monoclonal component on high resolution assay. Types II and III referred to as mixed cryoglobulinaemia (MC): 775% associated with HCV infection. \200 Chronic stimulus may initiate multistep process of B-cell clonal expansion leading to LPDs. Serology refl ects progression from polyclonal to oligoclonal to monoclonal IgM-RF and clonal expansion. Associated with wide range of conditions: Lymphoproliferative and hematological disorders. \200 Auto-immune diseases. \200 Infect ions (esp. HCV). \200 Renal and liver disorders. Clinical features and diagnosis \200 Type I rarely associated with vasculitis but with si gns of peripheral vessel obstruction and hyperviscosity: purpura, acrocyanosis, Raynaud \200\231s phenomenon, dystrophic manifestations, leg ulcers, gangrene; usually clinically i ndistinguishable from Waldenstr m macroglobulinaemia (WM), MM, or CLL; rare complication o f paraprotein precipitation at low temperature. MC characterized by purpura, weakness, and arthralgias with multisystem involvement includi ng chronic hepatitis, glomerulonephritis or peripheral neuropathy due to small and medium v essel vasculitis; biopsy of cutaneous lesions shows vasculitis. Diagnose by precipitation at 2 \200\2234 C in serum prepared from blood collected and allowed to clot at 37 C; immunofi xation for assessment of clonality and typ ing; serum immunoglobulins, plasma viscosity, complement levels, and RF activity. Exclude underlying LPD in cases with monoclonal IgM with type I or II cryoglobulinaemia. Treatment \200 Type I: treat underlying MM, WM or CLL and avoid the cold. \200 HCV-rela ted MC: interferon alfa ribavirin to eradicate HCV; may be followed by regression of established lymphoma. Non-HCV-related MC: mild \200\223moderate symptoms, low dose prednisolone and analgesia; severe symptoms, Cyclophosphamide prednisolone plasmapher esis; rituximab may control B-cell clone and also improve renal function in HCV-related dis ease. Further reading Tedeschi, A. et al. (2007). Cryoglobulinaemia. Blood Rev, 21, 183 \200\2232 00. 364 CHAPTER 8 Paraproteinaemias POEMS syndrome (osteosclerotic myeloma) Clinical features \200 Synonym: Crow \200\223Fukase syndrome. \200 Clonal plasma-cell d yscrasia. \200 Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes: rare paraneoplastic syndrome 2 to a plasma cell neoplasm. Other features: papilloedema, extravascular fl uid overload (oedema, pleural eff usions, as cites), lymphadenopathy, diabetes mellitus, male gynaecomastia and impotence, female amenor rhoea, hypertrichosis and hyperpigmentation, sclerotic bone lesions, thrombocytosis, Castle man disease, polycythaemia, and clubbing. Association of osteosclerotic plasmacytoma with chronic infl ammatory demyelinating progressive polyneuropathy causing predominantly motor disabili ty. Endocrinopathy occurs in 784% usually hypogonadism then thyroid abnormalities, diabetes and adrenal insuffi ciency; majority multiple. 11 \200\22330% have Castleman disease or Castleman-like disease with angiofollicular lymph node hyperplasia which may be unifocal or multifocal and associated with B-symptoms, auto-i mmune phenomena, more subtle sensory neuropathy, and polyclonal gammopathy. Diagnosis \200 Confi rm diagnosis by demonstrating monoclonal plasma cells in osteosclero tic plasmacytoma (>95% have monoclonal plasmacytoma or BM infi ltration) and elevated pl asma or serum levels of VEGF. (See Table 8.15.) BM usually <5% plasma cells (almost always monoclonal ); low-level paraprotein, usually I gG or IgA (median 11g/L, rarely >30g/L). Anemia, hypercalcaemia, and renal impairment are rare. \200 Diff erential diagnosis: Chronic infl ammatory demyelinating polyneuropathy (CIDP). \200 Guillain \200\223Barr s yndrome. \200 Monoclonal gammopathy-associated peripheral neuropathy. \200 AL amyloidos is. Treatment \200 Treat solitary sclerotic bone lesion with aggressive radiotherapy (45Gy) surgery ( \211 50% response); widespread lesions or diff use BM involvement requi res systemic therapy; treatments as for myeloma used. Autologous peripheral blood stem cell transplantation is the 1st- line treatment for younge r patients with normal organ function. High response rate and durable remission. Transplant ation-related morbidity and mortality signifi cantly reduced over the past 5 years. Melphalan and dexamethasone: eff ective and well-tolerated treatment for older patients or those with organ dysfunction. 