Chapter 70: 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.

• WM corresponds to lymphoplasmacytic lymphoma (LPL) as defined in the Revised European-American Lymphoma (REAL) and World Health Organization classification systems.

• Most cases of LPL are WM; less than 5 percent of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL.

• 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.

• The incidence rate is higher among Americans of European descent. Americans of African descent represent approximately 5 percent of all patients.

• Approximately 20 percent of patients are of Eastern European descent, specifically of Ashkenazi-Jewish ethnic background.

• 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.

Cytogenetic Findings

• Loss of all or part of chromosomes 17, 18, 19, 20, 21, 22, X, and Y have been commonly observed, and gains in chromosomes 3, 4, and 12 also occur.

• Chromosome 6q deletions encompassing 6q21–25 have been observed in up to half of WM patients.

Nature of the Tumor Cell

• The marrow B-cells in WM undergo maturation from small lymphocytes with large focal deposits of surface immunoglobulins, to lymphoplasmacytic cells or to plasma cells that contain intracytoplasmic immunoglobulins.

• Table 70–1 lists clinical and laboratory features at the time of diagnosis for 356 patients in a large study.

• Presenting symptoms most commonly are fatigue, weakness, weight loss, episodic bleeding, and manifestations of the hyperviscosity syndrome.

• Physical findings include:

  — Lymphadenopathy.

  — Hepatosplenomegaly.

  — Dependent purpura and mucosal bleeding.

  — Dilated tortuous retinal veins.

  — Multiple flesh-colored papules on extensor surfaces (deposits of IgM reacting to epidermal basement membrane antigens).

  — Peripheral sensory neuropathy.

  — Raynaud phenomenon, especially upon exposure to cold.

  — Splenomegaly and lymphadenopathy are uncommon.

Morbidity Mediated by the Effects of IgM

• Table 70–2 lists the physiochemical and immunologic properties of the monoclonal IgM Protein.

The Hyperviscosity Syndrome

• Symptoms usually occur when the monoclonal IgM concentration exceeds 50 g/L or when serum viscosity is >4.0 centipoises (cp) but can occur at lower serum concentrations of IgM.

• Presence of cryoglobulins contributes to increasing blood viscosity, as well as to the tendency to induce erythrocyte aggregation.

• Frequent symptoms are headache; impaired vision; mental status changes, such as confusion or dementia; altered consciousness that may progress to coma; ataxia; or nystagmus.

• Ophthalmoscopic changes include link-sausage appearance of retinal veins, retinal hemorrhages, and papilledema and/or distended and tortuous retinal veins, hemorrhages, and papilledema.

• Congestive heart failure may develop, particularly in the elderly.

• Inappropriate red cell transfusion can exacerbate hyperviscosity and may precipitate cardiac failure.

Cryoglobulinemia

• The monoclonal IgM can behave as a cryoglobulin (type I) in up to 20 percent of patients.

• 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.

IgM-Related Neuropathy

• Peripheral neuropathy occurs in up to 40 percent of cases.

• The nerve damage is mediated by diverse pathogenetic mechanisms:

  — IgM antibody activity toward nerve constituents causing demyelinating polyneuropathies.

  — Endoneurial granulofibrillar deposits of IgM without antibody activity, associated with axonal polyneuropathy.

  — Tubular deposits in the endoneurium associated with IgM cryoglobulin.

  — Amyloid deposits or neoplastic cell infiltration of nerve structures is less common.

• Half of patients with IgM neuropathy may have a distinctive clinical syndrome that is associated with antibodies against a minor 100-kDa glycoprotein component of nerve, myelin-associated glycoprotein (MAG).

  — 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.

  — Most patients present with sensory complaints; imbalance and gait ataxia, owing to lack of proprioception; and leg muscles atrophy in advanced stages.

• Patients with monoclonal IgM to gangliosides may have a demyelinating sensory neuropathy with chronic ataxic neuropathy sometimes presenting with ophthalmoplegia.

  — 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.

