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CHAPTER 108 WALDENSTRÖM MACROGLOBULINEMIA

CHAPTER 108 WALDENSTRÖM MACROGLOBULINEMIA
Williams Hematology

CHAPTER 108 WALDENSTRÖM MACROGLOBULINEMIA

THOMAS J. KIPPS

Definition and History

Lymphoplasmacytic Neoplasms

B-Lymphocytic Neoplasms

Essential Monoclonal Macroglobulinemia
Etiology and Pathogenesis

Etiology

Pathogenesis
Clinical Features

The Hyperviscosity Syndrome
Laboratory Findings

Serum Immunoglobulin and Blood Viscosity

Blood and Marrow Cells

Disorders of Hemostasis

Renal Abnormalities
Differential Diagnosis
Therapy, Course, and Prognosis

Therapy
Course and Prognosis
Chapter References

This chapter focuses on Waldenström macroglobulinemia, a B-cell malignancy in which there is abnormal production of a monoclonal IgM protein. It is important to distinguish this disorder from other causes of macroglobulinemia that also are described in this chapter. Recent observations are reviewed that provide insight into the potential etiology and pathogenesis of Waldenström macroglobulinemia. This chapter also discusses the clinical manifestations of this disease and outlines current approaches to therapy, including the use of purine analogues.

Acronyms and abbreviations that appear in this chapter include: CLL, chronic lymphocytic anemia; IgM, immunoglobulin M.

