Table of contents :

Epidemiology : 2% of all hematologic malignancies. The incidence rate for WM is higher among Caucasians, with African descendants representing only 5% of all patients. WM is a disease of the elderly, with a median age of 63 years (range 25–92), with a slight predominance of males over females^ref.
Aetiology :

• genetic factors appear to be an important factor. There have been numerous reports of familial disease, including multigenerational clustering of WM and other B cell lymphoproliferative diseases. In a recent study, approximately 20% of 181 serial WM patients presenting to a tertiary referral had a first-degree relative with either WM or another B cell disorder^ref. Frequent association with other immunological disorders in healthy relatives, including hypogammaglobulinemia and hypergammaglobulinemia (particularly polyclonal IgM), autoantibody (particularly to thyroid) production, and manifestation of hyperactive B cells have been reported
• individuals with hyaluronan synthase 1 (HAS1) 833G/G genotype (located on an exonic splicing enhancer motif) are predisposed toward aberrant HAS1 splicing and expression of HAS1 variants, resulting in an enhanced risk of developing WM^ref.
• the role of environmental factors in WM is undetermined. There is no clear association with chronic antigenic stimulation from infections, autoimmune diseases, or allergy or with specific occupational exposure. The relevance of viral infection remains to be established. Data regarding a possible link between HCV and HHV-8 and WM remain controversial.

Increased numbers of mast cells

• symptoms :
• weakness (66%)
• anorexia (25%)
• peripheral neuropathy (24%) is multifactorial
• weight loss (17%)
• fever (15%)
• Raynaud’s phenomenon (11%) and symptoms due to peripheral neuropathy may precede more serious manifestations by many years
• physical findings :
• hepatomegaly (> 2 cm from the costal margin) (20%)
• splenomegaly (19%)
• lymphadenopathy (15%)
• purpura (9%) is frequently associated with cryoglobulinemia and more rarely with AL amyloidosis
• hemorrhagic manifestations (7%) are multifactorial
• encephalopathies due to lymphoplasmocytoid infiltration^ref with intrathecal secretion of IgM^ref (Bing-Neel syndrome) : hyperprotidorrhachy^ref, bilateral sixth nerve paresis^ref, cognitive impairment (attentional deficit, short term memory disorders and behavioural disorders), accompanied by apraxia of gait and rectal and urinary incontinence^ref. Tumors, probably arising from confluence of infiltrative areas, are exceedingly rare^ref.

Therapy : 40 Gy radiation therapy and combination of cladribine, cyclophosphamide, and prednisone^ref
• malignant external otitis^ref

properties of the monoclonal IgM		resulting condition	clinical manifestations
physicochemical	intrinsic viscosity	hyperviscosity syndrome	fatigue, headache, blurred vision, easy mucosal bleeding, impaired mentation up to coma
	precipitation on cooling	cryoglobulinemia type I	Raynaud’s phenomenon, acrocyanosis,  necrosis, ulcers, purpura, cold urticaria
protein-protein interaction		hemostatic abnormalities	bleeding diathesis: bruising, purpura, mucosal  bleeding; rarely, brain hemorrhages
antibody activity versus:	nerve constituents	polyneuropathies	anti-myelin-associated glycoprotein (MAG)-related: symmetric, distal, progressive, sensorimotor neuropathy, ataxic gait, bilateral foot drop  IgM with other specificities: symmetric, distal, progressive painful sensory neuropathy prominent motor neuropathy
	IgG	cryoglobulinemia type II	weakness, purpura, arthralgias, proteinuria,  renal failure, progressive, symmetric distal  sensorimotor neuropathy combined with  mononeuropathies (e.g., foot or wrist drop)
	RBC antigens	cold agglutinin hemolytic  anemia	mild, chronic hemolytic anemia exacerbated  after cold exposure; Raynaud’s phenomenon,  acrocyanosis and livedo reticularis
tendency to deposit into tissues	as amorphous aggregates  in skin, GI tract, kidney	specific organ dysfunction	skin: bullous skin disease, papules on extremities  GI: diarrhea, malabsorption, bleeding  kidney: mild, reversible proteinuria, mostly  asymptomatic
	as amyloid fibrils (light chains)	AL amyloidosis	fatigue, weight loss, periorbital purpura, edema,  hepatomegaly, macroglossia  Dysfunction of organs involved: kidneys, heart,  liver, peripheral sensory and autonomic  neuropathies

