Risk stratification in Waldenström macroglobulinemia

Abstract

Waldenström macroglobulinemia is characterized by the production of serum monoclonal IgM and lymphoplasmacytic bone marrow infiltration. At least 25% of patients are asymptomatic at diagnosis and treatment is only mandatory in cases of symptomatic disease. Beside reports on treatment results, reviewing risk assessment is another way to describe the clinical course of the disease. This information may be particularly useful when numerous treatment options are available. While the introduction of new treatment approaches reinforces the need for careful risk assessment, the identification of useful prognostic information requires prolonged follow-up in patients who have not been treated with current therapeutic options. This limitation should be taken into account when using and interpreting available prognostic information, especially survival estimates.

Keywords::

• prognosis
• risk assessment
• therapy design
• Waldenström macroglobulinemia

Medscape: Continuing Medical Education Online

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians.

Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/experthematology; (4) view/print certificate.

Release date: April 4, 2012; Expiration date: April 4, 2013

Learning objectives

Upon completion of this activity, participants will be able to:

• • Assess the clinical presentation of Waldenström macroglobulinemia

• • Distinguish elements of the International Prognostic Scoring System for Waldenström macroglobulinemia

• • Evaluate other prognostic data for cases of Waldenström macroglobulinemia

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Editorial Director, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles P Vega, MD

Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA.

Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Pierre Morel, MD

Service d’Hématologie, Centre hospitalier Schaffner, Lens, France; Department of Biostatistics, University Lille Nord de France, Lille, France.

Disclosure: Pierre Morel, MD, has disclosed the following relevant financial relationships: he is supported by grants from the French Ministry of Health (Programme Hospitalier de Recherche Clinique: PHRC 2004, R1909).

Giampaolo Merlini, MD

Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Italy.

Disclosure: Giampaolo Merlini, MD, has disclosed the following relevant financial relationships: he is supported by grant N 9965 from the Associazione Italiana per la Ricerca sul Cancro Special Program Molecular Clinical Oncology and by Ricerca Finalizzata Malattie Rare, Italian Ministry of Health, Istituto Superiore di Sanità (526D/63), and Ministry of Research and University (2007AESFX2_003).

Figure 1. Survival rates of patients with IgM monoclonal gammopathy of undetermined significance and Waldenström macroglobulinemia.

Overall survival recorded in (A) 207 patients with IgM monoclonal gammopathy of undetermined significance, (B) 217 patients with A-WM and (C) 274 patients with S-WM compared with the corresponding survival of the general population, comparable for age, gender and calendar years of observation. A-WM: Asymptomatic Waldenström macroglobulinemia; IgM-MGUS: IgM monoclonal gammopathy of undetermined significance; SMR: Standardized mortality ratio; S-WM: Symptomatic Waldenström macroglobulinemia.Reproduced with permission from [31]

Figure 2. Survival after first treatment initiation according to subgroups defined by the International Scoring System for Waldenström Macroglobulinemia.

Int: Intermediate.

Reproduced with permission from [9]

Waldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by the production of serum monoclonal IgM (mIgM) and lymphoplasmacytic bone marrow infiltration [1,2]. Median age at diagnosis is approximately 65 years in most series [3–9]. At least 25% of patients are asymptomatic at diagnosis, and 50% of asymptomatic patients who are observed will not require therapy within 3 years [4,10]; one in ten will not require therapy for 10 years [4,10]. This highlights the importance of careful determination of the need for treatment.

Response rates between 26 and 92% and from 55 to 94% have been reported after single-agent first-line therapy [3,7,11–15] and combination chemotherapy or chemoimmunotherapy, ­respectively [16–20].

Median response durations from 7 to 29 months have been observed in most reports of single-agent regimens [3,7,12,15,21–24], whereas it was approximately 36 months after purine analogs alone [25] or chemoimmunotherapy [16,26]. Median overall survival (OS) ranged from 60 to 77 months in patients who received an alkylating agent or purine analogs alone as first-line therapy, with 10-year OS estimates at 41% [27] and approximately 10% of patients still alive after 15 years [5,15]. A recent study found no difference regarding objective response rate and OS between patients who started treatment before 1 January 2000, mostly with alkylating agent-based regimens and patients who started treatment later, mostly with rituximab-based regimens [28]. This absence of difference may be explained by the indolent course of WM in some patients, a limited effectiveness of therapy in patients with high-risk disease, the limited follow-up of latter patients and the use of new treatment options as salvage therapy in former patients. Clearly, unrelated deaths and progression of WM with cytopenias, symptoms related to marrow failure or transformation to high- grade lymphoma are the main causes of death [4,5]. Second malignancy and infection were the causes of 31 and 19% of deaths recorded in the Spanish series, respectively [4]. The indolent course of the disease, the advanced age of a large subset of patients and the presence of competing causes of death unrelated to the disease complicate the assessment of respective effects of concomitant disorders and WM on life expectancy. For this reason, disease-specific survival has been considered an appropriate end point because it controls for the many unrelated deaths [4,8,29]. Median disease-specific survival has been estimated as close to 11 years, confirming the indolent nature of the disease [8]. However, related and unrelated deaths may be very difficult to distinguish for many elderly patients (16%) because of the various disease-related complications that may occur during the course of the disease [5]. Therefore, the comparison of relative mortality with that observed in a general population of individuals with similar age and gender distribution may more accurately express the effects of the disease [30,31]. Because of the rarity of the disease and its usually indolent course, accurate risk stratification is needed in order to identify these few patients with an aggressive course that should receive an adequate treatment, but also patients who will probably follow an indolent course and should not ­compromise their quality of life by being overtreated.

Prognostic factors in WM: an overview

Most prognostic studies focused on OS, whereas other end points have been mainly reported with treatment evaluation studies performed in small series of patients. Several studies conducted before the description of treatment initiation criteria have pooled symptomatic and asymptomatic patients. The cutoff values and the statistical significance would probably have been different when only focusing on asymptomatic or symptomatic patients. In addition, one cannot rule out the possibility that other ­IgM-secreting lymphoma patients were included in the first studies.

The main adverse prognostic factors were older age [3–6,8,9,30,32,33], anemia [3–7,9,30,33], low serum albumin concentrations [5,7,30], high β2-microglobulin (B2M) values [4,7,8,34], leukopenia [3,5,8] and thrombocytopenia [3,5,6,8,32,33]. The different cutoffs associated with these covariates are summarized in Table 1.

The most frequently reported cutoff value for age is 65 years. All statistical analyses performed during the International Prognostic Scoring System for WM (IPSSWM) study (Fisher algorithm, recursive partitioning and Martingale residuals analyses) also identified this cutoff. The prognostic value of age reflects a characteristic of the overall population. Usually, standardized mortality ratio (SMR) studies confirm that the mortality is higher in younger patients than in elderly patients, because the loss in life expectancy is more significant in patients with a longer life expectancy. No difference in disease-specific survival was detected between young and elderly patients [35].

The strong prognostic value of low hemoglobin levels may be related to the extent of lymphoid bone marrow infiltration and to an increased plasma volume, mainly associated with a high concentration of mIgM [5].