DEFINITION AND HISTORY
The term macroglobulinemia describes an increase in the blood concentration of IgM. Although this term commonly connotes Waldenström macroglobulinemia, several other disorders also may be associated with a monoclonal macroglobulinemia.1,2 In addition, some conditions may be associated with an increase in polyclonal serum IgM protein.3
The types of disorders associated with a monoclonal macroglobulinemia vary with the study population. Physicians in specialized centers may see macroglobulinemia primarily associated with lymphoplasmacytic and B-lymphocyte neoplasms. On the other hand, physicians at primary treatment centers that use serum electrophoresis as a screening test more commonly may see patients with essential macroglobulinemia, or macroglobulinemia that is not associated with overt lymphoproliferative disease. Of 430 patients with monoclonal IgM investigated at the Mayo Clinic, 242 (56 percent) were classified as having essential monoclonal macroglobulinemia.4 Seventeen percent of these patients developed Waldenström macroglobulinemia, chronic lymphocytic leukemia, lymphoma, or amyloidosis, and an additional 8 percent had progressive increases in serum IgM to 5 g/liter or more.
LYMPHOPLASMACYTIC NEOPLASMS
WALDENSTRÖM MACROGLOBULINEMIA
In 1944, Jan Waldenström described two male patients who had fatigue, a tendency to bleed from the gums and nasal mucosa, lymphadenopathy, worsening normochromic anemia, a low serum fibrinogen despite an “excessive sedimentation of the erythrocytes,” and an extremely high serum viscosity secondary to a pathologic serum “eu-globulin” (macroglobulin) of approximately 1,000,000 kDa.5,6 These patients lacked any lytic bone lesions on X-ray and did not have any typical signs of myeloma, even on postmortem examination. Now known as Waldenström macroglobulinemia, this syndrome is the manifestation of a neoplastic disease in a clone of IgM-producing B cells. This chapter focuses primarily on this disorder.
Compared to myeloma, Waldenström macroglobulinemia is relatively less common. In the United States, the age-adjusted incidence rate per 1 million person-years at risk is 3.4 for men and 1.7 for women.7 These rates increase sharply with age, from 0.1 for those who are less than 45 to 36.3 and 16.4 for men and women, respectively, who are 75 or older.
IgM MYELOMA AND EXTRAMEDULLARY PLASMACYTOMA
Patients with monoclonal macroglobulinemia associated with lytic bone lesions or hypercalcemia may be diagnosed as having IgM myeloma. The neoplastic plasma cells have a surface phenotype with characteristics that overlap with those of Waldenström macroglobulinemia and plasma cell myeloma. Plasma cells of IgM myeloma have high-level expression of CD38 but weak or negligible expression of CD5, CD10, CD20, CD22, CD23, CD45, HLA-DR, FMC7, and surface immunoglobulin.8 Extramedullary plasmacytomas also may produce an excess in monoclonal IgM protein and have features in common with plasma cell myeloma. These conditions are discussed in Chap. 106.
B-LYMPHOCYTIC NEOPLASMS
Patients with low-grade B-cell lymphomas or B-cell chronic lymphocytic leukemia may have a monoclonal macroglobulinemia due to the IgM produced by the neoplastic B-cell clone. These diseases are discussed in Chap. 103 and Chap. 98, respectively.
ESSENTIAL MONOCLONAL MACROGLOBULINEMIA
Patients may have monoclonal macroglobulinemia without associated anemia, lymphadenopathy, hepatosplenomegaly, bone lesions, or evidence of disease progression. Such patients are classified as having essential monoclonal macroglobulinemia, a subtype of essential monoclonal gammopathy. Patients with essential monoclonal gammopathy are at increased risk for developing plasma cell myeloma or Waldenström macroglobulinemia.9 This condition is discussed in Chap. 105. Should the excess monoclonal IgM protein have binding activity for the “i” or “I” carbohydrate determinant found predominately on neonatal and adult erythrocytes, respectively, the macroglobulin may agglutinate red cells in the cold. Patients who have hemolytic anemia secondary to the continuous production of such autoantibodies have the cold agglutinin syndrome. This condition is discussed in Chap. 56.
ETIOLOGY AND PATHOGENESIS
ETIOLOGY
The etiology of Waldenström macroglobulinemia is unknown. Although there are a few reports of patients developing Waldenström macroglobulinemia years after radiation therapy,10 a significant increase in incidence of this disease has not been noted in persons previously exposed to ionizing radiation or other environmental toxins.11