365 POEMS SYNDROME (OSTEOSCLEROTIC MYELOMA) Systemic symptoms and skin changes may respond in 1 month, neuropathy may begin to respond at 3 \200\2236 months with maximum benefi t often taking 2 \200\2233 years. Prognosis is good with median survival 14.7 years; number of features does not aff ect survival; respiratory symptoms predict adverse outcome. Table 8.15 Criteria for the diagnosis of POEMS syndrome1 1. Polyneuropathya 2. Monoclonal plasma cell neoplasm Major criteria (almost always )a 3. Sclerotic bone lesions 4. Castleman disease 5. VEGF elevation Minor criteria 1. Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) 2. Extravascular volume overload (oedema, pleural eff usion, or ascites) 3. Endocrinopathy (adrenal, thyroid,b pituitary, gonadal, parathyroid, pancreaticb) 4. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid haemangiomata, plethora, acrocyanosis, fl ushing, white nails) 5. Papilloedema 6. Thrombocytosis/polycythaemia c Other symptoms and signs Clubbing, weight loss, hyperhidrosis, pulmonary hypertension/restrictive lung disease Possible associations Arthralgias, cardiomyopathy (systolic dysfunction) and fever a Polyneuropathy and monoclonal plasma cell neoplasm present in all patients; diagnosis req uires at least 1 other major criterion and 1 minor criterion. b Because of high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone insuffi cient to meet this minor criterion. c Anemia and/or thrombocytopenia are distinctly unusual in POEMS synd rome unless Castleman disease present. Reproduced from Dispenzieri, A. et al. (2007). POEMS syndrome. Blood Rev, 21, 285 \200\2239 9, with permission from Elsevier 2007 Reference 1. Dispenzieri, A. et al. (2007). POEMS syndrome. Blood Rev, 21, 285 \200\22399. Further reading Li, J. et al. (2013). New advances in the diagnosis and treatment of POEMS syndrome. Br J Haematol, 161(3), 303 \200\22315. Swerdlow, S.H. et al. (2008). WHO Classifi cations of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. 366 CHAPTER 8 Paraproteinaemias Plasmacytoma Solitary plasmacytoma of bone (SPB) Clinical features and diagnosis \200 Sol itary area of lytic bone destruction due to clonal plasma cells in an otherwise asymptomatic patient. Generally no serum/urine paraprotein though there may be small monoclonal band. BM from uninvolved site contains <5% plasma cells. \200 Otherwise n skeletal survey and M RI of spine and pelvis (exclusion of other lesions on MRI). No myeloma-related organ or tissue impairment (end-organ damage). \200 75% of plasma cell neoplasms: \231\202: \231\200 ratio 2:1; median age 55 years. \200 Lesion usually in ax ial skeleton; 66% in spine. \200 Generally presents with bony pain; may cause cord/root c ompression. \200 Diagnosis requires biopsy or FNA. \200 Diff erential diagnosis of MM a nd other malignancy. \200 Serum/urine paraprotein detected in 24 \200\22372%; generally l ow level. \200 Adverse prognostic factors for progression to MM include persistence of paraprotein >1 year after radiotherapy, immuneparesis and lesion >5cm. \210\222ve MRI of spine is good prognostic feature. Treatment and prognosis \200 Treat with fractionated radical radiotherapy 40Gy (50Gy for lesions >5cm); local control 80 \200\22395%; curative in 50% if solitary lesion; DFS 740% a t 5 years. Treat non-responders and those with a rising paraprotein or other evidence of symptomatic M M with MM treatment/chemotherapy. \200 Patients who meet diagnostic criteria for SPB but with evidence of clonal BM involvement should be treated with radiotherapy then monitored f or disease progression as for MGUS (<10% BM PCs or SMM \211 10% BM PCs). Regular follow-up to monitor paraprotein; disappears in 25 \200\22350% (often slowly over several years). 75% progress to MM (750% within 2 years of diagnosis); treat as de novo MM. High response rate; median survival 63 months. Some patients develop multiple solitary recurrences; treat each with local radiotherapy. Median survival >10 years; DFS 25 \200\22350% at 10 years. Solitary extraosseous plasmacytoma (SEP) Clinical features and diagnosis \200 Extramedull ary tumor of clonal plasma cells. \200 Rare; may occur anywhere but 90% in head and neck; most in upper airways: tonsils, nasopharynx, or paranasal sinuses. Generally no serum/urine paraprotein though may have small monoclonal band. BM from uninvolved site contains <5% plasma cells. \200 n skeletal survey and MRI of spin e and pelvis normal. \200 No myeloma-related organ or tissue impairment (end-organ damage ). 