Serum B2M concentration can be expressed as an absolute value or a ratio with the upper value of normal range. In the IPSSWM study, the two optimal cutoff values were 3 mg/l and 125%, respectively, and very few patients presented with discrepancies between the two methods of expressing B2M. Thus, the more convenient cutoff with an absolute value has been chosen.

Some studies concluded that mIgM levels had no prognostic value. Other analyses found an adverse prognostic value associated with high mIgM concentrations, whereas other studies observed an adverse prognostic value in cases with low mIgM concentration [7,19]. These latter studies enrolled untreated and previously treated patients.

Several studies supported the usefulness of lactate dehydrogenase (LDH) [27,32,36]. An update of the Southwest Oncology Group (SWOG) S9003 study indicated that LDH was an independent prognostic factor for survival after fludarabine therapy [27]. This series registered 231 patients; 118 received fludarabine as first-line therapy, 64 after previous therapy and 49 patients remained untreated. In this study, LDH also retained independent prognostic value in association with either age, B2M, previous therapy or high-risk IPSSWM alone. Further analyses should evaluate the prognostic information provided by LDH value in addition to hemoglobin and/or platelet count and the relationship between LDH and previous therapy in order to assess the prognostic role of LDH in untreated and previously treated patients. Reporting on 334 symptomatic patients, Kastritis et al. also observed an adverse prognostic value of LDH for OS. LDH retained a significant prognostic value in IPSSWM high-risk patients only [36].

An adverse prognostic value has also been reported in association with the following characteristics: a poor performance status (WHO classification) more than 1 [8,32], hepatomegaly [4,5], organomegaly, splenomegaly [8], two cytopenias or pancytopenia [5,32], cryoglobulinemia [6,30], male gender [3,5], hyperviscosity [4,8], urine monoclonal component [4], C-reactive protein levels of more than 1 mg/l [7], the presence of constitutional symptoms or weight loss [3,4,6] and a diffuse pattern of bone marrow histology [32].

The prognostic role of the free light chain (FLC) concentration has been evaluated at diagnosis in series of 42 [37] to 98 patients [38]. Symptomatic patients had significantly higher FLC values. FLC concentration, expressed as a continuous variable, was higher in patients with B2M more than 3 mg/l treatment [37,38], albumin less than 35 g/l treatment [37] or with hemoglobin concentration less than or equal to 11.5 g/dl [38]. It was found that the FLC and mIgM concentrations were not related to each other [38], but there was a correlation between maximum percentage reduction in involved FLC and mIgM [39]. The FLC value correlated with time to treatment [37,40], and more importantly to OS [40]. However, the last correlation was observed in a series of 44 patients, therefore further validation is required.

During the past few years, better understanding of the biology of the disease has also provided useful prognostic information. Combining conventional cytogenetic and FISH analysis, a deletion of the TP53 tumor suppressor gene and a 6q deletion have been detected in 7.5 [41] and 22–42% of symptomatic patients, respectively [41,42]. The frequency of the latter abnormality was 33% in asymptomatic patients [42], but it was found to be 7% using only conventional cytogenetics [42]. A deletion of the TP53 tumor suppressor gene has been associated with a shorter time to progression (15 vs 35 months) and 6q deletion with a longer time to progression (55 vs 24 months) in patients who responded to first-line single-agent therapy [41]. However, treatment-free ­survival was shorter in asymptomatic patients with the 6q deletion [42].

Decreased expression of six miRNAs was found to be significantly correlated with a low IPSSWM risk in a series of 20 patients [43]. High von Willebrand factor concentration was associated with an adverse prognostic value. It was associated with chronic endothelial activation, increased bone marrow microvessel density and the presence of VEGF, one of the mediators involved in von Willebrand factor exocytosis, on mast cells. Thus, von Willebrand factor concentration may also reflect the presence of a micro-environment that is favorable to growth and survival of tumor cells [44]. Similarly, the prognostic value of angiogenic cytokines has been explored: angiogenin correlated with albumin levels, while VEGF-A correlated with B2M. Angiopoietin-1/-2 ratio showed a negative correlation with B2M, and positive correlations with albumin, hemoglobin and lymphadenopathy [45]. Finally, genetic polymorphisms may also influence the outcome of WM patients. Thus, IL-6 (-174C/C) [46] and CXCL12 (-801G/G) genotypes [47] have been associated with adverse survival after first-line therapy initiation.

Despite the limitations listed above, it is concluded that besides age, hemoglobin and B2M concentrations, a large number of clinical or biological characteristics retained a prognostic value on the overall outcome of patients with WM. In order to identify the clinical usefulness of this information, the following section will focus on the prognostic importance of criteria for initiating therapy. Then, the prognostic tools available for asymptomatic and symptomatic patients will be reviewed.

Prognostic value of the presence of at least one of the criteria for initiating therapy

Because of the heterogeneity of WM, many varied situations require treatment. A consensus panel agreed that initiation of therapy was appropriate for patients with constitutional symptoms, such as fever, night sweats or weight loss. The presence of progressive, symptomatic lymphadenopathy or splenomegaly, the presence of anemia with a hemoglobin value of 10 g/dl or lower or a platelet count lower than 100 × 109/l due to marrow infiltration were additional reasons to begin therapy [48]. Hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency or symptomatic cryoglobulinemia also required treatment. Some of these characteristics retained no prognostic role in most studies designed in symptomatic patients only (lymphadenopathy or splenomegaly, hyperviscosity syndrome, constitutional symptoms or IgM-related disorder), however, the combination of these initiation treatment criteria is a strong prognostic factor as demonstrated by Gobbi et al. in a series of 217 asymptomatic and 274 symptomatic WM patients (Figure 1) [31]. Asymptomatic WM had a mortality rate (MR) equivalent to that of the general population, whereas the SMR of patients with symptomatic WM was 5.4. Within asymptomatic and symptomatic WM patients, the SMR values did not vary significantly in relation to marrow lympho-cyte counts or serum mIgM concentrations, supporting the importance of ­symptoms over serum mIgM concentration and marrow ­infiltration [31].