Hepatitis C infection has been associated with development of Waldenström macroglobulinemia.12 An association between macroglobulinemia and hepatitis C infection was noted in a study of B-cell malignancies in Japan that included four patients with Waldenström macroglobulinemia.13 Another report noted the unusual development of Waldenström macroglobulinemia in five young Americans of African descent with a median age of 38 that was associated with hepatitis C infection and a history of intravenous heroin and cocaine use.14 The finding that patients with hepatitis C may have an associated macroglobulinemia that can resolve after treatment with interferon alpha15 suggests a possible relationship between uncontrolled hepatitis C infection and the development of Waldenström macroglobulinemia. However, it is controversial whether hepatitis C is involved in all or most of cases of macroglobulinemia.16
Some investigators have speculated that infection of marrow stromal dendritic cells by human herpesvirus type 8 (HHV-8), also known as Kaposi’s sarcoma–associated herpesvirus, might be a key factor in the etiology and pathogenesis of monoclonal gammopathies, including Waldenström macroglobulinemia.17,18 However, in one survey of 20 patients, only one was found to have evidence of HHV-8 in the marrow.19
Although an uncommon disease, Waldenström macroglobulinemia has been noted in the kindred of certain families16,20,21 and 22 and in monozygotic twins.23 Moreover, occasionally “unaffected” family members may have macroglobulinemia or other serum immunoglobulin abnormalities.20,24 This has led some investigators to speculate that genetic factors contribute to the etiopathogenesis of this disease.
Various chromosomal abnormalities have been described in neoplastic cells of patients with Waldenström macroglobulinemia.25,26,27,28,29,30 and 31 In one study of 19 patients, 89 percent were found to have chromosome abnormalities, most commonly involving chromosomes 9, 10, 11, and 12.25 However, no one particular chromosomal abnormality is identified in the majority of patients with this disease. In this study, monosomy of chromosome 9 was associated with disease progression. In another study, a significant proportion of cases were found to carry the translocation t(9;14)(p13;q32) involving the PAX-5 gene.32 Yet another study using nonstimulated short-term marrow cell cultures identified chromosomal abnormalities in only 15 percent of the patients with Waldenström macroglobulinemia.31 Rearrangements in the long arm of chromosome 14, at band 32, also have been identified.26,31,33 Abnormalities of chromosome 6, particularly partial deletions affecting 6q, have been detected using sensitive G-banding techniques (see Chap. 10).28 Finally, the neoplastic cells of a few patients may be found to have mutations in the p53 tumor-suppressor gene that may be acquired during the evolution of the disease.34
PATHOGENESIS
Much of the morbidity associated with Waldenström macroglobulinemia is caused by the IgM produced by the neoplastic B cells. The blood viscosity increases when the concentration of IgM in the blood rises. High blood viscosity affects platelet function35 and impairs capillary blood flow, reducing oxygen delivery through the microcirculation.36 This may result in the patient developing the hyperviscosity syndrome, described below. High blood viscosity also has been associated with viscous pancreatic secretions, increasing the risk for developing pancreatitis.37 In addition, high serum levels of macroglobulins may cause abnormal cerebrovascular permeability, either by a direct toxic effect or by way of viscosity-related ischemia. This may lead to infiltration of the cerebral parenchyma by IgM and lymphoplasmacytic cells, and, ultimately, focal degeneration of the white matter, resulting in leukoencephalopathy.38
Occasionally, the monoclonal IgM protein may react with self-antigens to cause disease.39,40 and 41 For example, the monoclonal IgM may have rheumatoid factor activity or binding activity for the constant region of human IgG.42 IgM rheumatoid factors may form immune complexes with IgG, especially at low temperatures, leading to complement activation and tissue destruction secondary to immune complex deposition.43,44 Some patients can develop myopathy associated with monoclonal IgM proteins that react with muscle self-antigens.45 More often, the IgM protein reacts with red blood cells, particularly at low temperatures, sometimes causing autoimmune hemolytic anemia (see Chap. 56).46 On rare occasions, the monoclonal IgM may react with platelets, causing immune thrombocytopenic purpura.47
Although in most cases the monoclonal IgM protein does not react with any specific antigen,48 in some patients it reacts with the myelin-associated glycoprotein or other components of peripheral nerve sharing a common carbohydrate determinant with myelin-associated glycoprotein.49,50,51 and 52 Other patients may have an IgM that reacts with chrondroitin sulfate C,53 myelin basic protein,54 or nerve glycolipids, such as GM1 ganglioside.55,56 and 57 Patients with an IgM reactive with myelin-associated glycoprotein often develop a sensory demyelinating peripheral neuropathy, whereas elevated titers of anti-GM1 ganglioside antibodies are associated with lower motor neuron syndromes with multifocal motor conduction block.57 The severity of neuropathy may be related to the level of monoclonal IgM autoantibody.
