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The great B-cell debates


Christine Clark, BSc, MSc, PhD
FRPharmS, FCPP(Hon)

Editor HPE

Advanced follicular lymphoma
The first proposition was that CHOP-R is the induction therapy standard of care for advanced follicular lymphoma. Speaking for the motion, Gilles Salles (Professor of Haematology, Centre Hospitalier Lyon-Sud and head of the research unit ‘Pathologie des Cellules Lymphoïdes’, University of Lyon, France) said that despite the changes in treatment there were no changes in overall survival for follicular lymphomas during the 1990s. However, the introduction of rituximab, which improved the overall survival rate when added to standard treatment regimens, changed the paradigm of treatment for this condition. Moreover, patients who achieved a complete response (CR) had markedly better overall survival than those who achieved a partial response (PR). Longer survival raised new issues such as the possibility of histological transformation (which makes the disease more difficult to control), long-term cardiac side-effects and quality of life.  At the time, the standard treatment was alkylating agents together with either an anthracycline or fludarabine, both of which improved response rates and time to progression. The Prima study compared combinations of rituximab with three standard regimens, CHOP, CVP and FCM and showed that R-CHOP, with a response rate of 93%, was superior to the other two combinations. Furthermore, rituximab maintenance treatment was associated with 75% progression-free survival (PFS) at three years – a ‘significant landmark’, said Professor Salles. This was achieved with no more adverse events than with the other treatment regimens. R-CHOP elicited a better response rate than R-CVP and was easier to use and less toxic than the fludarabine-containing regimen, he concluded.

Another treatment option is the use of bendamustine. One part of the molecule is similar to nitrogen mustard and another part is similar to cladribine, he explained. Bendamustine itself interacts with DNA to induce two pathways leading to cell death.  It causes apoptosis via a p53-dependent pathway and ‘mitotic catastrophe’ through inhibition of mitotic checkpoints – a p53-independent process.  Early studies suggest that treatment with a rituximab-bendamustine combination provides a better progression-free survival than R-CHOP but further trials are needed to confirm the findings. Rituximab-bendamustine (R-B) is clearly better-tolerated  – causing less alopecia and neurotoxicity and having less potential cardiotoxicity than R-CHOP. However, long-term data are lacking and many questions remain to be answered here. “A single study does not provide enough information for a standard of care”, said Professor Salles.

The efficacy of R-CHOP is well-established and reproducible and the long-term safety of the regimen is well known. Therefore, it is the standard of care for first-line treatment of advanced follicular lymphoma, he concluded.
Speaking against the motion, Wolfram Brugger (Professor of Haematology and Oncology, Schwarzwald-Baar Clinic, Academic Teaching Hospital, University of Freiburg, Germany) said that the standard of care was probably not R-CHOP but any chemotherapy regimen including rituximab. He noted that about 50% of patients with follicular lymphoma receive chemotherapy with rituximab and 14% receive rituximab as monotherapy. There has been no head-to-head comparison of rituximab with any chemotherapy, he commented. There are now new agents available, including bendamustine and lenalidamide and there are also new National Comprehensive Cancer Network (NCCN) guidelines, which recommend
a range of treatment options. The goals of treatment are to improve symptoms and quality of life, to induce remissions and to prolong the time to next treatment whilst ensuring low short-and long-term toxicity.

In the pre-rituximab era patients with complete responses to chemotherapy fared considerably better than those with only partial responses. However, the addition of rituximab had eliminated the difference and improved overall survival, said Professor Brugger. When R-CHOP was used as induction therapy in indolent non-Hodgkin’s lymphoma (iNHL) the time to progression was prolonged (about 80 months) in previously untreated patients but not in previously treated patients. The survival advantage is clear when rituximab is combined with front-line chemotherapy regimens.

