Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + DEFINITION Download Section PDF Listen +++ ++ 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 (WHO) classification systems. Most cases of LPL are WM. Less than 5% of cases are IgA-secreting, IgG-secreting, or nonsecreting LPL. + EPIDEMIOLOGY Download Section PDF Listen +++ ++ The age-adjusted incidence rate of WM in the United States is 3.4 per 1 million among males and 1.7 per 1 million among females. The incidence rate is higher among Americans of European descent. Americans of African descent represent approximately 5% of all patients. Approximately 20% of patients are of Eastern European descent, specifically of Ashkenazi-Jewish ethnic background. Approximately 20% 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. + PATHOGENESIS Download Section PDF Listen +++ +++ Cytogenetic Findings ++ Loss of all or part of chromosomes 17, 18, 19, 20, 21, 22, X, and Y is 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. +++ Somatic Mutations ++ MYD88L265P and CXCR4WHIM mutations are highly prevalent and trigger transcriptional factors that support the growth and survival of lymphoplasmacytic cells. + CLINICAL FEATURES Download Section PDF Listen +++ ++ 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 on exposure to cold — Splenomegaly and lymphadenopathy (uncommon) +++ Morbidity Mediated by the Effects of IgM ++ Table 69–1 lists the physiochemical and immunologic properties of the monoclonal IgM protein. ++Table Graphic Jump LocationTABLE 69–1PHYSICOCHEMICAL AND IMMUNOLOGIC PROPERTIES OF THE MONOCLONAL IGM PROTEIN IN WALDENSTRöM MACROGLOBULINEMIAView Table||Download (.pdf) TABLE 69–1 PHYSICOCHEMICAL AND IMMUNOLOGIC PROPERTIES OF THE MONOCLONAL IGM PROTEIN IN WALDENSTRöM MACROGLOBULINEMIA Properties of IgM Monoclonal Protein Diagnostic Condition Clinical Manifestations Pentameric structure Hyperviscosity Headaches, blurred vision, epistaxis, retinal hemorrhages, leg cramps, impaired mentation, intracranial hemorrhage Precipitation on cooling Cryoglobulinemia (type I) Raynaud phenomenon, acrocyanosis, ulcers, purpura, cold urticaria Autoantibody activity to myelin-associated glycoprotein, ganglioside M1, sulfatide moieties on peripheral nerve sheaths Peripheral neuropathies Sensorimotor neuropathies, painful neuropathies, ataxic gait, bilateral foot drop Autoantibody activity to IgG Cryoglobulinemia (type II) Purpura, arthralgia, renal failure, sensorimotor neuropathies Autoantibody activity to red blood cell antigens Cold agglutinins Hemolytic anemia, Raynaud phenomenon, acrocyanosis, livedo reticularis Tissue deposition as amorphous aggregates Organ dysfunction Skin: bullous skin disease, papules, Schnitzler syndrome Gastrointestinal: diarrhea, malabsorption, bleeding Kidney: proteinuria, renal failure (light-chain component) Tissue deposition as amyloid fibrils (light-chain component most commonly) Organ dysfunction Fatigue, weight loss, edema, hepatomegaly, macroglossia, organ dysfunction of involved organs (heart, kidney, liver, peripheral sensory and autonomic nerves) Source: Williams Hematology, 9th ed, Chap. 109, Table 109–2. +++ The Hyperviscosity Syndrome ++ Symptoms usually occur when the monoclonal IgM concentration exceeds 5 g/dL or when serum viscosity is more than 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% 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% 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, which 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; 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 a chronic demyelinating neuropathy and severe sensory ataxia that are 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. — This disorder occurs in less than 10% 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%. Malabsorption, diarrhea, bleeding, or gastrointestinal obstruction may indicate involvement of the gastrointestinal tract at the level of the stomach, duodenum, or small intestine. Skin — This 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. + LABORATORY FINDINGS Download Section PDF Listen +++ ++ Anemia is the most common finding. Normocytic and normochromic anemia is present and rouleaux formation is often pronounced (Figure 69–1). 