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 Waldenström's Macroglobulinemia (WM). The cumulative probability of evolution 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=0.26). At a median follow-up of 45 months (12–233), 45 aIgM-MGs (11.7%) evolved to symptomatic WM (n=41), non-Hodgkin's lymphoma (NHL) (n=2), IgM multiple myeloma (n=1), and primary amyloidosis (n=1). At a median follow-up of 60 months (13–195), seven IgM-RDs (9.5%) evolved to symptomatic WM (n=6), and B-chronic lymphocytic leukaemia (n=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 multivariate 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.
The term asymptomatic IgM-monoclonal gammopathy (aIgM-MG) means the presence of an IgM monoclonal component (IgM-MC) without overt Waldenström's macroglobulinaemia (WM) or other lymphoid malignancy requiring treatment. It includes MG of undetermined significance (MGUS) and pre-clinical WM.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 In the absence of active lymphoproliferative disease, aIgM-MGs ought to be observed without treatment.2, 3, 6, 9 Although the majority will not develop symptoms, subsets of patients evolve to overt lymphoid malignancy with variable frequency.2, 3, 4, 5, 12, 13, 14, 15, 16, 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 unequivocal histopathological evidence of bone marrow lymphoplasmacytic (LP) lymphoma (LP-NHL) irrespective of IgM concentration has been suggested to distinguish smouldering WM (sWM) from IgM-MGUS.2, 3, 4, 5, 6, 7, 8, 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 immunosuppression 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 lymphoproliferative 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 Workshop 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 peripheral 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 other lymphoproliferative disease for at least 12 months from diagnosis.
The diagnosis of overt WM required the development of symptoms attributable to tumour infiltration such as constitutional symptoms, and/or cytopenia(s), and/or organomegaly, and/or the development of hyperviscosity syndrome in association with the histopathological evidence of LP-NHL on BM biopsy. IgM multiple myeloma (MM), amyloidosis, non-Hodgkin's lymphoma (NHL), and chronic lymphocytic leukemia (CLL) were diagnosed as previously described.19, 20, 21
Laboratory and clinical studies
The type and size of serum and urinary MC were defined according to previously described criteria.12 Serum polyclonal Ig were measured by means of nephelometry (normal ranges: IgG, 680–1445 mg/dl; IgA, 70–373 mg/dl; IgM, 50–248 mg/dl). At diagnosis, the following parameters were evaluated: physical examination, haemoglobin (Hb), white blood cell count with differential, platelet count, serum albumin, serum creatinine, serum calcium, serum liver function tests, urinalysis, serum MC size, presence and size of Bence Jones (BJ) proteinuria, polyclonal serum Ig quantification, erythrocyte sedimentation rate (ESR), serum β2-microglobulin (β2-M), serum LDH, plasma viscosity, research and characterization of cryoglobulins, hepatitis B virus (HBV) and hepatitis C virus (HCV) serology, BM biopsy and aspirate, abdomen ultrasound and chest and skeleton X-ray. Physical exam and laboratory tests were repeated with a 3–12-month frequency, at the discretion of the treating physician. sWM patients were monitored every 3 months.
Data were described as median and range when continuous, and absolute and relative frequency when categorical. To compare baseline clinical characteristics, Mann–Whitney U test and Fisher exact test were used for continuous and categorical variables, respectively. Cumulative survival probability and cumulative transformation probability were calculated by means of the Kaplan–Meier estimator; 95% confidence intervals (95% CI) were reported. Survival curves were compared by means of the log rank test. In order to identify possible predictors of transformation, a series of univariate Cox models were fitted. Continuous variables were categorized according to predefined cut-offs or quantiles of their distribution. Hazard ratios (HR) and 95% CI were calculated with respect to the lowest category for categorical variables. Age, sex, IgM MC size, BJ proteinuria, Hb level, neutropenia, thrombocytopenia, lymphocytosis, ESR, serum β2-M, LDH, polyclonal Ig reduction, type of light chain, and degree and pattern of BM LP infiltration were assessed as potential risk factors for transformation in both asymptomatic IgM-MGs and IgM-RDs. In the latter, type of cryoglobulinaemia and immunosuppressive treatment were further assessed. Due to their skewed distribution, IgM size and BM LP infiltration degree were log-transformed before being fitted into the Cox models. Variables with P-values <0.1 were introduced into a multivariate Cox model. Due to the large number of missing values, serum β2-M and degree and pattern of BM LP infiltration were not included in the multivariate model. No collinearity was observed among analysed factors. The linear predictor was calculated according to this model (called from here on prognostic index (PI)) and Kaplan–Meier's curves of the tertiles of its distribution were plotted to assess graphically the discriminative power of the model. In patients evolved to overt WM, the t-test for dependent samples was used to test changes of MC size from initial observation to time of symptoms development. Stata 7.0 (StataCorp, College Station, TX, USA) was used for computation. A P-value <0.05 was considered statistically significant.