The addition of an anthracycline to the regimen made no difference to overall survival, although progression-free survival and response duration both favoured anthracycline-containing regimens. However, cardiovascular disease was the second most common cause of death in patients who received anthracycline-containing regimens. The results of the Prima (Phase III) study showed that rituximab maintenance therapy had a favourable outcome for all patients who had received a rituximab-containing induction treatment, regardless of whether it was R-CHOP, R-CVP or R-FCM.  The important question was whether the R-CHOP protocol could be improved and toxicity reduced. The StiL NHL 1-2003 study compared R-CHOP with R-B. The primary outcome was non-inferiority, which was defined as a difference of less than 15% in PFS at three years. The majority of patients in this study were over 65 years of age, and were therefore representative of real-life patients, noted Professor Brugger. The overall response rate in both groups was about 92% but complete responses were seen in 40% of the R-B group and 30% of the R-CHOP group.  In addition, R-B was associated with progression free survival times of 55 months, compared with 35 months for R-CHOP. The R-B regimen caused less toxicity than the comparator and the use of GCSF was minimal in the R-B group. R-B did not cause alopecia and there were fewer infections in this group. There were more skin problems but they can be treated effectively with topical corticosteroids, said Professor Brugger.

In summary, R-CHOP is highly effective but there has been no head-to-head comparison demonstrating its superiority over other rituximab-containing regimens and it is not without complications.  R-B has at least equivalent efficacy, elicits an improved complete response rate and is less toxic and therefore better tolerated. For these reasons, rituximab in combination with bendamustine is an appropriate induction treatment for advanced follicular lymphoma patients, said Professor Brugger.

A poll of the audience showed that the majority believed that R-CHOP was still the treatment of choice for first-line treatment of advanced follicular lymphoma.

Chronic lymphocytic leukaemia
Peter Hillmen (Consultant Haematologist at the Leeds Teaching Hospital NHS Trust, Leeds, UK) argued that chlorambucil was still the chemotherapy of choice for unfit patients with chronic lymphocytic leukaemia (CLL).

The ‘gold standard’ treatment for fit CLL patients is fludarabine, cyclophosphamide and rituximab (FCR), regardless of age – the addition of rituximab doubles the complete response rate compared with fludarabine and cyclophosphamide alone. However, CLL is not primarily a disease of fit, young people – the median age at diagnosis is 72 years – and this influences patients’ ability to cope with treatment, he explained.

Patients could be divided into three groups – “go-go, slow-go and no-go” – according to their levels of independence, number of comorbidities and life expectancy, suggested Professor Hillmen.  The first group should receive aggressive treatment with FCR and the third group should receive palliative care. The question was what to give the middle group and where to draw the line, he said. A number of factors influence the decision to prescribe fludarabine – the drug is cleared by the kidneys and should not be given if the creatinine clearance falls below 30ml/min. Patients also need to be able to tolerate infections, he added.

Chlorambucil has been used for many years and the question arises whether it is used to its best advantage. When used at 60mg/m2, the overall response rate (ORR) is between two-thirds and three quarters. Increasing doses are associated with better responses. Chlorambucil does not work quickly and it is important to treat for long enough. Elderly patients do not tolerate intense therapy well. In elderly or unfit patients with CLL the outcome varies with the dose and duration of treatment. With higher doses and longer durations of therapy, overall response rates of more than 70% and CR rates of 5-10% can be achieved.  The median PFS is about 18 months in front-line CLL and the median overall survival is more than five years.

Turning to the question of whether the response to chlorambucil can be improved, Professor Hillmen said that alternative chemotherapy or the addition of monoclonal antibodies might be options.

Bendamustine is licensed for front-line CLL in patients for whom fludarabine combination therapy is not appropriate, he noted. It is administered intravenously, is cleared by the liver and requires no dose modification for renal failure until the creatinine clearance falls below 10ml/min). The European Phase III front-line CLL study, which compared bendamustine with chlorambucil, showed that the overall response was 68% (bendamustine) versus 31% (chlorambucil). The PFS rates showed a significant advantage for bendamustine.
Chlorambucil can be taken orally, whereas bendamustine must be given intravenously. Chlorambucil is well-tolerated by elderly patients but there are only limited data on bendamustine. Chlorambucil costs €26 per month cycle but bendamustine costs €1200.

