Chapter 109: Macroglobulinemia

Waldenström macroglobulinemia (WM) is a lymphoid neoplasm resulting from the accumulation, predominantly in the marrow, of a clonal population of lymphocytes, lymphoplasmacytic cells, and plasma cells, which secrete a monoclonal immunoglobulin (Ig) M.¹ WM corresponds to lymphoplasmacytic lymphoma (LPL) as defined in the Revised European-American Lymphoma (REAL) and World Health Organization (WHO) classification systems.^2,3 Most cases of LPL are WM; less than 5 percent of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL.

In 1944, Jan Waldenström, a Swedish physician-scientist, reported in Acta Medica Scandinavica three cases of a disease, he presciently thought was related to myeloma but for the absence of bone involvement and the scarcity of plasma cells in the infiltrate of small lymphocytes. He noted the increase in plasma protein concentration, marked increased serum viscosity, exaggerated bleeding and retinal hemorrhages, and virtually every other feature of the disorder in his case descriptions. In collaboration with a colleague, he showed, using ultracentrifugation and electrophoresis, that the abundant abnormal protein had a molecular weight of approximately 1 million and was not an aggregate of smaller proteins. The disease, which he described with such thoroughness, was later named in his honor.

The age-adjusted incidence rate of WM is 3.4 per 1 million among males and 1.7 per 1 million among females in the United States. It increases in incidence geometrically with age.^4,5 The incidence rate is higher among Americans of European descent. Americans of African descent represent approximately 5 percent of all patients.

Genetic factors play a role in the pathogenesis of WM. Approximately 20 percent of WM patients are of Ashkenazi-Jewish ethnic background.⁶ Familial disease has been reported commonly, including multigenerational clustering of WM and other B-cell lymphoproliferative diseases.^7,8,9,10 Approximately 20 percent of 257 sequential patients with WM presenting to a tertiary referral center had a first-degree relative with either WM or another B-cell disorder.⁹ Familial clustering of WM with other immunologic disorders, including hypogammaglobulinemia and hypergammaglobulinemia (particularly polyclonal IgM), autoantibody production (particularly to the thyroid), and manifestation of hyperactive B cells has also been reported in relatives without WM.^9,10 Increased expression of the BCL-2 gene with enhanced survival has been observed in B cells from familial patients and their family members.¹⁰

The role of environmental factors is uncertain, but chronic antigenic stimulation from infections and certain drug or chemical exposures have been considered but have not reached a level of scientific certainty. Hepatitis C virus (HCV) infection was implicated in WM causality in some series, but in a study of 100 consecutive WM patients in whom serologic and molecular diagnostic studies for HCV infection were performed, no association was found.^11,12,13

NATURE OF THE WALDENSTRÖM MACROGLOBULINEMIA CLONE

Examination of the B-cell clone(s) found in the marrow of WM patients reveals a range of differentiation from small lymphocytes with large focal deposits of surface immunoglobulins, to lymphoplasmacytic cells, to mature plasma cells that contain intracytoplasmic IgM (Fig. 109–1).¹⁴ Circulating clonal B cells are often detectable in patients with WM, although lymphocytosis is uncommon.^15,16 WM cells express the monoclonal IgM, and some clonal cells also express surface IgD.¹⁷ The characteristic immunophenotypic profile of WM lymphoplasmacytic cells includes the expression of the pan–B-cell markers CD19, CD20 (including FMC7), CD22, and CD79.^17,18 Expression of CD5, CD10, and CD23 can be present in 10 to 20 percent of cases, and their presence does not exclude the diagnosis of WM.¹⁹ Multiparameter flow cytometric analysis has also identified CD25 and CD27 as being characteristic of the WM clone, and found that a CD22^dim/CD25⁺/CD27⁺/IgM⁺ population may be present among clonal B lymphocytes in patients with essential monoclonal gammopathy (synonym: monoclonal gammopathy of unknown significance [MGUS]) of the IgM type who ultimately progressed to WM.²⁰

Somatic mutations in immunoglobulin genes are present with an increased frequency of nonsynonymous as compared to silent mutations in complement determining regions, along with somatic hypermutation, thereby supporting a postgerminal center derivation for the WM B-cell clone in most patients.^21,22 A strong preferential usage of VH3/JH4 gene families without intraclonal variation, and without evidence for any isotype-switched transcripts is present.^23,24 These data support an IgM⁺ and/or IgM⁺IgD⁺ memory B-cell origin for most cases of WM.

In contrast to myeloma plasma cells, no recurrent translocations have been described in WM, which can help to distinguish WM from IgM myeloma cases, as IgM myeloma cases often exhibit t11;14 translocations.^25,26 Despite the absence of IgH translocations, recurrent chromosomal abnormalities are present in WM cells. These include deletions in chromosome 6q21–23 in 40 to 60 percent of WM patients, with concordant gains in 6p in 41 percent of 6q-deleted patients.^27,28,29,30 In a series of 174 untreated WM patients, 6q deletions, followed by trisomy 18, 13q deletions, 17p deletions, trisomy 4, and 11q deletions, were observed.³⁰ Deletion of 6q and trisomy 4 were associated with adverse prognostic markers in this series. As 6q deletions represent the most recurrent cytogenetic finding in WM cases, there has been interest in identifying the region of minimal deletion and possible target genes within this region. Two putative gene candidates within this region are TNFAIP3, a negative regulator of nuclear factor kappa B signaling (NFκB), and PRDM1, a master regulator of B-cell differentiation.^29,31 The removal of a NFκB-negative regulator is of particular interest as the phosphorylation and translocation of NFκB into the nucleus is a crucial event for WM cell survival.³² The success of proteasome inhibitor therapy in WM may occur because the degradation of negative regulators of NFκB, such as the inhibitor of kappa B (IκB), is blocked^33,34.

MUTATION IN MYD88

A highly recurrent somatic mutation (MYD88^L265P) was first identified in WM patients by whole-genome sequencing (WGS), and confirmed by multiple studies through Sanger sequencing and/or allele-specific polymerase chain reaction (PCR) assays.^{35,36,37,38,39,40} MYD88^L265P is expressed in 90 to 95 percent of WM cases when more sensitive allele-specific PCR has been employed, using both CD19-sorted and unsorted marrow cells.^{36,37,38,39,40} By comparison, MYD88^L265P was absent in myeloma samples, including IgM myeloma, and was expressed in a small subset (6 to 10 percent) of marginal zone lymphoma patients, who surprisingly have WM-related features.^36,37,38,41 By PCR assays, 50 to 80 percent of IgM MGUS patients, also express MYD88^L265P, and expression of this mutation was associated with increased risk for malignant progression.^36,37,38,42 The presence of MYD88^L265P in IgM MGUS patient suggests a role for this mutation as an early oncogenic driver, and other mutations and/or copy number alterations leading to abnormal gene expression are likely to promote disease progression.²⁹

The impact of MYD88^L265P to growth and survival signaling in WM cells has been addressed in several studies (Fig. 109–2). Knockdown of MYD88 decreased survival of MYD88^L265P-expressing WM cells, whereas survival was enhanced by knock-in of MYD88^L265P versus wild-type MYD88.⁴³ The discovery of a mutation in MYD88 is significant given its role as an adaptor molecule in toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling.⁴⁴ All TLRs except for TLR3 use MYD88 to facilitate their signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer which then complexes with IRAK4 and activates IRAK1 and IRAK2.^45,46,47 Tumor necrosis factor receptor–associated factor 6 is then activated by IRAK1 leading to NFκB activation via IκBα phosphorylation.⁴⁸ Use of inhibitors of MYD88 pathway led to decreased IRAK1 and IκBα phosphorylation, as well as survival of MYD88^L265P expressing WM cells. These observations are of particular relevance to WM since NFκB signaling is important for WM growth and survival.⁴⁹ Bruton tyrosine kinase (BTK) is also activated by MYD88^L265P.⁴³ Activated BTK coimmunoprecipitates with MYD88 that could be abrogated by use of a BTK kinase inhibitor, and overexpression of MYD88^L265P, but not wild-type(WT) MYD88, triggers BTK activation. Knockdown of MYD88 by lentiviral transfection or use of a MYD88 homodimerization inhibitor also abrogated BTK activation in MYD88^L265P-mutated WM cells.

