Population-based study on the impact of familial form of Waldenström’s macroglobulinemia on overall survival Vilhjálmur Steingrímsson1, Sigrún Helga Lund1, Ingemar Turesson2, Lynn R. Goldin3, Magnus Björkholm4, Ola Landgren5, Sigurdur Y. Kristinsson1,4 d 1Faculty of Medicine, University of Iceland, 2Department of Hematology and Coagulation Disorders, Skane University Hospital, Malmö, Sweden, 3Division on Cancer Epidemiology and Genetics, National Cancer Institute, National Institute of Health, Bethesda, Maryland, 4Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden, 5Myeloma Service, Memorial Sloan-Kettering Cancer Center, USA. Results A total of 2185 LPL/WM patients and their 6460 first-degree relatives were included in the study (Table 1). Family history of any LP was not significantly associated with worse prognosis (HR=1.29; 95% CI 0.98-1.70), whereas family history of LPs known to aggregate was significantly linked to worse prognosis (HR=1.41; 95% CI 1.05-1.88). Of individual diseases, family history of NHL was associated with a significantly increased risk of death (HR=1.51; 95% CI 1.08-2.11), whereas others did not (Table 2). Increasing number of relatives diagnosed with LP was associated with worse overall survival (1.24; 95% CI 1.02-1.51). Introduction Waldenström’s Macroglobulinemia (WM) is a chronic lymphoproliferative disorder characterized by an IgM monoclonal gammopathy in the presence of lymphoplastocytic lymphomas (LPL) in the bone marrow. MYD88 L265P is a common somatic mutation found in over 90% of WM patients. We previously showed that first-degree relatives of LPL/WM patients have an increased risk of lymphoproliferative disorders (LPs), specifically there was a significantly increased risk of LPL/WM, non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and monoclonal gammopathy of undetermined significance (MGUS). In an earlier single-center study based on 135 WM patients, family history of LP was associated with worse response and shorter progression-free survival in patients treated with rituximab, however better response was observed in those treated with bortezomib. We conducted a large nationwide study to determine the impact of familial LPL/WM (compared to sporadic) on overall survival. Number of Individuals HR* 95% CIs Family history of any LP 88 1.29 0.98-1.70 Increasing number of affected relatives - 1.24 1.01-1.51 Family history of LPL/WM, NHL or CLL 77 1.41 1.05-1.88 1.31 1.04-1.64 Family history of MM 13 1.47 0.76-2.85 Family history of NHL 52 1.51 1.08-2.11 Family history of HL 4 0.51 0.13-2.03 Family history of CLL 17 1.43 0.71-2.88 Family history of LPL/WM 16 1.28 0.69-2.39 Family history of MGUS 11 1.12 0.53-2.37 Patients and Methods Through the nationwide Swedish Cancer Registry, the Swedish Inpatient Registry and a nationwide hospital network we identified 2185 LPL/WM patients and using information from the Swedish Multigenerational Registry we identified their 6460 first-degree relatives. Family history of any LP was defined as having a first-degree relative with LPL/WM, Hodgkin lymphoma (HL), NHL, multiple myeloma (MM) or CLL and family history of LPs known to aggregate was defined as having a first-degree relative with LPL/WM, NHL or CLL. A Cox proportional hazard model was used and hazard ratios (HR) obtained with 95% confidence intervals (CIs). All statistical analyses were performed using SAS Enterprise Guide 5.1. All Sporadic Familial Agg.* Total number 2185 2097 88 77 Sex (%female) 40% 34% 31% Age at diagnosis (years) 71 63 Median year at diagnosis 1996 1998 Alive at end of study 28% 27% 39% 38% Table 2 Survival in patients with family history (compared to sporadic). *Hazard ratios corrected for sex, age at diagnosis and year at diagnosis Conclusions In this large population-based study on more than 2000 LPL/WM patients and their almost 6500 first-degree relatives we have shown that family history of certain LPs was associated with inferior survival. Family history of NHL, LPs known to aggregate with LPL/WM, and having increasing number of relatives diagnosed with LP, was associated with significantly inferior survival. The effect of family history of any LP on overall survival was marginally significant. Our findings together with published papers suggest that familial form of LPL/WM may have a different biology and response to therapy. Table 1 Demographic features of familial and sporadic LPL/WM patients included in study. *LPs known to have a familial aggregation, i.e. LPL/WM, NHL or CLL There are no relevant conflicts of interest to disclose.