In this review, the key issues that pertain to Waldenström disease are discussed in a concise question-and-answer format. Diagnosis, prognosis, and indications for state-of-the-art therapy are updated. Current therapies presented at the 7th International Workshop for Waldenström Macroglobulinaemia are included.
What is Waldenström macroglobulinaemia and when should it be suspected?
Waldenström macroglobulinaemia (WM) is defined by the World Health Organization as a lymphoplasmacytic lymphoma (LPL) associated with a monoclonal immunoglobulin M (IgM) protein of any size (Owen et al, 2003; Swerdlow et al, 2008). The classic pentad of WM is (i) monoclonal protein on serum protein electrophoresis, (ii) the monoclonal protein confirmed to be IgM by immunofixation, (iii) bone marrow evidence of LPL, (iv) evidence of hyperviscosity syndrome in some patients and (v) normocytic anaemia in some patients (Gertz, 2012). According to data from the Surveillance, Epidemiology, and End Results program, WM represents 1·9% of all non-Hodgkin lymphomas (Wang et al, 2012). The median age at diagnosis is 73 years, with more men than women affected (5·4 vs. 2·7 million per year), and more whites than African Americans affected (4·1 vs. 1·8 million). The presence of an IgM monoclonal gammopathy of undetermined significance (MGUS) is associated with an increased risk of WM developing on long-term follow-up (Kyle et al, 2003a), and IgM-MGUS is believed to represent a precursor to WM (Landgren & Staudt, 2012). Familial clustering of B-cell neoplasms is known, and almost 20% of patients with WM have been reported to have at least 1 first-degree relative with WM, other non-Hodgkin lymphoma, multiple myeloma, chronic lymphocytic leukaemia, MGUS, acute lymphoblastic leukaemia, or Hodgkin lymphoma (Treon et al, 2006). First-degree relatives of patients with LPL/WM have a 20-fold increased risk of LPL/WM (Kristinsson et al, 2008).
Other IgM-related conditions include IgM-MGUS, smouldering WM, IgM-related cold agglutinin haemolytic anaemia, type II cryoglobulinaemia, peripheral neuropathy, and amyloidosis. IgM-MGUS is characterized by the presence of an IgM monoclonal protein, less than 10% clonal lymphoplasmacytic bone marrow cells, and no symptoms attributable to tumour mass or infiltrations (e.g, adenopathy, organomegaly, anaemia, or IgM-mediated symptoms). Smouldering WM is characterized by an IgM monoclonal protein, clonal lymphoplasmacytic bone marrow infiltration greater than 10%, no symptoms attributable to tumour mass or infiltration, and no IgM-mediated symptoms.
What genetic changes can be associated with WM?
Using whole genome sequencing, more than 90% of patients with WM or non-IgM LPL have been found to have a common mutation, L265P in the myeloid differentiation primary response 88 gene (MYD88) (Treon et al, 2012). This mutation, which acts as a trigger for NFκB signalling, appears to be useful in distinguishing WM/LPL from other B-cell lymphoproliferative disorders, such as splenic marginal zone lymphoma (Treon et al, 2012; Gachard et al, 2013). This mutation is present in more than half of patients with IgM-MGUS and may help identify patients that are more likely to progress to WM (Landgren & Staudt, 2012; Xu et al, 2013). The high frequency of this mutation also suggests that it may be an initiating event but not a transforming event. The discovery of the L265P mutation has been a very exciting development in WM research and raises the potential for targeting MYD88 signalling in therapy for WM/LPL. Metaphase cytogenetics demonstrates a deletion in the long arm of 6q in 40% to 50% of patients (Chang et al, 2009). In a comprehensive study of the cytogenetic profile of 172 untreated patients with WM using conventional cytogenetics and fluorescence in situ hybridization, the 6q deletion was the most common and was associated with a complex karyotype, hypoalbuminaemia, and high β2-microglobulin levels without having an adverse effect on patient outcome (Nguyen-Khac et al, 2012). That study also showed other cytogenetic aberrations, including trisomy 18 (15%) and a 13q14 deletion (13%). Less than 10% of patients had trisomy 4, a 17p13 (TP53) deletion, an 11q22 [ataxia telangiectasia-mutated (ATM)] deletion, trisomy 12, or 14q32 (IGH) translocations. Epigenetic dysregulation, aberrations in the phosphatidylinositol 3-kinase/mTOR, NFκB, and JAK/STAT signalling pathways, as well as bone marrow microenvironmental interactions, may be other key factors involved in the pathogenesis of WM (Elsawa et al, 2011; Hodge & Ansell, 2011; Issa et al, 2011a).
How are patients with WM risk-stratified?
The International Prognostic Staging System for WM identifies the following five factors associated with worse prognosis in WM (Morel et al, 2009). These include age older than 65 years, haemoglobin level less than 115 g/l, platelet count less than 100 × 109/l, β2-microglobulin value greater than 3 mg/l, and monoclonal IgM level greater than 70 g/l.
