TREATMENT of Waldenström’s Macroglobulinemia disease
This information is meant to provide you with general information only. It is not meant to replace the advice of your doctor, nurse or other healthcare practitioners. Your healthcare team can answer specific questions related to your personal treatment plan.
1a. NEW: Dutch Guideline for diagnosis and treatment of WM (2013): click here (PDF 167 kB)
1b. NEW: A survey on diagnostic methods and treatment strategies used in patients with WM in the Netherlands (2013): click here (PDF 252 kB)
2. Questionnaire Peripheral Neuropathy: click here (PDF 57 kB)
“Questionnaire that you can fill in if you notice any unusual tingling, weakness or pain in your hands or feet.
Early diagnosis and treatment offers the best chance for controlling your symptoms and preventing further damage to your peripheral nerves. It is advisable to fill in the questionnaire at the start of each treatment cyclus and discuss it with your doctor”.
3. Information on treatment of WM from Dutch Handbook for patients (2009)
Published with kind permission of the Dutch MM & WM Association (CKP)www.waldenstrom.nl. I
The information is a translation of chapter 17 of the CKP Patientbook, 2009,edited by H. Jansen and Dr. P.W. Wijermans. This chapter was written by Dr. M.J. Kersten and Dr. P.W. Wijermans and translated by M.G. Pitt.
According to the most recent classification Waldenstroms Macroglobulinemia (WM) is a form of lymphoplasmacytoid non-Hodgkin’s lymphoma. These are types with a low level of malignancy, and are also referred to as indolent lymphomas. Even without treatment the disease can in the early stages progress very gradually. Treatment is very possible, but a cure is, in general, not achievable—even with intensive therapy.
Wait and See’ policy
Because of the gradual progression in the early stages treatment is often not directly necessary. If immediate treatment does not lead to a better result in the sense of a longer survival, then it may be better to wait until treatment is absolutely necessary. This policy is referred to as ‘wait and see’ or ‘watchful waiting’. For those that have received this diagnosis, this can be difficult to accept. If a good form of treatment is possible, why is this not applied immediately? This is because immediate treatment does not improve the chance of survival, whilst the patient is exposed to the side effects of medicines, visits to the hospital for controls etc. From various large-scale studies it is apparent that ‘wait and see’ can be a safe option and additionally it ‘saves’ suitable medicines for the moment that they are really needed. For some patients it is possible that a watchful waiting approach is possible for a period of more than six years. Some patients have never reached the point where they have needed treatment.
In 2002 an international panel of experts in Athens made a clear statement regarding this: only begin with treatment when there is a clear indication that this is necessary. Also, during a more recent Waldenstroms workshop that was held on the island of Kos in 2007, the panel was of the opinion that there was still place for a ‘wait and see’ policy.
What then is the point at which one must start with treatment?
Reasons for this can be:
General complaints such as emaciation, increased perspiration etc.
Complaints as a result of the swelling of the lymph nodes or enlargement of the spleen
Problems resulting from hyperviscosity (thickening of the blood)
Reduction of the production of red blood cells (anaemia), white blood cells (resulting in reduced resistance to infections) and/or platelets (giving a reduction in blood clotting)
Problems with functioning of the kidneys
Problems with cryoglobulins (proteins that precipitate in the blood at low temperatures)
Complaints as a result of polyneuropathy. Polyneuropathy refers to damage to the nerves which can result in such complaints as pain (typically in the feet or hands), tingling or loss of feeling. In WM this is associated with damage to the nerve (myelin) by the IgM paraprotein
Treatment: what is the standard?
WM is a very rare disease. For this reason it is very difficult to carry out good comparative studies to determine the best course of treatment. There have been, however, a number of phase II studies carried out, where a limited group of patients have received a new form of medication or a combination of different medications. As a result of this we are fortunate to know which medications are effective (or not) against this disease. Because there have been very few, if any, comparative (phase III) studies, it is difficult to give a clear statement over what the standard first or second-line treatments should be.
Here various available therapies and combinations are discussed. Which therapy and in which stage it is prescribed is something that the specialist will discuss with the patient. Factors include the symptoms of the patient, their age and condition, and the necessity of a fast response to the therapy.