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 monoclonal IgM protein level is high and typically ranges from 1.5 to 4.5 g/dL; serum levels of IgG and IgA are normal or low. +++ Marrow Findings ++ The marrow is hypercellular, with diffuse infiltration of lymphocytes, plasmacytoid lymphocytes, and plasma cells (see Figure 69–1). It contains lymphoid cells with monoclonal surface membrane and/or cytoplasmic immunoglobulin. Increased numbers of mast cells admixed with aggregates of malignant lymphocytes are apparent. A solely paratrabecular pattern of lymphocyte infiltration is unusual and should raise the possibility of follicular lymphoma. The lymphocyte immunoprofile is Ig+CD19+CD20+CD22+CD79+. In up to 20% of cases, the lymphocytes may also express CD5, CD10, or CD23. ++ FIGURE 69–1 Waldenström macroglobulinemia. A. Blood film displaying the characteristic pathologic rouleaux seen as a result of the red cell aggregating properties of immunoglobulin M. B. Marrow film showing characteristic infiltrate of lymphocytes, lymphoplasmacytic cells, and plasma cells. A mast cell is evident lower center. Although not specific for this disease, mast cells are commonly present in the marrow. C. Marrow film showing infiltrate of lymphocytes with occasional plasma cells and a mast cell. D. Marrow film showing lymphocytic infiltrate with a “cracked” mast cell sometimes seen in this disease. The fraction of plasma cells varies as shown by the somewhat higher proportion in (B) as compared to (C) and (D). Lymphocytes and lymphoplasmacytic cells predominate. (Reproduced with permission from Lichtman’s Atlas of Hematology, www.accessmedicine.com.) Graphic Jump LocationView Full Size||Download Slide (.ppt) +++ 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% 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. + RADIOLOGIC FINDINGS Download Section PDF Listen +++ ++ Marrow involvement can be documented by magnetic resonance imaging of the spine in more than 90% of patients. Computed tomography of the abdomen and pelvis demonstrates enlarged nodes in approximately 40% of WM patients. + TREATMENT Download Section PDF Listen +++ ++ Initiation of therapy should not be based on the IgM level per se, because 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 less than or equal to 10 g/dL or a platelet count of less than or equal to 100 × 109/L owing to marrow infiltration also justifies treatment. Plasmapheresis is used to help manage the hyperviscosity syndrome. +++ Initial Therapy ++ Reasonable choices for the initial therapy of WM are alkylating agents (eg, chlorambucil), nucleoside analogs (cladribine or fludarabine), the monoclonal antibody rituximab, as well as combinations. Exposure to alkylating agents or nucleoside analogs should be minimized in patients who are candidates for autologous hematopoietic stem cell transplantation. +++ Oral Alkylating Agents ++ Chlorambucil has been administered on both a continuous (ie, daily dose schedule) and an intermittent schedule. — Oral chlorambucil on a continuous schedule: orally 0.1 mg/kg per day — Oral chlorambucil on an intermittent schedule: orally 0.3 mg/kg per day for 7 days, 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 (ie, reduction of IgM by > 50%) in 72% of patients. Pretreatment factors associated with shorter survival in the entire population of patients receiving single-agent chlorambucil are: — Age over 60 years, male sex, hemoglobin less than 10 g/dL, leukocytes less than 4 × 109/L, and platelets less than 150 × 109/L +++ Nucleoside Analog 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, results in major responses in 40% to 90% of patients who received primary therapy, whereas in the previously treated patients, responses ranged from 38% to 54%. Fludarabine (25 mg/m2 for 5 days) administered intravenously every 28 days to previously untreated or treated patients resulted in an overall response rate of 38% to 100% or 30% to 40%, respectively. Major toxicities of nucleoside