367 PLASMACYTOMA Diagnosis requires biopsy or FNA of the lesion. \200 Diff erential diagnosis of MM and ot her malignancy. \200 <25% have serum or urine paraprotein. Treatment and prognosis \200 Treat with radical radiotherapy (40Gy; 50Gy if lesion >5cm) including regional lymph nodes if possible (e.g. cervical). Radical surgery only for SEP outside head and neck, then usually followed with radiotherapy. Patients who meet diagnostic criteria for SEP but with evidence of clonal BM involvement sh ould be treated with radiotherapy then monitored for disease progression as for MGUS (<10% BM PCs or SMM \211 10% BM PCs). Most cured; <5% local recurrence; relapse <30%. \200 Treat non-responders and those with a rising paraprotein or other evidence of symptomatic MM with MM treatment/chemotherapy. \200 If monoclonal protein persists or reappears, patient may need further radiotherapy; i f plasmacytoma shrinks but does not disappear and/ or paraprotein persists, follow closely; persistent or rising paraprotein may indicate progression to MM and require treatment as s uch. >70% survival at 10 \200\22314 years; DFS 70 \200\22380% at 10 years. Further reading Alexiou, C. et al. (1999). Extramedullary plasmacytoma: tumor occurrence an d therapeutic concepts. Cancer, 85, 2305 \200\22314. BCSH/UKMF (2004). Guidelines on the di agnosis and management of solitary plasmacytoma of bone and solitary extramedullary plasmac ytoma. Br J Haematol, 124, 717 \200\22326. M http://www. bcshguidelines.com/pdf/Plasmacytom a080304.pdf International Myeloma Working Group (2003). Criteria for the classifi cation of monoclonal gammopathies, multiple myeloma and related disorders: a report of the Internati onal Myeloma Working Group. Br J Haematol, 121, 749 \200\22357. Liebross, R.H. et al. (1998 ). Solitary bone plasmacytoma: outcome and prognostic factors following radiotherapy. Int J Radiat Oncol Biol Phys, 41, 1063 \200\2237. Swerdlow, S.H. et al. (2008). WHO Classifi cat ions of Tumors of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: IARC. Tsang, R.W. et a l. (2001). Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome . Int J Radiat Oncol Biol Phys, 50, 113 \200\22320. 368 CHAPTER 8 Paraproteinaemias Waldenstr m macroglobulinaemia WM is an uncommon indolent chronic B-cell LPD characterized by BM infi ltration by lymphoplasmacytic cells and an IgM paraproteinaemia. It is classifi ed as lymphoplasmacytic lymphoma (LPC-L) in the WHO clas- sifi cations, a B-cell neoplasm( E See also p.191.). Epidemiology \200 Incidence 0.3 per 100,000 per annum; incidence higher in Caucasians; rare in black population. Median age 63 \200\22368; rare <40; \231\202: \231\200 72:1. \200 Cause unknown; no clea r link to environmental exposures. \200 Several familial clusters described; 720% of pati ents have at least 1 1st-degree relative with B-cell disorder; tend to be younger, have hig her % BM involvement and higher IgM level at diagnosis. Main risk factor for WM is pre-existing IgM MGUS (46 \227 relative risk). Pathophysiology WM appears from a late stage of B-cell diff erentiation, possibly a memory B-cell, arrested after somatic hypermutation in the germinal center and before terminal dif f erentiation to a plasma cell. Most cases have a normal karyotype; most frequent chromosomal abnormality del(6q21 \200\223 23). Presence of del(6q) may be associated with more aggressive disease. Del(6q) has not be en found in IgM MGUS and may be associated with disease progression; limited data at presen t. IL-6 is upregulated in WM explaining the elevated serum C-reactive protein; high levels of IL-6 may contribute to anemia. Slowly progressive accumulation of clonal cells; symptoms may be due to infi ltration of BM (BM failure), spleen (splenomegaly), or liver (hepato- megaly), or to hyperviscosity due t o i serum levels of monoclonal IgM. Clinical features and presentation \200 Occasional diagnosis following routine ESR/SPEP/F BC/blood-fi lm; otherwise usually insidious onset of weakness and fatigue. Patients often present with symptoms of anemia, epistaxis, recurrent infection, dyspnoea, CCF, and weight loss. Usually no bone pain and no evidence of destructive bone disease. \200 Symptoms of hyperv iscosity (headache, dizziness, visual upset, bleeding, ataxia, CCF and somnolence, stupor, and coma) 15 \200\22320%. \200 Peripheral n europathy \200\224usually sensory or sensorimotor (720%): distal, symmetrical, slowly progr essive, usually lower extremities. \200 Hepatomegaly (725%); splenomegaly and lymphadenop athy less frequent. Fundoscopy reveals distended sausage-shaped veins, retinal hemorrhage papilloedema. Cryoglobulinaemia (<5% present with symptoms though detectable in 20%) may cause Raynaud sy ndrome, arthralgia, purpura, and skin ulcers. \200 Haemorrhagic symptoms (e.g. epistaxis or easy bruising) may develop as a result of abnormalities of platelet function or coagulat ion due to the paraprotein. 