If the monoclonal IgM protein precipitates from the serum on cooling, it is called a cryoglobulin. Cryoglobulins in general may be classified as type I (monoclonal), type II (mixed), or type III (polyclonal). Monoclonal IgM of patients with Waldenström macroglobulinemia may be either type I or type II according to whether they form cryoprecipitates, respectively, by themselves or as an immune complex, usually with polyclonal IgG. Patients with cryoglobulinemia may develop cold hypersensitivity, particularly if the cryoglobulin precipitates at temperatures above 22°C (71.6°F) and is present at blood concentrations greater than 20 g/liter.58
In some patients, the abnormal monoclonal IgM protein interferes with hemostasis.59,60 Coating of platelets by the monoclonal IgM protein may produce defects in platelet aggregation secondary to impaired release of platelet factor 3.61 Also, some monoclonal IgM proteins bind coagulation factors and inhibit coagulation.59 For example, some IgM proteins bind to fibrin and inhibit fibrin monomer aggregation, resulting in a bulky, gelatinous, transparent clot with impaired clot retraction.43 When combined with impaired platelet function, this may produce a bleeding diathesis. Also, monoclonal IgM proteins have been noted to inhibit factor VIII, factor V, or factor VII.59 Such IgM proteins also may lead to depletion of one or more coagulation factors in vivo. Finally, the plasma of Waldenström macroglobulinemia patients may have strong lupus anticoagulant activity if the monoclonal IgM has binding activity for the phosphatidylserine or phosphatidylethanolamine of cephalin.62
CLINICAL FEATURES
Generally, patients with Waldenström macroglobulinemia are in their sixth or seventh decade of life. The median age at diagnosis is 63 years.4 Although occasionally young adults can develop Waldenström macroglobulinemia,14 less than 3 percent of patients are under age 40. The disease is more common in men.
The patients most commonly present with complaints of fatigue, weakness, and weight loss. They also often note episodic bleeding, particularly from the gums and nasal mucosa. Patients also may present with symptoms and signs of the hyperviscosity syndrome.
The most common physical findings are lymphadenopathy and hepatosplenomegaly. It is common to find dependent purpura and evidence of bleeding from the mucosal surfaces of the gastrointestinal tract. Secondary to serum hyperviscosity, Waldenström macroglobulinemia patients often have dilated and tortuous retinal veins.
The physical properties of the IgM paraprotein may produce symptoms. Patients with cryoglobulinemia may complain of cold hypersensitivity, noting that exposure to low temperatures precipitates urticaria, purpura, acral cyanosis, or Raynaud phenomenon. Some patients may have multiple flesh-colored, sometimes pruritic papules on extensor skin surfaces secondary to skin deposition of monoclonal IgM. In some cases, the IgM protein has been found to react with epidermal basement membrane antigens.41,63
Various skin lesions are associated with Waldenström macroglobulinemia. Patients can have purpura, ulcers, or urticarial lesions caused by hyperviscosity of the blood, immune complex-mediated vascular damage, paraprotein deposition, or amyloid deposition.64 In addition, some patients have translucent, flesh-colored papules, resulting from monoclonal IgM deposits. When such deposits occur in the tarsal conjunctiva and tarsus, the patient can develop eyelid thickening and ptosis.65 Some patients may develop a bullous dermatosis associated with the monoclonal IgM protein.66,67 In such cases, deposits of the macroglobulin often can be found lining the subepidermis at the point of separation in the upper dermis, suggesting that the monoclonal IgM has an unusual reactivity for skin-associated antigens. Finally, a few patients may develop violaceous skin lesions composed of lymphoplasmacytic infiltrates. The latter cutaneous manifestations may be a harbinger that the disease is undergoing transformation into high-grade lymphoma.
Not infrequently, patients may develop a peripheral neuropathy. Most commonly, this produces symptoms of a slowly progressive, symmetric, and predominantly sensory peripheral neuropathy that affects the legs more severely than the arms.68 These symptoms may antedate the diagnosis of Waldenström macroglobulinemia by several years and sometimes bear no defined relationship to the duration or severity of the macroglobulinemia, particularly if the monoclonal IgM protein does not react with nerve-associated antigens. Often one can detect high serum titers of antibodies to such antigens as myelin-associated glycoprotein.68 However, nearly half of the macroglobulinemia patients with neuropathy have monoclonal IgM proteins that have no detectable reactivity with such nerve components, implying that the pathogenesis of macroglobulinemia-associated neuropathy is heterogeneous.