Clinical characteristics of patients
Clinical characteristics at diagnosis are summarized in Table 1. Median MC and Hb levels were significantly higher in aIgM-MGs than in IgM-RDs (P=0.0001 and 0.013, respectively). Median β2-M level was significantly higher in IgM-RDs than in aIgM-MGs (P=0.0004). In all, 11 aIgM-MGs had a double MC (IgMκ/IgMκ: n=6, IgMκ/IgGκ: n=1, IgMκ/IgGλ: n=2, IgMλ/IgGλ: n=1, IgMλ/IgAκ: n=1). A total of 18 and 22 patients, respectively, had serologic evidence of HBV and HCV infection. Of aIgM-MGs, seven had connective tissue disorders (rheumatoid arthritis: n=5, Sjögren syndrome: n=2); four non-lymphoid haematological malignancies (myelodysplasia: n=1, policytemia vera: n=1, essential thrombocythemia: n=2); 25 a solid tumour (prostate: n=4, bladder: n=3, gastrointestinal: n=3, melanoma: n=3, breast: n=1, oral: n=2, endometrial: n=2, lung: n=2, seminoma: n=1, suprarenal gland: n=1, thyroid: n=1, breast plus thyroid: n=1, gastrointestinal plus prostate: n=1).
Of 74 IgM-RDs, the IgM MC had cryoglobulinaemic activity in 72, anti-neural and anti-platelet activity in two. In all, 19 patients had type I cryoglobulinaemia (IgMκ: n=15, IgMλ: n=1, IgMκ/IgMλ: n=1, IgMκ/IgGκ: n=1, IgMκ/IgGλ: n=1): 11 idiopathic, six HCV-related, two HBV-related. Of this group, four HCV-positive patients had hepatomegaly, and one required corticosteroids for vascular purpura. In total, 53 patients had type II cryoglobulinaemia (41 HCV-positive). In these, the IgMκ MC was associated with median polyclonal IgG levels of 1520 mg/dl (647–3640). In this group, 10 patients had hepatomegaly (mostly HCV-related), 14 arthralgias and/or vascular purpura (12 receiving corticosteroids), and seven peripheral neuropathy (all treated with cyclophosphamide or polychemotherapy with/without plasma-exchange). Of IgM-RDs, one had rheumatoid arthritis, and three a solid tumour (oral cavity: n=2, laryngeal: n=1). Overall, the prevalence of solid tumours was 6.1%, which proved higher than that expected in a general population matched for age and type of cancer in our country.22
Survival and probability of evolution
Total observation time of aIgM-MGs and IgM-RDs amounted to 23 020.3 and 5265.22 person months, respectively. The cumulative probability of survival at 5 and 10 years was 95.3% (95% CI, 91.6–97.4%) and 84.7% (95% CI, 76.3–90.3%), respectively, in aIgM-MGs, and 96.9% (95% CI, 88.1–99.2%) and 87.7% (95% CI, 66.7–95.8%), respectively, in IgM-RDs (P=0.76) (Figure 1a). At a median follow-up of 45 months (12-233), 319 patients with aIgM-MG remained asymptomatic, and 19 died from non-related diseases. Paraprotein disappeared in 12, at a median of 10.5 months (2–96) after first detection. In this subgroup, median MC level was 410 mg/dl (139–573). In all, 45 patients (11.7%) had malignant transformation (overt WM n=41, NHL n=2, IgM MM n=1, primary amyloidosis n=1). The median interval from diagnosis was 60 months (12–154). At a median follow-up of 60 months (13–195), 67 patients with IgM-RD remained stable, while seven (9.5%) transformed to symptomatic WM (n=6) and B-CLL (n=1), the median interval from diagnosis being 30 months (12–88). The cumulative probability of transformation into a symptomatic lymphoid malignancy at 5 and 10 years was 8% (95% CI, 5–13%) and 29% (95% CI, 21–38%), respectively, for patients with aIgM-MG. It was 9% (95% CI, 4–20%) and 16% (95% CI, 7–31%), respectively, in IgM-RDs (P=0.26) (Figure 1b). The low number of deaths in this series is probably due to the loss to follow-up and censoring at the time of last visit of many patients, as usually occurs in an elderly population seen periodically only because of a potential evolution to symptomatic disease.
The most frequent reasons for starting treatment in the 47 patients evolved to overt WM were development of organomegaly (hepatosplenomegaly 32%, lymphadenopathy 19%), constitutional symptoms (26%), hyperviscosity syndrome (17%), and anaemia (11%). Peripheral neuropathy developed in the presence of other signs/symptoms in three patients progressing from aIgM-MG. At the evolution to overt WM, a significant increase of MC (median 3.2 g/dl, range 0.8–7.4) was observed as compared to baseline levels (P=0.0001). The median BM LP-NHL infiltration was 34% (10–95%), with diffuse pattern in 73%. Nine patients with malignant transformation (overt WM: n=8, IgM MM: n=1) have died, median interval from progression being 30 months (1–149). The patient evolved to B-CLL, RAI stage I, died without treatment 6 months after transformation for a rapidly progressive lung cancer.