369 WALDENSTR \226M MACROGLOBULINAEMIA Amyloidosis may occur (<5%) causing cardiac, renal, hepatic, or pulmonary dysfunction, or macroglossia. Autoimmune disorders may also develop due to the paraprotein: cold agglutinin disease, Schn itzler syndrome (IgM monoclonal gammopathy, urticaria, fever, and arthralgia), neuropathy d ue to antimyelin associated glycoprotein (MAG) activity, glomerulonephritis, angioedema, an d acquired von Willebrand syndrome. Investigations and diagnosis \200 No disease-defi ning morphological, immunophenotypic, o r chromosomal abnormalities for WM (Table 8.16). FBC and \201 lm: normochromic normocytic anemia 80% (often spuriously low due to i plasma volume); rarely lymphocytosis or pancytopenia; blood fi lm s hows rouleaux or agglutination (cold agglutinins 75%); may see lymphoplasmacytic cells. ESR/plasma viscosity: i in almost all patients, often markedly (ESR commonly >100mm/h); risk of hyperviscosity symptoms when PV >4cP (5 \200\22310% at diagnosi s); most have symptoms when PV >6cP; most with PV <4cP will not have symptoms of hypervisco sity; PV often correlates well for symptoms in an individual though not between patients. Biochemistry: renal impairment rare; LFTs may be abnormal in advanced disease or cryoglobulinaemia; urate and LDH may be i. Serum 2-microglobulin: i in 33%; prognostic factor. \200 C-reactive protein: i in 766%; due to i IL-6 production. \200 Hepatitis C serology: association with WM. \200 Serum i mmunoglobulins: i IgM; may be mild immuneparesis of IgG (60%) and IgA (20%). Serum protein electrophoresis, immuno \201 xation and densitometry: to characterize and quantify IgM paraprotein. Urine electrophoresis: scanty Bence Jones protein in 750%. \200 BM aspirate: often hypoce llular; may show infi ltration by lymphoplasmacytic cells with variable diff erentiation; mast cells may be i. BM trephine biopsy: essential; usually hypercellular; demonstrates intertrabecular infi ltrate (diff use, interstitial, or nodular) of lymphoplasmacytic cells (NB paratrabecular infi ltrate suggests follicular NHL); immunochemistry demonstrates LC r estriction. \200 BM immunophenotyping: useful in diff erentiating WM from other B-cell disorders; characteristically pan B-cell marker (CD19, CD20, CD22, CD79) +ve (cf. my eloma plasma cells); LC restricted surface IgM; CD10 \210\222ve (cf. FL), CD23 \210\222ve (cf. CLL); 5 \200\22320% express CD5 (must diff erentiate from CLL and MCL); NB CD5+ does not rule out diagnosis of WM; CD103 and CD138 rarely +ve. Cytogenetics: optional; most have n karyotype; no consistent defect; most commonly del(6q;2 1 \200\22322.1) by FISH in up to 55% patients with WM; +3, +5, and \210\2228 also describe d; presence of IgH translocations (14q) suggests myeloma; may help rule out NHL. CT neck chest abdomen and pelvis: to detect organomegaly and lymphadenopathy. 370 CHAPTER 8 Paraproteinaemias Other potentially useful tests: cryoglobulins, cold agglutinins, coagulation screen, Congo red stain for amyloid on BM or fat aspirates, haemolysis screen, ECG, EEG, peripheral blood fl ow cytometry, EMG, or lymph node/organ biopsy may be useful in some patients. WM may be divided by the presence or absence of symptoms attributable to either the IgM paraprotein (e.g. hyperviscosity or neuropathy) or tumor infi ltration (B M failure or symptomatic organomegaly) into: \200 Symptomatic WM. \200 Asymptomatic WM (725%). Table 8.16 Diagnostic criteria for WM1 IgM monoclonal gammopathy of any concentration. \200 BM infi ltration by small lymphocyte s, plasmacytoid cells, and plasma cells. \200 Intertrabecular pattern of BM infi ltration . \200 Immunophenotype: monoclonal surface IgM+ (5:1 : ratio), CD19+, CD20+, CD5 , C D10 \210\222, CD19+, CD20+, CD22+, CD23 \210\222, CD25+, CD27+, FMC7+ Reproduced from NCCN Guidelines on Waldenstr m \200\231s Macroglobulinaemia/Lymphoplasmacy tic Lymphoma. Version 2.2013. NCCN.org, with permission. Copyright Elsevier 2003. Diff erential diagnosis \200 IgM MGUS: IgM monoclonal protein <30g/L; Hb >12g/dL; no BM i nfi ltrate (<10% clonal BM cells); no organomegaly or lymphadenopathy; no end-organ symptom s; 6q \210\222 is not seen in IgM MGUS; risk of progression 1.5% per year. IgM-related disorders: IgM monoclonal protein; no overt evidence of lymphoma; symptomatic c