituximab: 70% AET for the six-and eight-cycle R-CHOP14 patterns. The addition of eight doses of rituximab increases the efficiency of the CHOP14 scheme, which reduces the number of CHOP-pattern cycles and thus limits the toxic effects of intensified dose chemotherapy. The response to treatment, as measured by the RC and the unconfirmed RC, was similar, that patients received six or eight cycles of the CHOP14 regimen, although there was a very significant increase in the RC rate when the rituximab was added. These data confirm that the addition of rituximab to the CHOP14 scheme significantly prolongs survival without therapeutic failure and has a significantly positive effect on overall survival. The addition of the rituximab provides a masterful improvement in the results. Importantly, this improvement in results is not at the expense of tolerability.
The results of six cycles of the R-CHOP14 scheme as part of the largest randomized trial on LDGCB are the most promising ever published in older patients. The administration of six cycles of the R-CHOP14 scheme should be considered as the reference treatment, to conclude Dr. Schubert.
Maintenance treatment
In Dr. Linch's view, there is no doubt that the administration of the most potent first-line treatments will give the best rates of cancer-free survival from the time the diagnosis is made. On the other hand, there will not necessarily be better overall survival if the administration of these agents early in the evolution of the disease results in a decrease in their effect at a more advanced stage.
However, recent data from a landmark trial of the European Organisation for Cancer Research and treatment (EORTC) suggest that the monoclonal antibody-based maintenance treatment is very beneficial for the whole Patients suffering from indolent lymphoma, regardless of induction treatment. The main investigator of the trial noted that he had not witnessed such an improvement in survival parameters (survival without progression [SSP] and overall survival) over the past 30 years and stated that the administration of rituximab in Maintenance treatment was called to become the new standard of care for these patients.
According to Dr. Eva Kimby, associate professor of hematology, Karolinska University Hospital, Stockholm, Sweden, the two main objectives of the EORTC trial were to determine the effect of adding rituximab to the CHOP scheme on Day 1 of Each cycle for six cycles in patients with recurrent or refractory stage III follicular lymphoma and IV, on the other hand, to study the effect of monoclonal antibody on PHC in the long-term maintenance of remission in Patients who had responded to the R-chop or chop induction scheme, this latter aspect is of greater importance for its presentation. Patients were monitored for a median of 39 months after induction treatment and 33 months after randomization into two groups: standard observation (132 patients) or rituximab maintenance treatment at 375 mg/m2 every three months For two years or until recidivism (136 patients).
The addition of rituximab to induction treatment almost doubled the number of patients who obtained an RC (16% to 29%) and significantly extended the duration of cancer-free survival by more than 50% (20 months to 33 months) [P = 0,0003] After a median follow-up of 39 months. Both treatments gave similar partial response rates (52.5% and 53.7%), argues Dr. Kimby. A very significant benefit was observed in the PHC, our primary endpoint, in patients receiving rituximab in maintenance treatment compared with patients in the observation group, i.e., 38 months and 15 months, respectively [p < 0.0001]. " This represents a 60% decrease in the risk of lymphoma progression in patients receiving monoclonal antibody in maintenance treatment.
Dr. Kimby adds that, based on the most recent analysis of this EORTC trial, rituximab in maintenance treatment can provide significant gains in overall survival in patients with recurrent follicular lymphoma. After three years, patients treated for maintenance had an overall survival rate of 85%, compared to 77% in the observation Group (p = 0,011). After 33 months, Rituximab had reduced the risk of mortality by 48%.
Furthermore, a sub-group analysis revealed little difference in overall survival gain among the subjects in the maintenance treatment group, whether they received the R-Chop or chop scheme in induction treatment. The reduction in the risk of mortality was 50% for R-chop patients and 48% for those in the chop Group. Similarly, there were no significant differences in overall survival in the maintenance treatment group, whether the patients obtained a partial response or an RC under the effect of induction treatment. Administration of the monoclonal antibody in maintenance treatment significantly extended the SSP by almost 30 months in both subgroups. Patients in the R-CHOP induction subgroup who received active maintenance treatment obtained an SSP of 52 months, contrary to what was recorded in the observation group (23 months; p = 0,0043). The SSP in the maintenance treatment group that received the CHOP induction scheme was 42 months vs. 12 months in the non-treatment Monitoring Group (p < 0.0001).
Dr. Kimby also noted that the toxic effects of the chop and R-chop induction schemes were similar and that the rituximab-based maintenance treatment was accompanied by minimal toxicity. The Class 3 and 4 Leukopenia was, as expected, somewhat more frequent during active maintenance treatment, as was the Granulocytopenia. A few lung events were also recorded. However, the incidence of cardiotoxicity was not higher in the rituximab-based maintenance treatment group than in the non-treatment monitoring group. Rates of Class 3 and 4 infections in the maintenance treatment group were 7.2% and 1.8%, respectively, compared to 1.8% and 0.6% in the observation group. None of these infections were fatal.
