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Past Research Recipients

Marcel Spaargaren, PhD; Steven T. Pals, MD, PhD; and Marie Jose Kersten, MD, PhD – Amsterdam UMC, Amsterdam, The Netherlands – (Project Period 03/01/20 – 11/1/22). $398,000 over two years.

[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. One mechanism of action of ibrutinib is to dislodge WM cells from the bone marrow, where they grow best. This research seeks to identify specific kinases that allow WM cells to remain in the bone marrow. In a second part of the project, the researchers will seek to identify kinases that allow some of the ibrutinib-surviving cells to survive. In previous IWMF-funded research, Dr Spaargaren’s group identified a set of kinases with potential as new WM drug targets. In the present grant period, they will continue this work, first by validating the new targets in cellular tests (“in vitro”) and then by evaluating the role of the new targets in an innovative mouse model (“In vivo”). Identifying these new protein targets can help determine if there are existing drugs that may be re-purposed to treat WM, or could lead to development of new drugs specific to WM.

Yong Li, PhD – Institution: Baylor Medical School, Houston, USA (Project Period 10/15/19 – 10/01/22). $400,000 over three years.

This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. More than 90% of Waldenström’s macroglobulinemia (WM) patients have an abnormality (mutation) in the MYD88 protein, termed MYD88 L265P. This research aims to discover a drug to specifically block the abnormal MYD88 L265P protein in WM cells, while sparing the body’s normal MYD88. The work builds on Dr Li’s prior discovery that the abnormal MyD88 L265P, but not normal, wildtype MYD88, interacts with a specific protein called RING finger protein 138 (RNF138), leading to polyubiquitination that stimulates excessive NF-kB signaling. The project will perform a high-throughput screen to identify candidate molecules that either block RNF138 from interacting with MYD88 or inhibit RNF138 directly. Candidate molecules will be tested in additional cellular assays and in a mouse model. A new drug to block the abnormal function of MYD88 L265P would be useful to most WM patients, even though WM patients show a wide diversity of clinical disorders.




Steven Treon, MD, PhD, and Zachary Hunter, PhD– Dana-Farber Cancer Institute, Boston, MA, USA. (Project Period 9/1/2018-8/31/2020). $400,000. TITLE: TRANSCRIPTIONAL CHARACTERIZATION OF UNTREATED PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The genome is made up of DNA, a long, winding molecule that contains the instructions needed to build, maintain, and reproduce cells. For these instructions to be carried out, DNA must be “read” and transcribed—in other words, copied—into RNA molecules, which are called “transcripts.” A “transcriptome” is a collection of all the RNA transcripts present in a cell. A comprehensive characterization of the RNA transcriptome provides a snapshot of the inner workings of a cell at a particular moment in time. Studying the RNA transcriptome is a way in which researchers can determine when, where, and how each gene is expressed in a cell. This in turn can provide a basis for comparison between how genes are expressed in normal cells versus how they are expressed in cancer cells. Dr. Treon and Dr. Hunter propose to sequence the RNA transcriptome of a much larger set of WM patient samples than previously studied. Their sample set from 300 untreated patients should provide robust numbers for statistical analysis, thereby leading to better evaluation of gene expression from different types of MYD88 and CXCR4 mutations and better characterization of gene expression of other, less understood mutations in genes such as CD79B, ARID1A, and TP53, among others. Patients who provide samples will continue to be followed over time to investigate whether and how their gene expression patterns correlate with the clinical characteristics of their disease, such as: disease progression, response to therapy, subsequent progression-free survival and overall survival, and other events relevant to the natural course of WM.]

[Amyloidosis in WM is a rare condition that occurs when the free light chains produced by the clonal B-cells develop into an abnormally folded protein called amyloid that cannot be broken down. Amyloid can form deposits in different organs, most commonly the kidneys, and cause serious damage. There are currently no individualized treatment approaches for WM patients with amyloidosis. With the ultimate goal to determine the best therapeutic strategies for these patients, Dr. Gertz will perform in-depth studies to describe the clinical characteristics and biology of amyloidosis in WM.  This work is intended to discover the factors that trigger the condition in patients with WM and IgM-MGUS, to determine why the deposits of amyloid protein tend to occur in certain tissues, and to identify prognostic factors unique to this condition.]