Prognostic factors for malignant transformation
At univariate analysis, in aIgM-MGs IgM level (P=0.0001), Hb level (P=0.0002), absolute lymphocyte count (ALC) >4 × 109/l (P=0.0015), ESR ≥40 mm/h (P=0.0035), and degree of BM LP-NHL infiltration (P<0.0001) were significantly associated with the probability of evolution, while BJ proteinuria (P=0.067) and a diffuse BM infiltration (P=0.081) were associated with a trend for increased risk of transformation. Absolute neutrophil counts (ANC) <1.8 × 106/l, serum β2-M levels and reduced normal Ig levels were not associated with increased risk of transformation. In IgM-RDs, IgM level (P=0.0047), ALC >4 × 109/l (P=0.04), ESR ≥40 mm/h (P=0.015), detectable BJ proteinuria (P=0.003), and ANC <1.8 × 106/l (P=0.03), were associated with the probability of evolution. Hb level, serum β2-M levels, reduced normal Ig levels, degree and pattern of BM LP-NHL infiltration were not associated with increased risk of transformation.
Multivariate analysis in aIgM-MGs confirmed IgM size (P=0.005) and lymphocytosis (P=0.0001) to independently predict malignant evolution, while Hb level was associated with a trend for a higher risk of progression (P=0.076) (Table 2). Assuming a label (x) for each variable (x1=MC in mg/dl (log transformed), x2=Hb in g/dl, x3=1 if lymphocytes >4 × 109/l, x3=0 if lymphocytes ≤4 × 106/l, x4=1 if detectable BJ proteinuria and x4=0 if undetectable BJ proteinuria, and x5=ESR in mm/h), a prognostic index, PI (=1.2636x1–0.2684x2+2.4165x3−0.1190x4+0.4071x5) was calculated for each patient. The higher the PI, the greater the risk of transformation. Three risk groups were identified on the basis of PI distribution tertiles. The low-risk subgroup (first tertile, PI ≤8.97) had event-free survival (EFS) rates at 5 and 10 years of 100 and 89% (95% CI, 60–97%), respectively. The intermediate-risk subgroup (second tertile, 8.97 < PI≤10.06) had EFS rates at 5 and 10 years of 95% (95% CI, 85–98%) and 83% (95% CI, 64–93%), respectively. The high-risk group (third tertile, PI>10.06) had EFS rates at 5 and 10 years of 85% (95% CI, 72–92%) and 44% (95% CI, 24–63%), respectively. EFS of patients corresponding to the third tertile differed significantly (P<0.0001) from that of patients corresponding to the first two tertiles pooled together (EFS rates at 5 and 10 years of 97% (95% CI, 92–99%) and 86% (95% CI, 72–93%), respectively) (Figure 2).
Clinical and survival differences between IgM-MGUS and sWM
aIgM-MGs in which both BM aspirate and BM biopsy were available were divided in IgM-MGUS and sWM (Table 3). sWM represented 19% of 179 patients diagnosed as having WM during the same observation period at our Institutions. Of the remaining WM patients, 139 were treated within six months and six patients 6–12 months after diagnosis. IgM-MGUS and sWM significantly differed in IgM size, Hb level, ESR level, degree of BM LP-NHL infiltration, proportion of patients with polyclonal serum Ig reduction and with lymphocytosis. In all, 14 IgM-MGUS (10.1%) evolved to malignant lymphoproliferative disease (overt WM: n=13; IgM MM: n=1) after a median of 75 months (12–117) from diagnosis, and 13 sWM (38.2%) to overt WM after a median of 55 months (13–154). Overall survival did not differ significantly (P=0.76) between the two subgroups (Figure 3a). EFS at 5 and 10 years was 95% (95% CI, 87–98%) and 83% (95% CI, 71–90%), respectively, in IgM-MGUS. It was 77% (95% CI, 56–89%) and 42% (95% CI, 19–64%), respectively, in sWM (P=0.0001) (Figure 3b). In 79.4% of sWM patients, the PI by our prognostic model was >10.06 (third tertile).
The presence of symptoms is the only available means of differentiating overt WM immediately requiring treatment from asymptomatic IgM-MGs needing monitoring over time. Asymptomatic IgM-MGs (that include IgM-MGUS and sWM) have variable risk of evolution to symptomatic disease.7, 8, 9, 18, 23 The prevalence of transformation of IgM-MGUS has been reported to range from 6 to 13%.12, 17 Poorer outcomes have been described in sWM, with 8–13% long-term EFS rates.2, 3, 4, 5 The present study confirms the low probability of evolution of IgM-MGUS, and the high transformation rate of sWM. In addition, we demonstrate that the probability of evolution of IgM-RDs is similar to that of aIgM-MGs, with an overlapping of factors predicting malignant transformation in the two groups.
