Guideline for diagnosis and treatment of
Waldenström’s macroglobulinaemia
J.M.I. Vos1, M.C. Minnema2, P.W. Wijermans3, S. Croockewit4, M.E.D. Chamuleau5, S.T. Pals6,
S.K. Klein7, M. Delforge8, G.W. van Imhoff9, M.J. Kersten6
On behalf of the HOVON Multiple Myeloma Working Party and the HOVON Lymphoma Working Party
1St. Antonius Hospital Nieuwegein, the Netherlands, 2University Medical Centre Utrecht, the Netherlands, 3Haga Hospital, The Hague, the Netherlands, 4University Medical Centre Nijmegen, the Netherlands, 5VU University Medical Centre, Amsterdam, the Netherlands, 6Academic Medical Centre, Amsterdam, the Netherlands, 7Meander Medical Center, Amersfoort, the Netherlands, 8Catholic University Leuven, Belgium, 9University Medical Centre Groningen, the Netherlands, *corresponding author: e-mail: [email protected] a B s t r a C t
i n t r o d U C t i o n
On behalf of the lymphoma and multiple myeloma In the latest World Health Organisation (WHO) working parties of the Dutch/Belgian Haemato-Oncology classification (2008), Waldenström’s macroglobulinaemia Foundation for Adults in the Netherlands (HOVON), we (WM) is defined as a neoplasm composed of small B present a guideline for diagnosis and management of lymphocytes, plasmacytic lymphocytes and plasma cells, Waldenström’s macroglobulinemia (WM). Considering the accompanied by a paraproteinaemia of the IgM type, while indolent behaviour and heterogeneous clinical presentation not meeting diagnostic criteria for other small-cell B-cell of WM, it is crucial to determine the right indications for malignancies. The term lymphoplasmacytic lymphoma treatment, as well as to individualise therapeutic options. (LPL) refers to WM plus those rare cases lacking the IgM There are significant differences from the approach to M-protein (more than 95% of all LPLs are WM). In this multiple myeloma or the treatment of other indolent guideline we will use the term WM, but it is also applicable non-hodkgin lymphomas, and these results cannot always be extrapolated. There is a lack of large clinical trials due The Swedish physician Jan Gösta Waldenström (1906-1996) described this disease for the first time Based on the available data, we provide a practical in 1944. It is a rare type of lymphoma: worldwide the diagnostic classification, as well as recommendations for incidence is approximately 3 per million persons per year. first-line therapy and options for treating relapsed disease. The average age at diagnosis is 65 years. Some typical clinical features of WM, such as autoimmune phenomena and “IgM flare” after rituximab treatment, are Although there are a wide range of therapeutic options, WM still remains incurable. Therefore, in asymptomatic A more elaborate version of this guideline was published patients, a ‘wait and see’ policy is advocated, such as in in the “Nederlands Tijdschrift voor Hematologie” (Dutch other indolent lymphomas. The prognosis is very variable with survival ranging from five to more than ten years. Because WM occurs mainly in the elderly, combined with its indolent course, half of the patients die of a cause other K e y W o r d s
than the lymphoma. This guideline includes recommendations on the diagnosis Van Zuiden Communications B.V. All rights reserved.