Occasionally, organ-system disease may develop from direct involvement by the neoplastic B cells. Some patients may have involvement of the gastrointestinal tract with B-cell lymphoma.69,70,71 and 72 Furthermore, a few patients can have endobronchial lesions with direct infiltration of the pulmonary parenchyma by lymphocytes, plasma cells, and amyloid as the primary clinical manifestation of their disease.73,74 Hilar and mediastinal lymphadenopathy is not uncommon in such settings.
A few patients with Waldenström macroglobulinemia may develop features of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes),75 a syndrome that more commonly is noted for patients with plasma cell myeloma (see Chap. 106).
THE HYPERVISCOSITY SYNDROME
Waldenström macroglobulinemia patients may develop a hyperviscosity syndrome. Although usually associated with severe macroglobulinemia, this syndrome also may be noted occasionally in patients with IgG or IgA myeloma (see Chap. 106).
Symptoms generally do not develop unless the serum viscosity is more than four times that of water.36 However, plasma viscosity is not a perfect indicator of blood viscosity in macroglobulinemia, since red cell concentration also is an important determinant of blood viscosity.76 Possibly secondary to an expanded plasma volume and increased intracranial pressure, headache is a common early symptom. Patients also may complain of visual blurring. Occasionally, these patients may have mental status changes, ranging from impaired mentation to frank dementia. Ataxia, nystagmus, vertigo, confusion, disturbances of consciousness progressing to coma, and a diffuse brain syndrome, sometimes designated coma paraproteinaemicum, also may develop in patients with marked hyperviscosity. Patients with hyperviscosity-induced stroke77 and dementia78 who improve following plasmapheresis have been described. Secondary to anemia, an increased blood viscosity, and an expanded plasma volume, these patients also may develop symptoms and signs of congestive heart failure.
Funduscopic evaluation may reveal dilatation and segmentation of retinal and conjunctival vessels.79 This may give the retinal veins a “link-sausage” appearance. In addition, these patients often are noted to have retinal hemorrhages and sometimes frank papilledema. Less commonly, patients may develop central retinal vein occlusion.80
LABORATORY FINDINGS
SERUM IMMUNOGLOBULIN AND BLOOD VISCOSITY
By definition, the serum IgM level is elevated in macroglobulinemia. The blood levels of the other immunoglobulin classes usually are normal or depressed. On serum protein electrophoresis, the serum IgM usually produces a tall, narrow peak or a dense band that migrates to the g region of the serum electrophoresis pattern (see Chap. 104). Patients with macroglobulinemia who develop symptoms generally have serum IgM concentrations greater than 30 g/liter.
The IgM is usually a pentamer with a molecular weight of approximately 900,000 (see Chap. 83). Some patients also have a monomeric serum IgM protein of 165,000 molecular weight that diffuses more rapidly in a gel. This may create a double ring when the IgM is measured by immunodiffusion (see Chap. 104), causing some laboratories to overestimate of the amount of serum IgM.
The immunoglobulins expressed in Waldenström macroglobulinemia apparently constitute a skewed repertoire. The light chain of the monoclonal IgM is k in 75 percent of patients.4 In addition, these immunoglobulins often bear cross-reactive idiotypes that frequently are found on immunoglobulins expressed in chronic lymphocytic leukemia and by mantle zone B cells (see Chap. 98).81
The serum viscosity is elevated in most patients, but only 20 percent have symptoms related to hyperviscosity. Patients with a serum viscosity greater than four times that of water may develop the hyperviscosity syndrome. However, higher plasma viscosity can be offset by the anemia that commonly is associated with this disease. For this reason, blood rheology performed on whole blood at +32°C (+89.6°F) to +37°C (+98.6°F) at low shear rates may be the best indicator of the actual blood viscosity.76
BLOOD AND MARROW CELLS
Nearly four-fifths of the patients with Waldenström macroglobulinemia present with a hemoglobin concentration less than 120 g/liter.4 Leukopenia also may be present at diagnosis. The platelet count may be depressed47 but is usually in the normal range.
The anemia usually results from a mild decrease in red cell survival time and impaired erythropoiesis. The erythrocytes usually are normocytic and normochromic. However, the electronically measured mean corpuscular volume may be elevated spuriously due to erythrocyte aggregation. Also, the severity of the anemia often is exaggerated artificially due to an expanded plasma volume. This results from the increased oncotic pressure of plasma that contains an elevated concentration of IgM protein.82