Good first line treatments can be: chlorambucil (Leukeran), rituximab (MabThera®), CVP chemotherapy in combination with rituximab (R-CVP), or fludarabine, possibly in combination with rituximab. If the disease after a period of time returns, then, if the response has lasted relatively long, the same treatment can be given again. If the response has been relatively short, then it will be better to choose a different treatment or combination.
The cytogenic drug Leukeran (chlorambucil) has been available for over 40 years, but is still prescribed because of its efficacy and limited side effects. It has also the advantage of being available in tablet form. In general, it is easily tolerated. There are different schemes maintained:
A long term low dosage: around 0.05-0.1mg per kg bodyweight per day.
A so-called pulse dosage: 0.3 mg per kg per day for 5-7 days, once per month.
In this way a good result may often be obtained. However it does take a considerable time before a reduction in the IgM (M protein) is apparent. It is advised to take this for at least 6 months before concluding whether or not the medication helps or not.
Sometimes Leukeran is combined with prednisone. This appears not to be much more effective than Leukeran alone, but does give more side effects. However the combination may be necessary if, through the disease, there is an acute reduction in haemoglobin (red blood cells) or platelets (thrombocytes).
Fludarabine, together with cladribine, belongs to a new class of cytostatic drugs, the purine analogs. These medicines are extremely effective against chronic lymphatic leukaemia and non-Hodgkin’s lymphoma with a low level of malignancy such as WM. They are often used if Leukeran is no longer effective.
A course of treatment consists of tablets that are taken for five days. The courses are given once every four weeks, often six to eight times.
The chance that fludarabine (Fludara) shows a good response is around 40%. For a number of patients the disease remains stable. Thus, for around one half of patients the treatment is not a success, which is naturally extremely disappointing. The medicine can also be combined, for example with cyclophosphamide (Endoxan). This combination is more effective, but does lead to more side effects.
Because of the chance of damage to the immune system these drugs must be used very carefully in the case of patients with a low resistance to infection. Antibiotics are often prescribed in order to prevent infections.
The side effects of these cytostatic drugs are limited. Naturally the healthy blood production can be temporarily suppressed. With the use of many forms of chemotherapy one must be alert to the increased chance of infections. Extra caution is needed in the case of patients that have problems with the destruction of red blood cells or platelets by white blood cells that attack these cells (Auto-immune diseases). In the case that a blood transfusion is necessary, then a special precaution may be needed whereby the donor blood is first irradiated.
A commonly used drug combination is the CVP treatment, consisting of cyclophosphamide, vincristine (Oncovin) and prednisone. This combination can be given every three weeks and consists of tablets or an infusion of cyclophosphamide, an infusion of vincristine and tablets of prednisone. The tables are taken for five consecutive days. In general six to eight treatment cycles are needed.
The most important side effect of cell destroying medicines (cytostatics) is that they also damage the production of healthy cells. Here particularly it leads to the temporary suppression of the production of blood cells. Other side effects that can occur include nausea, vomiting and diarrhoea. In general these are worst with higher dosages. Cyclophosphamide (Endoxan) can also result in temporary hair loss. Possible side effects of vincristine are constipation and in some cases damage to the nerves (polyneuropathy). If tingling in the fingers or toes occurs or one has the feeling that one is “walking on cotton wool” then these should be discussed with ones specialist. Sometimes the dosage of the medicine can be adjusted, or even removed from the treatment.
Prednisone is a medicine that is used against many diseases. One of the indications is a malignant growth of lymphocytes. In practically all forms of non-Hodgkin’s lymphoma Prednisone is a part of the therapy. Many of the often annoying side effects appear only after long time use—longer than is generally the case for WM.
The most important side effects of Prednisone during short periods of treatment include:
Tendency to want to eat more
Exacerbation of pre-existing stomach problems
Instigation of stomach problems
Increase of the blood sugar level in patients with diabetes
Increased risk of diabetes
With regular treatments using prednisone, or use for longer periods of time, other side effects can occur, such as decalcification of the bones and thinning of the skin. The medicine leads in these cases also often to reduction of resistance against infections.
