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Cancer Medicine :: Waldenström's Macroglobulinemia

Waldenström's Macroglobulinemia

General information about treatment

In recent years, some progress has been made in treating people with Waldenstrom macroglobulinemia (WM). Studies have found a number of drugs that work against WM, but few studies compared different treatments to see which if one was better than another. That is why no single standard treatment is used for all patients. It is important to understand all treatment options so that you and your doctor can decide what is best for you. It is often a good idea to seek a second opinion, since it might give you more information and help you feel more confident about the treatment plan you choose.

Chemotherapy for Waldenstrom macroglobulinemia

Chemotherapy (chemo) uses anti-cancer drugs that are injected into a vein or a muscle, or are taken by mouth. These drugs enter the bloodstream and reach all areas of the body (this is called systemic treatment).

Many types of drugs are useful in treating patients with Waldenstrom macroglobulinemia (WM). They may be used alone or combined with other drugs or treatments.

Alkylating agents

This class of chemotherapy drugs includes chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®), and bendamustine (Treanda®).

Chlorambucil is a pill, and is usually given with a drug called prednisone, which is a corticosteroid.

Cyclophosphamide is given into an intravenous line. It is rarely used by itself — it usually is given along with other drugs to treat NHL and WM. The combination of cyclophosphamide, adriamycin (hydroxydaunorubicin), vincristine (Oncovin®), and prednisone (called CHOP) is used frequently to treat many types of non-Hodgkin lymphoma (NHL).

Nucleoside analogs

This category includes the drugs pentostatin (Nipent®), fludarabine (Fludara®) and cladribine (Leustatin®). These are given intravenously for several days at a time.

Corticosteroids

This includes the drugs dexamethasone (Decadron), prednisone, methylprednisolone (Solu-medrol®), hydrocortisone, and many others. Corticosteroids are an important part of the treatment of lymphoma, and have been shown to be helpful in treating WM. In addition, these drugs actually help decrease the nausea and vomiting that other chemotherapy may cause. These drugs can cause other side effects including problems sleeping and an increased appetite. These symptoms go away after the drug is stopped.

Other

Bortezomib (Velcade®) is a drug that was originally used to treat multiple myeloma but has been found to be helpful in some cases of WM. It belongs to a class of drugs called proteosome inhibitors.

Immunotherapy

This is discussed in the next section.

Chemo side effects

Chemotherapy drugs can also affect some of the normal, healthy cells in your body, causing side effects. Rapidly growing cells, like the blood-producing cells of bone marrow, the cells of hair follicles, and the lining of the digestive tract, are particularly sensitive to chemotherapy.

Chemotherapy side effects depend on which drugs are used, as well as the amount taken, and the length of time they are taken. Common side effects include:

Nausea and vomiting

Loss of appetite

Temporary loss of hair

Mouth sores

Diarrhea or constipation

Low blood counts

Chemo can damage the blood-producing cells of the bone marrow, leading to low blood cell counts. This can cause:

Increased risk of infections (from low white blood cell counts)

Problems with bleeding or bruising (from low blood platelet counts)

Fatigue (tiredness) and shortness of breath (from low red blood cell counts)

Other side effects can be seen with certain drugs used to treat WM. For example, bortezomib can damage nerves, causing pain in the feet and legs. The nerve damage usually gets better after the drug is stopped, but it may not go away completely. Fludarabine suppresses the immune system, making patients more likely to get certain serious infections.

If you have side effects, your cancer care team can suggest steps to ease them. For example, there are very good medicines that help prevent and control nausea and vomiting. Most side effects are temporary and go away after treatment is finished. If serious side effects occur, the chemotherapy may have to be reduced or stopped, at least temporarily.

Long-term side effects of chemotherapy

Some chemotherapy drugs cause long-term cell damage directly. This can affect almost any part of the body. One of the most serious late complications of successful chemotherapy is the possibility of developing leukemia. It affects a very small percentage of patients, but it is more common in patients who take fludarabine or alkylating agents.

Biological therapy or immunotherapy for Waldenstrom macroglobulinemia

Biological therapies use man-made versions of substances normally produced by the immune system. These substances may kill lymphoma cells, slow their growth, or may activate the patient's immune system to more effectively fight the lymphoma.

Immunotherapy with monoclonal antibodies

Antibodies are normally produced by the immune system to help fight infections. Monoclonal antibodies designed to attack lymphoma cells are made in the laboratory.