CXCR4^WHIM Mutations

The second most common somatic mutation after MYD88^L265P revealed by WGS was found in the C-terminus of the CXCR4 receptor. These mutations are present in 30 to 35 percent of WM patients, and impact serine phosphorylation sites that regulate CXCR4 signaling by its only known ligand, stromal cell-derived factor (SDF)-1a (CXCL12).^29,50,51,52 The location of somatic mutations found in the C-terminus of CXCR4 in WM are similar to those observed in the germline of patients with WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome, a congenital immunodeficiency disorder characterized by chronic noncyclic neutropenia.⁵³ Patients with WHIM syndrome exhibit impaired CXCR4 receptor internalization following SDF-1a stimulation, which results in persistent CXCR4 activation and myelokathexis.⁵⁴

In WM patients, two classes of CXCR4 mutations occur in the C-terminus. These include nonsense (CXCR4^WHIM/NS) mutations, which truncate the distal 15- to 20-amino-acid region, and frameshift (CXCR4^WHIM/FS) mutations, which compromise a region of up to 40 amino acids in the C-terminal domain.^29,50 Nonsense and frameshift mutations are almost equally divided among WM patients with CXCR4 somatic mutations, and more than 30 different types of CXCR4^WHIM mutations have been identified in WM patients.^29,50 Preclinical studies with WM cells engineered to express nonsense and frameshift CXCR4^WHIM-mutated receptors have shown enhanced and sustained AKT and extracellular signal-regulated kinase (ERK) signaling following SDF-1a relative to CXCR4^WT (see Fig. 109–2), as well increased cell migration, adhesion, growth and survival, and drug resistance of WM cells.^51,55,56

Other Somatic Events

Many copy number alterations have been revealed in WM patients that impact growth and survival pathways. Frequent loss of HIVEP2 (80 percent) and TNFAIP3 (50 percent) genes that are negative regulators of NFkB expression (Fig. 109–2), as well as LYN (70 percent) and IBTK (40 percent) that modulate B-cell receptor (BCR) signaling have been revealed by WGS.²⁹ WGS has also revealed common defects in chromatin remodeling with somatic mutations in ARID1A present in 17 percent, and loss of ARID1B in 70 percent of WM patients. Both ARID1A and ARID1B are members of the SWI/SNF family of proteins, and are thought to exert their effects via p53 and CDKN1A regulation. TP53 is mutated in 7 percent of sequenced WM genomes, while PRDM2 and TOP1 that participate in TP53-related signaling are deleted in 80 percent and 60 percent of WM patients, respectively.²⁹ Taken together, somatic events that contribute to impaired DNA damage response are also common in WM.

Impact of Waldenström Macroglobulinemia Genomics on Clinical Presentation

MYD88 and CXCR4 mutations are important determinants of the clinical presentation of WM patients. Significantly higher marrow disease involvement, serum IgM levels, and symptomatic disease requiring therapy, including hyperviscosity syndrome was observed in those patients with MYD88^L265PCXCR4^WHIM/NS mutations.⁵⁰ Patients with MYD88^L265PCXCR4^WHIM/FS or MYD88^L265PCXCR4^WT had intermediate marrow and serum IgM levels; those with MYD88^WTCXCR4^WT showed the lowest marrow disease burden. Fewer patients with MYD88^L265P and CXCR4^WHIM/FS or CXCR4^WHIM/NS, compared to MYD88^L265PCXCR4^WT presented with adenopathy, further delineating differences in disease tropism based on CXCR4 status. Despite the more-aggressive presentation associated with CXCR4^WHIM/NS genotype, risk of death was not impacted by CXCR4 mutation status. Risk of death was found to be 10-fold higher in patients with MYD88^WT versus MYD88^L265P genotype.⁵⁰

MARROW MICROENVIRONMENT

Increased numbers of mast cells are found in the marrow of WM patients, wherein they are usually admixed with tumor cell aggregates (see Fig. 109–1).^14,18,57 The role of mast cells in WM was investigated in one study wherein coculture of primary autologous or mast cell lines with WM cells resulted in dose-dependent WM cell proliferation and/or tumor colony formation, through CD40 ligand (CD40L) signaling.⁵⁷ WM cells release soluble CD27 (sCD27), which may be triggered by cleavage of membrane-bound CD27 by matrix metalloproteinase 8 (MMP8).⁵⁸ sCD27 levels are elevated in the serum of WM patients, and follow disease burden in mice engrafted with WM cells, as well as in WM patients.⁶⁰ sCD27 triggers the upregulation of CD40L and a proliferation-inducing ligand (APRIL) on mast cells derived from WM patients, and mast cell lines through its receptor CD70. Modeling in mice engrafted with a CD70-blocking antibody shows inhibition of tumor cell growth, suggesting that WM cells require a microenvironmental support system for their growth and survival.⁵⁹ High levels of CXCR4 and very late antigen-4 (VLA-4) have also been observed in WM cells.⁶⁰ In blocking experiments studies, CXCR4 supported migration of WM cells, while VLA-4 contributed to adhesion of WM cells to marrow stromal cells.⁶⁰

Table 109–1 presents the clinical and laboratory findings at time of diagnosis of WM in one large institutional study.¹⁶ Unlike most indolent lymphomas, splenomegaly and lymphadenopathy are uncommon (≤15 percent). Purpura is frequently associated with cryoglobulinemia and in rare circumstances with light-chain (AL) amyloidosis (Chap. 108). Hemorrhagic and neuropathic manifestations are multifactorial (see “Immunoglobulin M–Related Neuropathy” below). The morbidity associated with WM is caused by the concurrence of two main components: tissue infiltration by neoplastic cells and, importantly, the physicochemical and immunologic properties of the monoclonal IgM. As shown in Table 109–2, the monoclonal IgM can produce clinical manifestations through several different mechanisms related to its physicochemical properties, nonspecific interactions with other proteins, antibody activity, and tendency to deposit in tissues.^61,62,63

MORBIDITY MEDIATED BY THE EFFECTS OF IMMUNOGLOBULIN M

Hyperviscosity Syndrome

The increased plasma IgM levels leads to blood hyperviscosity and its complications.⁶⁴ The mechanisms behind the marked increase in the resistance to blood flow and the resulting impaired transit through the microcirculatory system are complex.^64,65,66,67 The main determinants are (1) a high concentration of monoclonal IgMs, which may form aggregates and may bind water through their carbohydrate component; and (2) their interaction with blood cells. Monoclonal IgM increases red cell aggregation (rouleaux formation; see Fig. 109–1) and red cell internal viscosity while reducing red cell deformability. The presence of cryoglobulins contributes to increasing blood viscosity, as well as to the tendency to induce erythrocyte aggregation. Serum viscosity is proportional to IgM concentration up to 30 g/L, then increases sharply at higher levels. Increased plasma viscosity may also contribute to inappropriately low erythropoietin production, which is the major reason for anemia in these patients.⁶⁷ Renal synthesis of erythropoietin is inversely correlated with plasma viscosity. Clinical manifestations are related to circulatory disturbances that can be best appreciated by ophthalmoscopy, which shows distended and tortuous retinal veins, hemorrhages, and papilledema (Fig. 109–3).⁶⁸ Symptoms usually occur when the monoclonal IgM concentration exceeds 50 g/L or when serum viscosity is greater than 4.0 centipoises (cp), but there is individual variability, with some patients showing no evidence of hyperviscosity even at 10 cp.⁶⁴ The most common symptoms are oronasal mucosal bleeding, visual disturbances because of retinal bleeding, and dizziness that rarely may lead to stupor or coma. Heart failure can be aggravated, particularly in the elderly, owing to increased blood viscosity, expanded plasma volume, and anemia. Inappropriate red cell transfusion can exacerbate hyperviscosity and may precipitate cardiac failure.