When the medicines previously named are no longer effective, or there is an indication that there is a transformation to a more aggressive form of lymphoma, then a stronger combination therapy may be recommended. A requirement is that the general condition of the patient will permit this. One of the most frequently used combinations known as CHOP consists of:
With the exception of prednisone these medicines are given by infusion. In general one treatment cycle is given every three weeks, in total six to eight times.
The previously noted side effects can appear in an intensified form. There are however effective medications available to counter the effects of, for example, nausea. The suppression of the healthy production of blood cells can be stimulated with growth factors. Someone in reasonable condition can in general cope with this type of treatment.
Intensive chemotherapy/ stem cell transplantation
In a number of forms of non-Hodgkin’s lymphoma very intensive chemotherapy may be used. This results in the normal blood cell production being strongly suppressed and in some cases no longer recovering through the toxic working of the chemotherapy on the stem cells in the bone marrow. Such treatment is only possible if the production of blood cells is guaranteed through first removing the needed stem cells (which can be frozen to store them), and to reintroduce them after chemotherapy (autologous stem cell transplantation).
Studies of small groups have shown that this treatment is technically also possible for patients with WM. However the results are really less promising than by other forms of non-Hodgkin’s lymphoma, as the illness invariably returns after transplantation.
With allogenic stem cell transplantation—transplantation with stem cells from a donor, usually a brother or sister—there is little experience in this form of treatment for WM.
In recent years immunotherapy has been introduced in the treatment of malignant blood diseases. Particularly by non-Hodgkin’s lymphoma it seems that this form of treatment has an important role to play and for some forms of NHL it has become the standard form of therapy.
Also for WM the treatment with antibodies against the malignant blood cells can be useful. The advantage of immunotherapy is, that this works in a totally different way to chemotherapy and has also far fewer side effects. Immunotherapy can also be combined with chemotherapy.
For the treatment of non-Hodgkin’s lymphoma of the B-cell type there are presently two immunotherapy drugs available: rituximab (MabThera®) and alemtuzumab (MabCampath®). There is little experience in the treatment of WM with the second of these medications and this will not be discussed further here.
A number of studies have been carried out on the use of MabThera® in the treatment of WM. If this medicine is given alone (4 infusions, 1x per week) 30-75% of patients have a response. In general this is not a complete response and the duration of the response is on average 8 to 11 months. Studies are being carried out to investigate whether it may be more effective to increase the number of infusions by carrying out a maintenance therapy. Apart from this it appears that this treatment is very promising when used in combination with chemotherapy (for example in combination with CVP or fludarabine).
Side effects that can occur by treatment with rituximab occur usually by the first infusion and often include fever, shivering, and occasionally a fall in blood pressure and shortness of breath. This can be easily treated and to a certain extent prevented by giving extra medication.
What is certainly an important side effect is that at the start of treatment the IgM level can initially increase, rather than decrease. Why this occurs by immunotherapy is not clear, but it can exacerbate the effects of hyperviscosity after the start of treatment. In some case plasmapheresis may be needed to reduce the IgM level.
Another new development is radioimmunotherapy. In Europe Zevalin® has been registered for the treatment of certain forms of non-Hodgkin’s lymphoma, and in the US there has also been a lot of research carried out on the use another treatment, Bexxar®. Here the antibody is coupled with a radioactive part, so this brings the radioactivity to the place of the tumour. Because in WM the tumour cells are located principally in the bone marrow this can lead to more side effects, as through the radiation, also the healthy bone marrow cells can be damaged. It is therefore questionable whether this form of therapy is safe for the treatment of WM.
There is a lot of research on new forms of medication. In part this comes from studies of non-Hodgkin’s lymphoma and in part from the treatment of multiple myeloma (MM). Two examples of treatments are:
Thalidomide: this is actually an old drug that is notorious because it was prescribed to pregnant women, where it caused severe abnormalities in their babies. It is now a medicine that can be prescribed under strictly controlled conditions for the treatment of multiple myeloma. Also in the case of WM around a quarter of patients receiving thalidomide obtained a response. It is often combined with dexamethasone. For multiple myeloma a much more effective medication, lenalidomide or Revlimid®, has been developed, that has fewer side effects. At the WM symposium on Kos the first results were presented on the treatment of patients using this medication. Unfortunately it appeared that in these patients severe anaemia occurred, although the cause was not entirely clear.
