Update on a Rare Lymphoma

Patients with Waldenström’s Macroglobulinemia Search for Effective Treatment

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Waldenström’s macroglobulinemia (WM) is a type of lymphoma that involves the antibody-producing cells. In particular, affected cells make too much of the antibody known as immunoglobulin M (IgM), and “macroglobulinemia” refers to this excess. Although it is considered a lymphoma, it mainly affects the bone marrow.

WM only occurs in about six cases per million people, and it is slow to progress compared to many other malignancies, but there is not yet a cure.

People who have abnormally high levels of IgM in their bloodstream have a 46-fold higher risk of developing WM, and the average age at diagnosis is in the mid-60s.

Genetic Links

According to recent research, 90 percent of people with WM have a specific mutation (change) in a gene known as MYD88. This gene normally helps immune cells to signal each other to stay in good shape, keeping them alive. The mutation in this gene may cause the cellular “on switch” to stay on, all the time, perhaps allowing WM cells to proliferate. There is hope that new therapies will effectively leverage this discovery.

The most common mutation as detected by FISH analysis has been a deletion, and it occurs on chromosome 6. This change is seen in up to 55% of people with WM. Many with WM have multiple genetic mutations.

What are the Symptoms of WM?

As many as 25 percent of patients don’t have any symptoms when they learn they have WM.

But most people do have symptoms and signs at the time of diagnosis, which are mainly due to the accumulation of cancer cells in the bone marrow or the circulating proteins in the blood. The most common symptoms are fatigue and weakness due to anemia.

Other symptoms are fever, night sweats, enlarged lymph nodes, enlarged spleen and liver, nerve problems or peripheral neuropathy, sometimes with weakness and numbness or tingling in the hands or feet.

People with WM also may describe feeling like they are fighting an infection that just won’t go away.

A distinguishing symptom of WM is hyperviscosity caused by the accumulation of  Ig M protein in the blood. Hyperviscosity syndrome may manifest like fatigue, abnormal bleeding, shortness of breath, headache, visual impairment (blurred vision), vertigo, or changes in mental status (confusion, memory loss, disorientation).

How is WM Treated?

There is no standard therapy for WM, and like other low-grade or “smoldering” lymphomas, patients who don’t have symptoms are generally observed only. Treatment depends on many different factors, both individual (e.g., age, overall health) and disease-specific (e.g., rate of progression, level of IgM protein).

Some treatments are aimed at avoiding symptoms and complications. Plasmapheresis is on such treatment. It's a little bit like dialysis—you get hooked up to a machine that can remove some of the IgM from the blood to help decrease the thickness of the blood.

Some agents aim to keep the out-of-control cells in check. Current treatments include alkylating agents (e.g. chlorambucil, and cyclophosphamide), nucleoside analogues (fludarabine and cladribine), the monoclonal antibody rituximab, and the proteasome inhibitor bortezomib. Combinations are also used. Unfortunately, there is not yet an option specifically approved by the U.S. FDA for the treatment of WM. In many situations, patients with WM are encouraged to consider whether clinical trials may be the best route.

Battling On

Treatment options for patients with relapsed disease include another round of the initial therapy, use of a different first-line agent, or high dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT).

In the last several years, there have been advances in scientific knowledge about how WM develops, and new therapies have been shown to have activity against WM cells. Some of these newer agents improve responses.

Investigational agents under study for patients with relapsed WM include:

  • Everolimus
  • Perifosine
  • Alemtuzumab
  • Imatinib mesylate
  • Panobinostat
  • Ixazomib
  • Oprozomib
  • Obinutuzumab
  • Bcl-2 antisense (oblimersen, Genasense)
  • Ibrutinib*
  • Sildenafil

*On October 20, 2014, Janssen announced the submission of a supplemental New Drug Application for ibrutinib to the U.S. Food and Drug Administration (FDA), seeking approval for the treatment of WM.

What Else May Be on the Horizon?

A better understanding of the biology of the disease is expected to drive further improvements.

  • Whole genome sequencing studies can help to identify specific mutations in subgroups of patients with WM.
  • Research on the epigenetic modifications in WM can help scientists learn whether and how certain changes might be targeted successfully.
  • Finally, the bone marrow environment plays a key role allowing tumor cells to grow and prosper, and scientists what to know how this support might be cut off.
  • Immunotherapy using T cells that have been reprogrammed or engineered to attack the cancer cells has shown promise in the treatment of some blood cancers.

Next Steps

For more information on WM, also consider the following sites:

The International Waldenström's Macroglobulinemia Foundation International
http://www.iwmf.com

National Cancer Institute
http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient

 

Sources

Leblebjian H, Agarwal A, Ghobrial I. Novel treatment options for Waldenstrom macroglobulinemia. Clinical Lymphoma, Myeloma & Leukemia. 2013;13 Suppl 2:S310-316.

MYD88 L265P mutation in Waldenstrom macroglobulinemia. http://www.bloodjournal.org/content/121/22/4504?sso-checked=true. Accessed October 2014.

Crowther-Swanepoel D, et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nature genetics. 2010; 42(2):132–6.

Fonseca R, Hayman S. Waldenstrom macroglobulinaemia. British Journal of Haematology. Sep 2007;138(6):700-720.

IMBRUVICA® (ibrutinib) Supplemental New Drug Application Submitted to the U.S. FDA for Waldenstrom's macroglobulinemia. http://www.prnewswire.com/news-releases/imbruvica-ibrutinib-supplemental-new-drug-application-submitted-to-the-us-fda-for-waldenstroms-macroglobulinemia-681133482.html. Accessed October 2014.

American Cancer Society. Waldenstrom Macroglobulinemia. http://www.cancer.org/acs/groups/cid/documents/webcontent/003148-pdf.pdf. Accessed October 2014.

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