Cryoglobulinemia

The monoclonal IgM can behave as a cryoglobulin in up to 20 percent of patients, and is usually type I and asymptomatic in most cases.^16,64,70 Cryoprecipitation is mainly dependent on the concentration of monoclonal IgM; for this reason plasmapheresis or plasma exchange are commonly effective in this condition. Symptoms result from impaired blood flow in small vessels and include Raynaud phenomenon, acrocyanosis, and necrosis of the regions most exposed to cold, such as the tip of the nose, ears, fingers, and toes (Fig. 109–4), malleolar ulcers, purpura, and cold urticaria. Renal manifestations are infrequent. Mixed cryoglobulins (type II) consisting of IgM–IgG complexes may be associated with hepatitis C infections.⁷⁰

Autoantibody Activity

Monoclonal IgM may exert its pathogenic effects through specific recognition of autologous antigens, the most notable being nerve constituents, immunoglobulin determinants, and red blood cell antigens.

Immunoglobulin M–Related Neuropathy

IgM-related peripheral neuropathy is common in WM patients, with estimated prevalence rates of 5 to 40 percent.^71,72,73 Approximately 8 percent of idiopathic neuropathies are associated with a monoclonal gammopathy, with a preponderance of IgM (60 percent) followed by IgG (30 percent) and IgA (10 percent) (Chap. 106).^74,75 The nerve damage is mediated by diverse pathogenetic mechanisms: (1) IgM antibody activity toward nerve constituents causing demyelinating polyneuropathies; (2) endoneurial granulofibrillar deposits of IgM without antibody activity, associated with axonal polyneuropathy; (3) occasionally by tubular deposits in the endoneurium associated with IgM cryoglobulin; and, rarely, (4) by amyloid deposits or by neoplastic cell infiltration of nerve structures.^73,76 Half of the patients with IgM neuropathy have a distinctive clinical syndrome that is associated with antibodies against a minor 100-kDa glycoprotein component of nerve known as the myelin-associated glycoprotein (MAG). Anti-MAG antibodies are generally monoclonal IgMκ, and usually also exhibit reactivity with other glycoproteins or glycolipids that share antigenic determinants with MAG.^77,78,79 The anti–MAG-related neuropathy is typically distal and symmetrical, affecting both motor and sensory functions; it is slowly progressive with a long period of stability.^72,80 Most patients present with sensory complaints (paresthesias, aching discomfort, dysesthesias, or lancinating pains), imbalance and gait ataxia, owing to lack proprioception; leg muscles atrophy in advanced stage. Patients with predominantly demyelinating sensory neuropathy in association with monoclonal IgM to gangliosides with disialosyl moieties, such as GD1b, GD3, GD2, GT1b, and GQ1b, have also been reported.^81,82 Anti-GD1b and anti-GQ1b antibodies were associated with sensory ataxic neuropathy. These antiganglioside monoclonal IgMs present core clinical features of chronic ataxic neuropathy sometimes with present ophthalmoplegia and/or red blood cell cold agglutinating activity. The disialosyl epitope is also present on red blood cell glycophorins, thereby accounting for the red cell cold agglutinin activity of anti-Pr2 specificity.^83,84 Monoclonal IgM proteins that bind to gangliosides with a terminal trisaccharide moiety, including ganglioside M₂ (GM₂) and GalNac-GD1A, are associated with chronic demyelinating neuropathy and severe sensory ataxia, unresponsive to glucocorticoids.⁸⁵ Antiganglioside IgM proteins may also cross-react with lipopolysaccharides of Campylobacter jejuni, whose infection is known to precipitate the Miller-Fisher syndrome, a variant of the Guillain-Barré syndrome.⁸⁶ Thus, molecular mimicry may play a role in this condition. Antisulfatide monoclonal IgM proteins, associated with sensory-sensorimotor neuropathy, have been detected in 5 percent of patients with IgM monoclonal gammopathy and neuropathy.⁸⁷ Motor neuron disease has been reported in patients with WM and monoclonal IgM with anti-GM₁ and sulfoglucuronyl paragloboside activity.⁸⁸ Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (the POEMS syndrome) are rare in patients with WM.⁸⁹

Cold Agglutinin Hemolytic Anemia

Monoclonal IgM may have cold agglutinin activity, that is, it can recognize specific red cell antigens at temperatures below 37°C, producing chronic hemolytic anemia. This disorder occurs in less than 10 percent of WM patients and is associated with cold agglutinin titers greater than 1:1000 in most cases.⁹⁰ The monoclonal component is usually an IgMκ and reacts most commonly with red cell I/i antigens, resulting in complement fixation and activation.^91,92 Mild to moderate chronic hemolytic anemia can be exacerbated after cold exposure. Hemoglobin usually remains above 70 g/L. The hemolysis is usually extravascular, mediated by removal of C3b opsonized red cells by the mononuclear phagocyte system, primarily in the liver. Intravascular hemolysis from complement destruction of red blood cell membrane is infrequent. The agglutination of red cells in the skin circulation also causes Raynaud syndrome, acrocyanosis, and livedo reticularis. Macroglobulins with the properties of both cryoglobulins and cold agglutinins with anti-Pr specificity can occur. These properties may have as a common basis the binding of the sialic acid-containing carbohydrate present on red blood cell glycophorins and on Ig molecules. Several other macroglobulins with antibody activity toward autologous antigens (e.g., phospholipids, tissue and plasma proteins) and foreign ligands have also been described.

Immunoglobulin M Tissue Deposition

The monoclonal protein can deposit in several tissues as amorphous aggregates. Linear deposition of monoclonal IgM along the skin basement membrane is associated with bullous skin disease.⁹³ Amorphous IgM deposits in the dermis result in IgM storage papules on the extensor surface of the extremities, referred to as macroglobulinemia cutis.⁹⁴ Deposition of monoclonal IgM in the lamina propria and/or submucosa of the intestine may be associated with diarrhea, malabsorption, and gastrointestinal bleeding.^95,96 Kidney involvement is less common and less severe in WM than in myeloma, probably because the amount of light chain excreted in the urine is generally lower in WM than in myeloma and because of the absence of contributing factors, such as hypercalcemia. Urinary cast nephropathy, however, has occurred in WM.⁹⁷ On the other hand, the IgM macromolecule is more susceptible to being trapped in the glomerular loops where ultrafiltration presumably contributes to its precipitation, forming subendothelial deposits of aggregated IgM proteins that occlude the glomerular capillaries.⁹⁸ Mild and reversible proteinuria may result and most patients are asymptomatic. The deposition of monoclonal light chain as fibrillar amyloid deposits (AL amyloidosis) is uncommon in patients with WM.⁹⁹ Clinical expression and prognosis are similar to those of other AL amyloidosis patients with involvement of heart (44 percent), kidneys (32 percent), liver (14 percent), lungs (10 percent), peripheral or autonomic nerves (38 percent), and soft tissues (18 percent). The incidence of cardiac and pulmonary involvement is higher in patients with monoclonal IgM than with other immunoglobulin isotypes. The association of WM with reactive amyloidosis has been documented rarely.^100,101 Simultaneous occurrence of fibrillary glomerulopathy, characterized by glomerular deposits of wide noncongophilic fibrils and amyloid deposits, has been described.¹⁰²

MANIFESTATIONS RELATED TO TISSUE INFILTRATION BY NEOPLASTIC CELLS

Tissue infiltration by neoplastic cells is uncommon but can involve various organs and tissues, including the liver, spleen, lymph nodes, lungs, gastrointestinal tract, kidneys, skin, eyes, and central nervous system.