Bortezomib (Velcade®): Also for this medication, which is registered for the treatment of multiple myeloma, it has been reported that it is effective for some patients with WM. There is still rather limited experience here and more study is needed in order to understand the role of this medicine, which is one of a completely new group of drugs. However it has many side effects, including polyneuropathy, suppression of the bone marrow and infections.
Local irradiation (radiation) can sometimes be useful in the treatment of WM, for instance in the irradiation of extremely enlarged glands that through their position and size cause severe problem. Sometimes this can be effective with a low radiation dose.
Removal of the spleen
Whilst removal of the spleen (splenectomy) is evident if this is too large and is causing problems, in practice this does not happen often. It is a radical operation, sometimes with severe complications. Also the size of the spleen can reduce through chemotom the removal of their spleen.
4. Summery of treatment of WM, published on the website of Orphanet, www.orpha.net :
Waldenström macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized by the accumulation of monoclonal cells in the bone marrow and peripheral lymphoid tissues, and associated with the production of an IgM serum monoclonal protein. The pathologic designation for WM is lymphoplasmacytic lymphoma, as proposed by the World Health Organization Classification of Tumors. WM has an overall incidence of 2.5/million/year and accounts for approximately 2% of all hematological malignancies. The median age at diagnosis is 63 years. WM has a wide clinical spectrum related to tumor infiltration, and the production and deposition of IgM in various tissues. The main clinical features are cytopenia, hepatosplenomegaly, lymphadenopathy, constitutional symptoms, oronasal bleeding and hyperviscosity syndrome. Fatigue related to normochromic normocytic anemia is the most common symptom. Visceral infiltration may target the stomach, small bowel, lungs, exocrine glands or skin. Retinal hemorrhage or serious neurologic complications may occur. Neurological presentations range from mild symptoms (headache, lightheadedness) to severe symptoms (mental confusion, stroke, focal neurological deficits, severe motor disease). Major complications include bone marrow failure, autoimmune cytopenia, large cell lymphoma and infections. WM clearly has a familial component, however, no susceptibility genes have yet been identified. Diagnosis is confirmed by the presence of an IgM (usually kappa) paraprotein and a bone marrow biopsy (showing infiltration by a lymphoplasmacytic lymphoma with a predominantly intertrabecular pattern, supported by appropriate immunophenotypic studies). Differential diagnosis includes multiple myeloma, chronic lymphocytic leukemia, non-Hodgkin lymphoma and amyloidosis (see these terms), as well as monoclonal gammapathies of undetermined significance (MGUS). Infections like hepatitis, AIDS, and various rheumatological disorders also raise IgM levels. Treatment includes cytostatics (alkylating agents, particularly chlorambucil), purine nucleoside analogs (fludarabine, cladribine), and most recently rituximab. Plasmapheresis with total plasma exchange is used for management of hyperviscosity and neuropathies. The median survival time is five years but in some cases the disease may progress slowly. *Author: Orphanet (February 2007)*.
5. Researchers identify genetic mutation responsible for most cases of Waldenström's macroglobulinemia December 12, 2011
Steven Treon. MD. PhD
Scientists at Dana-Farber Cancer Institute have identified a gene mutation that underlies the vast majority of cases of Waldenström's macroglobulinemia, a rare form of lymphoma that has eluded all previous efforts to find a genetic cause.
The research (abstracts 261, 300, 434 and 597), to be presented at the American Society of Hematology's 2011 annual meeting on Monday, Dec. 12 at 2:45 p.m. PST, points to an error in a single digit of DNA – one of three billion letters in the human genetic code – as the leading culprit in Waldenström's, and a prime target for new therapies against the disease. The discovery was made by sequencing the genome of tumor cells in Waldenström's patients, reading the cells' DNA letter by letter, and seeing where it differed from that of the patients' normal cells.
"We found that tumor cells in 90 percent of the patients we tested contained a single point mutation, an error in one of the bases that make up the 'rungs' of the DNA helix," says Steven Treon, MD, PhD, who led the research with his Dana-Farber colleague Zachary Hunter. "In subsequent experiments, when we treated the tumor cells with drugs that target the pathway activated by the mutated gene, the cells underwent apoptosis, or programmed cell death. These results suggest that new, effective treatments that target the tumor cells directly are now possible for people with the disease."
