Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disorders E Morra 1,7 , C Cesana 1,2,7 , C Klersy 3 , L Barbarano 1 , M Varettoni 4 , L Cavanna 5 , B Canesi 6 , E Tresoldi 1 , S Miqueleiz 1 , P Bernuzzi 5 , AM Nosari 1 , M Lazzarino 4 on behalf of the HOST (Hematology/Oncology Studies and Trials) Group 1 Division of Hematology Niguarda Ca’ Granda Hospital, Milan, Italy; 2 Blood Center, ‘‘Citta ` di Sesto San Giovanni’’ Hospital, Sesto San Giovanni, Italy; 3 Biometry and Clinical Epidemiology, Scientific Direction, IRCCS Policlinico S Matteo, University of Pavia, Italy; 4 Division of Hematology, IRCCS Policlinico S Matteo, University of Pavia, Italy; 5 Division of Hematology/Oncology, Ospedale Civile, Piacenza, Italy; and 6 Division of Rheumatology, Niguarda Ca’ Granda Hospital, Milan, Italy We evaluated the prognostic features of 384 asymptomatic IgM- monoclonal gammopathies (aIgM-MGs) and 74 IgM-related disorders (IgM-RDs), two clinically distinct groups as proposed by the Second International Workshop on Waldenstro ¨ m’s Macroglobulinemia (WM). The cumulative probability of evolu- tion to lymphoid malignancy at 5 and 10 years was 8% (95% CI, 5–13%) and 29% (95% CI, 21–38%), respectively, in aIgM-MGs; it was 9% (95% CI, 4–20%) and 16% (95% CI, 7–31%), respectively, in IgM-RDs (P ¼ 0.26). At a median follow-up of 45 months (12– 233), 45 aIgM-MGs (11.7%) evolved to symptomatic WM (n ¼ 41), non-Hodgkin’s lymphoma (NHL) (n ¼ 2), IgM multiple myeloma (n ¼ 1), and primary amyloidosis (n ¼ 1). At a median follow-up of 60 months (13–195), seven IgM-RDs (9.5%) evolved to symptomatic WM (n ¼ 6), and B-chronic lymphocytic leukaemia (n ¼ 1). At univariate analysis, in aIgM-MGs bone marrow lymphoplasmacytic infiltration, high erythrocyte sedimentation rate (ESR), haemoglobin level, IgM size, and lymphocytosis significantly correlated with evolution probability. At multi- variate analysis, the latter two parameters strongly correlated with prognosis, haemoglobin being associated with a trend for a higher progression risk. In IgM-RDs IgM size, neutropenia, lymphocytosis, detectable Bence Jones proteinuria, and high ESR were associated with evolution probability. In conclusion, asymptomatic IgM-MGs and IgM-RDs are distinct clinical entities with similar probability of transformation to lymphoid malignancy. Leukemia (2004) 18, 1512–1517. doi:10.1038/sj.leu.2403442 Keywords: IgM monoclonal gammopathy; IgM-related disorders; Waldenstro ¨m’s macroglobulinemia (WM); smouldering WM; malignant transformation; prognostic factors Introduction The term asymptomatic IgM-monoclonal gammopathy (aIgM- MG) means the presence of an IgM monoclonal component (IgM-MC) without overt Waldenstro ¨ m’s macroglobulinaemia (WM) or other lymphoid malignancy requiring treatment. It includes MG of undetermined significance (MGUS) and pre- clinical WM. 1–11 In the absence of active lymphoproliferative disease, aIgM-MGs ought to be observed without treat- ment. 2,3,6,9 Although the majority will not develop symptoms, subsets of patients evolve to overt lymphoid malignancy with variable frequency. 2–5,12–17 Studies defining factors predicting malignant transformation in aIgM-MGs are lacking, and no criterion exists reliably distinguishing subpopulations with different evolution probability to active disease. The unequi- vocal histopathological evidence of bone marrow lymphoplas- macytic (LP) lymphoma (LP-NHL) irrespective of IgM concentration has been suggested to distinguish smouldering WM (sWM) from IgM-MGUS. 2–9,11,17,18 Whether this criterion allows the identification of two different prognostic subgroups has not been formally proved yet. IgM-related disorders (IgM-RDs) are IgM-MGs characterized by the presence of specific properties of the IgM MC, such as cryoglobulinemic, anti-red blood cell, anti-platelet, and anti- neural activity, without evidence of lymphoma. The distinctive clinical features and the frequent requirement of immunosup- pression for MC-related symptoms suggest that IgM-RDs have a different natural history from that of aIgM-MGs. 11 No systematic investigation concerning the evolution probability of IgM-RD to overt lymphoproliferative disease is currently available. The aims of this study were: to evaluate the natural history of aIgM-MGs and IgM-RDs during long-term follow-up; to identify factors predicting transformation into malignant lymphoproli- ferative disease; to analyse among asymptomatic IgM-MGs clinical and survival differences between IgM-MGUS and sWM. Materials and methods Patients and diagnostic criteria A total of 384 patients with previously untreated asymptomatic IgM-MG and 74 patients with IgM-RD diagnosed from November 1975 to January 2001 with a minimum follow-up of 1 year were studied (Table 1). According to the Consensus Panel Recommendations from the second International Work- shop on WM, 11 asymptomatic IgM-MG was defined as follows: any size of serum IgM MC, any degree of BM LP infiltration, any LP infiltration pattern except for the paratrabecular pattern on BM biopsy, no symptoms attributable to either IgM MC or tumour infiltration, and no evolution to overt WM or other lymphoproliferative disease for at least 12 months from diagnosis. An aIgM-MG could be further subclassified into two subgroups (sWM and IgM-MGUS) on the basis of BM findings: (i) sWM diagnosis required the unequivocal histopathological evidence of LP-NHL with an intertrabecular (nodular, interstitial or diffuse) infiltration pattern on BM biopsy; (ii) IgM-MGUS diagnosis required the absence of morphological evidence of BM infiltrates, or equivocal evidence of BM infiltrates without confirmatory phenotypic studies. An IgM-RD was defined as follows: 11 any size of serum IgM MC, the presence of symptoms attributable to the IgM monoclonal protein such as cryoglobulinaemia, and/or periph- eral neuropathy, and/or cold agglutinin haemolytic anaemia, and/or idiopathic thrombocytopenic purpura in the absence of overt evidence of lymphoma, and no evolution to overt WM or Received 1 December 2003; accepted 11 June 2004 Correspondence: Dr E Morra, Division of Hematology, Ospedale Niguarda Ca’ Granda, Piazza Ospedale Maggiore, 3, 20162 Milano, Italy; Fax: þ 39 02 6444 2033; E-mail: ematologia@ospedaleniguarda.it 7 The authors contributed equally to this work Leukemia (2004) 18, 1512–1517 & 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00 www.nature.com/leu