Rituximab (Rituxan®) is the most widely used monoclonal antibody for lymphoma. Rituximab specifically recognizes and attaches to a protein that is found on the surface of lymphoma cells called CD20. This attachment tells the lymphoma cell to die. Patients receive rituximab by infusion into a vein (IV) at the oncologist's office or clinic. Side effects during the infusion are very common, and include chills, fever, nausea, rashes, fatigue, and headaches. Unlike regular chemotherapy, rituximab does not cause low blood counts or hair loss. This treatment is one of the standard treatments for lymphoma and Waldenstrom macroglobulinemia (WM). Rituximab can be given alone or with regular chemotherapy as a part of treatment.

Alemtuzumab (Campath®): Alemtuzumab is a monoclonal antibody that is directed at a different protein on lymphoma cells called CD52. This drug is more commonly used to treat patients with chronic lymphocytic leukemia, but it has also helped some patients with WM. A serious side effect of alemtuzumab is a large drop in the blood counts that can last weeks or even months. People on this drug can develop life-threatening infections that are hard to treat while their white blood cells are low.

Immunomodulating agents

Immunomodulating agents are substances that affect the immune system in an unclear (and nonspecific) way. Thalidomide and lenalidomide are examples of immunomodulating agents.

The drug thalidomide is used to treat multiple myeloma, and can also help some WM patients. A problem with this drug is that many patients have trouble tolerating some of its side effects. These include drowsiness, fatigue (tiredness), severe constipation, and neuropathy (painful nerve damage). The neuropathy can be severe, and may not go away after the drug is stopped. There is also an increased risk of serious blood clots that start in the leg and can travel to the lungs. Because thalidomide causes severe birth defects if it is taken during pregnancy, it can only be obtained through a special program run by the drug company that makes it. The best results with thalidomide in WM occurred when it was given along with other drugs, such as rituximab or dexamethasone.

Lenalidomide (Revlimid®) is a newer drug similar to thalidomide. It is often used to treat multiple myeloma. In studies of patients with WM, the patients showed improvement in their IgM and beta-2-microglobulin levels, but developed worsening anemia. The role of this drug in treating WM is still being explored. The most common side effects of lenalidomide are thrombocytopenia (low platelets) and low white blood cell counts. The risk of blood clots is not as high as that seen with thalidomide, but it is still elevated. Like thalidomide, access to lenalidomide is also tightly controlled out of concern about possible serious birth defects.

Cytokine treatment

Cytokines are hormone-like proteins naturally produced by white blood cells to help the immune system fight infections. Interferon is a cytokine that can be made in the lab to give to patients as a drug. Some studies have suggested that interferon can make some lymphoma tumors shrink. Side effects of this treatment include moderate to severe fatigue, fever, chills, headaches, muscle and joint aches, and mood changes. It is still not certain whether interferon is a good option for patients with non-Hodgkin lymphoma or WM. It is most often used only in patients who continue to get sicker after treatment with standard chemotherapy drugs.

Plasmapheresis for Waldenstrom macroglobulinemia

When the level of IgM gets very high, the blood becomes very thick (viscous). This is called hyperviscosity syndrome and can lead to brain damage (like a stroke) and bleeding problems. When that happens, the level of the abnormal IgM protein needs to be lowered right away.

Plasmapheresis does this using a machine that separates the plasma (the liquid part of the blood) that contains the abnormal protein from the blood cells. The blood cells are mixed with salt solution and new plasma and given back to the patient. The plasma containing the abnormal protein is discarded. Each plasmapheresis treatment takes a few hours.

A person having plasmapheresis can lie in bed or sit in a reclining chair. Two IV lines are required —- the blood is removed through one IV, and then is returned to the body through the other IV. Sometimes, a single large catheter is placed in the neck or under the collar bone for the pheresis —- instead of using IV lines in the arms. This type of catheter is called a central line and has both IVs built in. Plasmapheresis is not painful, but it can be hard to stay sitting or lying down in the same place for 2 or 3 hours. Also, sometimes calcium levels can drop on pheresis, causing numbness and tingling (especially in the hands and feet and around the mouth) and sometimes painful muscle spasms. These can easily be treated by giving the patient calcium.