analog therapy are myelosuppression and T-cell depletion, resulting in increased risk of opportunistic infections. Factors predicting a better response to nucleoside analogs: — 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 analog for relapsed disease Harvesting autologous peripheral blood stem cells succeeds on the first attempt in most patients who did not receive nucleoside analog therapy, compared with as few as one-third of patients who receive a nucleoside analog. +++ 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 (ie, four once-weekly infusions of 375 mg/m2) induced major responses in approximately 30% 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 less than 6.0 g/dL are more likely to respond. The objective response rate was significantly lower in patients who had either low serum albumin (< 3.5 g/dL) or a serum IgM monoclonal protein of more than 4.0 g/dL. 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. +++ Proteasome Inhibitors ++ 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%, with 10 and 13 patients achieving a minor (> 25%) and major (> 50%) decrease in IgM level, respectively. — Responses occurred at median of 1.4 months. — The median time to progression for all responding patients was 7.9 (range: 3–21.4+) months. — The most common grade III/IV toxicities were sensory neuropathies (22%), leukopenia (19%), neutropenia (15%), dizziness (11%), and thrombocytopenia (7%). — 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%, and a major response rate of 83%. — The incidence of grade 3 neuropathy was approximately 30% but was reversible in most patients following discontinuation of therapy. Carfilzomib has been evaluated in combination therapy. +++ Combination Therapies ++ A regimen of rituximab, cladribine, and cyclophosphamide used in 17 previously untreated patients resulted in a partial response in approximately 95% of WM patients. The combination of rituximab and fludarabine led to an overall response rate of 95%, with 83% 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% of patients on this study, and the 2-year progression-free survival was 67%. The combination of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) with rituximab (R-CHOP) has achieved major responses in approximately 80% to 90% 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% of patients and the median duration of response of 36 months. A study evaluating fludarabine plus cyclophosphamide reported a response in 78% of patients and median time to treatment failure of 27 months. Various combination therapy regimens: — Nucleoside analogs and alkylating agents — Rituximab in combination with nucleoside analogs — Rituximab, nucleoside analogs, plus alkylating agents — Rituximab and cyclophosphamide-based therapy — Carfilzomib in combination with rituximab and dexamethasone +++ Novel Therapeutics ++ Ibrutinib, which targets Bruton’s tyrosine kinase, is approved by the US Food and Drug Administration for the treatment of symptomatic patients. In a study of previously treated patients with WM, the overall response rate was about 90%. Everolimus is an oral inhibitor of the mammalian target of rapamycin pathway. An overall response rate of about 70% was reported in previously treated patients. +++ High-Dose Therapy and Hematopoietic Stem Cell Transplantation ++ The largest experience of hematopoietic stem cell transplantation for patients with WM was reported by the European Bone Marrow Transplant Registry. For autologous transplant recipients, the 5-year progression-free and overall survival rates were approximately 40% and 70%, respectively. Nonrelapse mortality at 1 year was 4%. Chemosensitive disease and fewer number of prior lines of therapy at time of the autologous transplantation were the most important prognostic factors for progression-free and overall survival. Allogeneic transplant recipients who underwent myeloablative conditioning had 5-year progression-free and overall survivals of approximately 60%; 3-year nonrelapse mortality was approximately 30%. + RESPONSE CRITERIA IN WM Download Section PDF Listen +++ ++ Major