Update on WM 2012 by Shirley D Sa

Update on WM 2012 by Shirley D’Sa

INTRODUCTION Waldenströms macroglobulinaemia (WM) is a rare B cell non-Hodgkin’s lymphoma (NHL) in which the tumour cells produce a protein called IgM. It is one of 60 different types of lymphoma that are cancers that arise from cells of the immune system known as lymphocytes. WM has a lot in common with other B cell NHL but also many significant differences which require special consideration during diagnosis and treatment. The biology of the disease is distinct from other subtypes of lymphoma. These important issues have been the focus of attention at a series of International Workshops that have been held since 2000, the most recent being in Newport, Rhode Island, USA on 23-26 August 2012. This article describes some of the recent advances that were presented at Newport 2012.

DIAGNOSIS AND GENETICS The diagnosis of any cancer depends on a careful examination of tissue samples (obtained by a biopsy), including special staining of the material to narrow down the tissue type. The tissue description for WM is ‘lymphoplasmacytic lymphoma’ (LPL), because there is a mixture of cells present in WM, including lymphocytes and plasma cells. As well as looking at the biopsy sample using a microscope, the pathologist uses specific antibodies to identify different cell types by targeting proteins on the cell surface. This helps to distinguish between different types of NHL, and may be relevant for treatment. In LPL, the lymphocytes have a protein o their surface called CD20, which acts as a target for antibody treatments such as Rituximab. When given in combination with chemotherapy, this drug can add efficiency to the ability of the chemotherapy to kill the LPL cells and produce a deeper remission (i.e. a better clearance of the LPL cells).

Several features of LPL cells have been studied in laboratories that are conducting research into WM, including genetic studies. Genetic events in tissues are central to the development of cancers. Normal cells receive growth signals which give them permission and/or encouragement to reproduce themselves in a controlled fashion. Control of cell growth is crucial to good health and when such control is lost, cells may reproduce themselves in an out- of-control way. Such genetic events include ‘mutations’ (accidental changes in the sequence of DNA) which may lead to excessive growth of cells or inadequate control of cell division and ultimately to the development of cancer. One such mutation has been reported to be found in >90% of WM cases by Dr Steven Treon and colleagues at the Dana Faber Cancer Institute, in the New England Journal of Medicine earlier this year (N Engl J Med 2012; 367:826- 833August 30, 2012). This mutation affects a gene called MYD88, which gives rise to a protein that is involved in a number of crucial cellular pathways in WM cells and leads to the growth and development of WM cells.

This mutation is now the subject of ongoing research to tease out the various pathways involved, with the hope of developing specific treatments that can target this gene/protein and hence treat the disease. It may also yield information about prognosis (predicting likely outcome). So far, very few laboratories carry out the MYD88 gene test, because it is still a research tool, but it is likely to be more widely carried out in time.

PROGNOSIS It is clear from clinical trials and other observations, that WM is a disease that can vary greatly between individuals. It is regarded as an indolent (gradually progressing) NHL which may not require treatment for many years after diagnosis. When treatment is needed, WM is generally responsive to chemotherapy agents. However, in some patients, the disease tends to behave in a more stubborn way, showing resistance to chemotherapy, or going into a remission that does not last long. It is clear that one size does not fit all in terms of treatment. To address this question, Dr Pierre Morel (Lens, France) and colleagues (Blood 113(18),4163–4170 (2009) looked at various parameters in a series of 587 WM patients that may identify factors that may be predictive of a poorer response to treatment or a shorter remission. These factors were incorporated into the International Prognostic Scoring System for WM (IPSSWM). The IPSSWM was based on analysis of the outcome of initial therapy in symptomatic patients treated with an alkylating agent (63%) or purine analogue (33%) or Rituximab (4%) as first- line therapy.

LOW RISK: INTERMEDIATE HIGH RISK: Age > 65 years RISK: β2-microglobulin > 3g/l ≤1 adverse > 2 adverse M-protein > 70 g/l characteristic 2 adverse characteristics Hb < 11.5 g/dl and age ≤65 characteristics Platelets < 100 x 109/l or > 65 years

27% of patients 38% of patients 35% of patients

87% 5-yr survival 68% 5-yr survival rate 36% 5-yr survival rate rate

In this system, patients fall in to one of 3 categories at diagnosis, depending on what factors are present at that time. It can be seen that the projected survival rate varies accordingly. It is important to note, however, that these figures include very few patients who received newer agents such as Rituximab. The hope is to devise a treatment approach that neutralises the adverse factors by intensifying treatment in those with high risk features. So far this system has not been validated for use in directing therapy, but it is a focus of ongoing clinical research to enable this to happen in the future. By providing individualised treatment plans of ‘risk- adapted’ therapy, the outcome for patients with WM should continue to improve.

