(2008 - 2010)
Treon, Steven P., MD, MA, PhD – Bing Center for Waldenstrom’s Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA. (Project Period 01/01/07-12/31/10). $1,038,942. TITLE: “Comprehensive Studies into the Genetic Basis and Pathogenesis of Waldenstrom’s Macroglobulinemia”
[Three identifiable clinical subtypes for WM predisposition were identified: 1. Sporadic WM subtype – the initial patient has WM but there is an absence of WM or other B-cell disorders in family members; 2. Familial, WM Only subtype – the initial patient has WM and only WM is present in family members; and 3. Familial, Mixed B-Cell Disorders subtype – the initial patient has WM and various other B-cell disorders are manifested by family members. Several distinct clinical, as well as genetic and epigenetic differences were identified among these subtypes. SNP (single nucleotide polymorphism) analysis indicated that the Familial, Mixed B-Cell Disorders subtype exhibited significant loss of GSTM1 and/or GSST1 gene expression, both of which are important in the glutathione S-transferase gene family. These gene losses have been previously associated with an increased risk for several other types of cancers. SNP analysis also identified several genes of significance to the predisposition of WM in the Familial, WM Only and Familial, Mixed B-Cell Disorders subtypes; these included RASSF4, FGF2, IL21, TRAPPC9, IL6, and IRAK1BP1. Gene expression profiling determined that Spi-B is overexpressed in WM. Spi-B is implicated in B-cell differentiation, and its overexpression may lead to a block in plasma cell differentiation while promoting growth and survival of WM cells. Distinct gene expression patterns were identified which distinguish sporadic vs. familial patients, as well as patients with more aggressive disease as defined by the WM International Staging System Score. These studies also helped establish epigenomic alterations in WM, with distinct microRNA patterns and methylation dysregulation in WM patients. These alterations represent novel targets for the treatment of WM. Finally, patients with familial disease were more likely to demonstrate symptomatic disease requiring treatment at the time of diagnosis than non-familial patients. Treatment outcome was also affected by familial status – patients with familial disease, particularly those with Familial, WM Only subtype, demonstrated inferior responses and progression free survival following treatment with rituximab-based therapy. Patients of the Familial, Mixed B-Cell Disorders subtype attained better responses to bortezomib-based therapy than did those of the Sporadic WM subtype.
Henry, Travis J., PhD and Fonseca, Rafael, MD – Mayo Clinic, Scottsdale, AZ, (01/01/2010 to 12/31/2010). $45,544. TITLE: “Impact of IL-6 Genes Dysregulation in Anemia of Chronic Disease and Hepcidin Levels in Waldenstroms Macroglobulinemia”
[Study to elucidate the role of IL-6 overproduction in WM and the development of anemia.]
2004 – 2008)
Tsingotjidou, Anastasia S., DVM, PhD – Aristotle University, Thessaloniki, Greece, (Project Period 1/15/2007-1/14/2008 extended to 1/12009). $45,900. TITLE: “Study of the Neuropathy Associated with Waldenstrom’s Macroglobulinemia Using a SCID-hu Bone Animal Model”
[Peripheral neuropathy (PN) often accompanies WM and causes painful suffering. Dr. Tsingotjidou showed that mice could be caused to develop WM in a previous IWMF supported project. In this project it was demonstrated that mice could be infected with WM and several of them exhibited signs of having peripheral neuropathy].
Ghobrial, Irene M., MD-Dana-Farber Cancer Institute, Boston MA. (Project Period 12/01/2006-11/30/2008). $216,000. TITLE: “Molecular and Functional Sequelae of the P13K Pathway in Waldenstrom’s Macroglobulinemia”
[There are numerous reactions occurring in the body which affect the generation, growth, and death of cancer cells like WM. Dr. Ghobrial has tested a chemical, perifosine, in mice with WM and in cell lines in “test tubes” and has shown that it inhibits the growth of WM cells. Her previous work has indicated that it interrupts a development pathway that causes WM cells to seek shelter in the bone marrow. It also appears to cause WM cells that are already “sheltered” in the bone marrow to be released into the peripheral blood where they can be destroyed by other reagents. This project enabled Dr. Ghobrial to test the blood of patients before and after they are treated with perifosine to determine if the same effects occur in humans. The results showed that perifosine alone prolonged the time to progression in patients with relapsed or refractory WM. The response rate was 36%, while 58% of the patients showed disease stabilization. It was also shown that perifosine in combination with rituximab and bortezomib increased WM cell death. Finally, the project showed that an imaging system used with myeloma can be employed to study the progression of the disease in live mice.]