Lung

Pulmonary involvement in the form of masses, nodules, diffuse infiltrate, or pleural effusions is uncommon; the overall incidence of pulmonary and pleural findings is approximately 4 percent.^103,104,105 Cough is the most common presenting symptom, followed by dyspnea and chest pain. Chest radiographic findings include parenchymal infiltrates, confluent masses, and effusions.

Gastrointestinal Tract

Malabsorption, diarrhea, bleeding, or obstruction may indicate involvement of the gastrointestinal tract at the level of the stomach, duodenum, or small intestine.^{106,107,108,109}

Renal System

In contrast to myeloma, infiltration of the kidney interstitium with lymphoplasmacytoid cell can occur in WM, and renal or perirenal masses are not uncommon.^110,111

Skin

The skin can be the site of dense lymphoplasmacytic infiltrates, similar to that seen in the liver, spleen, and lymph nodes, forming cutaneous plaques and, rarely, nodules.¹¹² Chronic urticaria and IgM gammopathy are the two cardinal features of the Schnitzler syndrome, which is not usually associated initially with clinical features of WM, although evolution to WM is not uncommon.¹¹³ Thus, close followup of these patients is important.

Joints

Invasion of articular and periarticular structures by WM malignant cells is rarely reported.¹¹⁴

Eye

The neoplastic cells can infiltrate the periorbital structures, lacrimal gland, and retroorbital lymphoid tissues, resulting in ocular nerve palsies.^115,116

Central Nervous System

Direct infiltration of the central nervous system by monoclonal lymphoplasmacytic cells as infiltrates or as tumors constitutes the rarely observed Bing-Neel syndrome, characterized clinically by confusion, memory loss, disorientation, and motor dysfunction (reviewed in Ref. 117).

BLOOD ABNORMALITIES

Anemia is the most common finding in patients with symptomatic WM and is caused by a combination of factors: decrease in red cell survival, impaired erythropoiesis, moderate plasma volume expansion, hepcidin production leading to iron reutilization defect, and blood loss from the gastrointestinal tract.^16,118,119 Blood films are usually normocytic and normochromic, and rouleaux formation is often pronounced (see Fig. 109–1). Mean red cell volume may be elevated spuriously owing to erythrocyte aggregation. In addition, the hemoglobin estimate can be inaccurate, that is, falsely high, because of interaction between the monoclonal protein and the diluent used in some automated analyzers.¹²⁰ Leukocyte and platelet counts are usually within the reference range at presentation, although patients may occasionally present with severe thrombocytopenia. Monoclonal B-lymphocytes expressing surface IgM and late-differentiation B-cell markers are uncommonly detected in blood by flow cytometry. A raised erythrocyte sedimentation rate is almost always present and may be the first clue to the presence of the macroglobulinemia. The clotting abnormality detected most frequently is prolongation of thrombin time. AL amyloidosis should be suspected in all patients with nephrotic syndrome, cardiomyopathy, hepatomegaly, or peripheral neuropathy. Diagnosis requires the demonstration of green birefringence under polarized light of amyloid deposits stained with Congo red.

MARROW FINDINGS

Central to the diagnosis of WM is the demonstration, by trephine biopsy, of marrow infiltration by a lymphoplasmacytic cell population characterized by small lymphocytes with evidence of plasmacytoid and plasma cell maturation (see Fig. 109–1).^1,14 The pattern of marrow infiltration may be diffuse, interstitial, or nodular, usually with an intertrabecular pattern of infiltration. A solely paratrabecular pattern of infiltration is unusual and should raise the possibility of follicular lymphoma.¹ The marrow cell immunophenotype should be confirmed by flow cytometry and/or immunohistochemistry. The cell immunoprofile: sIgM⁺CD19⁺CD20⁺CD22⁺CD79⁺ is characteristic of WM.^14,120,121 Up to 20 percent of cases may express either CD5, CD10, or CD23.¹⁹ In these cases, chronic lymphocytic leukemia and mantle cell lymphoma should be excluded. “Intranuclear” periodic acid-Schiff–positive inclusions (Dutcher-Fahey bodies)¹²² consisting of IgM deposits in the perinuclear space, and sometimes in intranuclear vacuoles, may be seen occasionally in lymphoid cells. An increased number of mast cells, usually in association with the lymphoid aggregates is commonly found, and their presence may help in differentiating WM from other B-cell lymphomas (Fig. 109–5).¹⁴ MYD88^L265P testing of marrow samples has been incorporated into many clinical laboratories, and may help in clarifying the diagnosis of WM from other IgM-secreting entities.^{35,36,37,38,39} The use of blood B cells may also permit determination of MYD88^L265P status by allele-specific PCR assays, particularly in untreated WM patients.

IMMUNOLOGIC ABNORMALITIES

High-resolution electrophoresis combined with immunofixation of serum and urine is recommended for identification and characterization of the IgM monoclonal protein. The light chain of the monoclonal IgM is κ in 75 to 80 percent of patients. More than one M component may be present. The concentration of the serum monoclonal protein is very variable but in most cases lies within the range of 15 to 45 g/L. Densitometry should be adopted to determine IgM levels for serial evaluations because nephelometry is unreliable and shows large laboratory variation. The presence of cold agglutinins or cryoglobulins may affect determination of IgM levels and, therefore, testing for cold agglutinins and cryoglobulins should be performed at diagnosis. If present, subsequent serum samples should be analyzed at 37°C for determination of serum monoclonal IgM level. Although Bence Jones proteinuria is frequently present, it exceeds 1 g/24 h in only 3 percent of cases. Whereas IgM levels are elevated in WM patients, IgA and IgG levels are most often depressed and do not recover after successful treatment.¹²³

SERUM VISCOSITY

Because of its large size (almost 1,000,000 daltons), most IgM molecules are retained within the intravascular compartment and can exert an undue effect on serum viscosity.⁶⁴ Serum viscosity can be measured if the patient has signs or symptoms of hyperviscosity syndrome, although serum viscosity levels are erratic because of a lack of standardization in most clinical laboratories.¹⁶ As such, inferences derived from serum IgM levels may be more reliable. Patients typically become symptomatic at serum viscosity levels of 4 cp and above, which relates to serum IgM levels above 6000 mg/dL.^124,125 Patients may be symptomatic at lower serum viscosity and IgM levels, and in these patients cryoglobulins may be present. Recurring nosebleeds, headaches, and visual disturbances are common symptoms in patients with symptomatic hyperviscosity.¹⁶ Funduscopy is an important indicator of clinically relevant hyperviscosity. Among the first clinical signs of hyperviscosity are the appearance of peripheral and midperipheral dot and blot-like hemorrhages in the retina, which are best appreciated with indirect ophthalmoscopy and scleral depression.⁶⁸ In more severe cases of hyperviscosity, dot, blot, and flame-shaped hemorrhages can appear in the macular area along with markedly dilated and tortuous veins with focal constrictions resulting in “venous sausaging,” as well as papilledema. The effects of hyperviscosity are mediated by the blood viscosity as a result of IgM-red cell interactions but measurement of serum viscosity is much simpler than is blood viscosity and is not shear rate dependent so easier to related to clinical manifestations.