On the basis of the number of risk factors present, the risk category is designated as low risk (zero or one risk factor, except age), intermediate risk (age older than 65 years or two risk factors), or high risk (more than two risk factors). These three risk categories are associated with median survivals of 142·5, 98·6, and 43·5 months respectively. The staging system is notable for the absence of lactate dehydrogenase level as a factor, but it may have a role in separating the high-risk patients into two distinct categories (Kastritis et al, 2010).
What are the indications for treatment of WM?
If patients are asymptomatic without significant cytopenia, observation is appropriate (Kyle et al, 2003b). The IgM level itself should not be a criterion to start treatment. Based on consensus panel recommendations from the Second International Workshop on WM, indications to start therapy included an increasing IgM level with progressive symptoms and signs of disease; haemoglobin level of 100 g/l or less and/or platelet count less than 100 × 109/l attributable to WM; bulky adenopathy/organomegaly; or disease-related symptoms severe enough to warrant therapy, including recurrent fever, night sweats, weight loss, fatigue, or symptom manifestations associated with WM including hyperviscosity, symptomatic neuropathies, amyloidosis, symptomatic cryoglobulinaemia, or evidence of disease transformation (Kyle et al, 2003b).
What is hyperviscosity syndrome and how is it managed?
Hyperviscosity syndrome is a potentially life-threatening complication of WM that is found in less than 15% of patients at diagnosis (Treon, 2009; Ghobrial, 2012). The risk of hyperviscosity depends on the IgM level and is rare at an IgM level less than 40 g/l (Treon, 2009). Symptoms may be nonspecific, with generalized fatigue, dizziness, and light-headedness. Blurred vision, headache, ataxia, epistaxis, and gingival bleeding may also occur, and severe cases of hyperviscosity syndrome may be associated with confusion, dementia, stroke, and coma (Stone & Bogen, 2012). Classic ophthalmological findings on funduscopic examination include sausaging of retinal veins from venous engorgement with haemorrhages. Hyperviscosity syndrome is rare unless the serum viscosity exceeds 4 mPa s (normal, ≤1·5 mPa s). The immediate institution of plasmapheresis, followed by chemotherapy, rapidly and effectively treats hyperviscosity syndrome. Increased viscosity without the presence of symptoms is not an indication for treatment. When single-agent rituximab is used, an initial IgM flare can develop, which may result in hyperviscosity after initiation of treatment (Ghobrial et al, 2004). It is important to monitor IgM and serum viscosity levels if single-agent rituximab is used and to have a low threshold for starting plasmapheresis. However, it is equally important to not change therapy during an IgM flare, because these patients can still respond to treatment.
How is response to treatment measured?
Response to treatment as defined by a consensus panel at the VIth International Workshop on WM (Owen et al, 2013) is shown in Table 1. A few important caveats to these definitions must be considered. First, patients may have a delayed response, especially after purine analogue (Dhodapkar et al, 2009) and monoclonal antibody therapy, and best response may not be achieved until 6 months after treatment. Although rituximab-naïve patients who achieve a complete response, very good partial response, and partial response appear to have longer progression-free survival with rituximab-based therapy (Treon et al, 2011a), patients with minor responses may do just as well clinically as patients with more complete responses (Gertz et al, 2009).
Table 1. Criteria for categorizing disease response in WM
IgM, immunoglobulin M; WM, Waldenström macroglobulinaemia.
Absence of serum monoclonal IgM protein by immunofixation; normal serum IgM level; complete resolution of extramedullary disease (organomegaly/lymphadenopathy) if present at baseline; morphologically normal bone marrow aspirate and trephine biopsy
Very good partial response
Monoclonal IgM protein is detectable; ≥90% decrease in serum IgM level from baseline; complete resolution of extramedullary disease (organomegaly/lymphadenopathy) if present at baseline; no new signs or symptoms of active WM
Monoclonal IgM protein is detectable; ≥50% but <90% decrease in serum IgM level from baseline; reduction in extramedullary disease if present at baseline; no new signs or symptoms of active WM
Monoclonal IgM protein is detectable; ≥25% but <50% decrease in serum IgM level from baseline; no new signs or symptoms of active WM
Monoclonal IgM protein is detectable; <25% decrease or <25% increase in serum IgM level from baseline; no progression in extramedullary disease; no signs or symptoms attributable to WM
≥25% increase in serum IgM level from lowest nadir (requires confirmation) and/or progression of clinical features attributable to WM
What are the standard and novel therapies in WM?
