Waldenström macroglobulinemia (WM)

Waldenström macroglobulinemia (WM) is an uncommon cancer derived from a specific type of white blood cell, known as a type of plasma cell, and is sometimes referred to as a lymphoplasmacytic lymphoma (LPL). In the United States, WM has an annual incidence of about 1,500 cases/year with patients having an average age of approximately 70 years. WM is one of the many subtypes of non-Hodgkin lymphoma (NHL), which in the US occurs in over 50,000 individuals per year.

The tumor cell in WM has experienced one or more mutations in its DNA and now grows in an uncontrolled manner. WM tumor cells typically produce unusually high amounts of a specific type of antibody known as immunoglobulin M (IgM). WM tumors grow mainly in the bone marrow (where normal blood cells are created) but also at other sites in the body such as the lymph nodes, liver and spleen, stomach, intestines or lung. Tumor growth may lead to a reduction in the number and function of normal blood cells, enlargement of lymph nodes, and to impaired organ function.

WM typically progresses slowly and may be managed with a careful watch-and-wait approach for about 20% of patients. More often, it requires treatment. The current therapies can control the disease for many years. The five-year-survival-rate is approximately 75% for patients with newly diagnosed WM. New therapies have significantly increased our ability to control the disease and may extend the median overall survival of WM patients for up to 15 years after diagnosis, although we are still collecting data to prove this projection. Nevertheless, recurrence is common in WM patients, and the disease is still considered incurable. The overarching goal of LLS is to understand the molecular basis of the disease and develop new effective therapies that ultimately will lead to a cure for WM.

LLS has supported most of the therapies in use for WM today. LLS is currently supporting several novel treatment approaches for WM, particularly through precision medicine and novel immunotherapy. Beyond this, LLS currently maintains a portfolio of over 50 active grants in NHLs, and much of the knowledge gained in our understanding of NHLs has been applied to WM.

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Symptoms & Diagnosis

WM does not cause any symptoms in about 20 percent of the total patient population and may be diagnosed because of abnormal results in a blood test. The most common early symptoms include fever, night sweat, and weight loss (the so-called “B-symptoms”) as well as enlargement of the lymph nodes, spleen and liver. Other symptoms may include reduced renal function, peripheral neuropathy (numbness or ‘pins and needles’ sensations in the limbs), central nervous symptoms, and bleeding from the mouth or nose.

Diagnostic evaluation of the potential WM patient is critically important since these test will determine the definitive diagnosis of WM, inform the best treatment, and later on assess if treatments are effective. In addition to the physical exam and blood test, a bone marrow biopsy and a funduscopic eye exam by an experienced ophthalmologist should be conducted. A specialized blood test can detect high levels of IgM which are a major characteristic of the disease. If these levels are exceedingly high, they can cause the blood to thicken and lead to the so-called ‘hyperviscosity syndrome’. This constitutes a medical emergency situation that requires plasmapheresis to remove the excessive IgM antibodies from the blood. WM tumor cells have characteristic mutations in their DNA and therefore genetic analysis should be part of the diagnostic evaluation. In particular, mutations in two proteins known as MYD88 and CXCR4 are present in over 90% and 30% of WM patients, respectively. (Mutations can also be found in the bone marrow and peripheral blood samples). CXCR4 mutations almost always occur in conjunction with MYD88 mutations. This mutational profile may help the physician to determine the best treatment strategy.

Treatments for WM

The treatment for WM changed dramatically once MYD88 mutations were discovered by Steve Treon M.D., Ph.D. and colleagues (Dana-Farber Cancer Center) in 2012. (Dr. Treon has been an LLS-funded investigators since 2014). Since MYD88 interacts with a protein called Bruton’s Tyrosine Kinase (BTK), BTK is known to promote other blood cancers (most notably chronic lymphocytic leukemia; CLL), and BTK inhibitors are highly effective in controlling CLL, the efficacy and safety of ibrutinib was explored in WM.

Before discussing ibrutinib, it is important to note that prior to the FDA-approval of ibrutinib in 2015, rituximab, a CD20-directed monoclonal antibody, used alone or more often in combination with other cytotoxic agents, was used to treat symptomatic WM patients. The cytotoxic agents included bendamustine, cyclophosphamide, alkylating agents, or nucleoside analogs. Rituximab and bendamustine, a common combination therapy, is given by intravenous (IV) infusion. Patients on these treatment regimens were able to achieve some long-lasting responses; however, complete responses (with no detectable disease) were rare. Combination therapies have significant side-effects, although they are manageable. Some clinicians still use rituximab-based therapies as the first therapy in newly-diagnosed symptomatic patients.