As we previously observed in MGUS on the whole,12 high ESR and detectable BJ proteinuria significantly correlate with prognosis in both aIgM-MGs and IgM-RDs. This study does not confirm the predictive role of high serum β2-M for disease evolution.2, 3, 24 β2-M levels, however, were higher in sWM than in IgM-MGUS, although not reaching statistical significance. Missing values in our study population could account for discrepancies with prior reports.
The degree of BM infiltration with LP-NHL cells and/or a diffuse BM pattern of infiltration were reported to predict poor outcome in both IgM-MGUS and in overt WM.25, 26 In the present study, we found in univariate analysis that the degree of BM LP-NHL infiltration significantly correlates with the progression of aIgM-MGs into lymphoid malignancy, while a diffuse pattern of BM infiltration is associated with only a trend towards increased probability of evolution. BM histopathological evidence of lymphoma identifies a subgroup of asymptomatic patients with high probability of evolution to overt lymphoproliferative disease. Therefore, patients with an IgM gammopathy and BM infiltration by lymphoplasmacytic lymphoma confirmed by immunophenotypic studies cannot be longer considered to have a ‘benign’ gammopathy.11
The presence of cytopenias was shown to predict poor survival in overt WM,2, 3, 4, 5, 8, 27 and low Hb levels correlated with poor outcome also in asymptomatic disease.2, 3, 19, 21, 24, 28 In our series, anaemia strongly correlated with progression of aIgM-MG, significantly lower Hb levels being detected in sWM than in IgM-MGUS. BM infiltration, hypersplenism, and hyperviscosity-related blood dilution are involved in the pathogenesis of anaemia in overt WM.2, 3, 4, 5 In our asymptomatic patients, with low plasma viscosity, absence of splenomegaly, and no relationship between Hb levels and BM findings, a ‘chronic disease anaemia’ component related to a preclinical phase of WM could explain the prognostic value of low Hb levels. In IgM-RDs, an additive ‘chronic disease anaemia’ component secondary to the MC-related syndrome, or the hypersplenism in patients with HCV-related hepatosplenomegaly, probably account for the lack of prognostic relevance of anaemia, and for the significantly lower Hb levels than in aIgM-MGs.
Peripheral lymphocytosis is frequently observed in WM and in other chronic lymphoproliferative diseases.21, 29 The prognostic significance of this parameter in overt WM, aIgM-MGs, and IgM-RDs, however, is undefined.3, 6, 7, 8, 9 In our series, ALC>4 × 109/l independently predicted transformation of aIgM-MGs. A higher proportion of patients with lymphocytosis was detected in sWM than in IgM-MGUS. Lymphocytosis significantly correlated with the probability of evolution also in IgM-RDs. Indeed, an increased number of peripheral lymphocytes seems to reflect the preclinical expansion of tumour burden preceding development of symptoms. Prospective studies of peripheral clonal B-cells in aIgM-MGs in early stages of the disease might be of predictive value for evolution to symptomatic WM.30
By using the clinical criterion of ‘no treatment requirement’ for patient enrolment, we confirm that a wide range of paraprotein levels can be found in both aIgM-MGs and IgM-RDs.11 According to the recommendations of the second International Workshop on WM,11 we considered that a diagnosis of WM could be made irrespective of IgM concentration if there is evidence of BM infiltration by lymphoplasmacytic lymphoma. In this study we show that as the MC size progressively increases, the transformation risk gets progressively higher. Indeed, as shown by Alexanian et al24 and by Kyle et al,28 in aIgM-MGs high MC levels independently predict progression, significantly higher IgM levels being detected in sWM than in IgM-MGUS. In addition, we demonstrated a correlation between the IgM size and the probability of transformation also in IgM-RDs.
In conclusion, this study shows that asymptomatic IgM-MGs and IgM-RDs are distinct clinical entities with similar probability of evolution to lymphoid malignancy. In asymptomatic IgM-MGs, peripheral lymphocytosis, IgM size, and Hb level predict disease transformation. By combining these three parameters with BJ proteinuria and ESR, one can identify patients needing careful monitoring in view of an early treatment of the disease. A large proportion of this population at high risk of evolution is represented by patients with asymptomatic WM, a distinct entity from IgM-MGUS with clear BM evidence of lymphoma, and shorter event-free survival.
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About this article
- IgM monoclonal gammopathy
- IgM-related disorders
- Waldenström's macroglobulinemia (WM)
- smouldering WM
- malignant transformation
- prognostic factors
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