Overview of Waldenstrom’s macroglobulinemia (WM)
Waldenstrom’s macroglobulinemia (WM) is a rare subtype of B-cell lymphoma, making up 1 to 2 percent of all non-Hodgkin lymphoma (NHL) cases. WM is considered to be an indolent (slow growing) lymphoma and it is primarily found in the bone marrow although lymph nodes can also be affected
WM is named after the scientist who first described it. The cancer cells make large amounts of a certain type of antibody (IgM), which is known as macroglobulin. A build-up of this protein can lead to symptoms such as excess bleeding, problems with vision, and the nervous system
WM causes the overproduction of monoclonal protein called ‘immunoglobulin M’ referred to as IgM. This overproduction in IgM can result in the thickening of the blood known as hyper viscosity which causes the blood to thicken and impairs blood flow.
WM is an incurable lymphoma, but it can respond very well to treatment with many patients achieving long-term remission periods. Some patients will be offered the ‘watch and wait’ approach if there are no symptoms or very few to manage. When treatments are needed, the treating clinician has a number of standard and new therapies to choose from.
Who is affected by Waldenstrom’s macroglobulinemia (WM)?
Most people who are diagnosed with Waldenstrom’s macroglobulinemia (WM) are over 65 years of age. WM affects twice as many men as women.
Scientists do not know what causes WM. Some infections, inflammatory conditions or autoimmune diseases such as Sjogren syndrome might increase the chance of developing WM.
If there is another family member with WM, another type of B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia there is a slightly higher risk than others of developing WM. However, the risk is incredibly low and most family members do not develop lymphoma.
Nine out of ten people with WM have a mutation (change) in a gene called ‘MYD88’.
Mutations in a gene called ‘CXCR4’ can also occur in one in three people with WM.
Symptoms of Waldenstrom’s (WM)
At least 25 percent of patients with Waldenstrom’s macroglobulinemia (WM) are asymptomatic and the lymphoma is diagnosed due to abnormal blood counts from a general blood test. Swollen glands are less common with WM than other types of lymphoma.
Some symptoms can include:
- Abnormal bleeding especially from nose, gums and lining of the gastrointestinal tract due to thrombocytopenia (shortage of platelets)
- Fatigue due to anaemia
- Shortness of breath due to anaemia (shortage of red blood cells)
- Recurrent infections due to neutropenia (shortage of neutrophils)
- Peripheral neuropathy due to abnormal antibodies attacking nerve cells
- Muscle cramps
- Changes in mental status such as poor concentration or confusion
Hyper-viscosity syndrome (although uncommon) can also happen
WM can also cause B symptoms, and theseinclude:
- Persistent fever (especially at night >38C)
- Night sweats (drenching sleepwear and bedding)
- Unexplained weight loss
In about one in one hundred cases of WM, abnormal lymphocytes and plasma cells build up in the central nervous system (brain and spinal cord). This is called ‘Bing-Neel syndrome’. It is rare and may cause headaches, fits, changes in thinking processes or abnormal movements.
Diagnosis and staging of WM
A biopsy is not always required for a diagnosis of Waldenstrom’s macroglobulinemia (WM).
A biopsy is an operation to remove a lymph node or other abnormal tissue to look at it under the microscope by a pathologist. The biopsy can be done under local or general anaesthetic depending on what part of the body is being biopsied. The biopsy can be done in one of three ways:
- Fine needle aspirate
- Core needle biopsy
- Excisional node biopsy
An excisional node biopsy is the best investigative option, as it collects the most adequate amount of tissue to be able to do the necessary testing for a diagnosis.
Waiting for results can be a difficult time. It may help to talk to your family, friends or a specialist nurse.
Staging of WM
Once a diagnosis of WM is made, further tests are required to see where else in the body the lymphoma has affected or is located. This is called staging. The staging of the lymphoma helps the clinician decide the best treatment
There are four stages from stage 1 (lymphoma in one area) through to stage 4 (lymphoma that is widespread).
- Early stage means stage 1 and some stage 2 lymphoma. This can also be referred to as ‘localised’. Stage 1 or 2 means that the lymphoma is found in one area or a few areas close together.
- Advanced stage means the lymphoma is stage 3 and stage 4 and it is widespread. In most cases, the lymphoma has spread to many parts of the body that are far from each other.
Staging scans and tests for WM
Some of the tests needed can include:
- Positron emission tomography (PET) scan
- Computed tomography (CT) scan
- Bone marrow biopsy
- Lumbar puncture (if there is a high risk of brain or spinal cord involvement)
Patients may also undergo a number of baseline tests prior to any treatment commencing to check organ functions. These are often repeated during and after the treatment has completed to assess whether the treatment has affected the functioning of organs. Sometimes the treatment and follow-up care may need to be adjusted to help manage side effects. These may include:
- Physical examination
- Vital observations (blood pressure, temperature, & pulse rate)
- Heart scan
- Kidney scan
- Breathing tests
- Blood tests
It may take some time for all the necessary biopsies and tests to be done (an average of 1-3 weeks), but it is important for the doctors to have a complete picture of the lymphoma and the general health of the patient in order to make the best treatment decisions
Many of the staging and organ function tests are done again after treatment to check whether the lymphoma treatment has worked and the effect this has had on the body.