Ibrutinib has become a key drug in WM therapy because it is effective, generally well tolerated, and this oral medication is approved by the FDA for use in WM. In patients who failed prior therapy for WM the overall response rate with ibrutinib (which includes partial and complete responses) was 90%, although complete responses were rare. The estimated 2-year progression-free survival (i.e., no relapses due to advancing disease) and overall survival rates were 69% and 95% of patients, respectively. Ibrutinib also proved to be highly active in treatment-naïve patients, where the overall response exceeded 83% and the 18-month progression-free survival was estimated at 92% of patients. Patients with both MYD88 and CXCR4 mutations tended to have slower, less robust responses to ibrutinib than patients with MYD88 mutations only. Unfortunately, ibrutinib is not effective in patients without MYD88 mutations.

Since the approval of ibrutinib, numerous BTK inhibitors, including acalabrutinib and zanubrutinib, have been developed and advanced into clinical trials. In a recent study, the efficacy and safety of zanubrutinib and ibrutinib were compared in WM patients. While the efficacy of the two agents was similar, zanubrutinib had fewer side effects than ibrutinib (including, importantly, a reduced risk of atrial fibrillation of 2 vs. 15%). Other BTK inhibitors, which bind and inhibit BTK in a manner distinct from ibrutinib, are now in clinical trials and may prove useful in patients who have failed ibrutinib or zanubrutinib therapy, especially if resistance is mediated by a mutation at a critical contact site between the drug and the BTK protein. Beyond these novel approaches to BTK inhibition, LLS is also supporting the development of CXCR4 inhibitors, which when used in combination with ibrutinib, may induce better responses in double-mutant WM patients.

The Future of WM Therapy and Research

There is still much to be learned about WM since the disease is still considered incurable in most, if not all, individuals with WM. LLS and the International Waldenstrom’s Research Foundation (IWMF) have joined forces to understand the mechanisms that induce WM, the basis of resistance to existing therapies, and to develop new therapies to eradicate WM tumor cells. If the disease can be fully eradicated, therapy may be discontinued and a cure will be achievable.

Promising New Therapies.

Venetoclax. Over the past 20 years LLS has supported the development of the BCL-2 inhibitor venetoclax from target identification to clinical trials. BCL-2 is a protein that controls the survival of tumor cells: If its function is inhibited, tumor cells will die. Venetoclax is already FDA-approved for the treatment of CLL and acute myeloid leukemia. Preliminary data from Steve Treon M.D., Ph.D. and Jorge Castillo, M.D. (Dana Farber Cancer Institute) showed that patients with previously treated WM (including those with prior ibrutinib therapy), achieve an overall response rate of greater than 80% with venetoclax. New trials are already in progress in treatment-naïve patients who are receiving a combination therapy of ibrutinib and venetoclax. Based on the exceptional efficacy of this combination in CLL patients, LLS is optimistic this new therapy will also be highly efficacious in WM and may lead to long-term disease control. In CLL patients, it is encouraging that venetoclax can be discontinued from the combination therapy with many patients continuing to have no detectable disease when maintained only on ibrutinib.
CXCR4 inhibitors. Since CXCR4 mutations blunt the response to BTK inhibitors and venetoclax in WM patients, LLS funded Dr. Treon to explore the use of a CXCR4 antibody, known as ulocuplumab, with ibrutinib in CXCR4 mutated, symptomatic WM patients. This combination therapy appeared to induce faster and more pronounced responses than ibrutinib alone. LLS is now supporting a clinical trial by X4 Pharmaceuticals with an oral CXCR4 inhibitor in WM through our venture philanthropy program, known as the Therapy Acceleration Program (TAP).
HCK inhibitors. LLS is funding new work by Dr. Treon and Nathanael Gray, Ph.D. (Dana-Farber Cancer Institute) to explore the development of potent HCK inhibitors. This protein interacts with MYD88 to promote WM. A potent candidate HCK inhibitor has remarkable activity in laboratory models of WM, including those that are resistant to ibrutinib.

Mechanistic basis of WM

LLS and IWMF have invested in laboratory research to better understand the molecular basis of WM. It is clear that additional molecular alterations beside those listed above can contribute to or induce WM. The focus of this new work is as follows:

Understand how the immune environment, which surrounds the WM cells, control WM. Based on a broad study of multiple types of NHL (funded by LLS) it is clear that lymphoma cells are receiving signals from surrounding normal cells, and that this interaction promotes tumor growth. In particular, there are numerous communication paths between tumor and immune cells that could be blocked by therapeutic agents. This blockade could enable a patient’s immune cells to be fully activated and kill WM tumor cells.
Identifying new proteins that drive WM. Work by Constantine Mitsiades, Ph.D., M.D. (Dana-Farber Cancer Institute) will use state-of-the-art genetic methods to identify new genes that cause WM.
Understand how gene regulators control WM. It is known that so-called “epigenetic” regulators control the expression of genes that induce many types of NHLs. Such epigenetic changes have not been explored in WM.
Identify the molecular basis of resistance to new therapies for WM. It is fully expected that certain WM patients will fail existing or new therapies. Laboratories studies, which are coordinated with the investigation of clinical samples from WM patients, will help explain the mechanistic basis of such treatment failures. This will lead to the development of novel therapies to circumvent resistance, and to new treatments for certain patients to avoid resistance.