Waldenstrom's Study


Trial update Spring 2013

The randomized WM1 study (Trial comparing Chlorambucil to Fludarabine in Patients with advanced Waldenström’s Macroglobulinemia) was undertaken in 101 centres in five countries enrolling 414 eligible patients (339 with WM, 37 with non–mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate.
Analysis is now complete and the results have finally been published in the Journal of Clinical Oncology. Below is a link to the journal website where the abstract can be viewed:


The overall conclusion is that Fludarabine is a safe and effective treatment in WM patients and other close-related disorders, even in the elderly and more effective than Chlorambucil with a duration of the response over 3 years
On behalf of the trial team, I would like to thank all those patients who contributed to the study.

For information about Waldenstrom's Macroglobulinaemia please read on. Other further information can also be gained from the International Waldenstrom's Macroglobulinaemia Foundation (www.iwmf.com).

What is Waldenström’s macroglobulinaemia?

Waldenström’s macroglobulinaemia (WM) was first described by a Swedish physician, Jan Waldenstrom in 1944. It is a cancer which affects cells of the lymphoid system and is therefore regarded as a form of Non-Hodgkin’s lymphoma. WM accounts for approximately 2% of all haematological cancers. WM affects all ages but it appears to be commoner in those aged over 50 years. The average age of patients in the UK is approximately 70 years. It appears to be commoner in men than women. WM is currently incurable but most patients benefit from treatment with chemotherapy drugs. The average survival with this disorder is 5 years although some patients survive for more than 10 years.

WM is a form of Non-Hodgkin’s lymphoma which originates in the bone marrow but it can affect other lymphoid organs such as the lymph glands and spleen. The tumour cells also produce an abnormal protein, called a paraprotein which is detectable in the blood. The clinical features seen in WM may therefore be related to tumour cells themselves or the presence of the paraprotein.

Features related to the tumour cells include:
  • Anaemia – this may cause tiredness and fatigue. The presence of lymphoma cells in the bone marrow suppresses the production of normal red blood cells. Less commonly the numbers of white blood cells and platelet cells is also suppressed which can lead to problems with infection and bleeding.
  • Enlargement of lymph glands and spleen
  • Weight loss
  • Sweats

Features related to the paraprotein include:
  • Hyperviscosity syndrome – large quantities of paraprotein makes the blood very thick which can result in symptoms such as blurred vision and heachache.
  • The paraprotein may sometimes attach to and damage certain tissues – most commonly the paraprotein attaches to nerves which can result in tingling and numbness of the fingers and toes. This occurs in 5-10% of patients.
  • Episodes of pain and whiteness affecting the hands particularly when cold – this is called Raynaud’s phenomenon. This occurs because the paraprotein precipitates when it is exposed to cold – the protein is then called a cryoglobulin.

Some patients are asymptomatic when they are diagnosed and do not require treatment. Patients with hyperviscosity syndrome may be treated by a procedure known as plasma exchange. The majority of patients with WM do however require treatment with chemotherapy. Historically most patients have received treatment with a drug called chlorambucil which is available in tablet form. Chlorambucil belongs to a family of drugs known as the alkylating agents. Chlorambucil is generally given at monthly intervals for 7-10 days in each cycle. Responses are seen in approximately 50% of patients but many patients require further treatment after an interval.

More recently a newer family of drugs, the purine analogues has become available for the treatment of WM. One of these drugs called Fludarabine has been used for many years in the treatment of chronic leukaemia. Fludarabine has been used in a limited number of patients who have previously received chlorambucil. The response rates are encouraging with approximately 40% of patients responding satisfactorily. Fludarabine is given by drip or tablet for five consecutive days in every month.

It is not known which of these treatments is most effective in WM. In this study patients will be randomly assigned to receive either chlorambucil tablets or fludarabine by drip or tablet. It is hoped that this study will greatly improve our understanding of WM and improve the outcome of future patients with the disorder.

Patients who relapse or become refractory to treatment may be treated at the clinicians discretion however they may be eligible for a study of Velcade (PS-341) which is being conducted at St Bartholomew's/The London Hospital; further information is available from Dr Sandra Strauss (s.j.strauss@qmul.ac.uk) tel +44 207 601 8929, fax +44 207 600 4265.