Risk assessment in asymptomatic patients

Very few studies have evaluated prognostic factors in patients who do not initially need to be treated. In patients with asymptomatic IgM monoclonal gammopathy, the cumulative probability of evolution to a symptomatic lymphoproliferative disorder (mostly symptomatic WM, non-Hodgkin’s lymphoma, IgM multiple myeloma or primary amyloidosis) have been estimated to be 8 and 29% at 5 and 10 years, respectively [49,50]. The risk of evolution is mainly influenced by mIgM and hemoglobin concentrations. In addition to these two characteristics, bone marrow ­lymphoplasmacytic infiltration, high erythrocyte sedimentation rate and lymphocytosis significantly correlated with the risk of progression. The latter two parameters were selected in ­multivariate analyses [49,50]. However, these studies included patients with lympho­cytosis, an unusual feature in WM. Similarly, Baldini et al. evaluated 217 patients with IgM monoclonal gammopathy of undetermined significance (MGUS) and 201 patients with asymptomatic WM diagnosed on the basis of serum mIgM concentrations and degree of bone marrow lymphoplasmacytic infiltration [51]. Patients with lymphocytosis were excluded. The variables adversely related to evolution were qualitatively the same in both groups of patients: high mIgM, low hemoglobin concentrations, and male gender. A scoring system based on these parameters identified three risk groups with highly significant differences in time to evolution in both groups (p < 0.0001) [51]. Indeed, the recommendations for the clinicopathological definition of WM [1] identified two subgroups of asymptomatic IgM monoclonal gammopathy patients with different outcome: patients with either IgM MGUS or asymptomatic WM. It has been reported that only 25% of patients with IgM MGUS will develop a symptomatic lymphoproliferative disorder within 15 years. Furthermore, the cumulative probability of progression in these patients is 1.5% per year [52]. Asymptomatic WM is defined as a serum IgM monoclonal protein concentration of 3 g/dl or higher and/or bone marrow lymphoplasmacytic infiltration of 10% or greater and no evidence of criteria for initiating therapy. Many of these patients can be observed without therapy for prolonged periods, and some may never require therapy. Several studies reported the risk of progression of asymptomatic to symptomatic WM. It has been estimated as 6% per year, and progression within 5 years has been observed in 55% of patients with asymptomatic WM [53]. In total, 21% of the previously untreated asymptomatic patients who enrolled in the prospective SWOG study [7] required therapy later, with a median follow-up of 100 months. The median time to progression has been estimated as 46–141.5 months for indolent WM [51,53,54]. The variables adversely related to progression were high mIgM [51,53,54], high hemoglobin concentrations [51,54], male gender [51], the degree of bone marrow infiltration [53] and the degree of reduction of uninvolved immunoglobulin [53,54]. In addition, a significant correlation between initial FLC level and time to treatment initiation was observed in the subgroup of asymptomatic patients (p = 0.047) [37].

Finally, in patients with an IgM-related disorder, such as cryoglobulinemias, peripheral neuropathies or autoimmune cyto-penias, the following risk factors of tumor development have been reported: male gender, IgM concentration more than or equal to 3 g/dl, detectable Bence Jones proteinuria, lymphocytosis and high erythrocyte sedimentation rate [49,55].

Risk assessment in symptomatic patients: IPSSWM

The IPSSWM has been designed only to predict survival after first-line therapy in symptomatic patients [9] in a series of 587 patients mostly treated with an alkylating agent (63%) or purine analog (33%). Remaining patients (4%) received rituximab as first-line therapy. It is expected that it may be less useful in other clinical conditions (asymptomatic patients or patients in advanced phase) or for predicting other end points, such as response rate or duration of response. IPSSWM takes five adverse features into account (age of more than 65 years, hemoglobin less than or equal to 11.5 g/dl, platelet count of less than or equal to 100 × 109/l, B2M more than 3 mg/l and serum mIgM concentration more than 70 g/l). Three risk groups were identified with 5-year survival rates of 87, 68 and 36% (Box 1, Table 2 & Figure 2) [9]. Beside age, all other prognostic factors included in the IPSSWM indicate the presence of a high tumor burden. IPSSWM retained prognostic value in patients aged younger or older than 65 years [9]. The median survival of young patients agreed with estimates from 82 to 141 months reported in relatively young patients (younger than 60–70 years), with few events during the first 4 years of follow-up [3–6,9]. Indeed, most prognostic systems identified only a limited subgroup of young high-risk patients (6–24% of young patients) [5,7,9,56]. Thus, the rarity of young high-risk patients who are most likely to benefit from new intensive treatment approaches may be a distribution feature mainly related to the disease itself rather than a drawback of the scoring system. IPSSWM has been obtained using follow-up data of patients mainly treated with chlorambucil or purine analogs as first-line therapy. This statistical tool has been validated in each treatment subgroup in patients prospectively treated with alkylating agents and nucleoside analogs [57]. However, the survival estimates provided by the IPSSWM suggested that these single-agent regimens may be considered satisfactory in only a limited subset of patients. IPSSWM has also been validated in patients who received rituximab-based therapy [29].

Twenty (3%) of the 587 patients included in the IPSSWM study received first-line therapy because of IgM-related disorder only, including amyloid light-chain amyloidosis [9]. IPSSWM was also effective in this very limited subgroup of patients characterized by the lack of characteristics related to high tumor burden (p = 0.01). Specific adverse prognostic factors for survival have been identified in patients who required therapy for IgM-related amyloidosis, namely a poor clonal response [58,59], a poor performance status [58,59], weight loss [60], cardiac involvement [58–60], liver involvement [58,60], a high number of involved organs [58,59], a low albumin level [59,60] and high NT-proBNP (a cardiac ­biomarker) concentration [59].

Prognostic role of response to treatment

Response criteria have been defined and updated in the last few years. Briefly, a complete response (CR) is defined as having resolution of all symptoms, normalization of serum IgM concentration with complete disappearance of IgM monoclonal protein by immunofixation, a bone marrow biopsy demonstrating no evidence of disease, and resolution of any adenopathy or spleno-megaly. A partial response and MR were defined as achieving a ≥50 and 25–49% reduction in serum IgM levels, respectively [61]. However, delayed IgM monoclonal protein responses may cause important difficulties in response assessment [61]. In addition, discrepancies between the kinetics of serum M protein reduction and the clearance of monoclonal B cells from the bone marrow have been reported [62].

The prognostic role of response on OS had been described in early reports [3]. The incorporation of rituximab into various regimens has improved depth of response in WM. Achievement of at least a very good partial response (VGPR; with >90% reduction in mIgM concentration) was associated with improved progression-free survival (PFS; p < 0.0001) in 159 WM patients who received rituximab-based therapy [63] and in patients who received the fludarabine–rituximab combination [17]. No difference in PFS was observed between CR and VGPR [63]. Similarly, a landmark ana­lysis showed the absence of significant difference in subsequent PFS or survival between patients who achieved a negative immunofixation test within the first 6 months after autologous stem cell transplantation (ASCT) and those patients who retained a positive immunofixation test [64]. However, patients who achieved a MR have been reported to fare as well as those achieving an objective response after rituximab single agent therapy [65]. Furthermore, achieving at least a MR to salvage therapy with a fludarabine-­containing regimen was also significantly associated with prolonged subsequent survival (2-year subsequent survival was 91% in case of response and 55% in case of stable or ­progressive disease) [66].

Risk factors associated with type of treatment & predictive factors of response

Reports on new treatment approaches have also provided valuable prognostic information, and predictive factors have been ­identified for some therapies.

Most treatment studies reported prognostic factors similar to covariates included in the IPSSWM. Prognostic factors reported with most commonly used therapy are summarized in the Table 3. Advanced age was associated with an increased risk of death or progression after salvage therapy with the bortezomib– dexamethasone–rituximab combination [67], and B2M of more than 3.5 mg/dl was associated with poor event-free survival (p = 0.002) after perifosine therapy [68]. Prognostic factors after alemtuzumab therapy and after the bortezomib–dexamethasone–rituximab combination in untreated patients have not yet been reported.