• Anti-sulfatide monoclonal IgM proteins are associated with sensory-motor neuropathy.

• The POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is rare in patients with WM.

Cold Agglutinin Hemolytic Anemia

• Monoclonal IgM may be cold agglutinins with binding activity for cell antigens at temperatures below 37°C, producing chronic hemolytic anemia (see Chap. 25).

  — This disorder occurs in <10 percent of WM patients.

  — It is associated with cold agglutinin titers greater than 1:1000 in most cases.

  — Mild to moderate chronic hemolytic anemia can be exacerbated after cold exposure.

  — The agglutination of red cells in the skin circulation also causes Raynaud syndrome, acrocyanosis, and livedo reticularis.

IgM Tissue Deposition

• The monoclonal protein can deposit in several tissues as amorphous aggregates.

• Amorphous deposits in the dermis are referred to as macroglobulinemia cutis.

• Deposition of monoclonal IgM in the lamina propria and/or submucosa of the intestine may be associated with diarrhea, malabsorption, and gastrointestinal bleeding.

• The incidence of cardiac and pulmonary involvement is higher in patients with monoclonal IgM than with other immunoglobulin isotypes.

Manifestations Related to Tissue Infiltration by Neoplastic Cells

• 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.

• Malabsorption, diarrhea, bleeding, or gastrointestinal obstruction may indicate involvement of the gastrointestinal tract at the level of the stomach, duodenum, or small intestine.

• 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.

  — 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.

• Anemia is the most common finding.

• Normocytic and normochromic anemia is present and rouleaux formation is often pronounced.

• Hemoglobin estimate can be inaccurate.

• Leukocyte and platelet counts are usually within the reference range at presentation.

• A raised erythrocyte sedimentation rate is almost always present.

• Thrombin time is often prolonged, and the prothrombin time and activated partial thromboplastin time may be prolonged.

• Serum levels of IgG and IgA are normal or low.

Marrow Findings

• Hypercellular, with diffuse infiltration of lymphocytes, plasmacytoid lymphocytes, and plasma cells (see Fig. 70–1).

• Contains lymphoid cells with monoclonal surface membrane and/or cytoplasmic immunoglobulin.

• Increased numbers of mast cells admixed with aggregates of malignant lymphocytes.

• A solely paratrabecular pattern of lymphocyte infiltration is unusual and should raise the possibility of follicular lymphoma.

• The lymphocyte immunoprofile is sIg+CD19+CD20+CD22+CD79+.

• In up to 20 percent of cases, the lymphocytes may also express CD5, CD10, or CD23.

Immunologic Abnormalities

• High-resolution electrophoresis combined with immunofixation of serum and urine is recommended for identification and characterization of the IgM monoclonal protein.

• 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.

Serum Viscosity

• Serum viscosity should be measured if the patient has signs or symptoms of hyperviscosity syndrome.

• Among the first clinical signs of hyperviscosity are the appearance of peripheral and midperipheral dot and blot-like hemorrhages in the retina.

• 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.

• 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.

• Major response: >50 percent decrease in serum Ig level (See Table 70–3).

• Minor response: based on ≥25 to <50 percent decrease in serum IgM level.

• An important concern with the use of IgM as a surrogate marker of disease is that it can fluctuate, independent of extent of tumor cell killing, particularly with newer biologically targeted agents such as rituximab and bortezomib.

• Initiation of therapy should not be based on the IgM level per se, as this may not correlate with the clinical manifestations of WM.

• 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 or splenomegaly provide additional reasons to begin therapy.

  — Anemia with a hemoglobin value of ≤10 g/dL or a platelet count of ≤100 × 10⁹/L owing to marrow infiltration, also justifies treatment.

• Plasmapheresis is used to help manage the hyperviscosity syndrome.

Initial Therapy

• Alkylating agents (e.g., chlorambucil), nucleoside analogues (cladribine or fludarabine), the monoclonal antibody rituximab, as well as combinations are considered reasonable choices for the initial therapy of WM.