• hemoglobin < 12 g/dL (63%) is caused by a combination of factors: mild decrease in red cell survival, impaired erythropoiesis, hemolysis, moderate plasma volume expansion, and blood loss from the gastrointestinal tract. Blood smears are usually normocytic and normochromic, and rouleaux formation is often pronounced. Electronically measured mean corpuscular volume may be elevated spuriously owing to erythrocyte aggregation. In addition, the hemoglobin estimate can be inaccurate, i.e., falsely high, because of interaction between the monoclonal protein and the diluent used in some automated analyzers.
• WBC < 3 x 10⁹/L (4%), usually normal
• platelets < 100 x 10⁹/L (16%), usually normal
• serum IgM monoclonal component : high-resolution electrophoresis combined with immuno-fixation of serum and urine are recommended for identification and characterization of the IgM monoclonal protein. The light chain of the monoclonal IgM is k in 75%–80% of patients. A few WM patients have > 1 M-component. The concentration of the serum monoclonal protein is very variable but in most cases lies within the range of 15–45 g/L. Densitometry should be considered to determine IgM levels for serial evaluations because nephelometry sometimes is unreliable and shows large intralaboratory as well as interlaboratory 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 under warm conditions for determination of serum monoclonal IgM level.
• k/l (80%/20%)
• > 30g/L (35%)
• Bence Jones proteinuria (38%) : it exceeds 1 g/24 hours in only 3% of cases^ref
• serum ß₂-microglobulin > 3 mg/L (62%)
• relative serum viscosity > 4 (17%)
• monoclonal B-lymphocytes expressing surface IgM and late-differentiation B cell markers are uncommonly detected in blood by flow cytometry
• raised ESR is almost constantly observed in WM and may be the first clue to the presence of the macroglobulin.
• clotting abnormality, most frequently prolongation of thrombin time
• demonstration of green birefringence under polarized light of amyloid deposits stained with Congo red.
• blood viscosity should be measured if the patient has signs or symptoms of hyperviscosity syndrome. Measurement of viscosity in whole blood at low shear rates may be the best indicator of hemorheological changes in patients with WM. In practice, a correlation between level of M-protein and symptoms may be used to anticipate repeat plasma exchanges as the M-protein approaches the level associated with hyperviscosity. Fundoscopy remains an excellent indicator of clinically relevant hyperviscosity
• cryoglobulins should be searched for in the presence of suggestive clinical features
• rheumatoid factor activity and low C4 levels (< 8 mg/dL) are common findings in type II cryoglobulinemia.
• bone marrow trephine biopsy (BMTB) is necessary since aspiration frequently yields a "dry tap." 3 cytological subtypes have been identified in conjunction with patterns of bone marrow infiltration: lymphoplasmacytoid, constituted by small lymphocytes and plasmacytoid cells characterized by a nodular pattern (47% of all patients); lymphoplasmacytic, in which small lymphocytes and mature plasma cells predominate and mast cells may be conspicuous, associated mainly with an interstitial/nodular pattern (42%); and polymorphous, with a packed marrow and characterized by a wide spectrum of cells, including small lymphocytes, plasmacytoid cells, plasma cells, large transformed cells, and immunoblasts with mitotic figures (11%)^ref. "Intranuclear" periodic acid-Schiff (PAS)⁺ inclusions (Dutcher-Fahey bodies) consisting of IgM deposits in the perinuclear space, and sometimes in intranuclear vacuoles, may be seen occasionally in lymphoid cells.