Specific predictive factors have been reported in patients treated with cladribine or rituximab. Former patients who achieved partial response or MR showed lower levels of hCNT1, a protein that mediates nucleoside transport across the plasma membrane, than those patients who achieved a CR [69]. In patients treated with rituximab, the expression of L/H or L/R at Fcγ receptors (FcgR)3A-48 and the expression of at least one valine (V/-) at FcgR3A-158 were associated with improved categorical responses, particularly attainment of CR or VGPR [63].

Risk assessment after relapse or before salvage therapy

The hazard ratio associated with previous therapy was estimated to be 1.61 in the SWOG study [7]. Few reports have focused on the prognosis after relapses or failures requiring therapy. Levy et al. found a strong prognostic value associated with the Lille scoring system based on the total number of cytopenia (mainly anemia and thrombocytopenia), age and serum albumin concentration [70]. The prognostic role of IPSSWM has been assessed before salvage therapy including fludarabine in 51 patients [66]. Patients had been more heavily treated before enrollment than patients of the previous report by Levy et al. [70]. Subsequent survival was estimated to be 67% at 48 months. Patients at high risk before the initiation of salvage therapy had a shorter subsequent survival than remaining patients (66 vs 96% at 2 years, p = 0.019) without difference in survival of low- and intermediate-risk patients. The lack of difference in outcome of low- and intermediate-risk patients may be related, at least in part, to long-term events recently recorded after fludarabine therapy [71]. Kyriakou et al. analyzed 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation: chemorefractory disease and a poor performance status at ASCT were associated with higher nonrelapse mortality in univariate analysis [64]. Having received at least three treatment lines before ASCT and having chemorefractory disease at ASCT were adverse prognostic factors for response rate after ASCT. Heavily pretreated patients, patients with refractory disease and those with poor performance status had shorter PFS and OS in univariate analysis.

Future studies should assess the prognostic role of previous therapy, because the hazard ratio estimate provided by the SWOG study has probably changed with the use of combination therapy as first-line therapy. In addition, it is conceivable that the type of previous therapy, initial response and the response duration may also have a prognostic role in addition to, or in place of, clinical covariates assessed at the time of initiation of salvage therapy.

Assessment of the risk of late complications

Previous studies have reported the occurrence of transformation to high-grade lymphoma in approximately 2% of patients [4,71,72] and the occurrence of solid tumors in 10–14% of patients during follow-up of patients with WM [4,5,72,73] or even before diagnosis [5]. Cumulative incidence of solid cancer and secondary malignancy have been estimated to be 17 and 8% at 15 years, respectively, with an overall risk of secondary cancer in WM 1.69 times higher than expected (p = 0.002). WM patients were at increased risk for diffuse large B-cell lymphoma (standardized incidence ratio [SIR]: 9.24, p < 0.0001), myelodysplastic syndrome/acute myeloid leukemia (SIR: 8.4; p < 0.0001) and brain cancer (SIR: 8.05; p = 0.0004) [72]. Secondary hemato­logic malignancy was not observed in untreated patients in the study by Leleu et al. [71]. This risk was fourfold higher in previously treated patients, but did not reach statistical significance in the Italian study [72]. An increased risk of hematologic malignancies (acute myelogenous leukemia or lymphoma) after purine analog exposure has been observed by some authors [71], but not others [57,72].

Expert commentary

Although the IPSSWM has been designed to be improved, especially with the possible integration of new biological characteristics, we conclude that it should be used for making treatment decisions in any situation at the time of initiation of first-line therapy. However, first-line therapy options have changed during the past few years. Therefore, available estimates of survival should be taken with caution when used for assessing risk in untreated patients. While waiting for the description of more specific staging systems, IPSSWM may also be used in relapsing or progressive patients. In addition, predictive factors and comorbidity assessments should also be considered for treatment decisions. The design of large international studies, using IPSSWM for stratification, would permit the definition of a subset of high-risk patients who will be the most likely to benefit from new treatment approaches. Reporting the relative mortality, as compared with that observed in the general population, would probably help to address the excess risk related to the disease.

Five-year view

The role of risk assessment in treatment decision probably depends on the heterogeneity of the disease, the knowledge of its natural history and the number of available therapeutic options. The latest update on treatment recommendations published stated that the first-line therapy choices should be based on comorbidity and IPSSWM covariates: age, cytopenias, M-protein concentration and candidacy of a patient for high-dose chemotherapy. This upfront treatment strategy should be considered for younger patients with high-risk disease, according to the IPSSWM in prospective trials [56]. It was recommended that randomized trials should at least use prognostic factors, such as IPSSWM, for stratifying the statistical tests used for comparison of treatment arms. The use of internationally recognized prognostic factors would probably help to better understand the treatment results. Future studies should provide updated survival estimates and check the effectiveness of IPSSWM in patients who will receive new treatment approaches, especially new chemoimmunotherapy combinations. The introduction of new characteristics may improve the effectiveness of IPSSWM, such effort would require new multivariate analyses in order to check whether some covariates of the IPSSWM should be dropped or whether the new covariate provides additional prognostic information. The ‘separation parameter’ statistical tool should be useful for demonstrating the role of new characteristics alongside IPSSWM. A Cox model with time-dependent covariate analysis could usefully assess the risk of occurrence of long-term complications and the prognostic role of response duration alongside IPSSWM [74]. Indeed, future studies should assess the interactions between the prognostic factors observed before therapy and response. For example, quantifying the positive prognostic influence associated with response after salvage regimen in patients, presenting with adverse prognostic features, might be particularly useful for identifying high-risk patients who may require intensive therapy, especially allogeneic stem cell transplantation, despite the achievement of a good response after therapy.

Conclusion

WM comprises a heterogeneous population of patients with markedly different evolution, from indolent courses, lasting more than 10 years, to rapidly progressing disease with a median survival of less than 2 years. The IPSSWM was constructed on a large patient population and currently represents the most effective and validated tool for stratifying patients for initial therapy. The use of IPSSWM facilitates the design of therapies with intensity graduated according to the risk severity. Furthermore, IPSSWM would facilitate the comparison of the outcomes of clinical trials. However, the IPSSWM presents limitations as it is based on patient populations treated before the availability of new agents. More research needs to be done on the biology of the disease in order to identify the molecular mechanisms underlying the different clinical courses. Similarly to multiple myeloma, WM may also comprise several subtypes, with dissimilar outcomes and requiring different therapeutic approaches [75–77]. Further clinical investigations are also warranted in order to define the clinical and biological changes that may modify the prognostic assessment during the follow-up, the risk of occurrence of long-term complications and the prognostic role of response achievement, the quality of the response and its duration. As more effective therapies are becoming available, reliable tools for the design of individualized therapy become essential for the optimal care of this indolent but resilient disease.

Table 1. Survival estimates according to main prognostic factors in Waldenström macroglobulinemia.