Marcel Spaargaren, PhD; Steven T. Pals, MD, PhD; and Marie Jose Kersten MD, PhD – Amsterdam UMC, Amsterdam, The Netherlands. Project Period: 01/01/17 – 01/01/19, $398,000 over two years.  TITLE: TOWARDS A RATIONAL TARGETED THERAPY FOR WALDENSTRÖM MACROGLOBULINEMIA BY KINOME-CENTERED LOSS-OF-ADHESION AND SYNTHETIC LETHALITY SCREENS.
This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Some patients have primary resistance to ibrutinib, while a significant subset of patients who receive prolonged treatment with it develop secondary resistance due to recurrent mutations in BTK or its substrate, resulting in a poor clinical outcome. Thus, there is a need for the identification of novel targets and development of novel therapies to prevent or overcome ibrutinib resistance. Dr. Spaargaren and his associates demonstrated that ibrutinib and idelalisib target the B-cell receptor, but not CXCL12/CXCR4-controlled integrin-mediated adhesion in WM. They hypothesize that producing “homelessness” in malignant B-cells by targeting integrin-mediated homing and retention may be a powerful general strategy to cure B-cell malignancies. This project aims to identify the signaling pathways that control integrin-mediated WM cell homing, retention, and outgrowth; to identify kinases whose inhibition makes WM cells sensitive to the effects of ibrutinib and idelalisib; and to explore and exploit their potential as therapeutic targets for novel targeted combination therapy for WM patients.

Bruno Paiva, PhD, and Jose Angel Martinez-Climent, MD, PhD-Clinica Universidad de Navarra (CUN) and Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.  (Project Period 9/15/17 – 3/15/20). $400,000. Sponsored by: Elting Family Research Fund of the IWMF.  TITLE: SINGLE-CELL NEXT-GENERATION FLOW AND SEQUENCING TO UNRAVEL THE PATHOGENESIS OF WALDENSTRÖM’S MACROGLOBULINEMIA AND TO DESIGN GENETICALLY-DRIVEN HUMAN-LIKE EXPERIMENTAL MODELS
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. The transformation from a normal cell to a cancer cell involves a series of changes driven by a step-wise accumulation of genetic alterations. The mechanisms behind the malignant transformation of WM remain largely unknown. Although the MYD88 L265P mutation may be considered an important event in this transformation, the mutation by itself cannot explain the development of WM from IgM-MGUS. In this research project, Dr. Pavia and Dr. Martinez-Climent will investigate the cellular origin of WM by using next-generation flow cytometry and gene sequencing technologies in samples of patients with IgM-MGUS and WM and use this information to develop genetically-driven experimental WM mouse models.]

Madhav Dhodapkar, MB, BS-Emory University. (Project Period 9/15/16 – 5/15/20). $400,000. TITLE: ORIGINS AND IMMUNOTHERAPY OF MACROGLOBULINEMIA
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. It proposes that a major proportion of WM and IgM MGUS cases involve the transformation of natural IgM memory B-cells and that chronic antigen stimulation of these cells by lipid antigens underlies the pathogenesis of WM. The ability to model/grow precursor states in mice in vivo combined with new insights into the antigenic origins of WM sets the stage to gain fundamental insights and provide a platform to test new biologic or immune-based approaches to test prevention and therapy of WM.]

Marzia Varettoni, MD-Fondazione Italiana Linfomi Onlus (FIL), Alessandria, Italy. (Project Period 10/15/2017 – 10/15/2019). $400,000. Sponsored by: Elting Family Research Fund of the IWMF. TITLE: NON-INVASIVE DIAGNOSTICS AND MONITORING OF MRD [MINIMAL RESIDUAL DISEASE] AND CLONAL EVOLUTION OF WALDENSTRÖM’S MACROGLOBULINEMIA.
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Dr. Varettoni hypothesizes that a reliable diagnosis, as well as the differentiation of IgM-MGUS from WM, may be done in the clinical setting without the need for invasive procedures such as bone marrow or lymph node biopsies. She also suggests that the assessment of minimal residual disease (MRD) is feasible in WM, that MRD can predict relapse in WM patients receiving therapy, and that this assessment can be performed on both bone marrow and peripheral blood samples. Dr. Varettoni also proposes that the dynamics of clonal evolution in WM can be monitored in bone marrow and peripheral blood and can potentially guide a tailored treatment choice.]