IMAGING

Magnetic resonance imaging (MRI) of the spine in conjunction with computed tomography (CT) of the abdomen and pelvis are useful in evaluating the disease status.¹²⁶ Marrow involvement can be documented by MRI studies of the spine in more than 90 percent of patients; CT of the abdomen and pelvis demonstrates enlarged nodes in approximately 40 percent of WM patients.¹²⁶

LYMPH NODE BIOPSY

Lymph node biopsy may show preserved architecture or replacement by infiltration of neoplastic cells with lymphoplasmacytoid, lymphoplasmacytic, or polymorphous cytologic patterns.

POLYMERASE CHAIN REACTION

The residual disease after high-dose chemotherapy with allogeneic or autologous stem-cell rescue can be monitored by PCR-based methods using primers specific for the monoclonal Ig variable regions.

DECIDING ON INITIATING TREATMENT

As part of the Second International Workshop on Waldenström Macroglobulinemia, a consensus panel was organized to recommend criteria for the initiation of therapy in patients with WM.¹²⁷ The panel recommended that initiation of therapy should not be based on the IgM level per se, as this may not correlate with the clinical manifestations of WM. The consensus panel did, however, agree that initiation of therapy is appropriate for patients with constitutional symptoms, such as recurrent fever, night sweats, fatigue as a consequence of anemia, or weight loss. Progressive symptomatic lymphadenopathy and/or splenomegaly provide additional reasons to begin therapy. Anemia with a hemoglobin value of 10 g/dL or less or a platelet count of 100 × 10⁹/L or less owing to marrow infiltration, also justifies treatment. Certain complications, such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, renal insufficiency, or symptomatic cryoglobulinemia, may also be indications for therapy.^16,127

INITIAL THERAPY

The International Workshops on Waldenström Macroglobulinemia have also formulated consensus recommendations for both initial therapy and therapy for refractory disease based on the best available evidence. The most recent recommendations emerged from the Seventh International Workshop on Waldenström Macroglobulinemia.¹²⁸ Individual patient considerations, including the presence of cytopenias, need for more rapid disease control, age, and candidacy for autologous transplant therapy, should be taken into account in making the choice of the drugs to use. For patients who are candidates for autologous stem cell transplantation, which typically is reserved for those patients younger than 70 years of age, the panel recommended that exposure to alkylating agents or nucleoside analogues should be limited. The use of nucleoside analogues should be approached cautiously in patients with WM as there appears to be an increased risk for the development of disease transformation, as well as myelodysplasia and acute myelogenous leukemia.

Oral Alkylating Agents

Oral alkylating drugs, alone and in combination therapy with glucocorticoids, have been extensively evaluated in the treatment of WM. Chlorambucil has been administered on both a continuous (i.e., daily dose schedule) and an intermittent schedule. Patients receiving chlorambucil on a continuous schedule typically receive 0.1 mg/kg per day, whereas on the intermittent schedule patients typically receive 0.3 mg/kg for 7 days, every 6 weeks. In a prospective randomized study, no significant difference in the overall response rate between these schedules was observed,¹²⁹ although the median response duration was greater for patients receiving intermittent-dose versus continuous-dose chlorambucil (46 vs. 26 months). Despite the favorable median response duration in this study for use of the intermittent schedule, no difference in the median overall survival was observed. Moreover, an increased incidence for development of myelodysplasia and acute myelogenous leukemia with the intermittent (three of 22 patients) versus the continuous (zero of 24 patients) chlorambucil schedule prompted the preference for use of continuous chlorambucil dosing. The use of glucocorticoids in combination with alkylating agent therapy has also been explored. Chlorambucil (8 mg/m²) plus prednisone (40 mg/m²) given orally for 10 days, every 6 weeks, resulted in a major response (i.e., reduction of IgM by more than 50 percent) in 72 percent of patients.¹³⁰ Alkylating agent regimens employing melphalan and cyclophosphamide in combination with glucocorticoids also have been examined.^131,132 This approach produced slightly higher overall response rates and response durations, although the benefit of these more complex regimens over chlorambucil remains to be demonstrated. Pretreatment factors associated with shorter survival in the entire population of patients receiving single-agent chlorambucil were age older than age 60 years, male sex, hemoglobin less than 10 g/dL, leukocytes less than 4 × 10⁹/L, and platelets less than 150 × 10⁹/L. Organomegaly, signs of hyperviscosity, renal failure, monoclonal IgM level, blood lymphocytosis, and percentage of marrow lymphoid cells were not significantly correlated with survival.¹³³ Additional factors to be taken into account in considering alkylating agent therapy for patients with WM include necessity for more rapid disease control given the slow response, as well as consideration for preserving stem cells in patients who are candidates for autologous stem cell transplantation therapy. A large randomized study showed an inferior response rate and time to progression in WM patients receiving chlorambucil versus fludarabine, as well as a higher incidence of secondary malignancies in the former. Neutropenia was, however, more pronounced in those patients on fludarabine.¹³⁴

Nucleoside Analogue Therapy

Cladribine administered as a single agent by continuous intravenous infusion, by 2-hour daily infusion, or by subcutaneous bolus injections for 5 to 7 days has resulted in major responses in 40 to 90 percent of patients who received primary therapy, whereas in the previously treated patients, responses have ranged from 38 to 54 percent.^{135,136,137,138,139,140,141} Median time to achievement of response in responding patients following cladribine ranged from 1.2 to 5 months. The overall response rate with daily infusion of fludarabine, administered mainly on 5-day schedules, in previously untreated and treated patients, ranged from 38 to 100 percent and 30 to 40 percent, respectively,^{142,143,144,145,146,147} similar to the responses to cladribine. Median time to achievement of response for fludarabine (3 to 6 months) was also similar to cladribine. In general, response rates and durations of responses have been greater for patients receiving nucleoside analogues as initial therapy, although in several studies in which both untreated and previously treated patients were enrolled, no difference in the overall response rate was reported.

Myelosuppression commonly occurs following prolonged exposure to either of the nucleoside analogues. A sustained decrease in both CD4+ and CD8+ T lymphocytes, measured 1 year following initiation of therapy, is notable.^135,136,137 Treatment-related mortality as a consequence of myelosuppression and/or opportunistic infections attributable to immunosuppression occurred in up to 5 percent of all treated patients in some series with nucleoside analogues.