The blood may contain a population of monoclonal B lymphocytes, even in asymptomatic patients.83,84 and 85 By flow cytometric analysis, these cells express pan–B-lymphocyte surface antigens CD19, CD20, and CD24 (see Chap. 13) and are monoclonal, as defined by immunoglobulin light-chain expression, idiotype expression, or Southern blot analysis of the rearranged immunoglobulin genes. Unlike normal circulating B cells, the monoclonal B cells often express CD5, CD10 (CALLA), CD11b, and CD9 and are heterogeneous in their expression of CD45 isoforms that are found on B cells at various stages of differentiation.85,86 The latter observation has been interpreted to indicate ongoing differentiation within the monoclonal B-cell population. The size of the circulating monoclonal B-lymphocyte population correlates with the clinical course of the disease, increasing in those who fail to respond or who progress.
The marrow aspirate often is hypocellular. However, marrow biopsy specimens generally are hypercellular and diffusely infiltrated with lymphocytes, plasmacytoid lymphocytes, and some plasma cells.87 Similar to the marrow in chronic lymphocytic leukemia (see Chap. 98), different patterns of marrow infiltration can be delineated. In a retrospective survey of patient marrow specimens, the patterns of lymphocyte infiltration were diffuse (seen in 45%), nodular-interstitial (22%), mixed paratrabecular-nodular (20%), and paratrabecular (13%).88 Mast cells also are often increased in number. The lymphocytes tend to be small, basophilic, and well-differentiated cells, often resembling plasma cells. Periodic acid–Schiff-positive material (Dutcher bodies) may be seen occasionally in lymphoid cells, in the interstitium, and in blood vessel walls. The lymphocytes, plasmacytoid lymphocytes, and plasma cells are monoclonal by an analysis of surface membrane and cytoplasmic immunoglobulins, using antisera that react specifically with the idiotype of the patient’s IgM.89 The monoclonal cells, however, are of different levels of maturity, consisting of small lymphocytes carrying surface IgM/IgD, or IgM plasmacytoid cells and mature plasma cells with only cytoplasmic IgM.
DISORDERS OF HEMOSTASIS
The clotting abnormality detected most frequently is prolongation of the thrombin time.43 Less frequently, a patient’s plasma may have an elevated prothrombin time or activated partial thromboplastin time secondary to depletion of a coagulation factor or factors or presence of lupus anticoagulant.59,62
Platelet function often is impaired, resulting in a prolonged bleeding time, impaired clot retraction, defective prothrombin consumption, poor thromboplastin generation with the patient’s platelets, defective platelet aggregation in vivo, and defective platelet adhesion in vitro.35,61,90
RENAL ABNORMALITIES
Renal insufficiency is less frequent in patients with Waldenström macroglobulinemia than in patients with plasma cell myeloma,91 although the blood urea nitrogen is elevated above 8 mmol/liter (25 mg/dl) in about one-third of patients.92,93 The urine of nearly 80 percent of patients has detectable immunoglobulin light chains that apparently are produced by the population of monoclonal B cells.4,94 However, since the amount of light chain excreted rarely exceeds 2.0 g/24 h,93 its detection generally requires that the urine sample be concentrated prior to zonal electrophoresis or immunoelectrophoresis.
Glomerular lesions are more frequent in patients with Waldenström macroglobulinemia than in those with myeloma. IgM may precipitate on the endothelial side of the glomerular basement membrane, forming deposits that are so large that they occlude the glomerular capillaries. In the renal parenchyma of a minority of patients there may exist amyloid deposits and interstitial infiltrates of lymphocytes and plasma cells similar to those found in the marrow.93
Some patients may develop an immunologically mediated glomerulonephritis associated with the nephrotic syndrome. One patient was noted to have monoclonal granular deposits of IgM, IgG, and the third component of complement along the glomerular basement membrane that was associated with a low serum complement level.95 Another was found to have a monoclonal IgM that reacted with glomerular antigens, resulting in the deposition of IgM in glomerular and interstitial capillaries.96
DIFFERENTIAL DIAGNOSIS
It is important to distinguish patients with essential monoclonal macroglobulinemia from those with Waldenström macroglobulinemia or IgM myeloma.97 The clinical and laboratory findings presented in Table 108-1 are helpful in making this distinction. In addition to being symptomatic, patients with IgM-producing lymphoplasmacytic neoplasms usually have anemia, a monoclonal IgM protein level greater than 30 g/liter, increased serum viscosity, and symptoms and signs that progress over time. For this reason, patients deemed to have essential monoclonal macroglobulinemia should receive follow-up evaluation for evidence of disease progression.