Sherie Morrison, PhD– David Geffen School of Medicine, University of California, Los Angeles, CA, USA. (Project Period 9/15/2017 – 9/15/2019). $400,000. Sponsored by: Elting Family Research Fund of the IWMF. TITLE: NOVEL ANTIBODY-TARGETED INTERFERONS IN COMBINATORIAL THERAPIES FOR WALDENSTROM’S MACROGLOBULINEMIA
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. Interferons are cell proteins with a broad spectrum of anti-cancer activities and have been used for cancer treatment. But to date, the side effects associated with interferon have limited its use as a therapeutic agent. By fusing an interferon with a targeted antibody, Dr. Morrison suggests that the interferon can be made more effective without resulting in systemic toxicity. Dr. Morrison proposes to determine the efficacy of antibody-IFN fusion proteins for the treatment of WM. She will compare 8 different fusion proteins, as single agents and in combinations, in the laboratory and then test these fusion proteins in mice engrafted with WM cell lines. She will also determine if IFN fusion proteins can synergize with the established WM therapies bortezomib and ibrutinib.]

Shahrzad Jalali, PhD-Mayo Clinic, Rochester, MN, USA. (Project Period 9/15/2017 – 9/15/2019). $400,000. Sponsored by: Elting Family Research Fund of the IWMF. TITLE: MODULATION OF T-CELL FUNCTION BY METABOLOMIC SIGNATURE OF THE BONE MARROW MICROENVIRONMENT IN WALDENSTROM’S MACROGLOBULINEMIA
[This project falls under the IWMF-LLS Strategic Research Roadmap Initiative. There are data to indicate that amino acids are key regulators of immune response and tumor growth in several cancers. For instance, L-arginine is an essential amino acid that regulates T-cell cycle progression, and depletion of L-arginine by myeloid derived suppressor cells (MDSCs) leads to an inhibition of T-cell proliferation. Depletion of the amino acids cysteine and cystine has also been shown to inhibit T-cell function and is mediated by MDSCs. Given that MDSCs are immunosuppressive cells that inhibit T-cell function, Dr. Jalali hypothesizes that the number and activity of these cells are increased in WM and that their accumulation results in depletion of key amino acids. To prove her hypothesis, Dr. Jalali plans to perform a targeted metabolomic analysis on bone marrow, serum, and urine samples in a larger group of WM patients, including smoldering and symptomatic WM, as well as patients who have had a response to therapy. She will assess MDSC cell number and activity in WM patients and study whether increased activity contributes to amino acid depletion in the bone marrow. She will determine whether MDSCs and amino acid depletion suppress T-cell function and promote tumor cell growth.]


Abdel Kareem Azab, PhD – Washington University in St. Louis (Project Period 2/1/2016 – 1/31/2018, extended to 5/30/2018). $187,141. TITLE: HYPOXIA-TARGETED PET-IMAGING FOR PREDICTION OF PROGRESSION FROM MGUS TO WALDENSTROM’S MACROGLOBULINEMIA 
[This study investigated the development of a molecularly targeted system to predict progression from MGUS to WM in order to indicate patients with high(er) risk of development of symptomatic WM. Dr. Azab hypothesized that hypoxia (low oxygen level) is the “switch” that induces MGUS to become the disseminated form of active WM.  He developed and used a special PET (positron emission tomography) imaging to detect hypoxic metabolism in WM cells, with the amount of binding an indication of their metastatic potential.]

Christian Buske, MD; Jan Münch, PhD; and Daniel Sauter, PhD – Ulm University, Ulm, Germany (Project Period 10/31/2016 – 10/31/2018). $389,000. TITLE: CHARACTERIZATION OF ENDOGENOUS CXCR4 INHIBITORY PEPTIDES TO TARGET WALDENSTROM’S MACROGLOBULINEMIA
[The focus of this study was on the biological role of CXCR4 mutations, using mouse modeling, and their possible regulation by naturally occurring CXCR4 inhibitors. Almost all CXCR4 mutations in WM cause prolonged signaling upon binding to CXCL12 and may act as cancer-causing partners for the MYD88 L265P mutation in WM. For this project, a novel mouse model that expresses the MYD88 L265P mutation was used, and the most frequent WM CXCR4 mutations were introduced. Mice were analyzed for disease development. The investigators also worked to determine the effects of CXCR4 inhibitors, as well as the drugs ibrutinib and AMD3100, on WM cell lines that have been encoded with either wild type or mutated CXCR4.]