Braggio, Esteban, in the laboratory of Dr. Rafael Fonseca, Mayo Clinic, AZ. (Project Period 10/01/2007-09/30/2008). $74,234. TITLE: "Genome-Wide Characterization of DNA Copy Number Changes Using Array-based Comparative Genomic Hybridization in Waldenstrom’s Macroglobulinemia and Delineation of the Minimal Region of 6Q Deletion"
[This project is a continuation of the work started by Dr. Fonseca on the genetic changes which occur with patients who have Waldenstrom's macroglobulinemia. Forty-two patients with WM were analyzed and 83% had genetic abnormalities. The most common chromosomal abnormality was found in 40% of the patients and was the deletion of the long chromosome arm 6q. At the gene level deletions and mutations were found in two genes that are known to protect cells from becoming cancerous. These genes are part of a regulatory pathway which can be controlled by inhibitors such as bortezomib.]
Pilarski, Linda M. – Cross Cancer Institute, University of Alberta, Edmonton, Canada. (Project Period 5/1/05-4/30/08). $307,152 CAD. TITLE: “Genetic Characteristics of Waldenstrom’s Macroglobulinemia”
[A study of the mutations occurring in cells of patients with Waldenstrom’s macroglobulinemia. Specifically the project showed that the HAS1 gene in WM patients generates abnormal proteins. The work identified targets for developing new and possibly more effective therapies.]
Ansell, Stephen M., MD – Mayo Clinic, Rochester, MN, (Project Period 7/1/04-6/30/06). $269,273. TITLE: “BlyS Inhibition in Immunoglobulin Producing B-cells”
[The research program has demonstrated that the BlyS protein stimulates the generation of IgM and increases the survival and proliferation of malignant cells (WM cells). The studies have also shown the sites on B cells which interact with BlyS. Agents have been identified which interfere with the actions of BlyS and future work will determine if these agents can be made in a form that will enter the body’s blood stream and reduce the effect of BlyS on the B cell life and its ability to produce IgM.]
Mitsiades, Constantine S., MD – Dana-Farber Cancer Institute, Boston, MA, (Project Period 01/01/04-12/31/05). $60,000. TITLE: “In Vitro and in Vivo Molecular Profiling of WM as a Framework for the Design of Novel Combination Therapies for the Disease”
[Dr. Mitsiades determined that WM cells have different sub-types. This finding may be indicative of why various patients with WM react differently to the same treatment. He also identified a number of proteins which regulate the activity of the WM cells. The proteasome inhibitor bortezomib (Velcade™, PS-341) can turn off expression in certain genes which in turn reduces the activity of proteins that prevent the death of WM cells and also affects the behavior of proteins that try to repair damage to the WM cells. Another compound called heat shock protein-90 was found to play a part in the proliferation of WM cells. By inhibiting the action of this protein death could be more easily induced in WM cells. A third category of proteins called histone deacetylases (HDACs) was determined to interact with DNA in such a manner as to assist in regulating the growth, survival and drug-resistance of WM cells. By identifying compounds which inhibit (HDACs) cell death could be increased.]
Tsingotjidou, Anastasia S., DVM, PhD – Aristotle University of Thessaloniki, Thessaloniki, Greece, (Project Period 7/01/04-6/30/05). $50,000. TITLE: “Establishment of a Waldenstrom’s Macroglobulinemia Animal Model”
[There has only been limited success in creating WM in mice so that the pathology of the disease can be studied and also new therapies can be tested prior to their use with humans. Dr. Tsingotjidou has successfully developed such a mouse for use in the studies of diseases such as multiple myeloma and prostate cancer. In this project the researcher has actually grafted human bone fragments from patients with WM to the bones of mice and determined that high concentrations of IgM are produced in an infected mouse. Studies are currently underway to determine the progression of the disease in the animals. Future work would involve using the mice to test promising agents identified by other IWMF studies.]
Bredeson, Christopher, MD, MSc, FRCPCA/ Parameswaren, Hari, MD – International Bone Marrow Transplant Registry, Medical College of Wisconsin, Milwaukee, WI. (Project Period 7/01/04-6/30/05). $28,674. TITLE: “High Dose Chemotherapy Followed by Autologous or Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Waldenstrom’s Macroglobulinemia”
[Introduction: The role of stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. The authors performed a retrospective analysis of 36 patients with WM who received autologous (N=10) or allogeneic (N=26) SCT and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).
Methods: Diagnostic and response criteria for WM were based on the Second International Workshop on WM definitions. The following outcomes were analyzed: non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS).