d i a G n o s i s a n d d i a G n o s t i C
C l i n i C a l s y M P t o M s , H i s t o r y
C l a s s i f i C a t i o n
t a K i n G a n d P H y s i C a l
e x a M i n a t i o n

For the diagnosis of WM, an IgM M-protein needs to be present in blood, as well as histological proof of a Approximately one third of the patients are asymptomatic lymphoplasmacytic infiltrate, virtually always localised at diagnosis. The symptomatology of WM is determined in the bone marrow. Depending on whether or not there by both the tissue infiltration and immunological activity are lymphoma-related symptoms, this can be classified of the lymphoma cells, as well as by the physico-chemical as a symptomatic WM (with treatment indication) or properties and immunological specificity of the monoclonal asymptomatic WM (the latter has a higher risk of progression IgM protein. The clinical presentation of WM is therefore than IgM monoclonal gammopathy of unknown significance often very different from other malignant lymphomas. (MGUS)). (See tables 1, 2 and 3). Of importance, an IgM In the workup of WM patients, a thorough review of the paraprotein of any level is not sufficient for the diagnosis systems during medical history taking is very important, as WM, since there are several other lymphoproliferative well as a complete physical examination, with special attention disorders that produce IgM (see differential diagnosis). The for lymphadenopathy, hepatosplenomegaly, neuropathy, IgM level is not predictive for the onset of symptoms, and is autoimmune phenomena and signs of hyperviscosity (for a also not necessarily a reliable marker for tumour burden.1-4 comprehensive list of symptomatology: see table 1).5 table 1. Symptomatology, frequency and mechanism
symptom or sign
Percentage at first diagnosis Mechanism and/or specific recommendations
Iron deficiency due to gastrointestinal bleeding Get an ophthalmology consult for fundoscopy When measured serum viscosity is >4.0 cp there is a high risk of IgM antibodies against myelin-associated glycoprotein (MAG), gan- glioside M1 (GM1) or myopathy (antidecorine antibodies) Aetiology is uncertain: tumour infiltration or local IgM deposition and/or abnormalities on MRI Raynaud’s phenomenon (11%), Reminder: immunoglobulins should be obtained in a warm bath to avoid cryoprecipitation and false lowering of serum IgM levels Hyperviscosity, sensorineural neuropathy, Antiphospholipid syndrome via IgM antibodies Schnitzler syndrome (nonpruritic urticaria), local tumour infiltra- tion, amyloidosis, cold agglutination/cryo Specific IgM-mediated glomerulonephritis, amyloidosis, vasculitis. When osteolytic lesions are present consider IgM multiple myeloma Hypogammaglobulinaemia, consider antibiotic prophylaxis or IVIG Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
table 2. Diagnostic workup (Items in bold font should be done in each new patient)
serum electrophoresis incl. quantative M-protein;
Light chain assay in serum/urine: not indicated immunofixation
Reminder: immunoglobulins should be obtained in a warm bath immuunglobulines iga, igM, igG
to avoid cryoprecipitation and false lowering of serum IgM levels in Complete blood count, Pt, aPtt
liver enzymes, renal function
Bone marrow biopsy for morphology and

Immunophenotyping and cytogenetics are optional, they can be helpful to distinguish WM from other small cell b-NHL Recommended for staging before starting treatment Haemolysis parameters (LDH, haptoglobin, reticulocytes, if positive followed by Coombs test and testing for cold agglutinins)
B2-microglobulin and albumin
Viscosity measurement and ophthalmology consult When there is clinical suspicion of hyperviscosity, obtain an ophthal- Measurement of serum viscosity is useful but the diagnosis of hyper- viscosity syndrome can be made on clinical grounds only Mixed (type II) cryoglobulinaemia is associated with hepatitis C, the Determining HCV and HBV status is relevant before starting therapy. Myelin-associated glycoprotein (MAG), ganglioside M1 (GM1) When polyneuropathy is present, in order to determine its cause (i.e. antibodies (in PNP) or antidecorine antibodies (in myopathy) neurological evaluation incl. EMGTargeted biopsy if amyloid is suspected Abdominal fat aspiration if targeted organ biopsy is difficult. Also test table 3. Diagnostic classification
symptomatic WM
igM-related disorder
* refer also to tables 1 and 3