• cytogenetics : several studies, usually performed on limited series of patients, demonstrated a great variety of numerical and structural chromosome abnormalities. Numerical losses involving chromosomes 17, 18, 19, 20, 21, 22, X, and Y have been commonly observed, though gains in chromosomes 3, 4, and 12 have also been reported. Chromosome 6q deletions encompassing 6q21-22 have been observed in 40–90% of WM patients, and at a comparable frequency among patients with and without a familial history^ref (Treon SP, Braverman E, Branagan AR, et al. Deletions in 6q21-22 are commonly present in patients with familial and non-familial Waldenstrom’s macroglobulinemia and IgM monoclonal gammopathy of unknown significance [abstract]. Blood. 102:682a). Several candidate tumor suppressor genes in this region are under study, including BLIMP1, a master regulatory gene implicated in lymphoplasmacytic differentiation. Notable, however, is the absence of IgH switch region rearrangements in WM, a finding that may be used to distinguish WM from cases of IgM myeloma where IgH switch region rearrangements are a predominant feature^ref.
• immunophenotype : CD5^-10 / CALLA^-11c^+/-19⁺20⁺22⁺25^+/-79⁺FMC7.2⁺ cIg⁺, IgM^{hiref1, ref2}. Expression of CD5, CD10, and CD23 may be found in 10–20% of cases, and does not exclude the diagnosis of WM (Cafarella T, Manning R, Hunter Z, et al. Heterogeneous expression of CD5, CD10, and CD23 in IgM secreting lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia) [abstract]. J Clin Oncol. 2004;22:614s). Moreover, expression of CD10 and CD23 may be clinically significant. A higher incidence of familial disease has been reported with CD10 expression, whereas more pronounced hypogammaglobulinemia was observed in patients with expression of either CD10 or CD23 (Cafarella T, Manning R, Hunter Z, et al. Heterogeneous expression of CD5, CD10, and CD23 in IgM secreting lymphoplasmacytic lymphoma (Waldenstrom’s macroglobulinemia) [abstract]. J Clin Oncol. 2004;22:614s).

• options for initial therapy : a precise therapeutic algorithm for the upfront treatment of WM remains to be defined given a paucity of randomized clinical trials in this uncommon disorder. The consensus panel of the 2nd International Workshop on WM considered the following as reasonable choices for upfront therapy of WM^ref. Importantly, the panel felt that 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 a first-line agent. For patients who are candidates for autologous transplant therapy, and in whom such therapy is seriously considered, the panel recommended that exposure to alkylator or nucleoside analogue therapy be limited.
• alkylator-based therapy : oral alkylating drugs, alone and in combination therapy with steroids, have been extensively evaluated in the upfront treatment of WM. The greatest experience with oral alkylator therapy has been with chlorambucil, which has been administered on both a continuous (i.e., daily dose schedule) as well as an intermittent schedule. Patients receiving chlorambucil on a continuous schedule typically receive 0.1 mg/kg per day, while on the intermittent schedule patients will typically receive 0.3 mg/kg for 7 days, every 6 weeks. In a prospective randomized study, Kyle et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) reported no significant difference in the overall response rate between these schedules, although interestingly the median response duration was greater for patients receiving intermittent versus continuously dosed 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 (3 of 22 patients) versus the continuous (0 of 24 patients) chlorambucil schedule prompted the authors of this study to express preference for use of continuous chlorambucil dosing. The use of steroids in combination with alkylator therapy has also been explored. Dimopoulos and Alexanian (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) evaluated chlorambucil (8 mg/m²) along with prednisone (40 mg/m²) given orally for 10 days, every 6 weeks, and reported a major response (i.e., reduction of IgM by greater than 50%) in 72% of patients. Non-chlorambucil-based alkylator regimens employing melphalan and cyclophosphamide in combination with steroids have also been examined by Petrucci et al and Case et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) producing slightly higher overall response rates and response durations, although the benefit of these more complex regimens over chlorambucil remains to be demonstrated. Facon et al have evaluated parameters predicting for response to alkylator therapy. Their studies in patients receiving single-agent chlorambucil demonstrated that age > 60, male sex, symptomatic status, and cytopenias (but, interestingly, not high tumor burden and serum IgM levels) were associated with poor response to alkylator therapy. Additional factors to be taken into account in considering alkylator therapy for patients with WM include necessity for more rapid disease control given the slow nature of response to alkylator therapy, as well as consideration for preserving stem cells in patients who are candidates for autologous transplant therapy.  Alkylator-based therapy in Waldenström’s macroglobulinemia (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004).

study	N	setting	regimen	major RR (> 50% reduction in serum IgM levels)	median response duration
Facon	110	UnRx	Chl (continuous)	31%	NA
Kyle	24	UnRx	Chl (continuous)	75%	26 months
	22	UnRx	Chl (intermittent)	64%	46 months
Dimopoulos	77	UnRx	Chl, P	72%	na
Petrucci	31	UnRx	melphalan, cyclophosphamide, prednisone => cyclophosphamide, prednisone (continuous)	74%	66 months
Case	33	UnRx and Rx	melphalan-2 (BCNU, vincristine, melphalan, prednisone)	82%	43 months (CR), 39 months (PR)