A study that examined the use of rituximab in combination with chlorambucil in first-line CLL compared the patients with a group of matched patients from the LRF CLL4 study (which had used chlorambucil alone). The results showed that rituximab-chlorambucil produced an overall resposnse of 80% compared with 66% for chlorambucil alone and a better CR.  However, this was not a randomised controlled trial, Professor Hillmen reminded the audience.

A number of other trials are now in progress, examining the effects of chlorambucil in combination with rituximab, ofatumumab and bendamustine. “The issue is to define the standard of therapy for unfit patients in the antibody era”, said Professor Hillmen.

He concluded that CLL in older patients is still a problem that needs to be solved. At present, FCR improves survival and is the ‘gold-standard’ for all patients who are fit enough for therapy. The most appropriate therapy for those unfit for FCR is chlorambucil monotherapy with appropriate dosing, he said.
Speaking against the motion, Wolfgang Knauf (Partner, Onkologische Gemeinschaftspraxis, Agaplesion Bethanien Krankenhaus, Frankfurt, Germany), who has extensive experience with bendamustine, explained that the treatment of CLL can appear to be a straightforward matter. FCR induces the highest remission rates ever reported, it may change the course of CLL and it should be the treatment of first choice in fit patients; all  others should receive chlorambucil. However, there is no consensus on how to assess fitness, and most trials used patients under 65 years of age but the median age at diagnosis is 72 years. Patients who are not eligible for fludarabine-based treatment include those with impaired renal function or peripheral neuropathy, those who are at risk of infections and those who are physically unfit.
Very fit patients are eligible for FCR and very unfit patients should be given chlorambucil with or without rituximab.  In between these two there is a ‘grey zone of patients who are too fit for chlorambucil treatment but not fit enough for FCR. The goal for these patients should be a durable remission and improved quality of life.

A comparison of chlorambucil dosing in a number of studies showed variable results. The lowest overall response rate (31%) was obtained in the only study that used blinded assessment, noted Professor Knauf. In addition to differences in dosing, the selection of patients and variable definitions of complete response could also have contributed to the variability, he added.

The European Phase III intergroup CLL compared chlorambucil and bendamustine. The results showed
that bendamustine produced a superior overall response (68% vs 31%) and improved PFS (22 months vs eight months). Moreover, neither PFS nor toxicity was influenced by age – the over-65s showed no difference from the under 65s. Neutropaenia was worse in the bendamustine group but infection rates did not differ between groups.

The time to progression was three times longer with bendamustine, which was a great benefit for patients. Although the trial was not powered to look at overall survival, it was noteworthy that those who achieved a complete response
also had good overall survivals – and these were patients who had received bendamustine.

Bendamustine in combination with rituximab in the treatment of CLL produced an overall response rate of
91% and this provided the basis for a randomised controlled trial comparing R-B with FCR. Both bendamustine and chlorambucil are associated with lower rates of infection than fludarabine-based regimens, commented Professor Knauf.
The second-line treatment for CLL in Germany is now largely R-B, according to German registry data, but first-line therapy is evenly split between R-B and FCR. “Bendamustine is a drug which we have known for forty years”, commented Professor Knauf. When considering the goal of a durable remission for fitter patients in the ‘middle zone’ then bendamustine in combination with a modern antibody is the best choice, he concluded.

A poll of the audience showed that the majority believed that R-B was the treatment of choice for chronic lymphocytic leukaemia.

In the discussion that followed, members of the audience raised two major concerns: first, the issue of how to apply trial data – gathered in a study sample with an average age of 62 years – to patients of 75 years of age; second, the need for a simple tool to assess ‘fitness’ (for treatment), so that the appropriate treatment could be given.

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