Characteristic	Cutoff value	Prognostic information (median survival or HR)
		Treated patients only	All patients
Advanced age	60 years	42 versus 120 months [3]	42 versus 96 months [3]
	65 years	56–88 versus 141–172 months [9,33]; HR = 2.5 [8]	51 versus 87 months [5] 80 versus 209 months [4]
	70 years	27 versus 85 months [6]; HR = 2 [7]
Low hemoglobin concentration	9 g/dl	40 versus 78 months [6]
	10 g/dl	32 versus 73 months [3]; 90 versus 116 months [3]; HR = 1.4 [8]	31 versus 72 months [3]
	10.5 g/dl		84 versus 209 months [4]
	11.5 g/dl	72 versus 123 months [9]
	12 g/dl	HR = 1.9 [7]	49 versus 107 months [5]
Low platelet count	100 × 10^9/mm^3	51–55 versus 90–107 months [9,32,33]
	150 × 10^9/mm^3	33 versus 75 months [3]; HR = 1.6 [8]	30–40 versus 67–72 months [3,5]
Low WBCC	4 × 10^9/mm^3	36 versus 66–70 months [3]; HR = 1.5 [8]	30–42 versus 51–66 months [3,5]
High B2M	3 mg/l	63 versus 122 months [9]; HR = 2.5 [7]
	4 mg/l	79 versus 115 months [4]
	ULN		84 months versus NR [4]
	Linear	HR = 1.4 [8]
Low serum albumin concentration	40 g/l	HR = 2 [8]	49 versus 107 months [5]
	35 g/l	77–79 versus 106–112 months [9,33]; HR = 1.7 [7]
mIgM concentration	40 g/l	HR = 2.4 [7]
	45 g/l		84 versus 209 months [4]
	25 g/l		59 versus 68 months [5]
	70 g/l	49 versus 90 months [9]

^† All series included more than 200 patients except [3,6,33], which included 122–167 patients.

B2M: β2-microglobulin; HR: Hazard ratio; mIgM: Monoclonal IgM; NR: Not reached; ULN: Upper limit of normal range; WBCC: White blood cell count.

Table 2. The International Prognostic Scoring System for symptomatic Waldenström Macroglobulinemia requiring therapy.

Stratum	Score (number of adverse characteristics)	Total number of patients (%)	Median survival (months)	95% CI	Hazard ratio
Low	0 or 1 (except age)	155 (27)	142.5	120.30–195.71	1
Intermediate	Age or 2	216 (38)	98.6	81.70–137.2	2.36
High	3 or more	203 (35)	43.5	36.60–55.1	6.61

Data taken from [9]

Table 3. Adverse prognostic factors for treatment effectiveness in Waldenström macroglobulinemia.

Treatment	Patients	Adverse characteristics for response rate	Adverse characteristics for response duration	Adverse characteristics for subsequent survival	Ref.
Fludarabine	Previously treated (71 patients)	Short interval between the first treatment and the start of fludarabine		Hemoglobin <9.5 g/dl and platelet count <75 × 10^9/l	[78]
Fludarabine	Untreated and previously treated (182 patients)	Age ≥70 years	B2M ≥3 mg/l and mIgM <40 g/l (PFS)	Age ≥70 years, previous therapy, disease duration >1 year, B2M ≥3 mg/l, mIgM <40 g/l and CRP ≥1 mg/l	[7]
Fludarabine Cyclophosphamide	Untreated and previously treated (49 patients)		Age >65 years and mIgM <40 g/l	Age >65 years and mIgM <40 g/l	[19]
Fludarabine Cyclophosphamide Rituximab	Untreated and previously treated (1 line; 43 patients)	High B2M concentration			[79]
Rituximab	Untreated and previously treated (58 patients)	Fcγ receptor IIIA(F/F) phenotype			[11]
Rituximab	Untreated and previously treated (51 patients)	mIgM ≥40 g/l and serum albumin <35 g/l	mIgM ≥40 g/l (TTP)	Serum albumin <35 g/l	[13]

B2M: β2-microglobulin; CRP: C-reactive protein; mIgM: Monoclonal IgM; PFS: Progression-free survival; TTP: Time to progression.

Box 1. Adverse characteristics included in the International Prognostic Scoring System for Waldenström macroglobulinemia.

• • Age more than 65 years

• • Hemoglobin less than or equal to 11.5 g/dl

• • Platelet count less than or equal to 100 × 109/l

• • β2-microglobulin more than 3 mg/l

• • Serum monoclonal protein concentration more than 7.0 g/dl (estimated by densitometry)

Key issues

• • The relatively long survival of Waldenström macroglobulinemia (WM) patients causes a significant divergence between the definition of prognostic factors and the availability of novel therapies.

• • The International Prognostic Scoring System for WM (IPSSWM) is, at present, the best-validated tool for stratifying patients for initial therapy, but more studies are needed to validate the IPSSWM with novel regimens.

• • Improved knowledge of the biology of WM will hopefully provide new parameters for guiding the management of patients with WM.

• • Additional studies are required to better understand the prognostic role of response and the prognosis of patients who require a second or subsequent line of therapy.