• nucleoside analogue therapy : both cladribine and fludarabine have been extensively evaluated in untreated as well as previously treated WM patients. Cladribine administered as a single agent by continuous intravenous infusion, by 2-hour daily infusion, or by subcutaneous bolus injections for 5–7 days has resulted in major responses in 40%–90% of patients who received primary therapy, while in the salvage setting responses have ranged from 38% to 54% (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). Median time to achievement of response in responding patients following cladribine ranged from 1.2 to 5 months^{ref1, ref2}. The overall response rate with daily infusional fludarabine therapy administered mainly on 5-day schedules in previously untreated and treated WM patients has ranged from 38% to 100% and 30% to 40%, respectively, which are on par with the response data for cladribine (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004)). Median time to achievement of response for fludarabine was also on par with cladribine at 3–6 months. In general, response rates and durations of responses have been greater for patients receiving nucleoside analogs as first-line agents, although in four studies wherein both untreated and previously treated patients were enrolled, no substantial difference in the overall response rate was reported (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). Myelosuppression commonly occurred following prolonged exposure to either of the nucleoside analogs, as did lymphopenia with sustained depletion of both CD4+ and CD8+ T lymphocytes observed in WM patients 1 year following initiation of therapy^ref. Treatment-related mortality due to myelosuppression and/or opportunistic infections attributable to immunosuppression occurred in up to 5% of all treated patients in some series with either nucleoside analogue. Factors predicting for response to nucleoside analogues in WM included age at start of treatment (< 70 years), pretreatment hemoglobin > 95 g/L, platelets > 75,000/mm³, disease relapsing off therapy, patients with resistant disease within the first year of diagnosis, and a long interval between first-line therapy and initiation of a nucleoside analog in relapsing patients (reviewed in21). There are limited data on the use of an alternate nucleoside analogue to salvage patients whose disease relapsed or demonstrated resistance off cladribine or fludarabine therapy. 3 of 4 patients (75%) responded to cladribine following relapse to fludarabine therapy, whereas only 1 of 10 (10%) with disease resistant to fludarabine responded to cladribine (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). In a study by Lewandowski et al (reviewed in 21), 2 of 6 patients (33%) responded to fludarabine, in spite of an inadequate response or progressive disease following cladribine therapy :

study		number of  patients	median  number  of courses	major response rate (RR) (> 50% reduction in serum IgM levels)	median  response duration
cladribine	Dimopoulos	26	2	85%	2+–39+ months
	Delannoy	5	2	40%	NA
	Fridrik	10	4	90%	NA
	Liu	7	3	57%	NA
	Hellman	9	4	44%	NA
fludarabine	Dimopoulos	2	3	100%	NA
	Foran	15	5.2 (mean number of infusions)	79%	40 months
	Thalhammer-Scherrer	7	6	85%	44+ months
	Dhodapkar	118	4-8	38%	59 months

Nucleoside analogues in previously treated Waldenström’s macroglobulinemia :

study		number of  patients	median  number  of courses	major response rate (RR) (> 50% reduction in serum IgM levels)	median  response duration
cladribine	Dimopoulos	46	2	43%	12 months
	Delannoy	13	2	38%	NA
	Betticher	25	3	40%	8 months
	Liu	13	3	54%	NA
	Hellman	13	4	38%	NA
fludarabine	Dimopoulos	26	3	31%	NA
	Zinzani	12	6	41%	10+ months
	Leblond	71	6	30%	32 months
	Dhodapkar	118	4-8	33%	30 months

Transformation to a DLBCL or extensive extramedullary involvement with rapid progression and refractoriness to chemotherapy has been reported. Both patients were pretreated with multiple courses of prednisone and chlorambucil, and transformation occurred shortly after therapy with cladribine^ref.
• monoclonal antibody therapy has been extensively evaluated as both upfront and salvage therapy in patients with WM.
most of these efforts to date have centered on the use of rituximab, a chimeric monoclonal antibody that targets CD20, an antigen which is widely expressed on tumor cells in WM. 5 years ago, case reports and small retrospective series indicated that treatment with single-agent rituximab may induce responses in patients with resistant WM. Subsequently several retrospective and prospective studies have indicated that rituximab, when used at standard doses (i.e., 4 weekly infusions at 375 mg/m²) induced major responses in approximately 27–35% of previously treated and untreated patients (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). Furthermore, it was shown in some of these studies, that patients who achieved minor responses or even stable disease benefited from rituximab as evidenced by improved hemoglobin and platelet counts, and reduction of lymphadenopathy and/or splenomegaly. The median time to treatment failure in these studies was found to range from 8 to 27+ months. Studies evaluating an extended rituximab schedule consisting of 4 weekly courses at 375 mg/m²/week, repeated 3 months later by another 4-week course, have demonstrated major response rates of 44%–48%, with time to progression estimates of 16+ to 29+ months^{ref1, ref2}.