ryoglobulinaemia, peripheral neuropathy, cold agglutinin disease, or amyloidosis; presence of constitutional or hyperviscosity symptoms, lymphadenopathy or organomegaly more suggesti ve of WM. Other B-cell LPDs: IgM monoclonal protein can be demonstrated in CLL/SLL and NHL (MCL, FL, MZL); generally very low levels; no lymphoplasmacytic BM infi ltration; hyperviscosity rare; features of other LPD e.g. phenotype, e.g. splenic marginal zone lymphoma (SMZL) associated with splenomegaly, BM infi ltration, and IgM paraprotein. IgM myeloma: very rare; BM contains plasma cells (cytoplasmic IgM+, CD20 \210\222, CD38+, C D138+) not lymphoplasmacytic cells; myeloma- associated cytogenetic abnormalities (esp. 14q translocations) and lytic bone lesions frequent. Prognostic factors IPSS is used. See Table 8.17. Predictors of early progression in asympto matic WM \200 Hb <11.5g/dL. \200 2-microglobulin \211 3mg/L. \200 IgM >30g/L. Predictors of shorter survival in WM \200 Age \211 60 years. \200 Hb <10g/dL. 371 WALDENSTR \226M MACROGLOBULINAEMIA High 2-microglobulin. \200 Other less consistently identifi ed factors \200\224cytopeni as: WBC <4.0 \227 109/L; neutrophils <1.8 \227 109/L; platelets <150 \227 109/L; d serum alb umin; \231\202 sex; constitutional symptoms. Table 8.17 International Prognostic Scoring System (IPSS) for WM2 Age >65 years \200 Serum 2-microglobulin >3mg/L \200 Monoclonal protein >70g/L \200 Hemoglobin \211 11.5g/dL \200 Platelets \211 100 \227 109/L \211 1 adverse risk fact ors, except age Adverse risk factors Low risk Median 5-year survival 87% 2 adverse risk factors or age >65 years Intermediate risk Median 5-year survival 68% >2 adverse risk factors High risk Median 5-year survival 36% Management The aims of treatment in WM are to relieve symptoms, reduce the risk of organ da mage, and improve QoL and survival duration with minimal adverse eff ects. Treatment should be reserved for symptomatic patients and continued to maximal response. There is no indica tion for therapy in asymptomatic WM but regular review (3 \200\2236-monthly) of clinical an d laboratory features is required. Consistently monitor paraprotein by densitometry (more r eliable than IgM nephelometry). Indications for therapy Initiation of therapy should not be based simply on IgM level alone as this does not correlate directly with clinical manifestations but for: \200 Constitut ional symptoms: recurrent fever, night sweats, fatigue due to anemia, weight loss. Progressive symptomatic lymphadenopathy or splenomegaly. \200 Hemoglobin \211 10g/dL due to BM infi ltration. \200 Platelets <100 \227 109/L due to BM infi ltration. \200 Sym ptomatic hyperviscosity. \200 Severe peripheral neuropathy. \200 Systemic AL. \200 Sy mptomatic cryoglobulinaemia. \200 Cold agglutinin disease. NB Avoid red cell transfusion simply to correct low Hb (plasma volume i causing spuriously low Hb; low Hb protects against clinical eff ects of hyperviscosity). NB Although therapy should not be initiated on IgM level alone, serum monoclonal protein >5 0g/L carries a high risk of hyperviscosity; exclude early symptoms and signs of hyperviscos ity by thorough history and examination including fundoscopy; do not postpone therapy. 372 CHAPTER 8 Paraproteinaemias At this time there are insuffi cient data to recommend one 1st-line therapy over another. C hoice of initial therapy is based on patient age and co-mor- bidities, need for rapid disea se control, cytopenias, and eligibility for SCT. Treatment recommendations and response criteria follow the NCCN 2013 guidelines. (See Table 8.18.) Although response rates may be higher with combination regimens these regimens may not be a ppropriate 1st-line therapies for patients with indolent disease and the long-term benefi t has yet to be demon- strated by direct comparison with single agent therapy. Table 8.18 Updated response criteria from the 6th International Workshop on WM and NCCN gui delines 20133 Response Criteria Complete response (CR) IgM in normal range, and disappearance of monoclonal protein by immunofi xation; no histolo gical evidence of bone marrow involvement, and resolution of any adenopathy/ organomegaly ( if present at baseline), along with no signs or symptoms attributable to WM. Reconfi rmatio n of the CR status is required by repeat immunofi xation studies A 90% reduction of serum IgM and decrease in adenopathy/ organomegaly (if present at baseli ne) on physical examination or on CT scan. No new symptoms or signs of active disease Very good partial response (VGPR) Partial