Prognosis for Waldenstrom’s macroglobulinemia (WM)
Waldenstrom’s macroglobulinemia (WM) is an indolent (slow growing) lymphoma that can develop over many years. It is usually treated with the aim of controlling it, rather than curing it. Although treatment is usually effective, WM is highly likely to come back (relapse).
WM can change (transform) into a faster growing (high-grade) type of lymphoma, usually Diffuse Large B-Cell Lymphoma (DLBCL).
Treatment for Waldenstrom’s macroglobulinemia (WM)
Once all the results from the biopsy and the staging scans have been completed, the doctor will review these to decide the best possible treatment for a patient. At some cancer centres, the doctor will also meet with a team of specialists to discuss the best treatment and this is called a multidisciplinary team (MDT) meeting.
Doctors take into consideration many factors about the lymphoma and the patient’s general health to decide when and what treatment is required.
This is based on:
- The stage of lymphoma
- Symptoms (including the size and location of the lymphoma)
- How the lymphoma is affecting the body
- Past medical history & general health
- Current physical and mental wellbeing
- Patient preferences
Some patients with WM who do not have any symptoms at diagnosis may not be treated for many years. In these cases, the patient is monitored closely in an approach known as “watch and wait’. Treatment is only started once the IgM protein is too high and symptoms are present.
If treatment is needed, the patient’s type and severity of the symptoms, age, overall health and degree of the thickness of the blood, will help determine which treatment is selected.
Standard first-line treatment may include:
- DRC (dexamethasone, rituximab and cyclophosphamide(oral))
- R-Benda (Rituximab and Bendamustine)
- Rituximab and Ibrutinib (BTK inhibitor)
- Ibrutinib only- if chemo-immunotherapy not suitable)
- Clinical trial
- Plasmapheresis if blood is too thick from high IgM levels
- Blood transfusions for low platelets and low red blood cells
- Immunoglobulin replacement therapy if antibody levels are low
Common side effects of treatment
There are many different side effects of the treatment and these are dependent on the treatment that has been given. The treating doctor and/or cancer nurse can explain the specific side effects prior to the treatment. Some of the more common side effects of treatment may include:
- Neutropenia (low type of white blood cell that helps to fight infection)
- Thrombocytopenia (low platelets that help with clotting or bleeding)
- Anaemia (low red cells that help provide oxygen to your body)
- Nausea and vomiting
- Bowel problems (constipation or diarrhea)
- Fatigue (tiredness or lack of energy)
The medical team, doctor, cancer nurse or pharmacist, should provide information about:
- What treatment will be given
- What are the common and possible side effects for the treatment
- What side effects do you need to report to the medical team
- What are the contact numbers, and where to attend in case of emergency 7 days a week and 24 hours per day
Once treatment has completed, post treatment staging scans are done to review how well the treatment has worked. The scans will show the doctor if there has been a:
- Complete response (CR or no signs of lymphoma remain) or a
- Partial response (PR or there is still lymphoma present, but it has reduced in size)
If all goes well regular follow-up appointments will be made for every 3-6 months to monitor the below:
- Review the effectiveness of the treatment
- Monitor any ongoing side effects from the treatment
- Monitor for any late effects from treatment over time
- Monitor signs of the lymphoma relapsing
These appointments are also important so that the patient can raise any concerns that they may need to discuss with the medical team. A physical examination and blood tests are also standard tests for these appointments. Apart from immediately after treatment to review how the treatment has worked, scans are not usually done unless there is a reason for them. For some patient’s appointments may become less frequent over time.
Relapsed or refractory WM
Waldenstrom’s macroglobulinemia (WM) usually responds well to immunochemotherapy, but in some people the lymphoma comes back (relapses) or in rare cases does not respond to the initial first-line treatment (refractory).
Before the next treatment begins a number of factors are considered:
- > 5 years since last treatment can repeat original treatment
- 2 years or less since initial treatment, a different treatment
- Rituximab and chemotherapy
- Ibrutinib (BTK inhibitor)
- Clinical trial
Treatments under investigation
There are many treatments that are currently being tested in clinical trials around the world and in Australia for patients with both newly diagnosed and relapsed or refractory WM. The treatments include:
- Idelalisib (Zydelig)
- Ofatumumab (Arzerra)
- Bortezomib (Velcade)
- Lenalidomide (Revlimid)
- Obinutuzumab (Gazyva)
- Venetoclax (Venclexta)
- Zanubrutinib (Brukinsa)
- Acalabrutinib (Calquence)
- Chimeric Antigen Receptor (CAR) T-cell Therapy
What happens after treatment?
Sometimes a side effect from treatment may continue or develop months or years after treatment has completed.
This can be a challenging time for many people and some of the common concerns can be related to:
- Mental wellbeing
- Emotional health
- Work, study and social activities
Health and wellbeing
A healthy lifestyle, or some positive lifestyle changes after treatment can be a great help after the treatment has been finished. Making small changes such as eating and increasing fitness can improve health and wellbeing and help the body to recover. There are many self-care strategies that can help during the recovery phase.