Waldenstrom’s macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder primarily characterized by lymphoplasmacytic cells infiltrating the bone marrow (BM), along with demonstration of an IgM monoclonal gammopathy Citation[1–4]. According to the Revised European American Lymphoma (REAL) and WHO systems, WM is classified as a lymphoplasmacytic lymphoma Citation[3,4]. Each year in the USA, there are 1500 new cases diagnosed and the median age of diagnosis is 60 years; the overall incidence of WM is approximately three per million persons per year Citation[5–7]. In 11 population-based registries within the USA, the age-adjusted rates for men and women are 3.4 and 1.7 per million, respectively. Rates increased sharply with age: 0.1 per million individuals under 45 years of age and 36.3 per million individuals over 75 years of age. These rates are comparable to those for hairy-cell leukemia, and do not appear to be increasing. In addition, the rates are clearly higher for Caucasians than for African–Americans Citation[5,8]. The median overall survival of patients with WM is 5–6 years; however, a recent study of 337 patients with symptomatic WM showed a median disease-specific survival of 11.2 years Citation[7].
Etiology & predisposing factors
Waldenstrom’s macroglobulinemia is a sporadic disease with unknown etiology; although a high familial incidence of this disease has been demonstrated in various studies, with 18.7% of patients having at least a first-degree relative with a B-cell neoplasm Citation[9,10]. The main risk factor for the development of WM is the presence of IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS) with a 46-fold higher relative risk than the general population Citation[11].
Clinical manifestations
Patients with WM can present with an extensive range of signs and symptoms Citation[2,3,7]. Frequent clinical presentations are related to cytopenias, specifically, anemia associated with the replacement of tumor cells in the bone marrow. Patients may also present with headache, blurred vision and epistaxis, which occur from hyperviscosity due to elevated IgM levels. Approximately 20% of patients will experience hepatosplenomegaly and lymphadenopathy, and, in addition, some patients may present with B symptoms, including night sweats, fever and weight loss. Other manifestations include neuropathy, cryoglobulinemia, skin rash (Shnitzler’s syndrome) Citation[12], cold-agglutinin hemolytic anemia and amyloidosis Citation[13,14].
Prognostic factors
Several studies have shown that poor prognosis for patients with WM is associated with the following factors: advanced age, high β2-microglobulin (b2M), cytopenias, low albumin, serum IgM monoclonal protein and organomegaly Citation[7,15–18]. In addition, an international prognostic scoring system for WM (ISS-WM) was recently defined using a series of 587 patients. This ISS-WM staging system is accepted as the uniform prognostic staging system for WM Citation[19]. The scoring system is based on five risk factors and the survival of the patients at 5 years. Patients with low-risk disease had a 5-year survival of 87%, while patients with high-risk disease had a 5-year survival of only 36%.
Timing & choice of therapy
The treatment of patients with WM depends on the presence of symptoms or signs of disease progression. Patients with asymptomatic disease should not be treated independent of the monoclonal protein level. Some of the clinical signs or symptoms that indicate time to initiate therapy include, platelet count less than 100 × 109/l, hemoglobin level less than 10 g/dl, symptomatic hyperviscosity, amyloidosis, bulky adenopathy or organomegaly, moderate, severe or advancing peripheral neuropathy, cryoglobulinemia or cold-agglutinin disease. Furthermore, important considerations to keep in mind when discussing treatment include age, occurrence of cytopenias and necessity of rapid disease control, as well as the patient’s eligibility for autologous transplant therapy. Certain therapeutic options should be avoided in patients eligible for autologous transplant therapy, such as alkylating agents and nucleoside analogues. A recent study has shown nucleoside analogue treatment leads to difficulty collecting stem cells, developing myelodysplasia or acute myelogenous leukemia, as well as increasing disease transformation risk, and, therefore, should be used judiciously with WM patients Citation[20].
Therapeutic options
Standard therapeutic options
Current therapies used in the upfront or relapsed settings include alkylator agents (e.g., chlorambucil or cyclophosphamide), nucleoside analogs (cladribine or fludarabine) and the monoclonal antibody rituximab Citation[21–24]. The overall response rates (ORRs) in the upfront setting vary from 30 to 70%; this includes complete response (CR), partial response (PR) and minimal response, with CR rates less than 10% and median durations of response averaging 2–3 years Citation[22,25]. In the salvage setting, the ORR is between 30 and 40%, with a median response duration of 1 year or less Citation[22,26]. The use of fludarabine or alkylating agents in combination therapy will stimulate high responses; however, with these elderly patients the consequence involves significant toxicities Citation[27,28]. Rituximab is the most widely used therapeutic agent in WM and standard treatment yielded response rates of 35–48% (four weekly infusions of 375 mg/m2 or extended treatment involving four weekly rituximab treatments repeated at 3 months) Citation[23,29–31]. Another important note involving rituximab treatment is the initial increase in the IgM level; this is termed IgM flare and is seen in approximately 54% of patients Citation[32,33]. Although these levels may remain elevated for 3–4 months, they do not indicate treatment failure. Alemtuzumab has also been tested in 25 patients with WM, 5 were untreated and 23 were treated. The ORR was 76%, with 32% PRs. In addition, the combinations of rituximab, cyclophosphamide, doxorubicin, oncovin, prednisone (R-CHOP) or R-CVP or R-CP have shown high responses with over 80% ORR in patients with WM in small prospective or retrospective reviews Citation[34–36].