• Exposure to alkylating agents or nucleoside analogues should be minimized in patients who are candidates for autologous stem cell transplantation, which typically is reserved for those younger than 70 years of age.

Alkylating Agents Therapy

• Chlorambucil has been administered on both a continuous (i.e., daily dose schedule) and an intermittent schedule.

  — Oral chlorambucil on a continuous schedule: Orally 0.1 mg/kg per day, every 6 weeks.

  — Oral chlorambucil on an intermittent schedule: Orally 0.3 mg/kg per day for 7 days once every 6 weeks.

• Median response duration was greater for patients receiving intermittent- versus continuous-dose chlorambucil (46 vs. 26 months).

• 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%) in 72 percent of patients.

• Pretreatment factors associated with shorter survival in the entire population of patients receiving single-agent chlorambucil are:

  — Patients older than 60 years, male sex, hemoglobin less than 10 g/dL, leukocytes less than 4 × 10⁹/L, and platelets less than 150 × 10⁹/L.

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 result in major responses in 40 to 90 percent of patients who received primary therapy, whereas in the previously treated patients, responses ranged from 38 to 54 percent.

• Fludarabine (25 mg/m² for 5 days) administered every 28 days to previously untreated or treated patients, resulted in an overall response rate of 38 to 100 percent or 30 to 40 percent, respectively.

• Major toxicities of nucleoside analogue therapy are myelosuppression and T-cell depletion, resulting in increased risk for opportunistic infections.

• Factors predicting a better response to nucleoside analogues:

  — Younger age at the start of treatment (<70 years).

  — Higher pretreatment hemoglobin (>9.5 g/dL).

  — Higher platelet count (>75 × 10⁹/L).

  — Disease that does not relapse while on therapy.

  — A long interval between first-line therapy and initiation of a nucleoside analogue in for relapsed disease.

• Harvesting autologous blood stem cells succeeds on the first attempt in most patients who did not receive nucleoside analogue therapy, compared with as few as one-third of patients who received a nucleoside analogue.

CD20-Directed Antibody Therapy

• Rituximab is a chimeric monoclonal antibody that targets CD20, a widely expressed antigen on lymphoplasmacytic cells in WM.

• Standard doses of rituximab (i.e., four once-weekly infusions of 375 mg/m²) induced major responses in approximately 30 percent of previously treated or untreated patients.

• The median time to treatment failure with rituximab ranged from 8 to over 27 months.

• A transient increase of serum IgM may be noted immediately following initiation of treatment with rituximab in many WM patients.

  — The increase in IgM following initiation of therapy with rituximab does not portend treatment failure and most patients return to their baseline IgM level by 12 weeks.

  — Plasmapheresis should be considered in these patients in advance of rituximab therapy.

• Rituximab should not be used as sole therapy for the treatment of patients at risk for hyperviscosity symptoms.

• Time to response to rituximab therapy exceeds 3 months on the average.

• Patients with baseline serum IgM levels of <60 g/L are more likely to respond.

• 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.

• 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.

Combination Therapies

• A regimen of rituximab, cladribine, and cyclophosphamide used in previously untreated patients resulted in a partial response in approximately 95 percent of WM patients.

• The combination of rituximab and fludarabine led to an overall response rate of 95 percent, with 83 percent of patients achieving a major response.

  — The median time to progression was 51 months.

• The combination of rituximab, dexamethasone, and cyclophosphamide achieved a major response in 74 percent of patients on this study, and the 2-year progression-free survival was 67 percent.

• A study using cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) in combination with rituximab (R-CHOP) achieved a major response in 77 percent of patients with relapsed or refractory disease.

• One study using two cycles of oral cyclophosphamide with subcutaneous cladribine as initial therapy reported a partial response in 84 percent of patients and the median duration of response of 36 months.

• A study evaluating fludarabine plus cyclophosphamide reported a response in 78 percent of patients and median time to treatment failure of 27 months.

• Various combination therapy regimens:

  — Nucleoside analogues and alkylating agents.

  — Rituximab in combination with nucleoside analogues.