Role of new biological agents
The first of the proteasome inhibitors to be clinically tested, bortezomib is a potent and selective inhibitor of proteasome, the main component of a cell's protein degradation pathway. It inhibits the proliferation of human myeloma cell lines and induces apoptosis while inhibiting the activation of the Kappa B nuclear factor, thereby circumventing resistance to treatment and enhancing the activity of dexamethasone, of Melphalan and doxorubicin on myeloma. Targeting the ubiquitin-proteasome pathway represents a valid and effective treatment of malignant hemic, including some NHL subtypes.
According to Dr. André Goy, Director, Lymphoma Division, Hackensack University Medical Center, New Jersey, the biological parameters of Bortezomib support tests on its association with biological agents, including rituximab. His team developed a randomized, multi-centre phase II trial for dose-setting. The researchers examined the association of BORTEZOMIB and Rituximab to determine the safety, response rate, and duration of the response in a group of 81 patients with follicular lymphoma or marginal area lymphoma (LZM) Recurrent or refractory. Patients received a dose of 1.6 mg/m2 of bortezomib and a dose of 375 mg/m2 of rituximab once a week or a dose of 1.3 mg/m2 of bortezomib and rituximab twice a week. The groups were well balanced in terms of prognostic cues.
Dr. Goy reported that the results did not indicate any differences between the groups with respect to RC, unconfirmed RC or partial responses, the overall response rate being approximately 52% in the treatment group twice a week (41 patients ) and 54% in the weekly treatment group (40 patients), when cases of lymphoma stabilization are included. Although few patients in the two groups with LZM responded to treatment; In subjects that had already received rituximab, response rates were 46% and 56% and included a number of RC's.
"The most important message from the toxic effects study is: When comparing groups A [treatment twice per week] and B [weekly treatment], the toxic effects of Class 3 and 4 were 54% in Gro UPE Treatment twice a week and 18% in the weekly treatment group, launches Dr. Goy. There were no cases of class 4 toxicity in the weekly group vs. 15% in Group A, including metabolic acidosis, sepsis and thrombocytopenia. Neutropenic or opportunistic infections have not been observed, although four reactivations of shingles have occurred in each group. I find it important to note the difference in the volume of bortezomib administered as a percentage of the maximum cumulative dose: 61% in Group A [treatment twice per week] and 98% in group B [weekly treatment]. There is no doubt that a smaller number of patients were able to receive all their treatment in the treatment group twice a week. Patients have indeed received a higher percentage of the cumulative dose expected in the weekly treatment group, he says.
The Association bortezomib/rituximab is viable and causes much less toxicity when administered once a week, concludes Dr. Goy, even when the patient actually receives a higher percentage of the expected dose. Its activity in the treatment of follicular lymphoma and recurrent or refractory LZM in patients in both groups was greater than 50%. "We have to wait for the follow-up to get to know the data in terms of survival and the duration of the response; A phase III study is just about to begin.
Questions and Answers
The following questions and answers are taken from an interview with Dr. Eva Kimby, associate professor of hematology, Karolinska University Hospital, Stockholm, Sweden, Dr. Philippe Solal-Céligny, chief, Hematology and Medical oncology, Centre for Oncology Jean-Bernard, le Mans, France, and Dr. David Linch, Department of Hematology, Royal Free and University College Medical School, London, UK.
Q: In the EORTC trial, were patients who had already received the R-CHOP regimen and who were randomized in the Rituximab group in maintenance treatment benefited as much from treatment as those who had only received the chop scheme?
Dr. Kimby: We had not thought about that eventuality in the first analysis. Once the patients are stratified, we believe that it is possible to draw conclusions. There was a significant improvement in these patients.
Q: If an association treatment is to be administered from the outset, should it include a anthracycline?
Dr. Solal-Céligny: Yes and No. Prior to the advent of anti-CD20 monoclonal antibodies, the administration of doxorubicin at first instance did not improve the prognosis of follicular lymphoma, and we still do not know whether the rituximab will have any effect in this regard, although some Data suggests that the R-CHOP scheme gives better results than the R-CVP scheme. Cardiac toxicity must be taken into account as these patients are now called to live for 15 years or longer. Early administration of a anthracycline is detrimental to the rescue treatment. In the case of histological transformation, it will be very difficult to re-administer a anthracycline.
Q: Do you plan to administer anthracyclines in a patient who is not part of a trial?
Dr. Solal-Céligny: After 65 years, No. Before 65 years, I might choose a anthracycline-based scheme, according to the IPI score. In patients with low or intermediate risk of disseminated lymphoma, I would first opt for an association without anthracycline.
Dr. Kimby: No. I believe that transformations are very common and I want to keep the anthracyclines for the cases where they would appear.
Q: Was there a correlation between lymphocyte counts and infections during the administration of rituximab in maintenance treatment?
Dr. Kimby: Some cases of neutropenia and Lymphopenia of Class 3 and 4 were noted, compared to the group that did not receive maintenance treatment, but these cases were not related to infections.
Q: Is follicular lymphoma curable? is rituximab simply a measure for delaying classical chemotherapy?
Dr. Linch: No data to date suggest that the association of Rituximab and Chemotherapy has a curative effect. But even if the cure rate was relatively low, in the order of 20%, it would still be phenomenal.
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