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Ed Forum 2016

Future Directions

This section of the website reviews some of the recent cutting edge research into the biology and genetics of WM and where this research may lead us. Fair warning – some of the links included here lead to journal articles which are technical in nature and may be difficult to understand by those without a scientific background. Also, keep in mind that some of this work is still preliminary and that not all of it will come to fruition – that is the nature of research, after all. However, we hope that much of it will result in a better understanding of what makes WM “tick” and lead to targeted and more personalized treatments. Indeed, we are already beginning to see such results.

Strategic Research Roadmap for WM

In 2008 the IWMF, the Leukemia & Lymphoma Society (LLS), and the Lymphoma Research Foundation convened a special meeting to identify research priorities in the search for a cure for WM. From that meeting, three major research priorities were developed: the need for a WM tissue bank, the need for better and more representative WM cell lines, and the need for a mouse model of WM. Subsequent projects, funded by the IWMF alone and in concert with the LLS, led to substantial success in these areas.

Because of new and exciting developments in the areas of cancer biology and personalized medicine, the IWMF decided in 2014 that the time was right to update its research strategy and enlist the cooperation of many of the major players in the WM research community. To this end, the IWMF partnered with LLS to sponsor a Strategic Research Roadmap Summit in New York City on May 16-17, 2015.

Dr. Lee Greenberger, Chief Scientific Officer of LLS, moderated the Summit, which was attended by the following notable WM researchers: Dr. Ranjana Advani of Stanford University, Dr. Stephen Ansell of Mayo Clinic in Rochester, Dr. Asher Chanan-Khan of Mayo Clinic in Jacksonville, Dr. Morton Coleman of NY Presbyterian Weill Cornell, Dr. Shirley D’Sa of University College in London, Dr. Richard Furman of NY Presbyterian Weill Cornell, Dr. Irene Ghobrial of Dana-Farber Cancer Institute, Dr. Zachary Hunter of Dana-Farber Cancer Institute, Dr. Larry Kwak of City of Hope, Dr. Robert Kyle of Mayo Clinic in Rochester, Dr. Ari Melnick of NY Presbyterian Weill Cornell, Dr. M. Lia Palomba of Memorial Sloan Kettering Cancer Center, Dr. Roger Owen of St. James’s Institute of Oncology in Leeds, and Dr. Steven Treon of Dana-Farber Cancer Institute. Dr. Ansell and Dr. Treon were the scientific co-leaders of the conference.

The IWMF was represented by its President, Carl Harrington, and its Vice President for Research, Dr. Guy Sherwood. In addition to Dr. Greenberger, other attendees from LLS included Dr. Erik Nelson, Director of Research Programs, and Dr. Yixian Zhang, Executive Research Director.

The Summit agenda was divided into four major topic areas, with two-person teams leading the discussion of each topic:

  • Signaling – What pathways do WM cells use for communication?
  • Immunology/immunotherapy – How can we better use our own immune system to fight WM?
  • Tumor microenvironment – How does the bone marrow environment affect WM cells?
  • Omics – What else can we learn about genomics, epigenomics, and WM mutations?

Part of the Summit was also set aside for presentations by pharmaceutical companies actively working on treatments for WM.

An explanation of the four major topic areas on the Summit agenda is offered by Dr. Stephen Ansell of the Mayo Clinic, scientific co-leader of the Roadmap Summit, in a short video entitled "An Exciting Time in Waldenstrom's!"

As a result of the Summit, the IWMF-LLS Strategic Research Roadmap Initiative was developed to implement a robust research program to support the four focus areas above. Under the Roadmap Initiative, the IWMF has awarded grants for 2-5 new research projects each year, depending on funding availability. Each project is 2 years in length, at a cost of up to $200,000 per year per project. For a current list of Roadmap grants, look here.

MYD88 L265P Mutation

Research into the genetics of WM made a major leap forward in 2011 with the discovery – by Dr. Steven Treon and his group at Dana-Farber Cancer Institute – of a single mutation in a gene called MYD88, with a prevalence in 90% or more of WM patients. This was the first time that the entire genome, or complete set of DNA, of patients with WM was sequenced. The goal was to determine which genes were present in the cancer cells of these patients that were not seen in their normal cells. The IWMF was a sponsor of this research. The same study also reported that the MYD88 mutation, designated MYD88 L265P, was not nearly as prevalent in most other types of lymphoma or in multiple myeloma. This groundbreaking study is available here. Subsequent follow-up studies by WM investigators around the world have validated these findings.

Although we do not yet know the role that the MYD88 mutation plays in the development and progression of WM, Dr. Treon’s group and others have continued to study the mutation’s effects on downstream cellular pathways. Researchers now have a fairly good idea of the complex pathways affected by this mutation and how they might in turn promote the growth and proliferation of WM cells. A summary of some of this follow-up work can be found here.

As a result of this work and its subsequent confirmation by other researchers, the US National Comprehensive Cancer Network (NCCN) recently updated its guidelines for WM to include AS-PCR testing for the presence of MYD88 L265P in the bone marrow cells of suspected patients and has characterized the test as essential for the diagnosis of WM.

The IWMF is also funding work by Dr. Treon and his team to study several potential therapies that target cellular pathways downstream from MYD88, and preliminary results are encouraging. Stay tuned…...

CXCR4 Mutations

Several other genetic mutations were discovered to be fairly common in WM patients, although not to the extent of the MYD88 L265P mutation. One such group of mutations occurs in the gene CXCR4 at a prevalence rate of about 30%. Studies suggest that such mutations cause significant tumor proliferation and spread to extramedullary organs (outside the bone marrow), thereby leading to disease progression and a less favorable prognosis. The CXCR4 mutations are discussed in much more detail here. Additional research is being funded by the IWMF to confirm these findings, to determine the mechanisms by which these mutations cause disease progression, and to test an inhibitor of CXCR4 to see if it has potential to be used as a treatment for WM patients who harbor CXCR4 mutations.

