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Genetic subgroups with poor survival and refractory disease are key challenges in CLL treatment. Engineered anti-CD20 antibodies may hold the key to successful treatment in future
BSc MSc PhD FRPharmS FCPP(Hon)
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults”, Stephan Stilgenbauer (department of haematology, oncology, rheumatology and infectious diseases, University of Ulm, Germany) told the audience at a satellite symposium sponsored by GSK. The diagnosis is straightforward but the clinical course can be variable with survival ranging from months to decades. There is also a wide range of treatment options and it is important to match the treatment to the patient.
Fludarabine as a single agent is superior to chlorambucil but even better results were obtained in 2008 at the MD Anderson Cancer Centre using fludarabine, cyclophosphamide and rituximab (FCR) with a six-year overall survival of 77%. The initial response to FCR treatment determines survival time; those who fail to respond have short survival time while those with complete responses have very good survival times and these differences appear to be related to genetic subgroups. The CLL8 study compared treatment with FC and FCR and very significant differences were seen after three years. “For almost all genetic subgroups the response was improved by the addition of rituximab”, said Dr Stilgenbauer. This was particularly marked for patients with an 11q deletion in the leukaemia cells. However, rituximab did little to improve the response in patients with 17p deletions.
Another study analysed the outcomes for patients receiving their first salvage treatment after first-line FCR. Overall survival after the first salvage treatment was 61% but the complete response (CR) rate was only 15%. The best result – a complete remission rate of 44% – was obtained with the combination of cyclophosphamide, fludarabine, alemtuzamab and rituximab, but this is probably not a combination that is suitable for everyone commented Dr Stilgenbauer. Another analysis showed that patients whose initial remission lasts for less than 24 months after first-line treatment have a very poor outcome after second line treatment, achieving a median survival of only about one year.
Turning to the management of refractory CLL, Dr Stilgenbauer said that patients who are refractory to fludarabine-based treatments are a real clinical challenge. Bendamustine, an agent that has been in use in Germany for many years, may have a role here. The CLL2M trial used a combination of bendamustine and rituximab (BR) – an alternative to the FCR regimen. Overall responses were good for all except the genetic subgroup with the 17p deletion where no CR was achieved. This suggests that alternative chemotherapeutic agents are unlikely to solve the problem of treatment when there is a 17p deletion, he noted.
Alemtuzamab treatment in chemo-refractory CLL is associated with a response rate of about 33%. The corresponding time to treatment failure and overall survival are six months and 18 months respectively. However, responses were not influenced by genetic subtype. Lasting improvements for the majority of patients can be achieved using anti-CD20 agents and FC, but these results have predominantly been obtained in young, medically fit patients, and there is still a question about how best to treat the elderly and those with comorbidities who are not eligible for intensive chemotherapy.
People who are refractory to fludarabine-based treatment have very poor outcomes and are very much in need of alternative treatment approaches. Biological factors such as 11q or 17p deletions or TP53 mutations clearly identify subgroups with poor survival that should be referred for treatment approaches that do not use classical chemotherapy as the backbone, said Dr Stilgenbauer. Targeted biological agents may be more suitable for this group, he added.
New anti-CD20 antibodies
“CD20 is an attractive target for drug action because it is expressed exclusively on B cells and on almost all malignant B cells”, explained John Gribben (professor of experimental cancer medicine, Barts and the London School of Medicine, Queen Mary University of London). It is stable on the B cell surface and it appears to be involved in B cell activation and signalling. Although its existence has been known for a long time its function remains unknown and there is still no known ligand for it. CD20 is a tetraspan molecule that is arranged in such a way that it crosses the cell surface twice leaving both a small loop and a large loop outside the cell membrane on to which antibodies can bind. CD20 is expressed at key stages of cell development, first appearing in early pre-B cells and is maintained until the memory to plasma cell transfer. Importantly, since many of the B cells of interest for study purposes arise from cells in that stage of differentiation, those malignant cells carry with them that CD20 expression which their normal counterparts would have. The antigen is not present on haematopoietic stem cells or on antibody-producing plasma cells – and this is important in terms of sparing the antibody-producing cells. So, hypogammaglobulinaemia does not occur during treatment with anti-CD20 monoclonal antibodies.
Monoclonal antibodies appear to destroy CD20 B cells by three mechanisms – complement activation, antibody mediated cytotoxicity and apoptosis. In complement activation, the antibody binds to the cell surface antigen and activates the membrane attack complex; there is then sequential activation of complement and a chain of events results in the formation of a pore that allows osmotic lysis of the cell. Antibody mediated cytotoxicity occurs when the CD20-bound monoclonal antibody binds to effector cells that release mediators that damage and destroy the malignant B cells, which are then phagocytosed by macrophages. Presumably, they are then presented to T-cells and therefore also initiate a T-cell mediated response against the tumour. This is probably an understudied component of the way in which these antibodies may be functioning, commented Professor Gribben. The most controversial mechanism is the potential induction of apoptosis. Binding of the antibody to CD20 may induce transmission of intracellular signals that trigger cell death.
