A Case-Control Epidemiological Study Of Waldenstrom Macroglobulinemia
Authors: Aljawai Yosra , McDiarmid Serena , Cappuccio Joseph , Campigotto Federico , Treon Steven Peter , Weller Edie A. , Birmann Brenda M. , Ghobrial Irene M 
Published: October 2019

Abstract

Introduction
Waldenstrom Macroglobulinemia (WM) is a distinct lymphoplasmacytic disorder characterized by bone marrow (BM) infiltration and IgM secretion. The etiology remains unknown, but a role for genetic and immune-related factors in the pathogenesis is suspected. To date, few etiologic studies have focused specifically on WM. Therefore, we initiated a large case-control study of WM to evaluate a comprehensive panel of potential risk factors. Here we describe the study design and report initial findings in the enrolled WM patients.

Methods
Patients are recruited into the study through the WM clinic at the Dana-Farber Cancer Institute, WM meetings or web-based invitations through the International Waldenstrom Macroglobulinemia Foundation (IMWF) website. For each patient, two controls are invited to participate: a family member of the patient, and an acquaintance of similar age and neighborhood of residence to the patient. Enrollment targets are for 1000 patients and an equal number of family members and non-family controls. From the WM patients we collect data on clinical presentation at diagnosis and from follow up of disease progression, as well as diagnostic tumor tissue and other biospecimens. Both patients with LPL/WM and controls completed a self-administered questionnaire that includes items related to personal characteristics, socioeconomic background, medical history, medication use and several lifestyle and environmental factors.

Results
We identified and invited 1144 WM patients. 396 WM patients and 83 family members of these patients completed the epidemiology survey. Of the 396 patients who completed the survey, 348 were diagnosed with LPL/WM and 48 with MGUS. The median age of patients at diagnosis was 67 years (range, 24-92 years). One patient was younger than 40 years of age, and 14 (4%) were younger than 50 years. 245 (62%) patients were males. Most patients self-reported Caucasian race (N=305, 77%), whereas others were of Ashkenazi Jewish (45, 11%), mixed (30, 8%), or other (16, 4%) racial backgrounds. Almost half (N=193, 49%) have completed graduate or professional school, and another 180 (45%) have completed some college education or a college degree; only seven patients (5%) have only a high school education or less, and education level is missing for 1%.” With regard to personal medical history, the WM patients most frequently reported a history of osteoporosis/osteopenia (20%), followed by that of lymph node enlargement (13%), thyroid disorder (11%), other autoimmune disease (10%), infectious mononucleosis (8%), hemolytic anemia (6%), renal insufficiency (5%), venous thrombosis and strokes (4%), inflammatory bowel disease (ulcerative colitis/Crohn's disease) (4%), diabetes mellitus (4%), and rheumatoid arthritis (3%). The WM patients reported a family history of several cancers in relatives: breast cancer (27%), prostate cancer (16%), colon cancer (14%), uterine cancer (14%) and lung cancer (17%). The most common hematological malignancies observed in relatives included leukemia (8%), WM (5%), other Non-Hodgkin’s lymphomas (5%), Hodgkin’s lymphoma (3%), and myeloma. The 396 patients also self-reported a history of exposure of at least eight hours per week for more than a year to some chemicals, including asbestos (11%), benzene and pesticides (9%), herbicides, fertilizers and gasoline or other solvents (7%), petroleum products, engine exhaust, and acrylic and oil based paints (6%). Five percent or less of the patients reported prior exposure to Agent White, Agent Orange, and Metals. Further patient and control recruitment is ongoing, as are preliminary statistical comparisons of the case and control patient populations to evaluate potential risk factors for the WM.

Conclusion
These preliminary descriptive data from the first case-control study to focus explicitly on WM confirm prior observations of familial history of B-cell lymphoproliferative disorders in patients with WM and suggest early success at collecting self-reported information on other potential risk factors in the patient population. By collecting and rigorously analyzing diverse risk factor data from both patients and controls, this study is likely to contribute important insights on the etiology of this rare and understudied lymphoma. Such knowledge is urgently needed to permit the development of strategies for WM prevention.

Disclosures:
Treon: Millennium: Consultancy. Ghobrial:BMS: Advisory board Other, Research Funding; ONYX: Advisory board, Advisory board Other; NOXXON: Research Funding; Sanofi: Research Funding.