study	number of  patients	median  number  of courses	major RR (>50% reduction in serum IgM levels)	median  response duration
Byrd	6	4	57%	6.6+ months
Weber	7	4	75%	9.0 months
Foran	7	4	29%	NA
Treon	30	4	27%	8.0 months
Gertz	69	4	27%	27+ months
Dimopoulos	27	8	44%	16+ months
Treon	26	8	48%	29+ months

Rituximab is a well-tolerated treatment. Approximately one-quarter of patients may develop grade 1 or 2 infusion-related symptoms consisting primarily of fever, chills and headache, while a cytokine-release syndrome has rarely occurred. Because myelosuppression is negligible, rituximab may represent the treatment of choice for patients who present with or develop cytopenias. Moreover, the lack of early or delayed myelosuppression makes rituximab an attractive treatment for patients who are candidates for stem cell collection and high-dose therapy. In many patients, a transient increase of serum IgM may be noted immediately following initiation of treatment. The mechanism for this phenomenon is under investigation. Such an increase, however, does not herald treatment failure, and most patients return to their baseline serum IgM level by 12 weeks. Some patients do continue to show prolonged spiking despite demonstrating a reduction in their bone marrow tumor load^ref (Ghobrial IM, Fonseca R, Greipp PR, et al. The initial "flare" of IgM level after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: An Eastern Cooperative Oncology Group Study. Blood. 2003;102:448a). However, patients with baseline serum IgM levels of > 50 g/dL or serum viscosity of > 3.5 cp may be particularly at risk for a hyperviscosity-related event, and in such patients plasmapheresis should be considered in advance of rituximab therapy (Ghobrial IM, Fonseca R, Greipp PR, et al. The initial "flare" of IgM level after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: An Eastern Cooperative Oncology Group Study. Blood. 2003;102:448a). Because of the decreased likelihood of response in patients with higher IgM levels, as well as the possibility that serum IgM and viscosity levels may abruptly rise, rituximab monotherapy should not be used as sole therapy for the treatment of patients at risk for hyperviscosity symptoms. Time to response after rituximab is slow and exceeds 3 months on the average. Patients with baseline serum IgM levels of < 60 g/L are more likely to respond, irrespective of the underlying bone marrow involvement by tumor cells^{ref1, ref2}. A recent analysis of 52 patients who were treated with single-agent rituximab has indicated that the objective response rate was significantly lower in patients who had either low serum albumin (< 35 g/L) or elevated serum monoclonal protein (> 40g/L M-spike). Furthermore, the presence of both adverse prognostic factors was related with a short time to progression (3.6 months). Moreover, 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 (Ghobrial IM, Fonseca R, Greipp PR, et al. The initial "flare" of IgM level after rituximab therapy in patients diagnosed with Waldenstrom macroglobulinemia: An Eastern Cooperative Oncology Group Study. Blood. 2003;102:448a). The genetic background of patients may also be important for determining response to rituximab. In particular, a correlation between rituximab response and polymorphisms at position 158 in the FcgRIIIa receptor (CD16), an activating Fc receptor on important effector cells that mediate antibody-dependent cell-mediated cytotoxicity (ADCC), was observed in WM patients. Individuals may encode either the amino acid valine or phenylalanine at position 158 in the FcgRIIIa receptor. WM patients who carried the valine amino acid (in either a homozygous or heterozygous pattern) had a 4-fold higher major response rate (i.e., 50% decline in serum IgM levels) to rituximab versus those patients who expressed phenylalanine in a homozygous pattern (Treon SP, Fox EA, Hansen MM, et al. Polymorphism in Fc gamma RIIIa (CD16) receptor expression are associated with clinical responses in Waldenström’s macroglobulinemia [abstract]. Blood. 2002;100:773a.). Because rituximab is an active and a nonmyelosuppressive agent, its combination with chemotherapy has a sound rationale. Weber et al^ref administered the combination of rituximab, cladribine and cyclophosphamide to 17 previously untreated patients with WM. A major response was documented in 94% of patients, with 18% of patients achieving a complete remission in this study. With a median follow-up of 21 months, no patient has relapsed in this study. Treon et al (Treon SP, Wasi P, Emmanoulilides C, et al. Combination therapy with rituximab and fludarabine is highly active in Waldenstrom’s macroglobulinemia [abstract]. Blood. 2002;100:211a) have explored the use of rituximab and fludarabine in WM. In recently updated studies, 42 patients, including some previously untreated patients, have been treated. At least a minor response was noted in 90% (83% major response rate) of patients, and only 2 of 37 patients have progressed with a median follow-up of 15 months.
• alemtuzumab is a monoclonal antibody against CD52 antigen and is effective treatment for patients with chronic lymphocytic leukemia who have previously received a purine analog. Several studies have demonstrated wide expression of CD52 in WM. Preliminary clinical data on 7 heavily pretreated patients who received treatment with alemtuzumab showed 4 partial and 1 complete response, and a median response duration of 13 months (Owen RG, Rawstron AC, Osterborg A, et al. Activity of alemtuzumab in relapsed/refractory Waldenstrom’s macroglobulinemia. Blood. 2003;102:644a). Infectious complications were common in this study and included cytomegalovirus (CMV) reactivation, herpes simplex reactivation, aspergillosis and tuberculosis. In ongoing studies by the Waldenström’s Macroglobulinemia Clinical Trials Group (WMCTG), 7 patients with 2 median prior therapies have received alemtuzumab. 6 of 7 patients demonstrated a response, 3 minor and 3 major. Toxicities were mainly hematologic with reversible grade III/IV thrombocytopenia, neutropenia and prolonged pancytopenia in 1 patient (Treon SP, Hunter Z, Branagan AR. Campath-1H in Waldenstrom’s macroglobulinemia [abstract]. Proceedings of the 2004 Clinical Investigator Meeting, Cambridge, Massachusetts, 2004)