TABLE 108-1 DISTINCTIONS BETWEEN ESSENTIAL VERSUS WALDENSTRÖM MACROGLOBULINEMIA

Monoclonal macroglobulinemia can develop in patients with a variety of lymphoid neoplasms. Patients with chronic lymphocytic leukemia generally have a monoclonal B-cell lymphocytosis of more than 5000/µl (5 × 109/liter). In contrast to the abnormal blood B cells of patients with Waldenström macroglobulinemia, the leukemic B cells of patients with CLL do not express CD10 (CALLA) and do not have lymphoplasmacytic features by morphology (see Chap. 98). Patients with lymphoma may be diagnosed by biopsy of a lymph node or other tissue (see Chap. 103). Lytic skeletal lesions and hypercalcemia indicate that the monoclonal macroglobulinemia is secondary to IgM myeloma (see Chap. 106).
THERAPY, COURSE, AND PROGNOSIS
THERAPY
Waldenström macroglobulinemia is an incurable disease. Therefore, therapy is directed toward prevention and/or palliation of the associated clinical sequelae of macroglobulinemia.
Asymptomatic patients may be followed without specific therapy. These patients should be evaluated periodically, however, for reduction in hemoglobin, rise in serum IgM, deterioration in renal function, or other clinical manifestations of the disease, such as hyperviscosity, lymphadenopathy, hepatosplenomegaly, bleeding tendencies, or neurologic changes. Symptomatic patients should receive chemotherapy.97
ALKYLATOR THERAPY
Chlorambucil is an effective agent. Patients may receive an initial daily dose of 2 to 8 mg orally. Alternatively, patients may receive oral high-dose intermittent chlorambucil of 0.7 mg/kg on day 1, or 0.2 to 0.3 mg/kg on days 1 through 4. This often is administered with 40 to 60 mg prednisone on days 1 through 4. This cycle may be repeated every 21 to 28 days. Hematologic monitoring is essential. The initial dose often needs to be altered, depending on the platelet and leukocyte count and the therapeutic response. Unfortunately, no randomized trials comparing the effectiveness of treatment for symptomatic macroglobulinemia have been reported.
The M-2 protocol (carmustine, cyclophosphamide, vincristine, melphalan, and prednisone) also may be effective for patients with this disease. In one institution, 33 patients with symptomatic Waldenström macroglobulinemia received therapy every 5 weeks for 2 years and every 10 weeks for an additional 1 to 3 years.98 Responses were observed in 27 patients (81%), of whom 21 (63%) had partial responses. Survival ranged from 1 to 120+ months, with 58 percent of patients projected to be alive at 10 years.
In another institution, 34 patients with Waldenström macroglobulinemia received 7 days of oral melphalan (6 mg/m2), cyclophosphamide (125 mg/m2), and prednisone (40 mg/m2).99 Courses were repeated every 4 to 6 weeks for a total of 12 courses. Responding patients subsequently received continuous treatment with chlorambucil and prednisone until relapse. Following the induction, 23 of 31 evaluated patients (74%) responded to induction therapy, and 8 (26% of the 31 evaluated patients) achieved a complete remission.
NUCLEOSIDE ANALOGUES
2-Chlorodeoxyadenosine (Cladribine)
The adenine nucleoside analogue 2-chlorodeoxyadenosine (cladribine) is an effective agent in the treatment of patients with newly diagnosed or refractory Waldenström macroglobulinemia. This drug usually is administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. This is often repeated 1 month later. In some cases, repeated treatments are given at monthly intervals to patients who fail to respond adequately to the first two courses.
Using this regimen, over 40 percent of the patients who are refractory to an alkylating agent therapy can experience reduction in IgM macroglobulinemia and resolution of symptoms.100 In one study, 46 alkylator-refractory patients received two courses of cladribine. Twenty of the patients (43%) had an objective response, with a median progression-free survival of 12 months. A higher response frequency was noted in patients with disease relapsing off therapy (78%) or with primary resistant disease within the first year (57%) than in those with later phases of disease (22%). The median survival after treatment was 28 months and the median progression-free survival of responding patients was 12 months.101
Patients who had not received any prior chemotherapy had even higher response rates. Twenty-six previously untreated but symptomatic patients with Waldenström macroglobulinemia each received two courses of cladribine, and responding patients were followed up without further therapy until relapse. Twenty-two of 26 patients responded (85%; 95% confidence interval, 65–96%), including 3 patients who achieved a complete response and 19 patients who had a partial response. A similar high response rate was noted in a study of 10 previously nontreated patients with Waldenström macroglobulinemia.102 The response rates are higher than that achieved using chlorambucil and prednisone or other nucleoside analogues. Nevertheless, patients who are refractory to fludarabine generally do not respond to cladribine and vice versa.103
Alternative methods for administering cladribine to patients with Waldenström macroglobulinemia have been examined. In one study 20 patients, including 7 who were not treated previously, each were given 2 h of intravenous infusion of cladribine at 0.12 mg/kg each day for 5 consecutive days. Three cycles were given to all patients at monthly intervals. Responding patients received an additional fourth cycle.104 One patient achieved a complete response (5%) and 10 achieved a partial response (50%). Overall, 4 of 7 (57%) untreated and 7 of 13 (54%) previously treated patients responded. The median duration of response follow-up was 28 months (range, 1–37 months). In another study, cladribine was given as subcutaneous bolus injections. In this phase II multi-institutional study, 25 patients received cycles of 0.5 mg/kg of cladribine administered in 5 equal daily subcutaneous bolus injections.105 All but one patient had been treated previously with more than one regimen (median 2, range 0–10). Ten patients (40%) achieved a partial remission. Maximum responses were reached no later than the third cycle. Median time to treatment failure and remission duration were 4.4 (range, 0.5–33) and 8 months (range, 5–29), respectively. These response rates are similar to those of patients who received the drug via continuous intravenous infusion through an indwelling central catheter. However, another study suggests that such alternative modes of drug delivery may be associated with higher rates of significant myelosuppression and less efficacy in the treatment of Waldenström macroglobulinemia than in continuous intravenous infusion.106
Cladribine has been used in combination with cyclophosphamide and prednisone in the treatment of macroglobulinemia. In one study of indolent lymphoproliferative disease in 19 patients that included 3 with macroglobulinemia, the subjects received cladribine at a dose of 0.1 mg/kg per day as a subcutaneous bolus injection on days 1 through 3.107 In addition, they were given intravenous cyclophosphamide at a dose of 500 mg/m2 on day 1 and oral prednisone 40 mg/m2 on days 1 through 5. This course was repeated every 4 weeks up to a maximum of six courses. The overall response rate was 88 percent, with only four (21%) achieving a complete clinical remission. Two patients developed grade 4 neutropenia, and one had grade 3 infection. During the follow-up, five patients had greater than grade 3 hematologic toxicity, and another five had grade 3 nonhematologic toxicity.