TREATMENT: WHEN AND WHAT Once the diagnosis (biopsy- usually of bone marrow) and extent of the disease (scanning, usually CT) is confirmed, the next step is to determine whether treatment is needed. Only patients with symptoms due to the disease need treatment. Those with ‘asymptomatic’ or ‘smouldering’ WM should be monitored without treatment until treatment is needed. At the Workshop, Dr Robert Kyle (Mayo Clinic) presented data on patients with smouldering WM, who showed a median time from diagnosis to needing treatment of 4.6 years and a risk of progression of 12% per year for first 5y then 2% per year for the next 5y. There is no evidence to suggest those patients with smouldering WM benefit from early treatment. On the other hand, chemotherapy has inherent risks and should not be given until essential. Accepted reasons to start treatment include symptoms due to the disease such as weight loss, progressive fatigue, low blood counts due to bone marrow inadequacy, recurrent infections due to disease- related immune suppression, or paraprotein-related problems such as hyperviscosity or peripheral neuropathy. Once the need for treatment has been established, the next step is to ascertain what treatment should be offered. There are many treatments available for the lymphomas, consisting of chemotherapy drugs, monoclonal antibodies like Rituximab, steroids and radiotherapy. Other biological agents such as Bortezomib are also being increasingly explored in clinical trials and a number of novel drugs are becoming available. Owing to its rare disease status, WM lags behind other lymphomas in terms of clinical trials. Fewer trials with fewer patients are done in WM patients compared to other lymphomas, but this situation is steadily improving.

CHLORAMBUCIL This is a member of the alkylator family of chemotherapy agents, which has been available for decades. It is still available because it is an effective agent; taken orally, it is well tolerated and produces a response in 50-60% of patients. It can induce a stable remission ranging from a few months to a few years. It induces a response slowly, so it is not the best choice for patients who need a quick response due to active symptoms. It is toxic to stem cells so should be avoided in patients whose stem cells may be used later. It has been compared to Fludarabine (see later) in an Anglo-French randomised trial. Although Fludarabine produced a deeper response and longer progression-free survival, there was no benefit in terms of overall survival. Both agents continue to be used widely in a range of patients.

DRC This is an acronym for a chemotherapy combination known as Dexamethasone, Rituximab and Cyclophosphamide. It is given intravenously, every 3 weeks for 6 cycles. In the trial published by Dr Meletious Dimopoulos (Athens) (JCO August 1, 2007 vol. 25 no. 22 3344-3349), a response to treatment was seen in 83% of previously untreated patients. It is a well tolerated treatment and the response appears to last for at least 2 years in 90% of patients. It is not toxic to stem cells, so can be used prior to stem cell transplantation.

NUCLEOSIDE PURINE ANALOGUES This category of chemotherapy drugs includes Fludarabine and Cladribine both of which are effective in WM when used alone or in combination with other chemotherapy drugs and/or Rituximab. On their own, they produce a response in 30-50% of patients, and in combination with other agents, a higher proportion of patients experience a response. In many cases, the response can be deep and long lasting. The role and place of these drugs in the treatment of WM was discussed extensively at the Workshop and remains under review through clinical trials. While they are undoubtedly effective agents, there are some emerging concerns about their longer term effects.

Some factors are not contentious; these agents should certainly be avoided in patients who may need an autologous stem cell transplant, as they may damage stem cells and make their collection more challenging. Also, there is increased reporting of second primary malignancies (SPMs) i.e. second unrelated cancers, in patients who have received these drugs. However the risk of this complication is small and the exact significance of this statistic remains to be established. Consideration is being given to using lower doses or fewer cycles compared to current practice.

Until more is known about the risk of second malignancies, there is no doubt that all patients with WM treated or not, should be vigilant for any signs and symptoms that may be related to cancer, such as a new or changing skin lesion, altered bowel habit, new lumps or bumps and unexplained weight loss. In addition, any nationally offered screening programmes such as mammograms and the bowel cancer screening programme should be availed of. BORTEZOMIB Bortezomib is a novel agent called a proteasome inhibitor that has been widely used in a related condition called myeloma. Its success in this setting has led to trials in WM, which have shown that Bortezomib, produces a high rate of response (78% responded overall) when given as a single agent at diagnosis or at relapse. The main side effects encountered include peripheral nerve damage (which is reversible in the majority), low blood counts and postural dizziness (due to so-called autonomic neuropathy which may cause the blood pressure to drop on standing). Also noted was that although the IgM level fell briskly in most patients, the number of LPL cells in the bone marrow often fell less precipitously; in other words there was a discrepancy between the fall in IgM levels and clearance of the bone marrow. Ongoing studies of Bortezomb/chemotherapy combinations are under way.