• treatment options for relapsed and refractory disease : a consensus panel on therapeutics for WM also considered options for patients with relapsed and refractory disease^ref. For patients in relapse or who have refractory disease, the use of an alternative first-line agent as defined above was considered as a reasonable choice, with the caveat that for those patients for whom autologous transplantation was being considered seriously, further exposure to stem cell–damaging agents (i.e., many alkylator agents and nucleoside analogue drugs) should be avoided, and a non-stem cell–toxic agent such as rituximab should be considered if stem cells have not been previously harvested.
• thalidomide, as a single agent and in combination with dexamethasone and clarithromycin, has also been examined in patients with WM, in view of the success of these regimens in patients with advanced multiple myeloma. Dimopoulos et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) demonstrated a major response in 5 of 20 previously untreated and treated patients (25%) who received single-agent thalidomide. Dose escalation from the thalidomide start dose of 200 mg daily was hindered by development of side effects, including the development of peripheral neuropathy in 5 patients, obligating discontinuation or dose reduction. Low doses of thalidomide (50 mg orally daily) in combination with dexamethasone (40 mg orally once a week) and clarithromycin (250 mg orally twice a day) have also been examined, with 10 of 12 (83%) previously treated patients demonstrating at least a major response. However, in a follow-up study by Dimopoulos et al33 using 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), only 2 of 10 (20%) previously treated patients responded.
• high-dose therapy and HSCT : the use of transplant therapy has also been explored in patients with WM (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004). 8 previously treated WM patients between the ages of 45 and 69 years received either melphalan at 200 mg/m2 (n = 7) or melphalan at 140 mg/m² along with total-body irradiation. Stem cells were successfully collected in all 8 patients, although a second collection procedure was required for 2 patients who had extensive previous nucleoside analogue exposure. There were no transplant-related mortalities and toxicities were manageable. All 8 patients responded, with 7 of 8 patients achieving a major response, and 1 patient achieving a complete response with durations of response raging from 5+ to 77+ months. Dreger et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) investigated the use of the DEXA-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) regimen followed by myeloablative therapy with cyclophosphamide, and total-body irradiation and autologous stem cell transplantation in 7 WM patients, including 4 untreated patients. Serum IgM levels declined by > 50% following DEXA-BEAM and myeloablative therapy for 6 of 7 patients, with progression-free survival ranging from 4+ to 30+ months. All 3 evaluable patients, who were previously treated, also attained a major response in a study by Anagnostopoulos et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) in which WM patients received various preparative regimens and showed event-free survivals of 26+, 31, and 108+ months. Tournilhac et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) recently reported the outcome of 18 WM patients in France who received high-dose chemotherapy followed by autologous stem cell transplantation. All patients were previously treated with a median of 3 (range 1–5) prior regimens. Therapy was well tolerated with an improvement in response status observed for 7 patients (6 PR to CR; 1 stable disease [SD] to PR), while only 1 patient demonstrated progressive disease. The median event-free survival for all nonprogressing patients was 12 months. Reports on the use of high-dose chemotherapy and allogeneic transplantation in WM are limited. Martino et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) reported event-free survivals of 3 and 9 years for 2 young patients (ages 34 and 39) with progressive disease, including 1 patient who progressed after high-dose chemotherapy and autologous stem cell transplantation. Tournilhac et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) reported the outcome of allogeneic transplantation in 10 previously treated WM patients (ages 35–46) who received a median of three prior therapies, including 3 patients with progressive disease despite therapy. 2 of 3 patients with progressive disease responded, and an improvement in response status was observed in 5 patients. The median event-free survival for nonprogressing, evaluable patients was 31 months. Concerning in this series was the death of 3 patients owing to transplantation-related toxicity. Similarly, Anagnostopoulos and Giralt (reviewed in 21) reported that 2 of 3 patients in their series who underwent allogeneic transplantation experienced an early death or death from complicating graft-versus-host disease. The third patient in this series did not respond to therapy. In view of the high rate of mortality associated with high-dose chemotherapy and allogeneic transplantation, Maloney et al (Merlini G, Treon SP. Waldenstrom’s disease. In: Multiple Myeloma and Related Disorders. Gahrton G, Durie B, Samson DM, editors. Oxford University Press Inc., New York N.Y. 2004) have evaluated the use of nonmyeloablative allogeneic transplantation in 5 patients with refractory WM. In this series, 3 of 3 evaluable patients (all of whom had matched sibling donors) responded, with 2 CR and 1 in PR at 1–3 years post-transplant.