References

• Owen RG, Treon SP, Al-Katib A et al. Clinicopathological definition of Waldenström’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenström’s Macroglobulinemia. Semin. Oncol. 30(2), 110–115 (2003).
   PubMed Web of Science ®Google Scholar
• Swerdlow SH, Berger F, Pileri SA, Harris NL, Jaffe ES, Stein H. Lymphoplasmacytic lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Swerdlow SH, Campo E, HarrisNL et al. (Eds). International Agency for Research on Cancer, Lyon, France (2008).
   Google Scholar
• Facon T, Brouillard M, Duhamel A et al. Prognostic factors in Waldenström’s macroglobulinemia: a report of 167 cases. J. Clin. Oncol. 11(8), 1553–1558 (1993).
   PubMed Web of Science ®Google Scholar
• Garcia-Sanz R, Montoto S, Torrequebrada A et al. Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. Br. J. Haematol. 115(3), 575–582 (2001).
   PubMed Web of Science ®Google Scholar
• Morel P, Monconduit M, Jacomy D et al. Prognostic factors in Waldenström macroglobulinemia: a report on 232 patients with the description of a new scoring system and its validation on 253 other patients. Blood 96(3), 852–858 (2000).
   PubMed Web of Science ®Google Scholar
• Gobbi PG, Bettini R, Montecucco C et al. Study of prognosis in Waldenström’s macroglobulinemia: a proposal for a simple binary classification with clinical and investigational utility. Blood 83(10), 2939–2945 (1994).
   PubMed Web of Science ®Google Scholar
• Dhodapkar MV, Jacobson JL, Gertz MA et al. Prognostic factors and response to fludarabine therapy in patients with Waldenström macroglobulinemia: results of United States intergroup trial (Southwest Oncology Group S9003). Blood 98(1), 41–48 (2001).
   PubMed Web of Science ®Google Scholar
• Ghobrial IM, Fonseca R, Gertz MA et al. Prognostic model for disease-specific and overall mortality in newly diagnosed symptomatic patients with Waldenström macroglobulinaemia. Br. J. Haematol. 133(2), 158–164 (2006).
   PubMed Web of Science ®Google Scholar
• Morel P, Duhamel A, Gobbi P et al. International prognostic scoring system for Waldenström macroglobulinemia. Blood 113(18), 4163–4170 (2009).
   PubMed Web of Science ®Google Scholar
• Gertz MA. Waldenström macroglobulinemia: 2011 update on diagnosis, risk stratification, and management. Am. J. Hematol. 86(5), 411–416 (2011).
   PubMed Web of Science ®Google Scholar
• Treon SP, Hansen M, Branagan AR et al. Polymorphisms in FcγRIIIA (CD16) receptor expression are associated with clinical response to rituximab in Waldenström’s macroglobulinemia. J. Clin. Oncol. 23(3), 474–481 (2005).
   PubMed Web of Science ®Google Scholar
• Chen CI, Kouroukis CT, White D et al. Bortezomib is active in patients with untreated or relapsed Waldenström’s macroglobulinemia: a Phase II study of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25(12), 1570–1575 (2007).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Alexanian R, Gika D et al. Treatment of Waldenström’s macroglobulinemia with rituximab: prognostic factors for response and progression. Leuk. Lymphoma 45(10), 2057–2061 (2004).
   PubMed Web of Science ®Google Scholar
• Kyrtsonis MC, Vassilakopoulos TP, Angelopoulou MK et al. Waldenström’s macroglobulinemia: clinical course and prognostic factors in 60 patients. Experience from a single hematology unit. Ann. Hematol. 80(12), 722–727 (2001).
   PubMed Web of Science ®Google Scholar
• Kyle RA, Greipp PR, Gertz MA et al. Waldenström’s macroglobulinaemia: a prospective study comparing daily with intermittent oral chlorambucil. Br. J. Haematol. 108(4), 737–742 (2000).
   PubMed Web of Science ®Google Scholar
• Weber DM, Dimopoulos MA, Delasalle K, Rankin K, Gavino M, Alexanian R. 2-chlorodeoxyadenosine alone and in combination for previously untreated Waldenström’s macroglobulinemia. Semin. Oncol. 30(2), 243–247 (2003).
   PubMed Web of Science ®Google Scholar
• Treon SP, Branagan AR, Ioakimidis L et al. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood 113(16), 3673–3678 (2009).
   PubMed Web of Science ®Google Scholar
• Tam C, Seymour JF, Brown M et al. Early and late infectious consequences of adding rituximab to fludarabine and cyclophosphamide in patients with indolent lymphoid malignancies. Haematologica 90(5), 700–702 (2005).
   PubMed Web of Science ®Google Scholar
• Tamburini J, Levy V, Chaleteix C et al. Fludarabine plus cyclophosphamide in Waldenström’s macroglobulinemia: results in 49 patients. Leukemia 19(10), 1831–1834 (2005).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Hamilos G, Efstathiou E et al. Treatment of Waldenström’s macroglobulinemia with the combination of fludarabine and cyclophosphamide. Leuk. Lymphoma 44(6), 993–996 (2003).
   PubMed Web of Science ®Google Scholar
• Johnson SA. Waldenström’s macroglobulinemia. Rev. Clin. Exp. Hematol. 6(4), 421–434; discussion 449–450 (2002).
   Google Scholar
• Gertz MA, Rue M, Blood E, Kaminer LS, Vesole DH, Greipp PR. Multicenter Phase 2 trial of rituximab for Waldenström macroglobulinemia (WM): an Eastern Cooperative Oncology Group study (E3A98). Leuk. Lymphoma 45(10), 2047–2055 (2004).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Zervas C, Zomas A et al. Treatment of Waldenström’s macroglobulinemia with rituximab. J. Clin. Oncol. 20(9), 2327–2333 (2002).
   PubMed Web of Science ®Google Scholar
• Treon SP, Anderson KC. The use of rituximab in the treatment of malignant and nonmalignant plasma cell disorders. Semin. Oncol. 27(6 Suppl. 12), 79–85 (2000).
   PubMed Web of Science ®Google Scholar
• Leblond V, Levy V, Maloisel F et al. Multicenter, randomized comparative trial of fludarabine and the combination of cyclophosphamide–doxorubicin–prednisone in 92 patients with Waldenström macroglobulinemia in first relapse or with primary refractory disease. Blood 98(9), 2640–2644 (2001).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC et al. Primary treatment of Waldenström macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J. Clin. Oncol. 25(22), 3344–3349 (2007).
   PubMed Web of Science ®Google Scholar
• Dhodapkar MV, Hoering A, Gertz MA et al. Long-term survival in Waldenström macroglobulinemia: 10-year follow-up of Southwest Oncology Group-directed intergroup trial S9003. Blood 113(4), 793–796 (2009).
   PubMed Web of Science ®Google Scholar
• Kastritis E, Kyrtsonis MC, Hatjiharissi E et al. No significant improvement in the outcome of patients with Waldenström’s macroglobulinemia treated over the last 25 years. Am. J. Hematol. 86(6), 479–483 (2011).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Kastritis E, Delimpassi S, Zomas A, Kyrtsonis MC, Zervas K. The International Prognostic Scoring System for Waldenström’s macroglobulinemia is applicable in patients treated with rituximab-based regimens. Haematologica 93(9), 1420–1422 (2008).
   PubMed Web of Science ®Google Scholar
• Merlini G, Baldini L, Broglia C et al. Prognostic factors in symptomatic Waldenström’s macroglobulinemia. Semin. Oncol. 30(2), 211–215 (2003).
   PubMed Web of Science ®Google Scholar
• Gobbi PG, Baldini L, Broglia C et al. Prognostic validation of the international classification of immunoglobulin M gammopathies: a survival advantage for patients with immunoglobulin M monoclonal gammopathy of undetermined significance? Clin. Cancer Res. 11(5), 1786–1790 (2005).
   PubMed Web of Science ®Google Scholar
• Owen RG, Barrans SL, Richards SJ et al. Waldenström macroglobulinemia. Development of diagnostic criteria and identification of prognostic factors. Am. J. Clin. Pathol. 116(3), 420–428 (2001).
   PubMed Web of Science ®Google Scholar
• Dimopoulos MA, Hamilos G, Zervas K et al. Survival and prognostic factors after initiation of treatment in Waldenström’s macroglobulinemia. Ann. Oncol. 14(8), 1299–1305 (2003).
   PubMed Web of Science ®Google Scholar
• Anagnostopoulos A, Zervas K, Kyrtsonis M et al. Prognostic value of serum β2-microglobulin in patients with Waldenström’s macroglobulinemia requiring treatment. Clin. Lymphoma Myeloma 7(3), 205–209 (2006).
   PubMedGoogle Scholar
• Ricci F, Tedeschi A, Vismara E et al. The impact of advanced age according to IPSSWM cut-off on the outcome of symptomatic and asymptomatic Waldenström’s macroglobulinemia at diagnosis. Clin. Lymphoma Myeloma Leuk. 11(1), 124–126 (2011).
   PubMed Web of Science ®Google Scholar
• Kastritis E, Kyrtsonis MC, Hadjiharissi E et al. Validation of the International Prognostic Scoring System (IPSS) for Waldenström’s macroglobulinemia (WM) and the importance of serum lactate dehydrogenase (LDH). Leuk. Res. 34(10), 1340–1343 (2010).
   PubMed Web of Science ®Google Scholar
• Itzykson R, Le Garff-Tavernier M, Katsahian S, Diemert MC, Musset L, Leblond V. Serum-free light chain elevation is associated with a shorter time to treatment in Waldenström’s macroglobulinemia. Haematologica 93(5), 793–794 (2008).
   PubMed Web of Science ®Google Scholar
• Leleu X, Moreau AS, Weller E et al. Serum immunoglobulin free light chain correlates with tumor burden markers in Waldenström macroglobulinemia. Leuk. Lymphoma 49(6), 1104–1107 (2008).
   PubMed Web of Science ®Google Scholar
• Leleu X, Xie W, Bagshaw M et al. The role of serum immunoglobulin free light chain in response and progression in Waldenström macroglobulinemia. Clin. Cancer Res. 17(9), 3013–3018 (2011).
   PubMed Web of Science ®Google Scholar
• Leleu X, Koulieris E, Maltezas D et al. Novel M-component based biomarkers in Waldenström’s macroglobulinemia. Clin. Lymphoma Myeloma Leuk. 11(1), 164–167 (2011).