Factors predicting for a better response to nucleoside analogues include younger age at start of treatment (<70 years), higher pretreatment hemoglobin (>95 g/L), higher platelet count (>75 × 10⁹/L), disease relapsing off therapy, and a long interval between first-line therapy and initiation of a nucleoside analogue in relapsing patients.^135,140,146 There are limited data on the use of an alternate nucleoside analogue in previously treated patients among whom disease relapsed or who had resistance when not on cladribine or fludarabine therapy.^148,149 Three of four (75 percent) patients responded to cladribine after progression following an unmaintained remission to fludarabine, whereas only one of 10 (10 percent) with disease resistant to fludarabine responded to cladribine.¹⁴⁸ A response in two of six patients (33 percent) and disease stabilization in the remaining patients to fludarabine, in spite of an inadequate response or progressive disease, following cladribine therapy has been reported.¹⁴⁹

Harvesting autologous blood stem cells succeeded on the first attempt in 14 of 15 patients who did not receive nucleoside analogue therapy as compared to two of six patients who received a nucleoside analogue.¹⁵⁰ A sevenfold increase in transformation to an aggressive lymphoma and a threefold increase in the development of myelodysplasia or acute myelogenous leukemia were observed among patients who received a nucleoside analogue versus other therapies for their WM.¹⁵¹ A meta-analysis of several trials in which patients were treated with nucleoside analogues in WM patients, included patients who had previously received an alkylating agent, and showed a crude incidence of approximately 8 percent for development of disease transformation and of approximately 5 percent for development of myelodysplasia or acute myelogenous leukemia.¹⁵² None of the risk factors—that is, gender, age, family history of WM, or B-cell malignancies, typical markers of tumor burden and prognosis, type of nucleoside analogue therapy (cladribine vs. fludarabine), time from diagnosis to nucleoside analogue use, nucleoside analogue treatment as primary or salvage therapy, or treatment with an oral alkylator (i.e., chlorambucil)—predicted for the occurrence of transformation or development of myelodysplasia or acute myelogenous leukemia in patients treated with a nucleoside analogue.¹⁵²

CD20-Directed Antibody Therapy

Rituximab is a chimeric monoclonal antibody that targets CD20, a widely expressed antigen on lymphoplasmacytic cells in WM.¹⁵³ Several retrospective and prospective studies indicated that rituximab, when used at standard doses (i.e., 4 weekly intravenous infusions of 375 mg/m²) induced major responses in approximately 30 percent of previously treated and untreated patients.^154,155 Even patients who achieved minor responses benefited from rituximab by improved hemoglobin and platelet counts, and reduction of lymphadenopathy and/or splenomegaly.¹⁵⁴ The median time to treatment failure in these studies was found to range from 8 to 27+ months. Patients on an extended rituximab schedule consisting of four weekly courses at 375 mg/m² per week, repeated 3 months later by another 4-week course have demonstrated major response rates of approximately 45 percent, with time to progression estimates of 16+ to 29+ months.^156,157

In many WM patients, a transient increase or flare of the serum IgM may occur immediately following initiation of rituximab treatment.^156,158,159 Such an increase does not herald treatment failure and most patients will return to their baseline serum IgM level by 12 weeks. Some patients continue to show a prolonged increase in IgM despite an apparent reduction in their marrow tumor cells. However, patients with baseline serum IgM levels of greater than 50 g/dL or serum viscosity of greater than 3.5 cp may be particularly at risk for a hyperviscosity-related event and plasmapheresis should be considered in these patients in advance of rituximab therapy.¹⁵⁸ Because of the decreased likelihood of response in patients with higher IgM levels, as well as the possibility that serum IgM and blood viscosity levels may abruptly rise, rituximab monotherapy should not be used as sole therapy for the treatment of patients at risk for hyperviscosity signs and symptoms.^128,156,157

Time to response after rituximab is slow and exceeds 3 months on the average. The time to best response in one study was 18 months.¹⁵⁷ Patients with baseline serum IgM levels of less than 60 g/dL are more likely to respond, regardless of the underlying marrow involvement by tumor cells.^156,157 An analysis of 52 patients who were treated with single-agent rituximab found the objective response rate was significantly lower in patients who had either low serum albumin (<35 g/L) or a serum monoclonal protein greater than 40 g/L.¹⁶⁰ The presence of both adverse prognostic factors was associated with a short time to progression (3.6 months). Patients who had normal serum albumin and relatively low serum monoclonal protein levels derived a substantial benefit from rituximab with a time to progression exceeding 40 months.

A correlation between polymorphisms at position 158 in the FcγRIIIa receptor (CD16), an activating Fc receptor on important effector cells that mediate antibody-dependent cell-mediated cytotoxicity, and rituximab response was observed in WM patients.¹⁶¹ Individuals may encode either the amino acid valine or phenylalanine at position 158 in the FcγRIIIa receptor. WM patients who carried the valine amino acid (either in a homozygous or heterozygous pattern) had a fourfold higher major response rate (i.e., 50 percent decline in serum IgM levels) to rituximab versus those patients who expressed phenylalanine in a homozygous pattern.

Proteasome Inhibitors

Both bortezomib and carfilzomib have been evaluated in prospective studies in patients with WM, although the latter only in combination therapy (discussed below). In a retrospective study, 10 patients with refractory or relapsed WM were treated with bortezomib administered intravenously at a dose of 1.3 mg/m² on days 1, 4, 8, and 11 in a 21-day cycle for a total of four cycles. Most patients had been exposed to all active agents for WM and eight patients had received three or more regimens. Six of these patients achieved a partial response which occurred at a median of 1 month. The median time to progression in the responding patients is expected to exceed 11 months. Peripheral neuropathy occurred in three patients and one patient developed severe paralytic ileus in this series.¹⁶² In a prospective study among 27 relapsed or refractory patients who received up to eight cycles of bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11, median serum IgM levels declined significantly from 4.7 g/dL to 2.1 g/dL.³³ The overall response rate was 85 percent, with 10 and 13 patients achieving a minor (≥25 percent) and major (≥50 percent) decrease in IgM level. Responses occurred at a median of 1.4 months. The median time to progression for all responding patients in this study was 7.9 (range: 3.0 to 21.4+) months, and the most common grades III/IV toxicities were sensory neuropathies (22.2 percent), leukopenia (18.5 percent), neutropenia (14.8 percent), dizziness (11.1 percent), and thrombocytopenia (7.4 percent). Sensory neuropathies resolved or improved in nearly all patients following cessation of therapy. Twenty-seven patients with both untreated (44 percent) and previously treated (56 percent) disease received bortezomib, using the standard schedule until they either demonstrated progressive disease or two cycles beyond a complete response or stable disease.¹⁶³ The overall response rate was 78 percent, with major responses observed in 44 percent of patients. Sensory neuropathy occurred in 20 patients following two to four cycles of therapy. Among the 20 patients developing a neuropathy, 14 showed resolution or improvement 2 to 13 months after therapy.

Combination Therapies

Because rituximab is not myelosuppressive, its combination with chemotherapy has been explored. A regimen of rituximab, cladribine, and cyclophosphamide used in 17 previously untreated patients resulted in a partial response in 94 percent of WM patients, including a complete response in 18 percent.¹⁶⁴ No patient had relapsed with a median followup of 21 months. The combination of rituximab and fludarabine used in 43 patients of whom 32 (75 percent) were previously untreated, led to an overall response rate of 95.3 percent, with 83 percent of patients achieving a major response (i.e., 50 percent reduction in disease burden).¹⁶⁵ The median time to progression was 51.2 months in this series, and was longer for those patients who were previously untreated and for those achieving a very good partial remission (i.e., 90 percent reduction in disease) or better. Hematologic toxicity was common: grade 3 neutropenia and thrombocytopenia observed in 27 and four patients, respectively. Two deaths occurred in this study from pneumonia. Secondary malignancies including transformation to aggressive lymphoma and development of myelodysplasia or acute myelogenous leukemia were observed in six patients in this series. The addition of rituximab to fludarabine and cyclophosphamide has also been explored in previously treated patients, of whom four of five patients had a response.¹⁶⁶ In another combination study, rituximab along with pentostatin and cyclophosphamide given to 13 patients with untreated and previously treated WM or LPL resulted in a major response in 77 percent of patients.¹⁶⁷ The combination of rituximab, dexamethasone, and cyclophosphamide was used as primary therapy to treat 72 patients with WM in whom a major response was observed in 74 percent of patients in this study, and the 2-year progression-free survival was 67 percent.¹⁶⁸ Therapy was well tolerated, although one patient died of interstitial pneumonia.