(bone marrow)WM-related signs or symptoms* No The most common presenting complaint is fatigue, often this is associated with vasculitis, Raynaud’s phenomenon caused by anaemia. The anaemia is often more pronounced and glomerulonephritis. Precipitation of the M-protein than expected based on the degree of bone marrow into amyloid can lead to organ damage: neuropathy, infiltration. Haemolysis, ‘anaemia of chronic disease’ cardiomyopathy, nephropathy or gastrointestinal problems. caused by proinflammatory factors, dilution through It is recommended to pay attention to the family history, increased plasma volume, and gastrointestinal bleeding since WM is sometimes associated with familial clustering of various lymphoproliferative diseases.6 An increased bleeding tendency (of various origins) Finally, because of the size of the IgM protein, occurs in up to 20% of patients. Hepatosplenomegaly hyperviscosity syndrome can develop with its typical and lymphadenopathy occur in only 15-20% of patients. symptoms: disturbed vision, headache, dizziness, IgM-mediated autoimmune disease is a very distinctive heart failure and neurological complications. When manifestation of WM and can also be the presenting hyperviscosity is suspected, an ophthalmological consult symptom. The most common autoimmune phenomena are neuropathy by anti-MAG (myelin associated glycoprotein) IgM antibodies, and autoimmune haemolysis caused by anti-I or anti-i IgM antibodies with complement activation d i a G n o s t i C e V a l U a t i o n
(cold agglutination). In about 10% of cases the IgM precipitates when the Please refer to table 2 for recommended diagnostic studies temperature drops below the 37 °C (cryoglobulinaemia); Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
Bone marrow evaluation
is recommended. A PET scan is not necessary, unless Bone marrow examination (biopsy) is required for the diagnosis, since this lymphoma is preferably, and often exclusively, located in the bone marrow. The infiltration typically consists of small B lymphocytes, plasmacytic C l a s s i f i C a t i o n o f i G M - r e l a t e d
lymphocytes and plasma cells (see histology illustrations d i s o r d e r s
in figure 1). The typical immunophenotype is: expression of B-cell As for diagnostic classification, WM is somewhere in antigens (CD19/20/22/79a), membrane-bound IgM, and between non-Hodgkin’s lymphomas (NHL) and plasma cytoplasmatic IgM in the plasma cells, with absence of cell dyscrasias. The WHO classification and important IgD, CD23, CD103, and CD10. CD5 is usually negative, if international guidelines are not entirely in agreement.1,4 positive chronic lymphocytic leukaemia (CLL) and mantle For the clinician, it is particularly relevant that in some cell lymphoma should be excluded. Additionally, CD38 cases a wait-and-see policy can be applied (IgM MGUS, and CD27 are often positive. The plasma cells are CD138 asymptomatic WM), while in other cases therapy is needed (symptomatic WM, IgM-related conditions) (table 3).
When immunohistochemistry is performed on biopsy material, immunophenotyping of the bone marrow igM MGUs / asymptomatic WM
aspirate is not mandatory. However, in some cases it can The risk of progression of IgM MGUS to WM is be helpful to discriminate WM from other low-grade B-cell approximately 1.5% per year. If clear bone marrow infiltration was present (classification: asymptomatic WM) then a treatment indication arose in 6% of patients after Cytogenetics/molecular markers
one year, 59% after five years, and 68% after ten years in Several cytogenetic abnormalities have been described in WM, such as 6q-deletion, and t(9, 14) (p13; q32) both in 40-50% of patients. Recently, Steve Treon et al. symptomatic WM and igM-related disease
found a specific point mutation (L265P) in the gene In patients with IgM M-protein, bone marrow infiltration MYD88 (involved in the NFkB cascade) in 27 of 30 and WM-related symptoms, the diagnosis ‘symptomatic patients.8 However, at this point these findings do not WM’ can be made and treatment is indicated. have solid prognostic or therapeutic value. Routine Sometimes a very small amount of IgM without evidence cytogenetic or molecular testing is therefore currently of LPL in the bone marrow can cause symptoms, for not indicated. Targeted fluorescent in situ hybridisation example amyloidosis, or autoimmune-mediated (FISH) analysis can be helpful if multiple myeloma or neuropathy. These patients do not meet the criteria for follicular lymphoma is suspected; see also the section on WM, but do have relevant symptomatology. For these cases, the term ‘IgM-related disorder’ was introduced. Despite a small tumour load, a treatment indication can occur in imaging studies
these cases, and the choice of therapy is determined mainly For staging purposes, i.e. before starting treatment, a conventional CT scan of the neck, thorax and abdomen d i f f e r e n t i a l d i a G n o s i s
figure 1. Bone marrow biopsy with localisation of
In the rare cases of LPL without IgM paraprotein (5%), diagnosis can be challenging and depends on the exclusion of other small-cell b lymphomas, such as the marginal zone lymphoma or CLL. Sometimes no definitive diagnosis can be made. When prominent paratrabecular infiltration is found, follicular lymphoma must be considered, which is usually CD10 positive and associated with t(14,18) translocation. When LPL is accompanied by an IgA or IgG type paraprotein, distinction from a multiple myeloma is difficult. Vice versa, multiple myeloma can be accompanied diffuse infiltration of bonemarrow by small lymphocytes (left). these
with an IgM paraprotein, although rare. IgM multiple cells are Cd20 positive (middle). some show plasmacellular differen-
myeloma, unlike WM, usually carries translocation t(11,14), tiation with intracytoplasmatic expression of igM (right).
