Waldenstrom's macroglobulinemia : population based studies of familial aggregation and prognostic factors

Background Waldenstrom’s macroglobulinemia (WM) is a rare lymphoproliferative disorder with a world-wide incidence of 3-4 patients per million persons per year. In Sweden, the incidence was about three times higher, and approximately 100 patients per year are reported to the Swedish Lymphoma Registry (SLR). Our aim was to study the WM population with focus on incidence and survival in relation to clinical prognostic factors and primary therapies (Paper I-II). We also discussed the diagnostic difficulties in patients with non-WM lymphoplasmacytic lymphoma (LPL). In Paper III-IV, we study familial WM from different aspects to better understand underlying pathogenetic factors. Patients and methods The patients in all four studies were collected from SLR. In papers I and II, a total of 1511 patients with WM and non-WM LPL were registered between 2000 and 2014, and medical records were retrieved for 1139 patients (75%). A retrospective review showed that 981 and 33 (after review by haematopathologist) of these patients fulfilled the World Health Organization (WHO) diagnostic criteria for WM and non-WM LPL, respectively. In Paper III and IV, we used SLR and the Northern Lymphoma Registry (NLR) for the years 1997- 2011. We identified 12 families with a family history of WM, IgM monoclonal gammopathy of undetermined significance (MGUS) and/or multiple myeloma (MM). Results In paper I, the overall survival (OS) for WM improved between the two time periods, 2000-2006 and 2007-2014, with a five-year OS of 61% and 70%, respectively. Significant prognostic factors for OS at the time of diagnosis in asymptomatic patients in no need of therapy were age, poor performance status (PS), haemoglobin ≤115 g/l, and female sex. Elevated lactate dehydrogenase (LDH) level and haemoglobin ≤115 g/l were significant prognostic factors for patients receiving therapy 0-3 months after diagnosis. The level of the IgM monoclonal immunoglobulin (MI) had no significant prognostic value. Rituximab included in first-line therapy was associated with improved survival. Paper II describes the differential diagnostic difficulties in non-WM LPL, especially with Marginal Zone Lymphoma (MZL). The non-WM LPL patients had more adverse prognostic factors as elevated LDH, anaemia, and lymphocytosis at diagnosis compared to the patients with WM. Despite this, the OS did not significantly differ between the groups (P = 0.249). The median OS for non-WM LPL was 71 months and the three-year and five-year survival was 71 % and 55%, respectively. The OS and RS were worse for males than females. In Paper III, we showed that age-adjusted incidence in Norrbotten and Västerbotten for WM and non-WM LPL was higher than expected – 17.5 and 14.8 per million person and year, respectively. The corresponding figure for Sweden was 10.5 per million persons per year. Autoimmune diseases or haematological malignancies in the medical history in patients or in their relatives were reported in nine and five of the 12 families, respectively. The relatives showed a high proportion abnormal serum protein electrophoresis (SPE): 12/56 (21%) showed MGUS and 13/56 (25%) showed abnormalities in the immunoglobulin levels (i.e., subnormal levels and poly/oligoclonality). Paper IV describes hyperphosphorylated paratarg 7 (pP-7), a target of 11% of the monoclonal immunoglobulin M (IgM) in WM and MGUS of IgM type, and distribution in Sweden and in familial WM. The frequency of pP-7 seems to be in line or lower in non-familial WM (7.1%) and higher in familial WM (16.7%) in the counties of Norrbotten and Västerbotten than in earlier published studies. Positive analysis for pP-7 was shown up to 10 years before diagnosis of WM. Conclusion We show that in a rare disease such as WM registry studies might bring new knowledge about incidence, disease characteristic, prognostic factors, treatments, and outcome. We also identified aggregation of families with WM in an effort to better understand the underlying pathogenesi