The standard therapy for WM may be alkylator-based (cyclophosphamide) or purine analogue-based (fludarabine, cladribine), with the addition of the anti-CD20 monoclonal antibody rituximab. There is a paucity of large, randomized controlled trials in WM. The first multicentre phase III study comparing fludarabine with chlorambucil was recently published, which showed superiority of single-agent fludarabine over chlorambucil in terms of overall response rate (53% vs. 43%, P =0·06), duration of response (38 vs. 19 months, P <0·001), 5-year overall survival (69% vs. 62%, P =0·046), and a 6-year cumulative incidence of second malignancies (4% vs. 21%, P <0·001), respectively (Leblond et al, 2013). The choice of therapy is often determined by patient age and comorbid conditions, as well as the clinical phenotype. Although there is currently no standard of care in WM, the first-line choice at our institution is combination chemotherapy with dexamethasone, rituximab, and cyclophosphamide (Fig 1) (Ansell et al, 2010).
Table 2 shows the various response rates with single-agent and combination chemotherapy options, with specific adverse effects, as well as newer drugs for WM that are in the pipeline. These newer drugs include alkylators (bendamustine), monoclonal antibodies (alemtuzumab), immunomodulatory drugs (thalidomide, lenalidomide), and proteasome inhibitors (bortezomib). Additional promising drugs are in various early stages of study in WM: everolimus, an mTOR inhibitor; perifosine, an AKT inhibitor; enzastaurin, a phosphatidylinositide 3 kinase/AKT inhibitor; panobinostat, a histone deacetylase inhibitor; ofatumumab, a third-generation anti-CD20 monoclonal antibody; and ibrutinib, a Bruton tyrosine kinase inhibitor; and newer drugs from known active subclasses, such as pomalidomide (immunomodulatory) and carfilzomib (proteasome inhibitor) (unpublished observations; Issa et al, 2011b).
Is there a role for rituximab in maintenance therapy?
The benefit of maintenance rituximab therapy is controversial. A retrospective analysis of rituximab maintenance therapy in patients treated with rituximab-containing regimens indicated an improvement in progression-free and overall survivals (Treon et al, 2011b). Maintenance rituximab given every 2 months for 2 years is currently being evaluated prospectively in WM (Rummel et al, 2012). Currently at our centre, we do not routinely use maintenance rituximab therapy, pending the outcome of this well-designed phase 3 study.
Should autologous stem cell transplantation be a first-line option?
Autologous stem cell transplantation produces durable responses with a low treatment-related mortality rate (Kyriakou et al, 2010; Usmani et al, 2011). Although no randomized clinical trials have addressed autologous stem cell transplantation in the first-line setting, it may be considered in transplant-eligible patients with high WM stage and increased lactate dehydrogenase level (i.e, patients with high-risk disease) (Bachanova & Burns, 2012). For transplant-eligible patients, we routinely collect and cryopreserve peripheral blood stem cells, and patients, particularly younger patients, are considered for autologous stem cell transplantation at first progression. Heavily pretreated patients (>3 regimens) and those with chemotherapy-refractory disease at the time of transplant are unlikely to benefit (Kyriakou et al, 2010).
How is relapsed disease managed?
The Mayo Clinic consensus approach to the management of relapsed WM is demonstrated in Fig 2.
Does allogeneic stem cell transplant have a role in WM?
Because WM tends to occur at older ages, the use of allotransplant can be more challenging. The largest review on allogeneic transplantation in WM comes from the European Bone Marrow Transplantation registry: 304 patients who received reduced-intensity conditioning or myeloablative conditioning between 2000 and 2011 showed overall survivals of 62% and 66%, and 3-year response rates of 21% and 26%, respectively (unpublished observations). We consider allogeneic stem cell transplant only in younger patients and consider it investigational in the setting of WM.
Which autoimmune disorders can be associated with WM?
The accumulation of monoclonal IgM protein in WM can result in several autoimmune conditions. Type I cryoglobulinaemia is common; all of the cryoglobulin is composed of the monoclonal IgM protein. Type II cryoglobulinaemia is composed of monoclonal and polyclonal immunoglobulins. Whereas type I cryoglobulinaemia tends to be an incidental finding without symptoms or signs (Gertz, 2012), patients with type II or mixed IgM-IgG cryoglobulinaemia can have various symptoms and signs related to cold sensitivity, purpura, arthralgias, and vasculitis (Stone, 2011). Additionally, type II cryoglobulinaemia has a marked effect on serum viscosity owing to the high thermal amplitude of the IgM-IgG cryoglobulin (Stone, 2011). Other autoimmune phenomena include cold agglutinin disease, in which a monoclonal IgM directed against the red cell I or i antigen results in red cell lysis. Symptoms include acrocyanosis, Raynaud phenomenon, and an immune haemolytic anaemia on cold exposure. The IgM protein can also attack neural proteins resulting in immune neuropathies (Figueroa et al, 2012).
