Fall 2007 - International Waldenstrom's Macroglobulinemia ...

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PAGE 6 Research Clinical Highlights, cont from page 1 Veronique Leblond, Irene Ghobrial, and Meletios Dimopoulos (principal organizer of the upcoming Kos workshop). Dr. Myers insisted, and Dr. Dimopoulos agreed, that the workshop should include a consensus panel charged with updating the treatment recommendations for both frontline and salvage therapy from the 3rd <strong>International</strong> Workshop on WM . As we are all aware, the pace of scientific research continues unabated, and numerous new treatments have come into existence and have been evaluated in rigorous clinical trials since October 2004. The IWMF is proud to have encouraged and facilitated the updated recommendations for new treatment guidelines for WM. It is important to note that the recommendations outlined in this article have not yet been fully implemented. Drs. Treon and Dimopoulos will now present the Kos recommendations to a number of WM clinical experts for final approval; scientific publication will follow in the clinical literature. The IWMF will also update two of its most important publications, “Treatment Options” (August 2003) and “Questions and Answers” (August 2003). What follows is an outline of the proposed recommendations for both frontline (initial) and salvage (after the first failed remission) therapy, updating the previous recommendations issued following the 3rd <strong>International</strong> Workshop on WM in 2004. I include as well my own comments and observations since I was privy to the interesting and lively debate which took place on the very warm island of Kos. 1. Frontline therapy Frontline (up-front) therapy for WM (in never-before treated patients) includes: Monotherapy (single agent therapy) • alkylator agents cyclophosphamide (Cytoxan), chlorambucil (Leukeran) • nucleoside analogs such as fludarabine (Fludara), cladribine (2CdA), and pentostatin (Nipent), which is used more commonly in Europe • the monoclonal antibody rituximab (Rituxan) Combination therapy • (RF, RC, RP) rituximab + fludarabine/cladribine/ pentostatin • (R-CHOP) rituximab + cyclophosphamide + doxorubicin (Adriamycin) + vincristine (Oncovin) + prednisone • nucleoside analogs + cyclophosphamide +/- rituximab • (DRC) dexamethasone (Decadron) + rituximab + cyclophosphamide • thalidomide (Thalomid) + rituximab Comments • Since WM patients are at increased risk of chemoinduced peripheral neuropathy, bortezomib (Velcade) was not considered upfront therapy because of the high risk of neuropathy. However, the incidence of Velcade-induced neuropathy decreases greatly with a reduced dosing schedule such as weekly versus twice weekly. New generations of proteosome inhibitors from the Velcade family show no neuropathy in early trials. • Alkylator agents are not recommended in young patients (
Research Clinical Highlights, cont from page 6 leukemia (AML), or transformation of WM to diffuse large B-cell lymphoma (DLBCL) with the use of nucleoside analogs, particularly fludarabine, was felt to need more data and review before a consensus statement could be made. • It is too early to recommend rituximab maintenance as long-term data are not yet available. • Age is an important factor for deciding which initial monotherapy to use (age 65 is the unofficial cut-off point); however, the measurable Performance Status of the patient is very important (a “young” 70 year old as opposed to a very sick 45 year old). • Special attention and caution are needed when using lenalidomide (Revlimid) in WM because of a possible rapid onset anemia (this is not seen in MM or CLL). • Autologous bone marrow transplants are increasingly viewed as valuable therapeutic options for the appropriate patient as the data on survival and duration of remissions are superior to many other conventional treatments. • Allogenic transplants should only be considered when absolutely necessary and in the context of a clinical trial. See the above comments on RIC or mini-allo transplants, which may be appropriate in exceptional cases. ORAL AND POSTER PRESENTATIONS Genetics, Pathophysiology and Staging System Many new and exciting discoveries are being made in the biology of WM. To date, however, problems still arise in the accurate differentiation between WM and other similar non- Hodgkins B-cell immunoglobulin (Ig) secreting lymphomas. Of particular interest