Shirley D’Sa, MD – University College London Hospitals (Project Period 5/1/2015 – 5/1/2017, extended to 7/31/2018). ₤40,000.00. TITLE: THE UCLH WM BIOBANK: FROM BIOLOGY TO TREATMENT 
[The University College London Hospitals NHS Foundation Trust, London, UK, has a large and growing patient base of IgM MGUS and WM patients, amounting to 150 WM/LPL patients and another 100 IgM patients including those with IgM MGUS, paraproteinemic neuropathies, Bing-Neel syndrome, cold agglutinin disease, and AL amyloidosis. There is a dedicated WM clinic in which 18-20 patients are seen each week, including 2 new patients on average. The center receives referrals from across the UK, and is closely allied to WMUK, a unique doctor-patient partnership that has been set up to act as the UK point of contact for patients with WM. Dr. D’Sa and associates systematically examined the clinical and biological characteristics of persons with these conditions and set up a Serum and Tissue Bank of samples for this patient group. This study was jointly funded by the IWMF and Waldenstrom’s Macroglobulinemia United Kingdom (WMUK).]


Steven P. Treon, MD, PhD, and Zachary Hunter, PhD – Dana-Farber Cancer Institute (Project Period 11/1/2014 – 10/31/2016. $361,152. TITLE: IDENTIFICATION OF GERMLINE AND SOMATIC VARIANTS ASSOCIATED WITH PREDISPOSITION OF WALDENSTROM MACROGLOBULINEMIA
[This project performed genome sequencing of DNA regions which have been identified as associated with WM predisposition in 1000 WM patients and their family members. Predisposing DNA codes that exist in these regions were assessed regarding how prevalent these inherited variants (mutations) are in familial WM cases, as well as the WM population in general. The information gained from these results was used to perform cellular studies to understand their contribution to the cell signaling that supports WM growth and survival. These predispositions were also studied to see if any of them lead to differences in overall survival and response to therapy or if any are associated with clinical characteristics such as high IgM or lymph node involvement.]

Brad H. Nelson, PhD, and Julie S. Nielsen, PhD – Tev and Joyce Deeley Research Centre, Victoria, BC, Canada (Project Period 10/15/2014 – 10/15/2016). $370,748 (CDN). TITLE: MUTANT MYD88: A TARGET FOR ADOPTIVE T CELL THERAPY OF WM
[A T cell receptor that recognizes an abnormal form of a protein called MYD88, found in the vast majority of WM tumors, was recently identified in WM. This T cell receptor can be used to endow patients’ T cells with the capacity to recognize and destroy their tumor. The researchers attempted a new treatment strategy in which T cells from WM patients were engineered to express this T cell receptor. The plan was to then infuse patients with large numbers of these engineered T cells in the expectation that the T cells would recognize and destroy tumor cells throughout the body, leading to improved tumor control and possibly a cure. This study was jointly funded by the IWMF, through the David and Janet Bingham Research Partners Fund, and by the Waldenstrom’s Macroglobulinemia Foundation of Canada.]

Irene Ghobrial, MD – Dana-Farber Cancer Institute (Project Period 9/1/2010 – 8/31/2016). $900,000. TITLE: LARGE SCALE GENOMIC AND PROTEOMIC PROFILING IN WALDENSTROM’S MACROGLOBULINEMIA
[This study included the development of a tissue bank of blood and bone marrow specimens linked to clinical characteristics of WM patients in different stages of the disease, the characterization of the genetics and proteomics of WM cells during disease progression, and the development of biomarkers to evaluate the in vivo activity of therapeutic agents in WM patients treated in clinical trials.]

[Mutations in CXCR4 gene may lead to dissemination of WM cells to distant organs and increased WM cell growth resulting in disease progression. Dr. Roccaro’s research project studied patients with extramedullary WM disease and evaluated whether or not mutations in the CXCR4 gene occur. This research led to the identification of possible novel common pathways of disease progression. Demonstrating genomic aberrations of the CXCR4 gene is crucial for identifying novel powerful anti-WM treatments. This study was funded by the IWMF, through the David and Janet Bingham Research Partners Fund.]

Sherine Elsawa, PhD – Northern Illinois University (Project Period: 11/15/2013 – 2/15/2016). $113,981. TITLE: TARGETING THE TUMOR MICROENVIRONMENT IN WALDENSTROM’S MACROGLOBULINEMIA
[This study determined the translational significance of targeting the CCR3-PI3K-AKT-GL12 pathway – a novel signaling pathway regulating the crosstalk between malignant compartments and the tumor microenvironment – and increased the understanding of the signaling pathways in the tumor microenvironment that contribute to progression of WM, with the purpose of facilitating the development of new targeted therapies for WM patients.]