There are two types of anti-CD20 agents. Type I antibodies cause CD20 to cluster on the membrane and appear to work through complement mediated lysis and possibly, to a lesser extent, antibody mediated cytotoxicity. Type II antibodies bind individually and appear to be more effective at inducing direct apoptosis. However, all these proposed mechanisms are still somewhat controversial, emphasised Professor Gribben.
Turning to the anti-CD20 agents themselves, Professor Gribben said that rituximab is approved for the treatment of non-Hodgkins lymphoma, CLL and rheumatoid arthritis. It has been validated for treatment of B-cell malignancies. Exactly how its actions work together with chemotherapy remains to be elucidated. One limitation of the use of rituximab is the low level of CD20 that is expressed in CLL cells. Rituximab needs a high density of CD20 for efficient killing (via complement-mediated lysis) and for this reason it has only limited efficacy when used as a single agent in CLL. This year rituximab was approved for treatment of untreated and refractory relapsed CLL, in combination.
Newer products are fully human antibodies, for example, ofatumumab, which is now approved in the USA and in the EU for treatment of CLL that is refractory to fludarabine and alemtuzamab. There are a number of anti-CD20 antibodies in development and products have been engineered to be more or less effective at inducing cell death through one or other mechanism, explained Professor Gribben. GA101 is the first type II engineered antibody. Compared with rituximab it has enhanced cell death induction activity and appears to have lower complement- mediated lysis activity. Initial clinical studies show that it is very effective as a single agent in several conditions including CLL.
Ofatumumab binds to the small loop on CD20 – a different site from rituximab; this brings the antibody closer to the cell membrane surface and this may account for its enhanced ability to induce complement-mediated lysis. Ofatumumab is effective in cells expressing low copy numbers of CD20, such as those typically found in CLL, and in rituximab resistant cells.
Novel strategies for refractory CLL
“Refractory CLL is a major challenge for clinicians”, said Anders Österborg (professor of oncology, Karolinska Institute, Stockholm, Sweden). Patients who are refractory to fludarabine have a poor prognosis and there is no standard treatment, but luckily there are many new and emerging treatment options.
Alemtuzamab is already approved for patients who are refractory to fludarabine or who have failed on fludarabine therapy. It may be possible to improve results by selecting patients carefully suggested Professor Österborg. For example, in patients with heavily infiltrated bone marrow and pre-existing thrombocytopaenia, an agent that is not toxic to stem cells such as alemtuzamab should be used. Moreover, in patients with haemolytic anaemia or thromocytopaenia, alemtuzamab may be a life-saving agent, he added.
Patients with bulky lymph nodes are always a challenge and it is well known that lymphadenopathy predicts a poor response. Combining alemtuzamab with high doses of prednisone – especially for the 17p- group – might be an effective strategy for inducing remission, he suggested.
The combination of rituximab with high doses of steroids produces good results in a small number of patients and this may be worthwhile if there is a desperate situation. Regarding bendamustine, there is still a lack of data to indicate the likely response to bendamustine in patients who are refractory to FC-based therapy. The question of whether there is cross resistance between bendamustine and FC still needs to be answered, said Professor Österborg.
Lenalidomide, an immune enhancer has extremely interesting effects. It definitely has clinical activity in CLL but at high doses it can be toxic – there is a risk of tumour lysis syndrome and tumour flare reactions, he noted. There are now three phase-3 trials ongoing so more information will soon be available. In particular, there is a need to define the safe starting dose.
The new agent GA101, now in phase 2 trials, is a promising agent and the results are awaited. Ofatumumab is already available and a pivotal study in double refractory patients who were not suitable for alemtuzamab treatment has been reported. The patients involved were close to end-stage CLL and they were treated with very high doses – up to 2000mg – because there was no other option. The response rate was 58%, which was better than expected in such sick patients. The same response rates were seen across all subgroups suggesting that ofatumumab was well-tolerated. There were insufficient data concerning the 17p- subgroup of patients to draw any conclusion on this group, Professor Österborg commented. The median response time was seven months. This study showed that ofatumumab treatment was associated with better progression free survival (PFS), better overall survival, half as many early deaths and fewer infections in spite of its evident greater activity.
In conclusion, Professor Österborg reminded the audience that there was still a large unmet need in CLL, especially in the elderly. “We need well-tolerated products and regimens”, he said.