In the UK, a randomised study of Bortezomib in combination with Cyclophosphamide and Rituximab (BCR) versus Fludarabine, Cyclophosphamide and Rituximab (FCR) in newly diagnosed patients is to open shortly. This study (Chief Investigator Dr Rebecca Auer, Barts Cancer Institute, London) will address the effectiveness of Bortezomib compared to Fludarabine in the upfront setting.

BENDAMUSTINE Bendamustine is a chemotherapy drug with a novel mechanism of action. It was originally developed in the 1960s in East Germany and used to treat lymphomas, myeloma and leukaemia. It was only available in East Germany until 1990 but then received approval by the German authorities for national use and later by the FDA in 2008 for chronic lymphocytic leukaemia and indolent NHL. Its uniqueness comes from its similarity to both alkylating agents (like Cyclophosphamide) and nucleoside purine analogues (like Fludarabine and Cladribine).

Dr Mathias Rummel (University Hospital Giessen, Germany) updated the Workshop on the results of a randomised trial of Bendamustine-Rituximab (BR) compared to R-CHOP (Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisolone) that was used in 514 patients with indolent B NHL, of which 44 patients had WM. R-CHOP is a widely used treatment in NHL patients, especially those with aggressive NHL. It is also used in indolent lymphomas and was the regimen chosen to compare to BR in this trial. The median time to progression of disease after treatment and achievement of remission was 54.8 months for BR compared to 31.2 months for R-CHOP overall. BR was reported to be better tolerated than R- CHOP, with no hair loss, fewer cases of low blood counts and infections and less peripheral neuropathy and mouth soreness. In this trial, the dose of Bendamustine was quite high (90mg per square metre), given on days 1 and 2 of a monthly cycle (for 6 cycles). Since then, in other trials and other settings, lower doses of Bendamustine have also been effective. The optimum dosing and schedule in WM remains to be determined.

Dr Rummel’s data are very encouraging and raise the prospect of using BR in WM. However, it is important to note that just 44 out of 514 patients in his trial had WM, makig the number of WM patients who received BR just 22 (the other 22 received R-CHOP) in that trial. As yet, there is no proof that an increased quality and duration of response to treatment translates into a increased survival in the long term. The follow up of these patients needs to continue to increase the meaningfulness of the results ad further trials are needed to clarify the role of Bendamustine in this disease. Also, in the UK, there are limited conditions for which Bendamustine can be prescribed under current authorisations and WM is not one of them. Dr Rummel will be discussing the use of Bendamustine in WM at the forthcoming WMUK Patient Conference to be held at the Royal College of General Practitioners in London on 17 March 2013. A UK-based trial of Bendamustine (with a new anti-CD20 monoclonal antibody, Ofatumumab) is in the process of being developed and likely to be launched in 2013 for previously treated patients.

RITUXIMAB MAINTENANCE The rationale for using Rituximab maintenance after initial chemotherapy is to hold on to a response gained from initial treatment (which should also include Rituximab). This approach has been rigorously assessed in the setting of follicular lymphoma (FL, another much more common type of indolent lymphoma), in which initial Rituximab-chemotherapy was followed by an injection of Rituximab every 3 months for 2 years. Another FL study looked at providing extended treatment with Rituximab every two months for up to two years. This was found to almost halve the risk of relapse after three years, compared with the routine practice of observation only. Importantly, the maintenance approach is not unduly problematic in terms of on going side effects or impact on quality of life. This approach is already available National Health Service in the UK for patients receiving second-line therapy and has now been approved by NICE for patients receiving first-line treatment in patients with FL.

WM shares many parallels with follicular lymphoma, but is a distinct disease entity. Dr Treon and colleagues analysed 248 WM patients who had received Rituximab+chemotherapy, of which 35% went on to receive maintenance Rituximab. This was a retrospective analysis of patients. In this group, there was a significant improvement in the median progression free survival of 56.3 months in the maintenance group vs. 28.6 months in those who did not receive maintenance. In other words, those who received maintenance kept their remission for 56.3 months on average compared to 28.6 months in those who did not. In addition, lower IgM levels were seen and deeper remissions noted in the maintenance group. However, those on maintenance had lower antibody (the normally produced by the immune system) levels and higher rates of infections, mainly of the lungs.

This issue was debated at the Workshop, with points for and against as follows: FOR • Rituximab (once weekly for 4 weeks) used as a single agent works, with an overall response rate of 20-30% • Extended schedule (an additional course at week 12) improves the overall response rate to 40-50% • There is evidence for improvement in the duration of remission in other NHLs AGAINST • Results seen in follicular lymphoma may not apply to WM • Optimum dosage schedule unknown • No randomised trial evidence: Dr Treon’s study was a look-back at a group of patients in which a proportion received maintenance but it was not a prospective comparison, so interpretation of the results needs to be cautious. • Unlike FL, the risks of immunosuppression in WM patients may outweigh the benefits of Rituximab maintenance: WM patients frequently have reduced levels of antibodies at diagnosis and may be more vulnerable to the effects of Rituximab than patients with follicular lymphoma.