  — Rituximab, nucleoside analogues, plus alkylating agents.

  — Rituximab and cyclophosphamide-based therapy.

Therapy for Relapsed or Refractory Patients

Proteasome Inhibitor

• Bortezomib is a proteasome inhibitor that induces apoptosis of primary WM lymphoplasmacytic cells.

  — All but 1 of 27 patients with relapsed or refractory disease, who received up to eight cycles of bortezomib at 1.3 mg/m² on days 1, 4, 8, and 11, had a response.

  — The overall response rate was 85 percent, with 10 and 13 patients achieving a minor (< 25%) and major (< 50%) decrease in IgM level.

  — Responses occurred at median of 1.4 months.

  — The median time to progression for all responding patients in this study was 7.9 (range: 3–21.4+) months.

  — The most common grade III/IV toxicities were sensory neuropathies (22.2%), leukopenia (18.5%), neutropenia (14.8%), dizziness (11.1%), and thrombocytopenia (7.4%).

  — Major responses occurred in 6 out of 10 (60%) previously treated patients.

• The combination of bortezomib, dexamethasone, and rituximab as primary therapy in patients with WM resulted in an overall response rate of 96 percent, and a major response rate of 83 percent.

  — The incidence of grade 3 neuropathy was approximately 30 percent but was reversible in most patients following discontinuation of therapy.

CD52-Directed Antibody Therapy

• Alemtuzumab is a humanized monoclonal antibody that targets CD52, an antigen expressed on marrow lymphoplasmacytic cells in WM patients, as well as on mast cells, which are increased in the marrow of patients with WM.

• Patients received three daily test doses of alemtuzumab (3, 10, and 30 mg intravenously) followed by 30 mg alemtuzumab intravenously three times a week for up to 12 weeks.

  — Among 25 patients evaluable for response, the overall response rate was 76 percent, which included 8 (32%) major responders and 11 (44%) minor responders.

• High rates of response to alemtuzumab as salvage therapy have also been reported.

Thalidomide and Lenalidomide

• Thalidomide as a single agent, and in combination with dexamethasone and clarithromycin, was examined in patients with WM.

  — Dose escalation from the thalidomide start dose of 200 mg daily was hindered by development of side effects.

  — A higher thalidomide dose (200 mg orally daily) along with dexamethasone (40 g orally once a week) and clarithromycin (500 mg orally twice a day) achieved a response in only 2 of 10 previously treated patients.

• In a study of lenalidomide and rituximab in WM, patients were started on lenalidomide at 25 mg daily on a syncopated schedule in which therapy was administered for 3 weeks, followed by a 1-week pause for an intended duration of 48 weeks.

  — Patients received 1 week of therapy with lenalidomide, after which rituximab (375 mg/m²) was administered once weekly on weeks 2 to 5, and again on weeks 13 to 16.

  — The overall and major response rates in this study were 50 and 25 percent, respectively, and the median time to progression for responders was 18.9 months.

  — Most patients continued to have anemia despite treatment with lenalidomide.

High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation

• High-dose chemotherapy followed by autologous stem cell transplantation in WM patients, previously treated with a median of three (range: 1–5) prior regimens, was well tolerated with an improvement in response status observed for seven patients.

• WM patients who received autologous transplantation, which included primarily relapsed or refractory patients, the 5-year progression-free and overall survival rate was 61 and 33 percent, respectively.

• Chemosensitive disease at time of the autologous transplantation was the most important prognostic factor for nonrelapse mortality, response rate, and progression-free and overall survival.

• Table 70–4 lists several scoring systems that have been proposed for WM.

• Median duration of survival is 5 to 10 years.

• Major negative prognostic factors:

  — Age older than 65 years.

  — Anemia.

  — Thrombocytopenia (platelet count of < 100 to 150 × 10⁹/L) or neutropenia (< 1.5 × 10⁹/L) as adverse prognostic factors.

  — Elevated serum β₂-microglobulin levels (> 30 g/L).

  — Level of monoclonal IgM protein.

  — The presence of cyroglobulins.