Ruben Carrasco, MD, PHD – Dana-Farber Cancer Institute (Project Period: 12/01/2012 – 11/30/2015). $225,000. TITLE: DEVELOPMENT OF A MOUSE GENETIC MODEL OF WALDENSTROM’S MACROGLOBULINEMIA
[This was a study jointly funded by the Leukemia & Lymphoma Society and Waldenstrom’s Macroglobulinemia Foundation of Canada (an IWMF affiliate) to generate a mouse model of the disease that recapitulates its clinicopathologic features by engineering the MYD88 L265P mutation in the mice. These mice were evaluated for LPL/WM involvement over time as well as biochemical and functional characterization of transgenic B-cells to define the role of the MYD88 L265P mutation in oncogenesis.]

Steven P. Treon, MD, PhD – Dana-Farber Cancer Institute (Project Period: 06/01/2013 – 05/31/2015). $500,000. TITLE: DEVELOPMENT OF TARGETED THERAPIES FOR WALDENSTROM’S MACROGLOBULINEMIA
[This was a continuation of a previous project proposed by Dr. Treon and partially funded by the IWMF. This study proposed to define the oncogenic signaling of MYD88 L265P in WM, to identify and validate inhibitors of MYD88-directed signaling in WM, and to characterize MYD88 pathway inhibitors in vivo and initiate early clinical phase studies in WM patients.]

[This was a continuation of previous projects proposed by Dr. Ansell and funded by the IWMF. This study proposed to characterize the expression and activation of STAT5A and STAT5B in WM cell lines and patient-derived tumor cells, to determine the individual influence of STAT5A and STAT5B on the subsequent expression of downstream targets in WM, and to evaluate the effects of isoform-specific STAT5 inhibition on the biology of the WM tumor.]

(2012 – 2014)

Abdel Kareem Azab, PhD – Washington University, St. Louis, MO (USA) (Project Period: 07/01/2012 – 08/01/2014). $93,486. TITLE: THE ROLE OF HYPOXIA IN THE DISSEMINATION OF WALDENSTROM MACROGLOBULINEMIA
[This study was to determine the role of hypoxia in WM cell dissemination in vivo, to characterize molecular changes regulated by hypoxia in WM cells in vitro, and to determine the role of a signaling pathway called Hypoxia Inducible Factor (HIF) in WM cell response to hypoxia and the effect of HIF inhibitors on the progression of WM in vitro and in vivo.]

(2010 – 2012)

Janz, Siegried, MD, DsC – University of Iowa, Iowa City, IA. (Project Period: 08/01/2010 – 07/31/2012). $540,000. TITLE: DEVELOPMENT OF A TRANSGENIC MOUSE MODEL OF WALDENSTROM’S MACROGLOBULINEMIA
[This project proposed to develop a transgenic mouse with disease characteristics of WM, including monoclonal IgM secretion and the presence of lymphoplasmacytic cells in the bone marrow and other tissues. Transgenic mice are genetically engineered to “model” certain disease characteristics, and they are able to pass these characteristics to their offspring, resulting in mouse colonies that can be used for testing of therapeutic agents prior to human clinical trials.]

Nelson, Brad, PhD – Tev and Joyce Deeley Research Centre, Victoria, BC, Canada (Project Period: 01/01/2010 – 12/31/2011). Project sponsored entirely by Waldenstrom Foundation of Canada at $99,935Can. TITLE: THE IMMUNE RESPONSE TO WM: IMPLICATIONS FOR IMMUNOTHERAPY
[This study proposed the development of strategies that can be used for future immune based treatments for WM. These strategies included (1) identifying tumor-specific sequences and reactive T-cells from WM patients and (2) deriving T-cell lines recognizing tumor-specific peptides and characterizing their functionality and phenotype. The goal was to develop an idiotype-based vaccine strategy for the treatment of WM.]

Ansell, Stephen M., MD, PhD – Mayo Clinic, Rochester, MN. (Project Period: 11/01/2006 – 10/31/2011). $903,702. TITLE: FACTORS REGULATING IMMUNOGLOBULIN PRODUCING B-CELLS IN PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA
[This was a study to help identify genetic predisposition, growth factors, and prognostic indications of IgM production by WM cells. Specifically BlyS and various cytokines (small proteins) were studied for their effect on IgM production.]