responses include partial, very good partial, and complete responses. (Table 69–2) Minor response is based on at least 25% to 50% 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. ++Table Graphic Jump LocationTABLE 69–2SUMMARY OF CONSENSUS RESPONSE CRITERIA FOR WALDENSTRÖM MACROGLOBULINEMIAView Table||Download (.pdf) TABLE 69–2 SUMMARY OF CONSENSUS RESPONSE CRITERIA FOR WALDENSTRÖM MACROGLOBULINEMIA Complete response CR Absence of serum monoclonal IgM protein by immunofixation. Normal serum IgM level. Complete resolution of extramedullary disease (ie, lymphadenopathy/splenomegaly) if present at baseline. Morphologically normal marrow aspirate and trephine biopsy. Very good Partial response VGPR Monoclonal IgM protein is detectable. 90% reduction in serum IgM level from baseline, or normalization of serum IgM level. Complete resolution of extramedullary disease (ie, lymphadenopathy/splenomegaly) if present at baseline. No new signs or symptoms of active disease. Partial response PR Monoclonal IgM protein is detectable. ≥ 50% but < 90% reduction in serum IgM level from baseline. Reduction in extramedullary disease (ie, lymphadenopathy/splenomegaly) if present at baseline. No new signs or symptoms of active disease. Minor response MR Monoclonal IgM protein is detectable. ≥ 25% but < 50% reduction in serum IgM level from baseline. No new signs or symptoms of active disease. Stable disease SD Monoclonal IgM protein is detectable. < 25% reduction and < 25% increase in serum IgM level from baseline. No progression in extramedullary disease (ie, lymphadenopathy/splenomegaly). No new signs or symptoms of active disease. Progressive disease PD > 25% increase in serum IgM level from lowest nadir (requires confirmation) and/or progression in clinical features attributable the disease. Reproduced with permission from Owen RG, Kyle RA, Stone MJ, et al: Response assessment in Waldenström macroglobulinaemia: update from the VIth International Workshop, Br J Haematol. 2013 Jan;160(2):171–176. + COURSE AND PROGNOSIS Download Section PDF Listen +++ ++ Table 69–3 lists several prognostic 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 less than 9 to 12 g/dL — Thrombocytopenia (platelet count of < 100 to 150 × 109/L) or neutropenia (< 1.5 × 109/L) — Elevated serum β2-microglobulin levels (> 3.0 to 3.5 mg/L) — Level of monoclonal IgM protein ++Table Graphic Jump LocationTABLE 69–3PROGNOSTIC SCORING SYSTEMS IN WALDENSTRÖM MACROGLOBULINEMIAView Table||Download (.pdf) TABLE 69–3 PROGNOSTIC SCORING SYSTEMS IN WALDENSTRÖM MACROGLOBULINEMIA Study Adverse Prognostic Factors Number of Groups Survival Gobbi et al Hgb < 9 g/dL 0–1 prognostic factors Median: 48 months Age > 70 years 2–4 prognostic factors Median: 80 months Weight loss Cryoglobulinemia Morel et al Age ≥ 65 years 0–1 prognostic factors 5-year: 87% of patients Albumin < 4 g/dL 2 prognostic factors 5-year: 62% Number of cytopenias: 3–4 prognostic factors 5-year: 25% Hgb < 12 g/dL Platelets < 150 × 109/L WBC < 4 × 109/L Dhodapkar et al β2M ≥ 3 mg/L β2M < 3 mg/L + Hgb ≥ 12 g/dL 5-year: 87% of patients Hgb < 12 g/dL β2M < 3 mg/L + Hgb < 12 g/dL 5-year: 63% IgM < 4 g/dL β2M ≥ 3 mg/L + IgM ≥ 4 g/dL 5-year: 53% β2M ≥ 3 mg/L + IgM < 4 g/dL 5-year: 21% Application of International Staging System Criteria for Myeloma to WM (Dimopoulos et al) Albumin ≤ 3.5 g/dL Albumin ≥ 3.5 g/dL +β2M < 3.5 mg/L Median: NR β2M ≥ 3.5 mg/L Albumin ≤ 3.5 g/dL + β2M < 3.5 or Median: 116 months β2M 3.5–5.5 mg/L Median: 54 months β2M > 5.5 mg/L International Prognostic Scoring System for WM (Morel et al) Age > 65 years 0–1 prognostic factors (excluding age) 5 year: 87% of patients Hgb < 11.5 g/dL 2 prognostic factors (or age > 65 years) 5 year: 68% Platelets < 100 × 109/L 3–5 prognostic factors 5 year: 36% β2M > 3 mg/L IgM > 7 g/dL β2M, β2-microglobulin; Hgb, hemoglobin; NR, not reported; WBC, white blood cell count. Source: Williams Hematology, 9th ed, Chap. 109, Table 109–4. ++ For a more detailed discussion, see Steven P. Treon, Jorge J. Castillo, Zachary R. Hunter, and Giampaolo Merlini: Macroglobulinemia, Chap. 109, in Williams Hematology, 9th ed.