   PubMed Web of Science ®Google Scholar
• Nguyen-Khac F, Lejeune J, Chapiro E et al. Cytogenetic abnormalities in a cohort of 171 patients with Waldenström macroglobulinemia before treatment: clinical and biological correlations. ASH Annual Meeting Abstracts 116(21), 801 (2010).
   Google Scholar
• Ocio EM, Schop RF, Gonzalez B et al. 6q deletion in Waldenström macroglobulinemia is associated with features of adverse prognosis. Br. J. Haematol. 136(1), 80–86 (2007).
   PubMed Web of Science ®Google Scholar
• Roccaro AM, Sacco A, Chen C et al. microRNA expression in the biology, prognosis, and therapy of Waldenström macroglobulinemia. Blood 113(18), 4391–4402 (2009).
   PubMed Web of Science ®Google Scholar
• Hivert B, Caron C, Petit S et al. Clinical and prognostic implications of low or high level of von Willebrand factor (VWF) in Waldenström macroglobulinemia (WM) patients (pts). A clinicopathological study on 72 pts. ASH Annual Meeting Abstracts 116(21), 2438 (2010).
   Google Scholar
• Anagnostopoulos A, Eleftherakis-Papaiakovou V, Kastritis E et al. Serum concentrations of angiogenic cytokines in Waldenström macroglobulinaemia: the ration of angiopoietin-1 to angiopoietin-2 and angiogenin correlate with disease severity. Br. J. Haematol. 137(6), 560–568 (2007).
   PubMed Web of Science ®Google Scholar
• Poulain S, Dervite I, Leleu X, Coiteux V, Duthilleul P, Morel P. The IL6(-174G/C) polymorphism is a prognostic factor for survival after treatment initiation in Waldenström macroglobulinemia patients aged 65 years or less. Haematologica 93(7), 1109–1111 (2008).
   Google Scholar
• Poulain S, Ertault M, Leleu X et al. SDF1/CXCL12 (-801GA) polymorphism is a prognostic factor after treatment initiation in Waldenström macroglobulinemia. Leuk. Res. 33(9), 1204–1207 (2009).
   Google Scholar
• Kyle RA, Treon SP, Alexanian R et al. Prognostic markers and criteria to initiate therapy in Waldenström’s macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenström’s Macroglobulinemia. Semin. Oncol. 30(2), 116–120 (2003).
   PubMed Web of Science ®Google Scholar
• Morra E, Cesana C, Klersy C et al. Clinical characteristics and factors predicting evolution of asymptomatic IgM monoclonal gammopathies and IgM-related disorders. Leukemia 18(9), 1512–1517 (2004).
   PubMed Web of Science ®Google Scholar
• Morra E, Cesana C, Klersy C et al. Predictive variables for malignant transformation in 452 patients with asymptomatic IgM monoclonal gammopathy. Semin. Oncol. 30(2), 172–177 (2003).
   Google Scholar
• Baldini L, Goldaniga M, Guffanti A et al. Immunoglobulin M monoclonal gammopathies of undetermined significance and indolent Waldenström’s macroglobulinemia recognize the same determinants of evolution into symptomatic lymphoid disorders: proposal for a common prognostic scoring system. J. Clin. Oncol. 23(21), 4662–4668 (2005).
   Google Scholar
• Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. Clin. Lymphoma Myeloma 6(2), 102–114 (2005).
   PubMedGoogle Scholar
• Kyle RA, Benson J, Larson D et al. IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström’s macroglobulinemia. Clin. Lymphoma Myeloma 9(1), 17–18 (2009).
   PubMedGoogle Scholar
• Cesana C, Miqueleiz S, Bernuzzi P et al. Smouldering Waldenström’s macroglobulinemia: factors predicting evolution to symptomatic disease. Semin. Oncol. 30(2), 231–235 (2003).
   Google Scholar
• Cesana C, Barbarano L, Miqueleiz S et al. Clinical characteristics and outcome of immunoglobulin M-related disorders. Clin. Lymphoma 5(4), 261–264 (2005).
   PubMedGoogle Scholar
• Dimopoulos MA, Gertz MA, Kastritis E et al. Update on treatment recommendations from the Fourth International Workshop on Waldenström’s Macroglobulinemia. J. Clin. Oncol. 27(1), 120–126 (2009).
   PubMed Web of Science ®Google Scholar
• Leblond V, Lejeune J, Tournilhac O et al. International Phase III study of chlorambucil versus fludarabine as initial therapy for Waldenström’s macroglobulinemia and related disorders: results in 414 patients on behalf of FCGCLL/WM, GOELAMS, GELA and NCRI Annals Oncol. 22(Suppl. 4), 128 (2011) (Abstract 134).
   Google Scholar
• Wechalekar AD, Lachmann HJ, Goodman HJ, Bradwell A, Hawkins PN, Gillmore JD. AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood 112(10), 4009–4016 (2008).
   PubMed Web of Science ®Google Scholar
• Palladini G, Russo P, Bosoni T et al. AL amyloidosis associated with IgM monoclonal protein: a distinct clinical entity. Clin. Lymphoma Myeloma 9(1), 80–83 (2009).
   PubMedGoogle Scholar
• Terrier B, Jaccard A, Harousseau Jl et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore) 87(2), 99–109 (2008).
   PubMed Web of Science ®Google Scholar
• Kimby E, Treon SP, Anagnostopoulos A et al. Update on recommendations for assessing response from the Third International Workshop on Waldenström’s Macroglobulinemia. Clin. Lymphoma Myeloma 6(5), 380–383 (2006).
   PubMedGoogle Scholar
• Varghese AM, Rawstron AC, Ashcroft AJ, Moreton P, Owen RG. Assessment of bone marrow response in Waldenström’s macroglobulinemia. Clin. Lymphoma Myeloma 9(1), 53–55 (2009).
   PubMedGoogle Scholar
• Treon SP, Yang G, Hanzis C et al. Attainment of complete/very good partial response following rituximab-based therapy is an important determinant to progression-free survival, and is impacted by polymorphisms in FCGR3A in Waldenström macroglobulinaemia. Br. J. Haematol. 154(2), 223–228 (2011).
   PubMed Web of Science ®Google Scholar
• Kyriakou C, Canals C, Sibon D et al. High-dose therapy and autologous stem-cell transplantation in Waldenström macroglobulinemia: the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J. Clin. Oncol. 28(13), 2227–2232 (2010).
   PubMed Web of Science ®Google Scholar
• Gertz MA, Abonour R, Heffner LT, Greipp PR, Uno H, Rajkumar SV. Clinical value of minor responses after 4 doses of rituximab in Waldenström macroglobulinaemia: a follow-up of the Eastern Cooperative Oncology Group E3A98 trial. Br. J. Haematol. 147(5), 677–680 (2009).
   PubMed Web of Science ®Google Scholar
• Hivert B, Tamburini J, Vekhoff A, Tournilhac O, Leblond V, Morel P. Prognostic value of the International Scoring System and response in patients with advanced Waldenström macroglobulinemia Haematologica 96(5), 785–788 (2011).
   Google Scholar
• Ghobrial IM, Hong F, Padmanabhan S et al. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenström macroglobulinemia. J. Clin. Oncol. 28(8), 1422–1428 (2010).
   PubMed Web of Science ®Google Scholar
• Ghobrial IM, Roccaro A, Hong F et al. Clinical and translational studies of a Phase II trial of the novel oral Akt inhibitor perifosine in relapsed or relapsed/refractory Waldenström’s macroglobulinemia. Clin. Cancer Res. 16(3), 1033–1041 (2010).
   PubMed Web of Science ®Google Scholar
• Laszlo D, Andreola G, Rigacci L et al. Rituximab and subcutaneous 2-chloro-2´-deoxyadenosine combination treatment for patients with Waldenström macroglobulinemia: clinical and biologic results of a Phase II multicenter study. J. Clin. Oncol. 28(13), 2233–2238 (2010).
   PubMed Web of Science ®Google Scholar
• Levy V, Morel P, Porcher R, Chevret S, Wattel E, Leblond V. Advanced Waldenström’s macroglobulinemia: usefulness of Morel’s scoring system in establishing prognosis. Haematologica 90(2), 279–281 (2005).
   Google Scholar
• Leleu X, Soumerai J, Roccaro A et al. Increased incidence of transformation and myelodysplasia/acute leukemia in patients with Waldenström macroglobulinemia treated with nucleoside analogs. J. Clin. Oncol. 27(2), 250–255 (2009).
   PubMed Web of Science ®Google Scholar
• Varettoni M, Tedeschi A, Arcaini L et al. Risk of second cancers in Waldenström macroglobulinemia. Ann. Oncol. doi:10.1093/annonc/mdr119 (2011) (Epub ahead of print).
   Google Scholar
• Stalnikiewicz L, Carrotte-Lefebvre I, Detourmignies L et al. Prognostic factors in Waldenström’s macroglobulinemia: description of the complications during the evolution-preliminary results on 101 patients. Semin. Oncol. 30(2), 216–219 (2003).
   Google Scholar
• Guidez S, Duhamel A, Morel P. Prognostic value for the overall survival of the reduction in serum monoclonal immunoglobulin concentration as response criteria in patients with symptomatic Waldenström macroglobulinemia. VIth International Workshop on Waldenström Macroglobulinemia. Venice, Italy, 6–10 October 2010 (Abstract).
   Google Scholar
• San-Miguel JF, Mateos MV. Can multiple myeloma become a curable disease? Haematologica 96(9), 1246–1248 (2011).
   PubMed Web of Science ®Google Scholar
• Kumar SK, Uno H, Jacobus SJ et al. Impact of gene expression profiling-based risk stratification in patients with myeloma receiving initial therapy with lenalidomide and dexamethasone. Blood 118(16), 4359–4362 (2011).
   PubMed Web of Science ®Google Scholar
• Fonseca R, Bergsagel Pl, Drach J et al. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia 23(12), 2210–2221 (2009).
   PubMed Web of Science ®Google Scholar
• Leblond V, Ben-Othman T, Deconinck E et al. Activity of fludarabine in previously treated Waldenström’s macroglobulinemia: a report of 71 cases. Groupe Cooperatif Macroglobulinemie. J. Clin. Oncol. 16(6), 2060–2064 (1998).
   PubMed Web of Science ®Google Scholar
• Tedeschi A, Benevolo G, Varettoni M et al. Fludarabine plus cyclophosphamide and rituximab in Waldenström macroglobulinemia: an effective but myelosuppressive regimen to be offered to patients with advanced disease. Cancer doi:10.1002/cncr.26303 (2011) (Epub ahead of print).
   Google Scholar