The combination of bendamustine and rituximab (BR) has recently been compared with R-CHOP in a large cohort of newly diagnosed untreated low-grade lymphomas, which included 42 patients with WM Citation[37,38]. The ORR in 40 evaluable patients was 96% for BR versus 94% for R-CHOP. BR was associated with lower incidences of grade 3 and 4 cytopenias, infectious complications and alopecia.
Novel therapeutic agents
Novel therapeutic agents that have demonstrated efficacy in WM include bortezomib, thalidomide, lenalidomide, everolimus and perifosine Citation[22,39–41]. The range of the ORR to these agents is between 25 and 80% Citation[22,39–41].
The use of bortezomib as a single agent in WM has been tested in two Phase II clinical trials in relapsed WM. The agent was used in the standard dose of 1.3 mg/m2 twice a week on days 1, 4, 8 and 11. To determine the effectiveness in the general WM patient population, Chen et al. administered bortezomib to 27 WM patients, 44% of whom were previously untreated and 56% were treated previously with bortezomib Citation[42]. The ORR was 78% and major responses (PR or better) were seen in 44% of patients; there were no CRs observed in these studies. Sensory neuropathy was the primary toxicity in 20 out of 27 patients. A recent study using the combination of bortezomib, rituximab and dexamethasone (BDR) was tested in newly diagnosed patients with WM and showed an exciting ORR of 96%, including 83% achieving PRs Citation[43]. However, neuropathy was again a major toxicity with this regimen. Therefore, treatment of bortezomib in current clinical trials has been reduced to once a week at 1.6 mg/m2 in an attempt to reduce the occurrence of peripheral neuropathy Citation[43]. Two recent clinical trials have been conducted using weekly bortezomib in combination with rituximab in newly diagnosed or in relapsed WM. The results in relapsed WM showed a response rate of 81% ORR, with 46% PRs.
The combination of thalidomide and rituximab has been tested in WM, using thalidomide 200 mg daily for the first 2 weeks followed by 400 mg daily for a total of 1 year. In total, 23 patients were evaluable for this study and showed an ORR of 78% with 65% PRs. Dose reductions of thalidomide occurred in all patients and led to discontinuation of therapy in 11 patients Citation[44]. Lenalidomide 25 mg/day in combination with rituximab has been tested in 16 patients. Of these, 12 were evaluable for response with an ORR of 67%, including four PRs. Acute decreases in hematocrit were observed during the first 2 weeks of lenalidomide therapy in 13 out of 16 (81%) patients with a median hematocrit decrease of 4.4% (1.7–7.2%), resulting in four patient hospitalizations Citation[45].
Everolimus or RAD001 was studied in a Phase II clinical trial of 50 patients Citation[38]. The treatment regimen included everolimus 10 mg orally daily and patients were evaluated monthly. The ORR was 70%, with 42% PR. The estimated progression-free survival (PFS) at 6 and 12 months was 75 and 62%, respectively. The most common grade 3 or 4 toxicities were anemia (18%), thrombocytopenia (16%), neutropenia (14%), diarrhea (6%), fatigue (10%) and stomatitis (8%).
A Phase II clinical trial using perifosine was performed involving 37 patients. In this study, the ORR was 35%, with four patients achieving PR (11%). The median PFS was 12.6 months, which was longer than the PFS observed in patients with relapsed or relapsed/refractory WM treated with bortezomib. Perifosine was generally well tolerated; adverse events related to therapy were cytopenias (grade 3–4, 13%), gastrointestinal symptoms (grade –2, 81%) and arthritis flare (all grades, 11%) Citation[8].
Ongoing and planned future clinical trials include those using protein kinase inhibitors, such as enzastaurin, new proteasome inhibitors, such as carfilzomib, histone deacetylase inhibitors, such as LBH589, and immunomodulatory drugs, such as pomalidomide (CC-4047). These agents have revolutionized the therapeutic options for WM. Future combinations of these agents will probably lead to higher responses, longer remissions and better quality of life for patients with WM.
Financial & competing interests disclosure
Irene Ghobrial has received honoraria from Novartis, Celgene, Millenium and is on the Advisory board of Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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