and often features osteolytic bone lesions. Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
P r o G n o s i s
C H o i C e o f s y s t e M i C t r e a t M e n t
Survival is between five and ten years with a wide first-line therapy
range, and there is small group of patients who remain Immunochemotherapy: In one of the few randomised asymptomatic without treatment for a long time (>10 studies conducted in patients with WM, Buske et al.15 years). The International Prognostic Scoring System for showed that the addition of rituximab to chemotherapy WM (IPSS-WM) gives some idea about the individual leads to higher response rates and a longer time to prognosis (table 4). This scoring system is based on progression in patients with WM. Immunochemotherapy pre-rituximab patient data, but has since been validated in is considered the standard for first-line treatment. at least one study. The IPSS score does not help in making The combination of alkylating agents such as treatment decisions, but can be important when comparing cyclophosphamide with rituximab and steroids is usually outcomes of patients in clinical trials.11 a well-tolerated regime. A comparative review article (no randomised studies are available here) showed that the response rates and duration for rituximab- t r e a t M e n t
cyclophosphamide prednisone vs addition to this regimen of adriamycin and/or vincristine (R-CHOP or R-COP) seem Because WM is rare and randomised studies are mostly similar, while the last two regimens tend to give more lacking, it is not easy to establish evidence-based guidelines toxicity (mainly neutropenic fever and neuropathy).16 for treatment. This also applies to the choice of first-line A good alternative is DRC: dexamethasone, rituximab, therapy. Some recently published reviews summarise cyclophosphamide, which is less myelosuppressive due to the published data (mostly retrospective series) on the lower dose of cyclophosphamide, while effectiveness remains high.17 DRC will be used as the standard arm of When choosing treatment it is important to realise that the first-line study by the European Myeloma Network. there are many options available, and that therapy needs Also chlorambucil, whether or not in combination with to be adapted to the individual patient, taking into account rituximab, is still an option when there is no hyperviscosity age, life expectancy, (co)morbidity (i.e. neuropathy) and or other need for rapid response. Chlorambucil and clinical need for rapid response (i.e. hyperviscosity). combination chemotherapy have never been compared head to head. In younger patients, who are potential Plasmapheresis and prevention of igM flare
candidates for autologous stem cell transplantation, the When a patient presents with hyperviscosity syndrome, long-term use of alkylating agents such as chlorambucil is there is an indication for plasmapheresis, and treatment not recommended, also because of concerns about the risk with a rapid-acting agent should be started in order to halt of developing myelodysplastic syndromes/acute myeloid the production of the M-protein. When serum viscosity is >4.0 cp, there is a high risk of hyperviscosity-related Rituximab combined with purine analogues (fludarabine, events. Plasmapheresis may also be applied as a preventive cladribine) with or without cyclophosphamide (e.g. measure when rituximab is started in a patient with a total FC-R) is very effective, and often leads to fast responses IgM of >40 g/l, to prevent hyperviscosity due to IgM flare. A (median after 2.5 months). In a large randomised study by practical alternative in this situation is to start chemotherapy Leblond et al., which will be published soon, monotherapy and only add rituximab once IgM levels are lower. fludarabine seems to be more effective than monotherapy with chlorambucil.18 Regarding purine analogues, there are concerns about a higher risk of MDS/AML and transformation to aggressive table 4. IPSS-WM]
NHL; however, data in WM are somewhat conflicting. It is still advised to give a maximum of 4-6 courses. There are fewer data on cladribine, but it seems equally effective. Purine analogues must be avoided in patients who are candidates for autologous stem cell transplantation.