• complete response : complete disappearance of serum and urine monoclonal protein by immunofixation, resolution of lymphadenopathy and of organomegaly, and no signs or symptoms that are directly attributable to WM. These findings must be confirmed 6 weeks later. Absence of malignant cells by bone marrow histologic evaluation is required.
• partial response : a  50% reduction of serum monoclonal protein concentration on electrophoresis and  50% reduction of lymphadenopathy and of organomegaly on physical examination or computed tomography. Symptoms and signs that are directly attributable to WM must resolve.
• relapse from CR : reappearance of serum monoclonal protein as determined by immunofixation confirmed by a second measurement or reappearance of clinically significant symptoms and signs attributable to WM or development of any other clinically significant disease-related complication.
• progressive disease : a > 25% increase in serum monoclonal protein levels from the lowest attained response value as determined by serum electophoresis, confirmed by measurement 3 weeks later. For monoclonal protein nadirs  20 g/L, an absolute increase of 5 g/L is required to determine progressive disease (PD). PD may also be documented if there is worsening of anemia, thrombocytopenia, leukopenia, lymphocytosis, lymphadenopathy, or organomegaly directly attributable to WM or appearance of disease-related complications such as unexplained fever, night sweats, weight loss, neuropathy, nephropathy, symptomatic cryoglobulinemia, or amyloidosis. Serum monoclonal protein should ideally be measured by serum protein electrophoresis because in some settings the use of nephelometry to determine total serum IgM may be unreliable, particularly when the levels of the monoclonal protein are high. The presence of cryoglobulin or cold agglutinin may affect determination of IgM. Testing of these at baseline should be considered and if present serum samples should be re-evaluated at 37°C to ensure accurate and consistent determination of the monoclonal protein levels.

• age >= 70 years, hemoglobin < 90 g/L, weight loss, cryoglobulinemia^ref
• age <= 65 years, serum albumin < 40 g/L, hemoglobin < 120 g/L, cytopenias (platelets < 150 x 10⁹/L, leukocytes < 4.0 x 10⁹/L, neutrophils < 1.5 x 109/L)^ref
• serum ß₂-microglobulin <= 3 mg/L, hemoglobin < 120 g/L, serum IgM < 40 g/L^ref

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