response (PR) A 50% reduction of serum IgM and decrease in adenopathy/ organomegaly (if present at baseli ne) on physical examination or on CT scan. No new symptoms or signs of active disease Minor response (MR) A 25% but < 50% reduction of serum IgM. No new symptoms or signs of active disease Stable disease (SD) A <25% reduction and <25% increase of serum IgM without progression of adenopathy/organomeg aly, cytopenias, or clinically signifi cant symptoms due to disease and/or signs of WM Progressive disease (PD) A 25% increase in serum IgM by protein electrophoresis confi rmed by a 2nd measurement or p rogression of clinically signifi cant fi ndings due to disease (i.e. anemia, thrombocytopen ia, leukopenia, bulky adenopathy/organomegaly) or symptoms (unexplained recurrent fever 38. 4 C, drenching night sweats, 10% body weight loss, or hyperviscosity, neuropathy, symptoma tic cryoglobulinaemia or amyloidosis) attributable to WM Many treatments now exist for WM/LPC-lymphoma. Guidelines list treatments in alphabetical o rder. No standard treatment exists. Treatment must be tailored to the patient. If adequate and durable responses are achieved patients could receive similar/same treatment at relapse (see Tables 8.19 \200\2238.21). Plasmapheresis4 \200 Indicated in acute management of pa tients with symptoms of hyperviscosity; 1 \200\2231.5 volume exchange effi ciently reduces plasma viscosity (PV) (8 0% of large IgM molecule is intravascular) with a 60 \200\22375% reduction in plasma IgM an d 50% reduction in PV; 1 \200\2232 373 WALDENSTR \226M MACROGLOBULINAEMIA procedures will reduce PV to near-n and prevents return of paraprotein to pre-treatment lev els for several weeks. Rarely required on a regular basis in treatment of neuropathic or chemo-intolerant patients. In an emergency, if plasmapheresis is unavailable, venesection and exchange transfusion will d plasma viscosity. Alkylating agents \200 Chlorambucil previously frequently used alkylator; range of dosage schedules, from 0.1mg/kg/d continuously to 0.4mg/kg/d \227 2d every 14d prednisolone 60 mg/m2; 6 \200\22310mg/d (0.1mg/kg/d) for 7 \200\22314d every 28d. Responses usually slow; 3 1 \200\22375% achieve \211 50% reduction in paraprotein; CR uncommon. Addition of steroids does not aff ect response rate or survival; benefi cial if associated autoimmune phenomena. Continue to maximum response; optimum duration of therapy not established; no evidence that maintenance improves survival. Duration of response 2 \200\2234 years; median survival 75 years. \200 Reinstitute therap y when paraprotein approaches previously symptomatic levels; often eff ective on several occasions; resistance ultimately develops; side eff ects; myelosuppression; AML. Cyclophosphamide prednisolone may achieve comparable results; no directly comparative data. Risk of myelodysplasia and stem cell toxicity make alkylating agents less attractive in younger patients; tolerability and ease of administration render them appropriate therapy for elderly patients. Purine analogs5 \200\2237 \200 Fludarabine most widely used purine analog (40mg/m2 PO \227 5d or 25mg/m2 IV \227 5d repeated monthly for 4 \200\2236 cycles); response rate 40 \200\22386% in previously untreated patients; response duration 40 \200\22350 months; patie nts who achieve response >1 year, may respond again at progression; as salvage treatment, 1 7 \200\22350% responses. Cladribine (0.1mg/kg continuous infusion \227 7d) response rate 64 \200\22390% with genera lly 2 \200\2234 cycles in previously untreated patients; as salvage treatment, 38 \200\2236 3% responses; recommended limit of 2 cycles due to risk of myelosuppression; autoimmune com plications occur as in CLL. These agents generally achieve more rapid responses in untreated WM than chlorambucil. Some studies found higher response rates in 1 refractory than refractory relapsed WM. Fludarabine and cladribine are cross-resistant. \200 Side eff ects: myelosuppression (may be severe: >60% \211 grade 3 neutropenia) and profound immunosuppression; need Pneumocystis jirovecii prophylaxis and ir radiated blood products; consider antimicrobial and antiviral prophylaxis. Purine analogs are appropriate for initial and subsequent treatment of WM but should be avo ided as initial therapy in patients eligible for SCT; no consensus on which agent is superi or or optimum duration of therapy. 