Plasmapheresis works quickly to get the IgM level down to a safe level. However, without further treatment to kill the cancer cells (like chemotherapy) the protein level will go back up again. Plasmapheresis is usually given to help the patient until chemotherapy has a chance to work. Sometimes plasmapheresis is used for those whose Waldenstrom macroglobulinemia is not controlled by chemotherapy, biological therapy, or other treatments. When patients have symptoms from elevated IgM, they need to have plasmapheresis right away to prevent complications.

Stem cell transplantation for Waldenstrom macroglobulinemia

Stem cell transplants (SCT) let doctors use higher doses of chemotherapy than would normally be tolerated. High-dose chemotherapy destroys the bone marrow, which keeps new blood cells from forming. This could lead to life-threatening infections, bleeding, and other problems due to low blood cell counts.

Doctors try to get around this problem by giving an infusion of stem cells after treatment. Stem cells can create new blood cells.

Blood-forming stem cells used for a transplant are obtained either from blood (for a peripheral blood stem cell transplant, or PBSCT) or from the bone marrow (for a bone marrow transplant, or BMT). Peripheral blood stem cells are obtained using a procedure similar to that for a blood donation, while bone marrow donation is usually done in an operating room (while the donor is asleep under general anesthesia). Bone marrow transplants were more common in the past, but they have largely been replaced by PBSCTs.

There are 2 main methods of SCT: allogeneic and autologous.

Autologous stem cell transplant

This is the type of transplant used most often in Waldenstrom macroglobulinemia (WM). In an autologous stem cell transplant, a patient's own blood-forming stem cells are removed from his bloodstream and stored to use later. Then high doses of chemotherapy are given to kill the WM cells. The high doses of chemotherapy kill the normal bone marrow cells as well as the cancer cells. After chemotherapy, the frozen stem cells are thawed and returned to the body (like a blood transfusion). Autologous transplants can help some people with WM, but doctors are still trying to figure out which patients will benefit the most.

Allogeneic stem cell transplant

This is a treatment that is still being studied for WM, and experts recommend it be done as part of a clinical trial. In an allogeneic stem cell transplant, the stem cells that the patient receives after chemotherapy are from someone else (a donor). The donor has to match the patient in certain inherited basic cell characteristics, so the donor is usually a close relative — often a brother or sister. If there is no sibling that matches, someone who isn’t related who matches may be a donor, although this makes the transplant more risky.

Blood-forming stem cells can be taken from the bone marrow (usually in the operating room) or they can be separated from the peripheral (circulating) blood by a process known as apheresis.

Allogeneic transplantation has more risks and side effects than an autologous transplant. It is also difficult sometimes to find a matched donor.

A newer approach to allogeneic (donor) stem cell transplant is called non-myeloablative transplant. In this type of transplant, lower doses of chemotherapy or radiation therapy are used than in traditional allogeneic transplant. Patients are given drugs to suppress their immune reaction. This allows the donor cells to grow and partly take over the patient's immune system. The donor cells then begin reacting against the lymphoma cells and killing them. The problem is that the donor cells also react against the patient's normal cells. This leads to graft-versus-host disease (GVHD), which can make patients very sick. Doctors are trying to refine this treatment so that the reaction against the lymphoma cells will occur but not the reaction against normal cells.

Stem cell transplant is a complex treatment. If the doctors think the patient may benefit from transplantation, the best place to have it done is at a cancer center where the staff has experience with the procedure and with managing the recovery period. Patients should not hesitate to ask the doctor about the number of times he or she has done this procedure and how patients responded to the treatment. Experience and knowledge are key factors in providing the best care.

Radiation therapy for Waldenstrom macroglobulinemia

Radiation therapy uses high-energy rays to kill cancer cells. This type of treatment is used sometimes to treat early stage non-Hodgkin lymphoma (NHL). It may also rarely be used to shrink an enlarged spleen or lymph nodes if they are causing symptoms in Waldenstrom macroglobulinemia (WM).

The type of radiation therapy most often used to treat NHL and WM is called external beam radiation. It involves focusing radiation from a source outside the body. The treatment is much like getting an x-ray, but the radiation is more intense. The procedure itself is painless. Before the treatments start, the radiation team takes careful measurements to determine the correct angles for aiming the radiation beams and the proper dose of radiation. Each treatment lasts only a few minutes, although the setup time — getting you into place for treatment — usually takes longer. Most often, radiation treatments are given 5 days a week for several weeks.