Ansell, Stephen M., MD, PhD – Mayo Clinic, Rochester, MN; Chanan-Khan, Asher A., MD – Roswell Park Cancer Institute, Buffalo, NY; Chen, Suning, PhD – Jiangsu Institute of Hematolology, First Affiliated Hospital of Soochow University, China; and Ghobrial, Irene, MD – Dana-Farber Institute, Boston, MA. (Project Period: 06/01/2010 – 06/30/2011). IWMF portion of grant: $100,000. TITLE: DEVELOPMENT AND VALIDATION OF WALDENSTROM’S MACROGLOBULINEMIA CELL LINES
[This was a study jointly funded with the Leukemia & Lymphoma Society to develop stable and representative WM cell lines to be made widely available to researchers. Under the agreement, these four independent laboratories received initial funding for one year; continued fundign to one or more of these researchers, potentially for up to two additional years, was contingent on the progress toward the goal of developing and validating suitable cell lines.]

Leleu, Xavier, MD, PhD – Service des maladies du sang, Hopital Huriez. (Project Period: 11/01/2011 – 10/31/2013, terminated 2012). $132.500. TITLE: PRE CLINICAL STUDY OF THE ROLE OF POMALIDOMIDE IN WALDENSTROM’S MACROGLOBULINEMIA
[This study was to determine the efficacy profile of the immunomodulatory drug pomalidomide in WM primary tumor cells, in the BCWM.1 and MWCL1 cell lines, and in other low grade B-cell lines. The anti-tumor effect of pomalidomide and its safety were to be confirmed in an in vivo xenograft mouse model. The grant was terminated in 2012 because the use of pomalidomide in the study’s experiments did not affect the proliferation or viability of WM cell lines. The amount actually spent at the time of grant termination was $66,250.]

(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: 01/01/2007 – 12/31/2010). $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 (Project Period: 01/01/2010 – 12/31/2010). $45,544. TITLE: IMPACT OF IL-6 GENES DYSREGULATION IN ANEMIA OF CHRONIC DISEASE AND HEPCIDIN LEVELS IN WALDENSTROMS MACROGLOBULINEMIA
[This study proposed to elucidate the role of IL-6 overproduction in WM and the development of anemia. In this study, WM patients with increased tumor burden experienced a significant increase in anemia. The increased occurrence of anemia in WM patients with increased tumor burden may be due to the significant increase in serum IL-6 expression measured in anemic patients. Further, a significant increase in hepcidin levels was identified in WM patients with anemia, suggesting that increased IL-6 secretion may cause an increase in hepcidin production, thereby degrading ferroportin and causing iron sequestration and subsequent anemia.]

(2004 – 2008)

Tsingotjidou, Anastasia S., DVM, PhD – Aristotle University, Thessaloniki, Greece (Project Period: 01/15/2007 – 01/14/2008 extended to 1/2009). $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.]

[This project was 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., MD – Cross Cancer Institute, University of Alberta, Edmonton, Canada. (Project Period: 05/01/2005 – 04/30/2008). $307,152 CAD. TITLE: GENETIC CHARACTERISTICS OF WALDENSTROM’S MACROGLOBULINEMIA
[This was 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, PhD – Mayo Clinic, Rochester, MN (Project Period: 07/01/2004 – 06/30/2006). $269,273. TITLE: BLYS INHIBITION IN IMMUNOGLOBULIN PRODUCING B-CELLS
[Dr. Ansell’s research demonstrated that the BlyS protein stimulates the generation of IgM and increases the survival and proliferation of malignant cells (WM cells). The studies also showed the sites on B cells which interact with BlyS. Agents were identified which interfere with the actions of BlyS, with future work to 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: 01/01/2004-12/31/2005). $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: 07/01/2004 – 06/30/2005). $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 successfully developed such a mouse for use in the studies of diseases such as multiple myeloma and prostate cancer. In this project the researcher 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.]

Bredeson, Christopher, MD, MSc, FRCPCA/Parameswaren, Hari, MD – International Bone Marrow Transplant Registry, Medical College of Wisconsin, Milwaukee, WI (Project Period: 07/01/2004 – 06/30/2005). $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) had 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) had 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 – Dana-Farber Cancer Institute, Boston, MA (January 2000)
[This study was 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].

[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: 11/01/2001 – 10/31/2003). $109,834. TITLE: WALDENSTROM’S MACROGLOBULINEMIA GENOMICS
[This project 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.]