Two studies examined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in combination with rituximab (R-CHOP). In a randomized trial involving 69 patients, most of whom had WM, the addition of rituximab to CHOP resulted in a higher overall response rate (94 percent vs. 67 percent) and median time to progression (63 vs. 22 months) in comparison to patients treated with CHOP alone.¹⁶⁹ R-CHOP was also used in 13 WM patients, 10 of whom had relapsed or refractory disease.¹⁷⁰ Among 13 evaluable patients, 10 patients achieved a major response (77 percent), including three complete and seven partial remissions. Two other patients achieved a minor response. In a retrospective study of symptomatic WM patients who received either R-CHOP; rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP); or cyclophosphamide, prednisone, and rituximab (R-CP) and were similar in most pretreatment variables, the overall response rates to therapy were comparable among all three treatment groups—R-CHOP (96 percent), R-CVP (88 percent), and R-CP (95 percent)—although there was a trend for more complete remissions among patients treated with R-CVP and R-CHOP.¹⁷¹ Adverse events attributed to therapy showed a higher incidence for neutropenic fever and treatment related neuropathy for R-CHOP and R-CVP versus R-CP. The results of this study suggest that in WM, the use of R-CP may provide analogous treatment responses to more intense cyclophosphamide-based regimens while minimizing treatment-related complications. The extended alkylator bendamustine has also been evaluated in combination with rituximab in both untreated, as well as previously treated WM patients. A randomized study by the German STiL Group examined bendamustine plus rituximab (BR) versus R-CHOP in patients with untreated, indolent B-cell lymphomas including WM.¹⁷² Patients with WM in this study showed similar overall responses (96 percent vs. 94 percent), although progression-free survival was significantly longer (69 vs. 29 months) in patients who received BR versus R-CHOP. Treatment was also better tolerated in patients receiving BR. In the relapsed or refractory setting, an overall response rate of 83 percent was observed with bendamustine in combination with a CD20 monoclonal antibody.¹⁷³ The median time to progression was 13 months in this study. Prolonged myelosuppression was more common in patients who received prior nucleoside analogues.

The use of two cycles of oral cyclophosphamide along with subcutaneous cladribine to 37 patients with previously untreated WM led to a partial response in 84 percent of patients and the median duration of response was 36 months.¹⁶⁴ Fludarabine in combination with intravenous cyclophosphamide resulted in partial responses in six of 11 (55 percent) WM patients with either primary refractory disease or who had relapsed on treatment.¹⁷⁴ The combination of fludarabine plus cyclophosphamide was also evaluated in 49 patients, 35 of whom were previously treated. Seventy-eight percent of the patients achieved a response, and the median time to treatment failure was 27 months.¹⁷⁵ Hematologic toxicity was frequent, and three patients died of treatment-related toxicities. Two important findings in this study were the development of acute leukemia in two patients, histologic transformation to diffuse large B-cell lymphoma in one patient, and two cases of solid malignancies (prostate and melanoma), as well as failure to mobilize stem cells in 4 of 6 patients.

The combination of bortezomib, dexamethasone, and rituximab (BDR) as primary therapy in patients with WM resulted in an overall response rate of 96 percent, and a major response rate of 83 percent.¹⁷⁶ The incidence of grade 3 neuropathy was approximately 30 percent, but was reversible in most patients following discontinuation of therapy. An increased incidence of herpes zoster was also observed prompting the prophylactic use of antiviral therapy. Alternative schedules for administration of bortezomib (i.e., once weekly at higher doses) in combination with rituximab in patients with WM have achieved overall response rates of 80 to 90 percent.^177,178 The European Myeloma Network (EMN) recently showed that transitioning bortezomib from twice weekly intravenous dosing during the first cycle to weekly administration thereafter reduced grade 3 neuropathy to less than 10 percent in patients treated with BDR.¹⁷⁹ There have been no studies addressing the safety and efficacy of subcutaneous bortezomib use in WM.

Carfilzomib which is associated with a low risk of treatment-related peripheral neuropathy has been evaluated in combination with rituximab and dexamethasone (CaRD) in WM patients.³⁴ Carfilzomib was administered intravenously at 20 mg/m² (cycle one), then 36 mg/m² (cycles two to six), together with dexamethasone (20 mg) on days 1, 2, 8, and 9 as part of a 21-day cycle. As part of this regimen, rituximab 375 mg/m² was given on days 2 and 9 every 21 days. Maintenance therapy was given 8 weeks following induction therapy with intravenous carfilzomib (36 mg/m²) and dexamethasone (20 mg) administered on days 1 and 2 and rituximab 375 mg/m² on day 2 every 8 weeks for up to eight cycles. Overall response rate with this regimen was 87.1 percent (one complete response, 10 very good partial responses, 10 partial responses, and six minimal responses) and was not impacted by MYD88^L265P or CXCR4^WHIM mutation status. With a median followup of 15.4 months, 20 patients remained progression free. Grade 2 or higher toxicities included asymptomatic hyperlipasemia (41.9 percent), reversible neutropenia (12.9 percent), and cardiomyopathy in one patient (3.2 percent) with multiple risk factors. Treatment-related neuropathy, which was grade 2, occurred in one patient (3.2 percent). Declines in serum IgA and IgG were common, and some patients required intravenous gammaglobulin therapy for recurring sinus and bronchial infections.

Novel Therapeutics

The use of Ibrutinib was recently approved by the FDA for the treatment of symptomatic patients with WM. Ibrutinib targets BTK, a target of ibrutinib that is activated by MYD88^L265P.⁴³ In a multicenter study that examined the role of ibrutinib in previously treated (median: two prior therapies, 40 percent refractory) WM patients, the overall response rate was 91 percent.¹⁸⁰ Patients on this study received 420 mg/day of ibrutinib by mouth. Posttherapy, median serum IgM levels declined from 3610 to 915 mg/dL; hemoglobin rose from 10.5 to 13.5 g/dL; and marrow involvement declined from 60 percent to 25 percent. Decreased or resolved adenopathy was observed in 60 percent of patients with extramedullary disease, and five of nine patients with IgM-related peripheral neuropathy had symptomatic improvement. The 24-month estimate for progression-free and overall survival was 70 percent and 95 percent, respectively. Although major response rates were lower in patients with MYD88^WT and CXCR4^WHIM mutations, it is not recommended that genotyping be used to select which patients should go on ibrutinib until further data is available. Grade 2 or higher treatment-related toxicities included neutropenia (25 percent) and thrombocytopenia (14 percent), which were more common in heavily pretreated patients; atrial fibrillation associated with a prior history of arrhythmia (5 percent); and bleeding associated with procedures and marine oil supplements (3 percent). Serum IgA and IgG levels were unchanged following treatment with ibrutinib, and treatment-related infections were infrequent.

Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway that is active in WM. A multicenter study examined everolimus in 60 previously treated patients that showed an overall response rate (ORR) of 73 percent, with 50 percent of patients attaining a major response.¹⁸¹ The median progression-free survival in this study was 21 months. Grade 3 or higher related toxicities were observed in 67 percent of patients, with cytopenias constituting the most common toxicity. Pulmonary toxicity occurred in 5 percent of patients, and dose reductions as a result of toxicity occurred in 52 percent of patients. A clinical trial examining the activity of everolimus in 33 previously untreated patients with WM has also been reported that included serial marrow biopsies in response assessment.¹⁸² The ORR in this study was 72 percent, including partial or better responses in 60 percent of patients. However, discordance between serum IgM levels upon which consensus criteria for response are based, and marrow disease response were common and complicated response assessment. In a few patients, discontinuation of everolimus led to rapid increases in serum IgM levels, and symptomatic hyperviscosity. Grade 2 or higher hematologic and nonhematologic toxicities in this study that were related to everolimus were predominately hematologic, including anemia (40 percent), thrombocytopenia (12 percent), and neutropenia (18 percent). Nonhematologic toxicities included oral ulcerations (27 percent), which improved with oral dexamethasone swish and spit solution, and pneumonitis (15 percent), which led to treatment discontinuation.