Possible side effects

Immediate side effects of radiation therapy may include sunburn-like skin problems, fatigue, and low blood counts. Other side effects depend on the area being treated. Radiation of the abdomen may cause nausea, vomiting, or diarrhea. Radiation to the head and neck area can lead to mouth sores and trouble swallowing. Often these effects go away a short while after treatment is finished.

A rare long-term side effect of radiation is a new cancer developing in the treated area.

What happens after treatment for Waldenstrom macroglobulinemia?

Current treatments for Waldenstrom macroglobulinemia (WM) are not likely to result in a cure. Most patients are treated for some time, followed by a break, and then may be treated again when the disease comes back. Learning to live with cancer that does not go away can be difficult and very stressful. It has its own type of uncertainty. Our document, When Cancer Doesn't Go Away, talks more about this.

Follow-up care

Even during treatment breaks, your doctors will still want to watch you closely. It is very important to go to all of your follow-up appointments. During these visits, your doctors will ask questions about any problems you may have and may do exams and lab tests or x-rays and scans to look for signs of cancer or treatment side effects. Almost any cancer treatment can have side effects. Some may last for a few weeks to months, but others can last the rest of your life. This is the time for you to talk to your cancer care team about any changes or problems you notice and any questions or concerns you have.

Regular follow-up exams will be very important for you. Follow-up usually includes a careful general physical exam. They will also check how you are feeling. Be sure to tell your doctor about any new or persistent symptoms right away. Your blood counts, IgM, and beta-2-microglobulin levels will be checked. Blood chemistry tests to look at kidney and liver function will also be done. Other tests may also be done to see whether the abnormal antibody is causing damage to the kidneys, liver, or other organs. The choice of studies and tests depends on your symptoms and what treatment (if any) you have received.

It is important to keep your health insurance. Tests and doctor visits cost a lot, and even though no one wants to think of their cancer coming back, this could happen.

What`s new in Waldenstrom macroglobulinemia research and treatment?

Genetics

As noted in the section, "Do we know what causes Waldenstrom macroglobulinemia?" scientists are making great progress in understanding how changes in DNA can cause normal lymphocytes to develop into lymphoma. Greater understanding of the genes (regions of DNA) involved in certain translocations that often occur in lymphoma is providing insight into why these cells grow too rapidly, live too long, and do not develop into mature cells that take part in normal immune reactions. Scientists are now looking at how these abnormal chromosomes lead to the development of lymphoma. Once this is understood, drugs may be developed that block this process.

Chemotherapy

Clinical trials are studying new chemotherapy drugs. Other trials are studying ways to use drugs already known to be effective in treating lymphoma by combining them in new ways, using different doses, or different sequences of drugs, one after another.

Everolimus (Afinitor®), a drug more commonly used to treat kidney cancer, has been shown to be useful in treating WM. It is not a traditional chemo drug — it belongs to a class of drugs known as mTOR inhibitors. Common side effects with this drug include fatigue (tiredness), mouth pain, diarrhea, and infections.

Doctors observed that an anti-cholesterol medication (simvastatin) seems to help lower IgM levels in the lab. A study to see if this drug can help patients with WM is going on now.

Biological therapy

Another new approach to non-Hodgkin lymphoma treatment is the use of biological response modifiers that stimulate the patient's own immune system to attack and destroy the lymphoma cells. Some of the substances currently being tested include interferons and interleukins.

It has recently been discovered that the bone marrow support tissues (stromal cells) produce a substance called interleukin 6 (IL-6). IL-6 is a strong growth factor for multiple myeloma cells. IL-6 also helps cause the bone destruction of the myeloma cells. Some current research efforts are focused on trying to develop ways to block these functions of IL-6.

Bone marrow and peripheral blood stem cell transplantation

Researchers are continually improving bone marrow and peripheral blood stem cell transplantation methods.

Vaccines

Doctors have always known that it was possible for people with cancer to develop antibodies to their cancer. In rare instances these people's immune systems have rejected their cancers and they have been cured. Now, scientists have developed ways of encouraging this immune reaction by the use of vaccines. The difference from the usual use of vaccines in children is that in children's vaccinations, the object is to prevent an infectious disease from ever taking hold. With cancer vaccines, the goal is to create an immune reaction in patients who have very early disease or in patients whose disease is in remission. So far, there have been a few successes with this approach. It is a major area of research in lymphoma treatment.

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