Risk stratification in Waldenström macroglobulinemia

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education (CME) credit, please go to www.medscape.org/journal/experthematology. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, [email protected]. For technical assistance, contact [email protected]. American Medical Association’s Physician’s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activities. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits™. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate and present it to your national medical association for review.

Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. Your patient is a 63-year-old man with newly diagnosed Waldenström macroglobulinemia (WM). He is currently asymptomatic, and he and his family have multiple questions about his condition. What can you tell them?

• □ A The median age of onset is in the fifth decade of life

• □ B At least 25% of patients are asymptomatic at the time of diagnosis

• □ C Current guidelines recommend treatment for all patients, regardless of symptoms, within 1 year

• □ D The presence of WM does not influence the risk for a subsequent second cancer

2. You evaluate this patient for his prognosis. Which of the following is an element of the International Prognostic Scoring System for WM (IPSSWM) criteria?

• □ A Functional status

• □ B Symptoms such as fatigue and anorexia

• □ C Serum monoclonal protein concentration

• □ D Serum lactate dehydrogenase level

3. What else should you consider regarding prognostic factors for WM in this case?

• □ A The most common cutoff value for age is 50 years

• □ B Lactate dehydrogenase has been dismissed as having any relevant prognostic value

• □ C Deletion of the 6q gene is associated with longer survival time

• □ D A large number of clinical and biological characteristics beyond the IPSSWM criteria inform prognosis in cases of WM

4. What else can you tell this patient regarding his prognosis?

• □ A Serum monoclonal IgM concentrations are more important than symptoms in predicting mortality risk among asymptomatic patients with WM

• □ B Marrow lymphocyte counts are more important than symptoms in predicting mortality risk among asymptomatic patients with WM

• □ C Patients with asymptomatic WM have a mortality rate similar to that of the general population

• □ D There are now clear criteria for prognosis based on treatment failure with initial therapy