Type II cryoglobulinaemia or cold agglutinin disease can be asymptomatic. Symptomatic patients with IgM-related autoimmune disorders may be treated with single-agent rituximab (Berentsen, 2007) if no bulky disease, cytopenias, or B symptoms are present (Fig 1). Treatment of cold agglutinin disease with the combination of fludarabine and rituximab has been shown to produce a high and durable response (Berentsen et al, 2010). We reserve adding cytotoxic therapy with rituximab for patients who do not respond to single-agent rituximab or who have other symptoms related to WM.
When should AL amyloidosis be suspected?
Primary systemic (AL) amyloidosis is a rare complication of WM. This should be suspected in all patients with symptoms of peripheral neuropathy and is an important complication to identify, because the development of amyloidosis can cause substantial morbidity, as well as mortality from organ deposition, over the risk of progression of WM (Gertz et al, 1993). In a large series from Italy, IgM-associated amyloidosis was seen in 7% of patients. These patients were found to have more lymph node involvement, with less advanced organ dysfunction (Palladini et al, 2009). In another series of 22 patients with IgM-associated amyloidosis studied at Mayo Clinic, these patients were older, with more peripheral nerve involvement and less cardiac involvement, when compared with patients with non-IgM amyloidosis (Gertz et al, 2011). Rarely, patients with WM can have localized AL amyloidosis primarily affecting the lymph nodes (Wechalekar et al, 2008). This tends to be a more indolent form of amyloidosis, with amyloid deposition occurring peritumourally at the site of lymphoma cells and without involvement of distant organs (Telio et al, 2010). Treatment of IgM amyloidosis is similar to treatment of primary systemic amyloidosis (Gertz et al, 2011). Evidence suggests that treatment directed at the lymphoma cells with drugs such as rituximab may be of benefit (Cohen et al, 2004). All patients with an IgM monoclonal protein, proteinuria, unexplained cardiomyopathy (heart failure with preserved systolic function), hepatomegaly, and peripheral neuropathy should be screened for amyloidosis by staining bone marrow and fat aspiration samples with Congo red at a minumum. Suspicion is heightened if the monoclonal IgM protein is associated with a λ light chain.
What are the various neurological manifestations of WM?
The most common neurological complication of WM is peripheral neuropathy, which may be seen in up to half of all patients (Lopate et al, 2006). The clinical presentation and neurological findings are identical to those seen with IgM-MGUS and are probably related to immune-mediated axonal loss (Klein et al, 2011). Known neural targets against which monoclonal IgM may be directed include myelin-associated glycoprotein or sulfatide, but not all patients have these autoantibodies. Other mechanisms of peripheral nerve damage may include direct infiltration of nerves by tumour cells or IgM directed against unidentified neural proteins; other known complications of WM, such as AL amyloidosis and cryoglobulinaemia, may also result in peripheral neuropathy (Lopate et al, 2006). Chemotherapeutic drugs used to treat WM, such as bortezomib and thalidomide, also can worsen existing peripheral neuropathy.
The central nervous system can also be affected in WM. Independent of the hyperviscosity syndrome, WM can involve the meninges, brain, and cerebrospinal fluid, termed Bing-Neel syndrome. According to a review of 31 cases of Bing-Neel syndrome (Ly et al, 2012 2012), patients may have evidence of lymphoplasmacytoid cells within the brain or cerebrospinal fluid, or may have an autoimmune mechanism mediated by IgM. White matter changes were seen on brain magnetic resonance imaging in 65% of patients, and spinal cord syndromes were seen in 67% of patients. Treatment of the WM provided improvement in 42% of patients, with sustained response from 6 months to 4 years.
Which survivorship issues should be considered in WM?
Patients with WM may present unique challenges to the treating haematologist. Nearly half of these patients may have an associated IgG and IgA hypogammaglobulinaemia (Hunter et al, 2010), but there is no evidence yet that replacing immunoglobulins is beneficial. Patients with WM/LPL may also have an increased risk of venous thrombosis (Hultcrantz et al, 2012).
The long survival and advanced age of presentation in WM must be considered when selecting the most appropriate treatment. Treatment-associated morbidity can be serious: prolonged risk of secondary infections with monoclonal antibodies and purine analogues, risk of myelodysplasia from fludarabine (Leleu et al, 2009), and worsening of peripheral neuropathy related to bortezomib, among others.
Patients with WM are also at increased risk for second malignancies, including transformation to diffuse large B-cell lymphoma, myelodysplastic syndrome, acute myeloid leukaemia, and solid cancers (Varettoni et al, 2012; Leblond et al, 2013). Physicians caring for these patients should have a high index of suspicion for this possibility in the appropriate clinical setting.
D'Souza and Gertz conceived the project, approved the manuscripts used in the review, and wrote and reviewed the manuscript. Drs Ansell and Reeder helped define data to include in the review, critically reviewed the data, helped edit, and approved the manuscript.