Results: Median age at the time of SCT was 51 years and median time from initial treatment to SCT was 29 months. 78% of the patients had>2 prior chemo regimens and 52% had disease resistant to salvage chemotherapy. 58% of patients in the allogeneic SCT group received myeloablative conditioning regimens (agents that changed the bone marrow). Only 5/26 allogeneic SCT cases received non-myeloablative/reduced intensity conditioning. After a median follow-up of 65 months, 21/36 (58.3%) patients have died. Primary disease accounted for 29% and 25% of the deaths in the allogeneic and autologous SCT groups respectively. Relapse rate at 3 years was 29% and 24% for the allogeneic and autologous SCT group respectively. PFS at 3 years was 31% and 65% and OS was 46% and 70% respectively for the allogeneic and autologous SCT group.
Conclusion: The role of stem cell transplantation (SCT) in Waldenstrom’s macroglobulinemia (WM) has not been extensively studied. A retrospective analysis of patients with WM who received autologous or allogeneic SCT and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) was performed. The major conclusions as presented at the IWMF meeting in Tampa by Dr. Parameswaran were that autologous SCT is a safe (1 yr nonrelapse mortality [NRM] of 11%) and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Nucleoside analogues and alkylators that may affect stem cell mobilization should therefore be avoided before stem cell collection in patients who may be candidates for ASCT. Allogeneic SCT carries a much higher (40%) NRM risk and should not be considered outside the context of a clinical trial.]
Al-Katib, Ayad, MD-Wayne State University, Cleveland, OH. January 2000, TITLE: “A Study of the Response of WM to Treatments with Bryostatin l and 2-CdA”.
[Dr. Al-Katib had previously established what was believed to be an immortal WM cell line from a patient. This line could be grown in mice and cultured in vitro for research purposes. At the time it was one of the few known WM cell lines. The study used bryostatin 1, a natural product derived from a marine animal, and 2CdA to determine the optimum dosage and schedule for treating the cell line in mice and in vitro WM cells. Results of the in vitro culture showed that WM cells are relatively sensitive to 2CdA but not to bryostatin 1 when each agent is used alone for treatment. When the cells were pre-exposed to bryostatin 1 and then treated with 2CdA significant growth inhibition was observed. A similar interaction was observed in a chronic lymphocytic leukemia model (CLL). When WM cells were treated with both agents, after nine days tumor weight was reduced. The preliminary results suggest a useful interaction between the agents which could lead to enhanced therapeutic action against WM.]
Treon, Steven P., MD, MA, PhD, Harvard University, Dana Farber Cancer Institute, Boston, MA – January 2000
TITLE: “Treatment of Waldenstrom’s Macroglobulinemia by Antibody-Mediated Immunotherapy and Induction of Tumor Selective Antigens”.
[Description: To develop an antibody-mediated immunotherapy for treating WM by identifying novel tumor selective antigens to target WM plasma cells, as well as identifying agents which could be used clinically to induce such plasma cell selective antigens. The study sought to (1) identify how Rituxan, a monoclonal antibody (MoAb) works in WM patients; (2) to develop strategies to overcome the body’s resistance to Rituxan; (3) to identify how protein markers on the surface of WM tumor cells block the immune system activity; and (4) to identify new therapies for use in WM. Resistant proteins were located on the WM cells, but they did not interfere with the Rituxan reaction. Other immune mechanisms appeared to be more important in determining the response to Rituxan. During the project another suitable antigen target labeled CD52 was identified on WM cells and an FDA approved monoclonal antibody (Campath-1H) has been shown to have activity against that site].
Rajkumar, Vincent, MD, Mayo Clinic, Rochester, MN – January 2000 TITLE: “Blood Vessel Development and Cell Division and Growth in Waldenstrom’s Macroglobulinemia.”
[Description: This study sought to determine the degree of blood vessel development and its prognostic value in WM. Dr.Rajkumar had previously shown that multiple myeloma tumors had excessive new blood vessels feeding the tumor and were predictive of the disease progression. In this study it was demonstrated that WM tumors do not develop an increased network of blood vessels, as is the case with myeloma. This study predicted that a chemical such as thalidomide would probably not be as effective in treating WM as it was in myeloma.]
Fonseca, Rafael, MD – Mayo Clinic, Scottsdale, AZ, (Project Period 11/01/01-10/31/03); $109,834; TITLE: “Waldenstrom’s Macroglobulinemia Genomics”
[This study followed a previous one in which he studied the chromosomal and molecular abnormalities of the diseased cells of WM patients. In the first study it was shown that about 50% of WM patients had a deletion of the long arm of chromosome 6(6q). In this project the 6q arm of the chromosomes of patients with monoclonal gammopathy of undetermined significance (MGUS) was compared with that of WM patients. No 6q deletions were found in patients with MGUS, whereas 55% of the WM patients showed the deletion. This result could be useful in separating WM patients from those with MGUS.]