Novel Treatments Based on Targeted Cellular Pathways

Our rapidly expanding knowledge about the cellular pathways involved in the development and progression of blood cancers, including WM, is now being applied to translational research, which takes this basic research and converts it into the synthesis of treatments that are targeted to these pathways.

Two of the newer treatments already in clinical use for WM include ibrutinib (Imbruvica), which targets Bruton’s tyrosine kinase (BTK), and everolimus (Afinitor), which inhibits mechanistic target of rapamycin (mTOR). Both targeted molecules are downstream from MYD88. In a groundbreaking moment in the history of WM, Imbruvica was specifically approved for its treatment by the US Food and Drug Administration on January 29, 2015, in an announcement presented here. It has since been approved by the European Medicines Agency for use in the European Union and by Health Canada. Some treatments, such as acalabrutinib and BGB-3111, are newer BTK inhibitors developed to improve the effectiveness and reduce the side effects of ibrutinib, while others, such as venetoclax, target different cellular pathways. These are in clinical trials for WM and other blood cancers...information about these and other clinical trials can be found by searching www.clinicaltrials.gov.

These new targeted pathway treatments are different from traditional therapies in several ways, and these differences have important implications for patients. They are more specific for tumor cells than chemotherapy, which often damages normal cells. Almost all of them are oral medications administered daily or several times a week, which means that they can be taken at home. This makes them more convenient, but it also means that patients must be compliant about when and how to take their medication. These treatments do not damage stem cells in the bone marrow, although they all have side effects that may lead patients to discontinue their use. They can result in dramatic improvements in disease status, but they appear to slow or arrest tumor cell growth rather than completely eliminate the cancer.  This means that, once patients begin these treatments, they may need to continue until the treatments no longer work or until side effects become intolerable. This represents a significant change from the older therapies which are typically administered cyclically for a period of time and then discontinued after a patient achieves a response. Because cancer cells are very adept at developing resistance mechanisms, it is highly likely that combinations of targeted pathway therapies will be necessary, or that targeted pathway therapies will be combined with monoclonal antibodies, such as Rituxan.

The novel oral agents are very expensive, and not all insurers pay for them. Federal and state regulations are being changed so that Medicare, Medicaid, and private insurers may eventually be required to cover their cost to the same extent that they cover intravenous and injectable drugs (so-called “oral parity” laws), but for now this remains an ongoing issue for many cancer patients.


Immunotherapy is a term referring to treatments that use one’s own immune system to fight cancer. Cancer cells, including WM cells, exist in an environment that includes immune system cells such as T-cells, macrophages, and natural killer cells, part of whose job it is to recognize and eliminate diseased cells such as cancer cells. Immunotherapy is a way to use this interaction to “rev up” the immune system to target and kill cancer cells more effectively. While there are still some hurdles to be overcome with the newer immunotherapies, their future looks very promising.

Most of us are familiar with the type of immunotherapy that targets cancer cells by utilizing monoclonal antibodies. Two such therapies in current use for WM are Rituxan (rituximab) and Arzerra (ofatumumab). When these monoclonal antibodies attach to the CD20 molecule on the surface of a WM B-cell, they effectively “paint” a “bullseye” on the B-cell so that T-cells, macrophages, and natural killer cells will recognize the antibody-coated cell and attack it. There are many other monoclonal antibody therapies besides Rituxan and Arzerra that target surface molecules on cancer cells. In addition to the “new and improved” CD20 monoclonal antibodies Gazyva (obinutuzumab) and ublituximab, an antibody called daratumumab that targets the CD38 surface molecule is about to be studied in WM patients.   

Another and newer type of immunotherapy, called an immune checkpoint inhibitor, can help to rejuvenate our immune systems. When a normal T-cell becomes activated, it also needs a “stop” signal in order to make sure it doesn’t become over-activated. One way this is done is through the expression of a cell receptor called PD-1. After activation, T-cells increase the expression of PD-1 on their surface, allowing them to receive the shut-down signal. Cancer cells take advantage of this system by expressing binding molecules to PD-1 and prematurely shutting down the action of T-cells. The use of inhibitors to PD-1 prevent the cancer cells from binding to PD-1, allowing the T-cells to stay active and go about their important task of killing cancer cells. The PD-1 inhibitors used now for solid tumors include Opdivo (nivolumab) and Keytruda (pembrolizumab), and they are being studied in blood cancers, including WM.

Yet another new strategy to overcome immune suppression and target cancer cells is to “engineer” one’s own T-cells to make them more effective. This is called chimeric antigen receptor T-cell therapy (CAR-T cell therapy). Treatment involves collecting a patient’s T-cells from the peripheral blood, growing them in a laboratory to increase their number, and introducing an artificial “docking site” into the cells. In most cases so far, the artificial docking site that is introduced binds to a surface molecule on B-cells called CD19. These engineered CAR T-cells are then reinfused into the patient, where they travel throughout the body, recognizing and directly attacking the cancer cells that express CD19. The effectiveness of CAR T-cell therapy has been successfully and rather dramatically demonstrated in cases of leukemia and lymphoma, with reporting in mainstream publications. CAR T-cells are now being considered as a treatment for WM. 

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Did you know?

Did you know the goal of the IWMF Imagine a Cure campaign is to raise $25,000,000 to fight WM?