is the family tree of the WM cell and determining the cell of origin along the B cell developmental path that gives rise to the WM tumor cell. Most current research has centered on the WM cell’s inability to “switch” from the initial production of IgM to the production IgG or IgA (see the IWMF publication “Introduction to Immunology in WM”). From the study of this “class switch” phenomenon (from IgM to IgG and IgA), which is arrested at the IgM level in WM (neoplastic arrest), and from the study of the immunoglobulin gene rearrangements, mutations, and class switch recombination, scientists are gaining insight into the dissimilarities between WM and IgM-MGUS. (MGUS refers to “monoclonal gammopathy of undetermined significance,” which is specified as IgM-MGUS in cases where the monoclonal protein is IgM.) This could suggest a distinct differentiation process between WM and IgM- MGUS. Furthermore, these studies will enable scientists to identify the differences and similarities between WM and other B-cell lymphoproliferative disorders, and this, in turn, can help to explain how the WM tumor cell is produced in the B-cell differentiation process. Dr. Linda Pilarski, a research scientist at the University of Alberta Cross Cancer Institute and a recipient of a large IWMF research grant, has focused her research on hyaluronan synthase 1 (HAS1). This large sugar molecule is important in cell motility, signaling, and mitosis (cell division). Dr. Pilarski’s laboratory has identified three different gene variants of HAS1, two of which are the result of partial retention of a particular segment of DNA in the gene (an intron) that is found only in patients with WM or multiple myeloma. “Intronic splicing” is seen only in cancer cells and is not found in the cells of healthy individuals. The identification of these gene variants holds promise of the development of a DNA lab test permitting not only individual risk assessment strategies for early detection and monitoring of malignancy before, during and after therapy, but also assessment of response and prediction of relapse. Furthermore, the pattern of tumor-specific DNA mutations may provide a common marker, or ID tag, for all such patients. It may also be possible to use DNA lab testing to monitor IgM-MGUS for the early stages of emerging malignancy, response to treatment, and identification of the monoclonal gammopathies that have the greatest risk of transformation to WM. Dr. Rafael Fonseca, a clinical researcher from the Mayo Clinic in Scottsdale, Arizona, and an IWMF research grant recipient, has also focused on the genetics of WM. His prolific gene expression profile studies have recently suggested that WM shares more similarities with chronic lymphocytic leukemia (CLL) than multiple myeloma (MM). Dr. Pilarski, however, contests this observation because her lab research suggests that WM is closer to MM, not CLL. Dr. Fonseca argues that, while clinically similar, the cytogenetics and genomics underlying MM and WM are quite different. The genetics of WM appears to be much simpler than those of MM, with fewer abnormalities (the 6q deletion is the most frequent abnormality in WM, observed in 16% of WM patients). Newer laboratory tools, such as array-based comparative genomic hybridization and gene expression profile, enable researchers to realize high-resolution whole genome screenings for abnormalities and to gain insight into the consequences of genomic alterations noted in WM. As is the hope of many WM patients, future therapeutic decisions may be based solely on practical clinical tools such as genomic studies. Dr. E. Morra of Italy evaluated the existing diagnostic criteria used to separate IgM-MGUS from SWM (smoldering or asymptomatic WM). Until recently, a reliable distinction of asymptomatic populations with different risks of transformation into active disease was not available. The 2 nd Research Clinical Highlights, cont on page 8 PAGE 7
Page 1 and 2: iwmf torch Fall 2007 INTERNATIONAL
Page 3 and 4: President's Corner, cont from page
Page 5: Medical News, cont from page 4 in i
Page 9 and 10: More Funds, More Research, cont fro
Page 11 and 12: FROM IWMF-TALK by Mitch Orfuss Over
Page 13 and 14: NEW ENGLAND (cont.) Western MA, VT
Page 15 and 16: Support Group News, cont from page
Page 17 and 18: SOCIAL SECURITY DISABILITY Howard P
Page 19 and 20: In memory of Harold Zfaney (cont.):

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