Every rituximab-containing therapy can cause an IgM flare. Please refer to the plasmapheresis section.
risk group
Median survival
Rituximab single agent and IgM flare: In patients with contraindications for chemotherapy, for example cytopenia or severe neuropathy, single agent rituximab may be an option. However, the chances of response are lower and Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
responses are very slow compared with the combination of of approximately 80% in three studies with 64 mostly rituximab with (mild) chemotherapy and steroids.5 Again, pretreated patients (e.g. Kastritis et al.12). The response the phenomenon ‘IgM flare’ is of importance: in about half was quick (1.5 months) while with most classic therapies of the patients the IgM rises first, and only starts to drop responses only start after four months. The progression-free after four months. The initial rise of IgM after rituximab survival was at least one year. In a small first-line study using should not be interpreted as progressive disease! Whether the combination of bortezomib, rituximab, dexamethasone this phenomenon has prognostic implications is unknown. (BRD) even higher response rates were seen, and after two years 80% of patients had no signs of progression.21 treatment of igM-related disease: polyneuropathy and
The main adverse effect is neuropathy (about 70% of haemolytic anaemia
patients, up to 30% grade 3, often reversible after dose These patients do not meet the criteria for WM but have reduction) and this seems to occur more frequently WM-related symptoms and an IgM paraproteinaemia.4 compared with the use of bortezomib in multiple myeloma. There is a wide array of rare syndromes, ranging from Perhaps using once weekly and subcutaneous dosing may acquired haemophilia to vasculitis, and they all deserve reduce rates of neuropathy. Of course, it is important to their own therapeutic approach, although little clinical pay close attention to neuropathic symptoms and adjust or data are available. We will only discuss the two most withhold therapy when necessary. Clinical studies in WM common presentations of IgM-related disease, namely patients are underway with the new proteasome-inhibitor polyneuropathy (PNP) and cold autoimmune haemolytic carfilzomib, which seems markedly less neurotoxic. The European Myeloma Network (EMN) is preparing an Approximately 50% of patients with demyelinating international study for first-line treatment randomising polyneuropathy related IgM paraproteinemia carry anti-MAG antibodies (amyloidosis should also be considered as a cause of PNP in WM patients). Treatment is not always necessary because these PNPs usually In a large study by Rummel et al., which was presented progress very slowly. Single-agent rituximab is considered at the American Society of Hematology Congress in the treatment of choice with responses and symptom relief 2009 but has not yet been published, 546 patients with seen in up to 50% of patients. For patients with rapidly various low-grade lymphomas were randomised to progressive and/or recently diagnosed PNP, immunochem- first-line treatment with rituximab-bendamustine versus otherapy could be considered because reduction of the IgM rituximab-CHOP, including 40 patients with WM. The response rate in patients with WM was very high in both In a cohort of 66 patients with cold agglutination, 50% arms (96% and 94%). However, bendamustine was less met the criteria for WM. Almost all of the remaining toxic (fewer infections, no alopecia, and less neuropathy) patients had an IgM paraprotein and in most of them cold while the progression-free survival was significantly agglutination was diagnosed as an IgM-related disorder. Treatment is difficult and again not always necessary. In a series of 30 patients with relapsed or refractory WM Rituximab monotherapy yields a response in about 50% published by Treon et al. bendamustine with rituximab of patients. When there is no response to single agent resulted in response in 83% of cases; the median rituximab, or when rapid response is needed, there are progression-free survival was 13 months. The therapy several options, such as combining it with fludarabine but was well tolerated, the main side effect being myelosup- other combinations of immunochemotherapy could also pression, especially in patients who were previously treated with purine analogues. 23 Based on a small group of patients in two studies salvage therapy
bendamustine, combined with rituximab, seems a very The same indications for treatment are applicable (treat only effective option with relatively little toxicity. Little is known if there is WM-related symptomatology and not just based about the long-term side effects of bendamustine in WM on a rising IgM) as in the first-line setting. If the response after first-line treatment lasts for more than two years the same treatment can be repeated. If not, one of the other Therapeutic options currently not recommended options can be chosen, as mentioned above, or alternatively There is very little experience with alemtuzumab, and consider novel agents or transplantation as discussed below. it seems to give much toxicity in patients with WM.24 Thalidomide has too little effectiveness to be applied as monotherapy. But, it is not so myelosuppressive and Proteasome inhibitors prove very effective in the treatment when combined with rituximab, results are slightly better. of WM. Monotherapy with bortezomib gave response rates However, there is little experience with this combination Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