Waldenström's macroglobulinemia is a slow-growing form of non-Hodgkin lymphoma that originates in white blood cells known as B lymphocytes. When abnormal B cells begin to multiply out of control, they produce excessive amounts of a protein called monoclonal immunoglobulin, which causes the blood to thicken and flow less smoothly. In some patients, the disease produces no major symptoms; in others, problems can include weakness, fatigue, excessive bleeding, and weight loss. In severe cases, vision and neurological problems can occur. Approximately 2,000 to 3,000 people are diagnosed with Waldenström's each year in the United States; it is more common in men than women, more prevalent in people of Ashkenazi (Eastern European Jewish) descent, and arises more often in older people than young.
Although there isn't a cure for Waldenström's, treatments include drugs such as rituximab, bortezamib, and bendamustine. High-dose chemotherapy with autologous stem cell transplantation is infrequently also used.
Since the disease was first described 70 years ago, all previous efforts to track down a genetic cause have been fruitless, Treon remarks. For the current research, Treon and his colleagues conducted whole genome sequencing of tumor cells and normal cells from 30 patients with Waldenström's. In collaboration with Complete Genomics of Mountain View, Calif., researchers "lined up" the sequences of the tumor and non-tumor cells to identify differences. Ninety percent of the tumor cells had a point mutation in the gene MYD88.
"The mutation causes the cells to produce a distorted protein, which switches on the IRAK complex pathway, leading to activation of NF-kB, a protein that is essential for the growth and survival of Waldenström's tumor cells," Treon comments. "When we shut down the pathway by blocking the abnormal protein with drug molecules, the tumor cells entered apoptosis." Equally important, the tested molecules had no adverse effect on normal cells.
The discovery of a genetic signature for Waldenström's will enable doctors to definitively determine which patients have the disease and not a similar condition such as other forms of lymphoma or multiple myeloma, Treon says. Drugs that block the abnormal protein or other proteins in the NF-kB pathway could, theoretically, short-circuit the disease process in many patients. Some of these drugs already exist, having been developed for other conditions. Treon and his colleagues are currently working to develop others and are testing them in experimental models.
Funding for the research was provided by the International Waldenstrom’s Macroglobulinemia Foundation, the Bing family and the Coyote Fund.
6. Blood, 17 September 2009, Vol. 114, No. 12, pp.
How I treat Waldenström macroglobulinemia,
Bing Center for Waldenstrom's Macroglobulinemia, Dana-Farber
Cancer Institute, Harvard Medical School, Boston, MA
Waldenström macroglobulinemia (WM) is a distinct B-cell disorder resulting from the accumulation, predominantly in the bone marrow, of clonally related IgM-secreting lymphoplasmacytic cells. Genetic factors play an important role, with 20% of patients demonstrating a familial predisposition. Asymptomatic patients should be observed. Patients with a disease-related hemoglobin level less than 10 g/L, platelet count less than 100 x 109/L, bulky adenopathy or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or evidence of disease transformation should be considered for therapy. Plasmapheresis should be considered for symptomatic hyperviscosity and for prophylaxis in patients in whom rituximab therapy is contemplated. The use of rituximab as monotherapy or in combination with cyclophosphamide, nucleoside analog, bortezomib, or thalidomide-based regimens can be considered for the first-line therapy of WM and should take into account specific treatment goals, future autologous stem cell transplantation eligibility, and long-term risks of secondary malignancies. In the salvage setting, the reuse or use of an alternative frontline regimen can be considered as well as bortezomib, alemtuzumab, and stem cell transplantation. Newer agents, such as bendamustine and everolimus, can also be considered in the treatment of WM.
The full text of this article "How I treat Waldenström macroglobulinemia" you can find on the website of "BLOOD": You have to type in Google the following text: "bloodjournal.hematologylibrary.org/content/114/12/2375.full"
The documents contained in this website are presented for information purposes only. The material is in no way intended to replace professional medical care by a qualified specialist and should not be used as a basis for diagnosis or treatment.