In the upcoming UK treatment guidelines for WM (2013), maintenance Rituximab will not be recommended due to insufficient evidence for benefit. Further studies are needed. OUTLOOK AND SURVIVAL

When considering how long a person with a particular disease is likely to survive following diagnosis, it is important to be aware of the methods used in the analysis of trials and the implications of those results for individuals.

The term ‘survival’ is widely used in the reporting of trials. This includes ‘progression-free survival’, which refers to the time it takes before the treated disease shows signs of progression (e.g. a rising M protein or falling blood counts due to build up of the disease). Also widely mentioned in trials is ‘overall survival’. This refers to the time that a person survives after treatment, but includes other causes of death, including treatment-related effects, or other unconnected conditions.

Also important is to note the term ‘median’ in discussions of trial statistics. The median refers to the middlemost value in a series, which ranges from a low value to a higher one. So when a median overall survival of 7 years is typically applied to WM, there is a range of actual outcomes. A small number of patients survive for decades (with treatment given intermittently) whereas a few may die from their disease after a few years.

However, owing to the fact that WM is diagnosed most frequently in patients aged 65 and over, the co-existence of unrelated health problems such as diabetes, chronic lung problems or a high cholesterol is significant, people with WM may succumb to an unrelated cause, such as heart disease or stroke- just like the general population- rather than WM. Thus, when assessing the effectiveness of various treatments, care has to be used when interpreting the results to ensure that proper conclusions can be reached.

At the workshop, this was addressed by Dr Pierre Morel who asked whether WM studies should report overall survival or WM-specific survival. Currently, median overall survival remains in the region of 7-9 years, whereas median WM-specific survival is approximately 11 years. By taking individual patient fitness into account, it can be seen that WM itself can be a more chronic disease than is traditionally reported.

FUTURE DIRECTIONS There are a number of new drugs available and being trialled in WM. These include:

EVEROLIMUS: Everolimus, also known as RAD001 is an inhibitor of MTORC1, a component of the so-called Akt- MTOR pathway which regulates the growth and survival of LPL cells. There is previous evidence for its activity in the setting of previously treated WM as reported by Dr Irene Ghobrial and colleagues in 2010. At the Workshop, Dr Treon reported a prospective study of treatment of Everolimus in 33 patients with previously untreated WM. The median time to best response was 3 months but the reduction of LPL cells in the bone marrow was less impressive than that of the IgM level. The main toxicities were low blood counts in <10%, mouth ulcers in 20%, fatigue and rash in a small number. So far, at a median follow up of 15 patients remain on treatment; 11 out of 33 have stopped due to disease progression.

It seems likely, as with most new agents, that Everolimus will work better in combination with other drugs but further studies are needed to establish this. CARFILZOMIB Carfilzomib, recently FDA-approved for myeloma, is a drug that has shown anti-tumour activity by inhibiting the proteasome, a cellular organ responsible for degrading or breaking down a wide variety of proteins within cells. It is a cousin to Bortezomib but unlike Bortezomib, it is an irreversible inhibitor and so may be more effective. It is currently undergoing trials in WM patients. It is being given intravenously in combination with Rituximab and Dexamethasone as the CARD regimen in a trial running at the Dana Faber Cancer Institute. So far, the treatment appears well tolerated and acts quickly to lower IgM levels and improve the degree of anaemia.

IBRUTINIB B cell lymphoma cells depend on a cascade of signals via proteins (B cell receptors) on the surface of the cell, in order to grow and survive. Btk is a critical signalling molecule positioned early in this ‘signalling cascade’. Blockade of Btk function is a promising approach in the treatment of WM. Ibrutinib is a Bruton's tyrosine kinase (Btk) inhibitor drug which interrupts B cell receptor (BCR) signalling in lymphomas by selectively and irreversibly binding to the Btk protein, which then results in malignant cell death. A trial of Ibrutinib in patients with WM is being conducted at the Dana Faber Cancer Institute by Dr Treon. Ibrutinib is being trialled in some UK sites for B cell disease other than WM, including mantle cell lymphoma and CLL.

To conclude, a concerted effort is underway to address the diagnosis, prognosis and treatment of WM; a number of emerging and innovative approaches to assessing and treating WM were discussed at the Newport 2012 workshop, which are exciting and encouraging for WM patients, their carers and their doctors.