and because of its neurotoxicity thalidomide is not an table 5. Response criteria
attractive option in WM. Lenalidomide should not be used, response
because in WM patients deep anaemia has been described, Disappearance of monoclonal protein by immuno- which also persisted after dose reduction or cessation. (e.g. fixation; no histological evidence of bone marrow involvement, and resolution of any adenopathy/ organomegaly (confirmed by CT scan), along with no signs or symptoms attributable to WM; recon- firmation of the CR status is required at least 6 The majority of patients are not candidates for stem A >50% reduction of serum monoclonal IgM con- cell transplantation due to age and comorbidity. For centration on protein electrophoresis and >50% a select group of younger and fit patients who relapse decrease in adenopathy/organomegaly on physical examination or on CT scan; no new symptoms or quickly after immunochemotherapy, autologous stem cell transplantation can be considered. In a recent series in A >25% but <50% reduction of serum monoclonal heavily pretreated WM patients, the non-relapse mortality IgM by protein electrophoresis; no new symptoms was 4-6% in the 1st year. The median progression-free A <25% reduction and <25% increase of serum survival was about 4 years and after 5 years 60% of patients monoclonal IgM by electrophoresis without pro- gression of adenopathy/organomegaly, cytopenias, or clinically significant symptoms resulting from After allogeneic stem cell transplantation, non-relapse mortality is very high in WM patients: in the largest Progressive A >25% increase in serum monoclonal IgM by series 23-40% after 1 year, depending on the conditioning protein electrophoresis confirmed by a second measurement or progression of clinically signifi- (reduced-intensity or myeloablative, respectively).27 The cant findings resulting from disease (i.e., anaemia, five-year progression-free survival was about 45-50% thrombocytopenia, leukopenia, bulky adenopa- thy/organomegaly) or symptoms (unexplained and the overall survival 50-60%. Chronic graft versus recurrent fever >38.4 °C, drenching night sweats, host disease was associated with higher non-relapse >10% body weight loss, or hyperviscosity, neuropa- mortality and lower relapse rates. Considering the available thy, symptomatic cryoglobulinaemia, or amyloido- alternatives and the high treatment-related mortality, allogeneic stem cell transplantation should only be considered in the rare young patient with a very aggressive disease course. or slower (chlorambucil, rituximab). After chlorambucil therapy, there is often a reduction of clonal B lymphocytes, There are no prospective studies on the role of but the plasma cells remain and may be the source of the maintenance therapy in WM. In a retrospective series 86 of 248 WM patients received maintenance therapy with rituximab: a median of eight doses in the two years after induction therapy with a rituximab-containing regimen. C o n C l U s i o n s a n d
Both the progression-free survival (56 vs 29 months) and r e C o M M e n d a t i o n s
the overall survival (not reached vs 116 months) were better in the maintenance group. Regarding symptomatology, pathophysiology as well Maintenance therapy with rituximab in WM can be as treatment, WM holds a special position within the considered after second-line treatment, similar to the low-grade malignant lymphomas. There is definitely room for improvement in treatment results in this relatively rare disease, both regarding effectiveness and toxicity, and therefore it is important to treat patients in clinical r e s P o n s e a s s e s s M e n t
trials when possible, stratifying for WM-IPSS score and using uniform response criteria. One of the challenges At the 3rd International WM workshop uniform response for the future, as in many non-Hodgkin’s lymphomas, criteria were established,29 which are summarised in table 5. is to determine response to treatment faster and more accurately, in order to identify high-risk patients sooner Because the M-protein sometimes responds very slowly, and the level of the M-protein is an unreliable indicator Because of treatment toxicity, which can be very disease- of tumour mass, it is recommended to repeat bone specific (deep anaemia after lenalidomide, higher risk marrow examination when in doubt about the response. of neuropathy with proteasome inhibition), clinical Depending on the agent used, lowering the IgM level experience in treatment of other indolent lymphomas can be faster (purine analogues, proteasome inhibition) Vos, et al. Diagnosis and treatment of Waldenström’s macroglobulinaemia.