374 CHAPTER 8 Paraproteinaemias Rituximab8,9 \200 Monoclonal anti-CD20 antibody (375mg/m2 IV \227 4) achieves 727% \211 MR in untreated and previously treated WM; improves haematocrit and platelet counts i n >50%; useful in patients with marked cytopenia. Better responses if paraprotein <40g/L or IgM <60g/L. \200 Responses occur at median 73 m onths but best response may be delayed for several months. Response duration generally 9 \200\22316 months; administration of 8 doses over 4 weeks ini tially, repeated at 12 weeks, improves response rate (44 \200\22348%) and may extend durati on. Abrupt elevation in serum paraprotein and PV may occur after rituximab therapy in up to 50% ( \200\230rituximab fl are \200\231); patients should be closely monit ored and may require plasmapheresis to prevent hyperviscosity. May be benefi cial for symptomatic neuropathy associated with anti-MAG antibodies. Use of rituximab monotherapy discouraged in patients with paraprotein >50g/dL due to risk of \200\230fl are \200\231 eff ect. Role of maintenance Rituximab and should be considered. Combination regimens10 \200\22315 \200 Higher response rates are achieved with combination regimens but i toxicity. Fludarabine (30mg/m2 IV d1 \200\2233) + cyclophosphamide (CTX; 300mg/ m2 IV d1 \200\2233) ( FC) achieved 78% responses \211 MR with median duration >2 years; cladribine + CTX achieve d 58% \211 MR but with signifi cant myelosuppression. FC + rituximab (FCR) achieved responses \211 MR in 5/9; pentostatin (4mg/m2 IV) + CTX (600mg/m2) rituximab (375mg/m2) every 21d in 14 patients achieved 65% responses \211 MR, including 12%CR; cladribine, CTX + rituximab achieved 94% \211 PR (18% CR) in 17 untreated patients with no relapse after median follow-up of 21 months. Standard 1st-line treatment in many centers. R-CVP: standard in many centers. \200 R-CHOP \227 6 with rituximab maintenance achieved \211 MR in 11/13 and \211 PR in 10/13. Rituximab, dexamethasone, and CTX active (78% \211 MR) and well tolerated; response in most patients without myelosuppression or immunosuppression. Bortezomib, rituximab, and dexamethasone highly active (100% OR after median 4 cycles) and well tolerated. Active in relapsed/ refractory WM with 85% achie ving \211 MR; responses prompt (median 1.4 months) with 78 months median TTP; discordance between BM and serum IgM responses was observed in some patients. Becoming more popular. Newer agents16,17 \200 Thalidomide has shown activity in WM, with i RR with added rituximab. Active with 5/20 achieving \211 MR with <3 months TTP; may have role steroid s in 1st-line failures with pancytopenia. \200 Alemtuzumab achieves responses but with si gnifi cant toxicity and is rapidly going out of fashion. Ofatumumab: has a role in patients intolerant of rituximab. 375 WALDENSTR \226M MACROGLOBULINAEMIA Everolimus: mTOR inhibitor with promising results in WM. \200 Bendamustine: an old drug c oming back into fashion. Adequate response rated seen; added benefi t with rituximab. High dose therapy and autologous or all ogeneic SCT6,18 \200 Limited data due to age of most patients with WM; high response rate s (generally PR) achieved after autograft but relapse rate high. \200 HDT and ASCT have a role in 1 refractory or relapsed disease in eligible patients; patients in whom SCT is planned should have limited prior exposure to al kylator and purine analog therapy. The role of allografts in WM remains uncertain but due to the reduced TRM with RIC allogene ic transplant, they should be considered in younger fi t patients. Treatment of relapse \200 If response of >1 year achieved most patients will respond to s ame therapy. Table 8.19 Options for 1st-line and salvage therapy: updated from the NCCN guidelines 2013 1st-line therapy Salvage therapy Non-stem cell toxic Alemtuzumab Bortezomib rituximab Bortezomib/dexamethasone Bortezomib /dexamethasone/ rituximab Cyclophosphamide/doxorubicin/ vincristine/prednisone/rituximab Ev erolimus Ofatumumab Rituximab Rituximab/cyclophosphamide/ prednisone Rituximab/cyclophospha mide/ dexamethasone Thalidomide rituximab Non-stem cell toxic Bortezomib rituximab Bortezomib/dexamethasone Bortezomib/dexamethaso ne/ rituximab Cyclophosphamide/doxorubicin/ vincristine/prednisone/rituximab Rituximab Ritu ximab/cyclophosphamide/ prednisone Rituximab/cyclophosphamide/ dexamethasone Thalidomide rituximab Possible stem cell toxicity and/or risk of transformation (or unknown) Bendamustine ritu ximab Cladribine rituximab Chlorambucil Fludarabine rituximab Fludarabine/cyclophosph amide/ rituximab Possible stem cell toxicity and/or risk of transformation (or unknown) Bendamustine ritu ximab Cladribine rituximab Chlorambucil Fludarabine rituximab Fludarabine/cyclophosph amide/ rituximab Stem cell transplant (in selected cases) HDT and auto-SCT Allo-SCT Order of schedules alphabetical and does not indicate preference. 