Maintenance Therapy

A large retrospective study examined the categorical responses outcome of rituximab-naïve patients who were either observed or received maintenance rituximabwere.¹⁸³ Categorical responses improved after induction therapy in 42 percent of patients who received maintenance rituximab versus 10 percent in patients on observation. Additionally, both progression-free survival (56.3 vs. 28.6 months) and overall survival (>120 vs. 116 months) were longer in patients who received maintenance rituximab. Improved progression-free survival was evident despite previous treatment status or induction with rituximab, either alone or in combination therapy. Best serum IgM response was also lower and hematocrit higher in those patients who received maintenance rituximab. Among patients who received maintenance rituximab therapy, an increased number of infectious events, predominantly grade 1 or 2 sinusitis and bronchitis were observed, along with lower serum IgA and IgG levels. A prospective study examining the role of maintenance rituximab was also initiated by the German STiL group.¹⁸⁴ In this study, patients received up to six cycles of bendamustine and rituximab, and responders randomized to either observation or maintenance rituximab every 2 months for 2 years. Enrollment for this study is complete and response outcome for maintenance rituximab therapy is awaited.

HIGH-DOSE THERAPY AND STEM CELL TRANSPLANTATION

The European Bone Marrow Transplant Registry reported the largest experience for both autologous as well as allogeneic stem cell transplantation (SCT) in WM.^185,186 Among 158 WM patients receiving an autologous SCT, which included primarily relapsed or refractory patients, the 5-year progression-free and overall survival rate was 39.7 percent and 68.5 percent, respectively.¹⁸⁵ Nonrelapse mortality at 1 year was 3.8 percent. Chemorefractory disease, and the number of prior lines of therapy at time of the autologous SCT were the most important prognostic factor for progression-free and overall survival. In the allogeneic SCT experience from the European Bone Marrow Transplant, the long-term outcome of 86 WM patients was reported.¹⁸⁶ A total of 86 patients received allograft by either myeloablative or reduced-intensity conditioning. The median age of patients in this series was 49 years, and 47 patients had three or more previous lines of therapy. Eight patients failed prior autologous SCT. Fifty-nine patients (68.6 percent) had chemotherapy-sensitive disease at the time of allogeneic SCT. Nonrelapse mortality at 3 years was 33 percent for patients receiving a myeloablative transplant, and 23 percent for those who received reduced-intensity conditioning. The overall response rate was 75.6 percent. The relapse rates at 3 years were 11 percent for myeloablative, and 25 percent for reduced-intensity conditioning recipients. Five-year progression-free and overall survival for WM patients who received a myeloablative allogeneic SCT were 56 percent and 62 percent, respectively, and for patients who received reduced intensity conditioning were 49 percent and 64 percent, respectively. The occurrence of chronic graft-versus-host disease was associated with improved progression-free survival, and suggested the existence of a clinically relevant graft-versus-WM effect in this study.

Table 109–3 summarizes the response categories and criteria for progressive disease in WM based on the most recent consensus recommendations.¹⁸⁷ The term overall response is used to characterize all responses, including minor responses. Major responses only include partial, very good partial, and complete responses. The attainment of very good partial or complete responses is associated with improved progression-free survival.^{155,165,176,179,188} Response assessments in WM rely primarily on serum IgM or IgM paraprotein levels, although complete responses require disappearance of the IgM monoclonal protein, and resolution of marrow and/or extramedullary WM disease.¹⁸⁷ An important concern with the use of IgM as a surrogate marker of disease is that it can fluctuate, independent of tumor-cell killing with some agents. By way of example, rituximab can induce a flare in serum IgM levels, whereas everolimus, bortezomib, and ibrutinib can suppress IgM levels independent of tumor-cell killing in some patients, a finding referred to as IgM discordance.^{158,159,162,181,183,189} Moreover, with selective B-cell–depleting agents such as rituximab and alemtuzumab, residual IgM-producing plasma cells are spared and continue to persist, thus potentially skewing the relative response and assessment to treatment.¹⁹⁰ sCD27 levels have been investigated as an alternative surrogate marker in WM given their correlation with WM disease burden, and may remain a faithful marker of disease in patients experiencing a rituximab-related IgM flare, as well as after plasmapheresis.^59,191 The use of quantitative allele-specific PCR assays to assess serial MYD88^L265P burden in WM patients is also under investigation.^36,38

WM typically presents as an indolent disease. The presence of 6q deletions may have prognostic significance, although this is disputed.^20,21 Age is an important prognostic factor (>65 years),^192,193,194 but is influenced by comorbidities. Anemia that reflects both marrow involvement and the serum level of the IgM monoclonal protein (because of the impact of IgM on intravascular fluid retention) has emerged as a strong adverse prognostic factor with hemoglobin levels of less than 9 to 12 g/dL associated with decreased survival in several series.^192,193,194 Other cytopenias also may be significant predictors of survival.¹⁹³ The precise level of cytopenias with prognostic significance has not been determined. Some series have identified a platelet count of less than 100 to 150 × 10⁹/L and a granulocyte count of less than 1.5 × 10⁹/L as independent prognostic factors.^193,194 The number of cytopenias in a given patient has been proposed as a prognostic factor.¹⁹³ Serum albumin levels also correlate with survival in WM patients in some studies, using multivariate analyses.^193,195 Elevated serum β₂-microglobulin levels (>3.0 to 3.5 g/dL) have also shown strong prognostic correlation in WM.^{193,194,195,196} Several scoring systems have been proposed based on these analyses (Table 109–4), including the WM International Prognostic Scoring System (WM IPSS) which incorporates five adverse covariates: advanced age (>65 years), hemoglobin less than or equal to 11.5 g/dL, platelet count less than or equal to 100 × 10⁹/L, β₂-microglobulin greater than 3 mg/L, and serum monoclonal protein concentration greater than 7 g/dL.¹⁹⁷ Among 537 WM patients evaluated in the development of WM IPSS, low-risk patients (27 percent) presented with none or one of the adverse characteristics and advanced age, intermediate-risk patients (38 percent) with two adverse characteristics or only advanced age, and high-risk patients (35 percent) with more than two adverse characteristics. Five-year survival rates for these patients were 87 percent, 68 percent, and 36 percent, respectively. Importantly, the WM IPSS retained its prognostic significance in subgroups defined by age, treatment with alkylating agent and nucleoside analogues. Recent data from the Surveillance, Epidemiology, and End Results (SEER) database involving 7744 WM patients showed that the relative survival of WM patients has improved over time. Patients diagnosed during the years 2001 to 2010 had higher 5-year (78 percent vs. 67 percent) and 10-year (66 percent vs. 49 percent) relative survival rates versus patients diagnosed during the years 1980 to 2000.¹⁹⁸ A Greek study that included 345 patients with WM failed to show any overall or cause-specific survival improvement in recent years, although the study might have been too underpowered to detect any expected benefit.¹⁹⁹ A Swedish study of 1555 patients diagnosed with WM between 1980 and 2005 showed that the 5-year relative survival rate improved from 57 percent in 1980 to 1985 to 78 percent in 2001 to 2005.²⁰⁰