The major toxicity of cladribine is acute myelosuppression and chronic immune suppression secondary to depletion of CD4+ T cells. This results in a higher risk of both common and opportunistic infections in patients after treatment with this drug.108 One case report described a patient who, following treatment with cladribine, developed Epstein-Barr-virus–associated lymphoproliferative disease and lymphoma similar to that seen in posttransplant patients receiving systemic immunosuppressive therapy.109
Fludarabine The adenine nucleoside analogue fludarabine also is effective in the treatment of Waldenström macroglobulinemia. This drug generally is given as a daily intravenous dose of 25 mg/m2 for 5 days every 4 weeks. Many patients receive up to six courses of treatment, although fewer courses also may be effective.
Fludarabine is effective in treating patients who are refractory to alkylating agent therapy. Twenty-six patients with Waldenström macroglobulinemia who were resistant to therapy with chlorambucil received fludarabine.110 Of these, 31 percent responded, achieving a nonmaintained remission that lasted for a median of 38 months. In another institution, fludarabine was given to 11 patients, 10 of whom had failed prior standard chemotherapy.111 Five patients (45%) responded with more than a 50 percent reduction of IgM tumor mass for a projected median duration of longer than 1 year. This response rate is similar to that noted in another study of 12 alkylator-refractory patients (5 of 12 responders, or 41%).112 Finally, in a more recent study of 71 patients who were resistant to alkylator therapy, 21 (30%) achieved a partial response and 50 (70%) were considered treatment failures after a median of six courses of fludarabine.113 The overall median survival time of all treated patients was 23 months, and the time to treatment failure was 32 months. The only factor that favorably influenced the response to fludarabine was a longer interval between the first treatment and the start of fludarabine. Pretreatment factors associated with shorter survival in the entire population were hemoglobin level less than 95 g/liter (P = .02) and platelet count less than 75 × 109/liter (P = .02). These studies indicate that fludarabine is an effective agent for patients with Waldenström macroglobulinemia, with response rates in alkylator-resistant patients that are similar to those of cladribine.112,114
Higher response rates to fludarabine are noted in previously nontreated patients.110 In a phase II multicenter trial, newly diagnosed and nontreated patients were given single-agent intravenous fludarabine until they achieved a maximum response, plus two further cycles as consolidation.115 Myelosuppression was relatively common, and the treatment-related mortality rate was 5 percent, mostly associated with pancytopenia and infection. This regimen yielded an overall response rate of 63 percent in patients with macroglobulinemia (and a 15% complete response rate), with a median duration of response of approximately 2.5 years.115
After treatment with fludarabine, patients may be at increased risk for developing opportunistic infections.116 One case report described a patient who, following treatment with fludarabine, developed watery diarrhea, nausea, and vomiting secondary to uncontrolled infection with astrovirus that was successfully treated with intravenous immunoglobulin infusions.117
MARROW TRANSPLANTATION
Marrow transplantation has been tried in only a few patients, with anecdotal success. Two patients with aggressive Waldenström macroglobulinemia who progressed in spite of multiagent chemotherapy and autologous stem cell transplantation underwent allogeneic stem cell transplantation using stem cells from HLA-matched donors.118 The patients were reported to be alive with event-free survivals of 3 and 9 years, respectively.
PLASMAPHERESIS
Patients with symptomatic hyperviscosity should be treated with plasmapheresis. In some cases, plasmapheresis can be used to alleviate the autoimmune pathology resulting from a self-reactive monoclonal IgM protein.119 Conventional plasma exchange is superior to cascade filtration, in which proteins are removed as a function of their size.120 Daily plasma exchanges of 3000 to 4000 ml with albumin, rather than plasma, are particularly effective in reducing the serum IgM level and serum viscosity.36,121 This often is initiated concomitantly with chemotherapy to reduce the production of the abnormal monoclonal IgM protein.
RED CELL TRANSFUSIONS
Patients with Waldenström macroglobulinemia may require periodic transfusions of packed red cells because of symptomatic anemia. However, it should be recognized that these patients often have artificially low hemoglobin and hematocrit levels due to an expanded plasma volume. Consequently, these patients should not receive red cell transfusions simply on the basis of low hemoglobin. Moreover, because of the increased serum viscosity of macroglobulinemia, these patients actually may have reduced capillary blood flow following transfusions of packed red cells due to increased blood viscosity. For this reason, patients with symptomatic hyperviscosity should not be transfused unless therapy is implemented to reduce the serum IgM level. In addition, patients should be monitored for signs of fluid overload or congestive heart failure prior to and during red cell transfusion. Packed red cells should be administered slowly, at a rate not to exceed 1 unit per 2-h period.
COURSE AND PROGNOSIS
Waldenström macroglobulinemia is an indolent disease that generally progresses over a period of years. The median survival from diagnosis is approximately 5 years.4 However, the clinical course is variable. Features that are associated with poorer prognosis are hemoglobin levels below 9 g/dl, age of greater than 70 years, weight loss, and cryoglobulinemia.122 Patients with the worse prognosis have at diagnosis two or more of these features or any one associated with low platelet count, splenomegaly, lymphadenopathy, and/or high levels of serum macroglobulin.88 Elevated serum beta-2-microglobulin also may be associated with a poorer prognosis. However, marrow histology or plasma cell expression of proliferating cell nuclear antigen does not have an apparent relationship to survival.88
Hyperviscosity, anemia, hemorrhage, thrombosis, or infections often are contributory causes of death. Neoplastic lymphocytes may infiltrate the liver, spleen, marrow, lymph nodes, lung, skin, and/or gastrointestinal mucosa. In some patients, the concentration of IgM paraprotein may fall as the tumor burden increases. Further dedifferentiation of the neoplastic cells and loss of their ability to produce IgM protein may explain this effect. This suggests that the neoplastic cells may dedifferentiate and lose their ability to produce IgM protein. This often is associated with an accelerated deterioration in the clinical course. In some cases, the disease evolves into a high-grade lymphoma with characteristics similar to those of Richter transformation in chronic lymphocytic leukemia.123,124 In such cases, the patient may develop hypercalcemia or infiltrative skin lesions as an early manifestation of the transformation to high-grade lymphoma.64,124 Some patients develop acute myelogenous leukemia,125,126 and 127 or chronic myelogenous leukemia131 as a preterminal event. Most of these cases have occurred after treatment with alkylating agents.
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