r e C o M M e n d a t i o n s f o r C l i n i C a l
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3. The level of the M-protein is no reason for treatment if 8. Treon SP, Xu L, Yan G et al. MYD88 L265P Somatic Mutation in the patient is asymptomatic. Vice versa, a small amount Waldenstrom’s Macroglobulinemia. NEJM. 2012;367826-33.
of M-protein can give rise to symptoms and thus be a 9. Kyle RA, Dispenzieri A, Kumar S, Larson D, Therneau T, Rajkumar SV. IgM monoclonal gammopathy of undetermined significance (MGUS) and smoldering Waldenstrom’s macroglobulinemia (SWM). Clin Lymphoma 4. In patients with hyperviscosity syndrome, plasmapheresis should be started immediately. In 10. Kyle RA, Benson JT, Larson DR, Therneau TM, Dispenzieri A,Kumar addition a rapidly acting therapy to halt IgM production S, Melton LJ, Rajkumar SV. Progression in smolderingWaldenstrom macroglobulinemia: long-term results. Blood. 2012; 119:4462-66).
should be instituted. Wait until the IgM has dropped before giving rituximab because of potential IgM flare.
11. Morel P, Duhamel A, Gobbi P et al. International prognostic scoring system for Waldenstrom macroglobulinemia. Blood. 2009;113:4163-70.
5. As a first-line treatment combination immunochemo- 12. Kastritis E, Terpos E, Dimopoulos MA. Emerging drugs for Waldenstrom’s therapy is recommended, such as the dexamethasone, macroglobulinemia. Expert Opin Emerg Drugs. 2011;16:45-57.
rituximab, cyclophosphamide (DRC) regimen, or 13. Dimopoulos MA, Gertz MA, Kastritis E, et al. Update on treatment rituximab plus cyclophosphamide/prednisone (R-CP). recommendations from the Fourth International Workshop on Waldenstrom’s Macroglobulinemia. J Clin Oncol. 2009;27:120-26.
Chlorambucil, combined with rituximab and/or steroids, is a good alternative, especially in the older 14. Rourke M, Anderson KC, Ghobrial IM. Review of clinical trials conducted in Waldenstrom macroglobulinemia and recommendations for reporting clinical trial responses in these patients. Leuk Lymphoma. 6. In younger patients (and/or patients who are potential candidates for autologous stem cell transplantation): 15. Buske C, Hoster E, Dreyling M, et al. The addition of rituximab to front-line therapy with CHOP (R-CHOP) results in a higher response rate prolonged use of purine analogues and alkylating and longer time to treatment failure in patients with lymphoplasmacytic lymphoma: results of a randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Leukemia. 2009;23:153-61.
7. When starting a WM patient on rituximab, be aware of 16. Ioakimidis L, Patterson CJ, Hunter ZR, et al. Comparative outcomes following CP-R, CVP-R, and CHOP-R in Waldenstrom’s macroglob- 8. When a treatment indication emerges two years or ulinemia. Clin Lymphoma Myeloma. 2009;9:62-66.
longer after first-line treatment, the same treatment 17. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC et al. Primary treatment of Waldenstrom macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. J Clin Oncol. 2007;25:3344-49.
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Source: http://www.ewmnetwork.eu/documenten/newsletter/2013-03-28_Minnema_Guideline_MW_in_NL.pdf


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Microsoft word - lice treatment-english.doc

Placentia-Yorba Linda USD Health Services Your Child May Return to School Immediately After Lice Treatment Your child may return to school under the following conditions. Your child’s hair will be checked prior to classroom entry. You Must: • Treat your child and any family member who has lice or nits with a pediculocidal shampoo. Be sure directions are followed carefu

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