376 CHAPTER 8 Paraproteinaemias Table 8.20 NCCN practice guidelines for WM (2013) Initial treatmenta Response Advise Combination chemo or mono-Ra CR Observe Consider maint-Rb Combination chemo or mono-R PR & asymptomatic Observe Consider maint-R Combination chemo or mono-R PR and symptoms Relapse strategy Combination chemo or mono-R SD/PD Relapse strategy a Monotherapy rituximab.b Maintenance rituximab Table 8.21 NCCN practice guidelines for WM for relapse strategy (2013) Time since response Advise Relapse <12 months Choose alternative strategy Relapse \211 12 months Choose previous treatment or consider alternative therapy No response Choose alternative therapy Follow-up19 \200 Review FBC, quantitative immunoglobulins, and paraprotein quantitation after every 2 treatment cycles with PV in symptomatic patients; repeat CT at 3 \200\2236-month intervals if abnormal at diagnosis. After response to therapy, patients should be monitored every 2 \200\2233 months without maintenance therapy. Prognosis5 \200\2237,20 \200 Median time to progression of asymptomatic WM 77 years. \200 Median survival of patients with WM 75 years with 10% alive at 15 years. Patients who achieve CR with chlorambucil have median survival of 711 years. Up to 20% die of unrelated causes and 33% from infection; others from disease progression, transformation and bleeding. Indolent course may be interrupted by transformation to diff use large B-cell NHL; worsenin g constitutional symptoms, profound cytopenias, i serum LDH, lymphadenopathy, extramedullar y disease, and organomegaly; often poorly responsive to treatment; poor tolerance of aggres sive treatment due to poor marrow reserve. 377 WALDENSTR \226M MACROGLOBULINAEMIA References 1. NCCN Guidelines on Waldenstr m \200\231s Macroglobulinaemia/Lymphoplasmacyti c Lymphoma. Version 2.2013. M www.NCCN.org 2. Rajkumar, S.V. et al. (2006). Monoclonal gammopathy of undetermined signifi cance, Walde nstr m macroglobulinemia, AL amyloidosis and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc, 81, 693 \200\223703. 3. Treon, S.P. et al. (2011). Report from the Sixth International Workshop on Waldenstr m \200\231s Macroglobulinemia. Clin Lymph Myeloma Leukemia, 11, 69 \200\22373. 4. Buskard, N.A. et al. (1977). Plasma exchange in the long-term management of Waldenstr m \200\231s macroglobulinemia. Can Med Assoc J, 117, 135 \200\2237. Johnson, S.A . et al. (2006). Guidelines on the management of Waldenstr m macroglobulinaemia. Br J Haem atol, 132, 683 \200\22397. M http://www.bcshguidelines.com/pdf/ waldenstroms_151106.pdf 5. 6. Fonseca, R. and Hayman, S. (2007). Waldenstr m macroglobulinaemia. Br J Haematol, 138, 700 \200\22320. 7. Vijay, A. and Gertz, M. (2007). Waldenstr m macroglobulinemia. Blood, 109, 5096 \200 \223103. 8. Dimopoulos, M.A. et al. (2002). Treatment of Waldenstr m \200\231s macroglobul inemia with rituximab. J Clin Oncol, 20, 2327 \200\22333. 9. Treon, S.P. et al. (2005). Extended rituximab therapy in Waldenstr m \200\231s macroglo bulinemia. Ann Oncol, 16, 132 \200\2238. 10. Treon, S.P. et al. (2005). CHOP plus rituximab therapy in Waldenstr m \200\231s macroglobulinemia. Clinical Lymphoma, 5, 273 \200\2237. 11. Tamburini, J. et al. (2005). Fludarabine plus cyclophosphamide in Waldenstr m \200\231 s macroglobulinemia: results in 49 patients. Leukemia, 19, 1831 \200\2234. 12. Tam, C.S. et al. (2006). Fludarabine, cyclophosphamide and rituximab for the treatment of chronic lymphocytic leukemia or indolent non-Hodgkin lymphoma. Cancer, 106, 2412 \200 \22320. 13. Hensel, M. et al. (2005). Pentostatin/cyclophosphamide with or without rituximab: an eff ective regimen for patients with Waldenstr m \200\231s macroglobulinemia/lymphoplasmac ytic lymphoma. Clin Lymphoma Myeloma, 6, 131 \200\2235. 14. Weber, D. et al. (2003). 2-chlorodeoxyadenosine alone and in combination for previously untreated Waldenstr m \200\231s macroglobulinemia. Semin Oncol, 30, 243 \200\2237. 15. Treon, S. et al. (2006). Bortezomib, dexamethasone and rituximab (BDR) is a highly acti ve regimen in the primary therapy of Waldenstr m \200\231s macroglobulinemia: planned inte rim results of WMCTG Clinical Trial 05-180. Blood, 108, abstract 2765. 16. Treon, S.P. et al. (2007). Multicentre clinical trial of bortezomib in relapsed/refract ory Waldenstr m \200\231s macroglobulinemia: results of WMCTG Trial 03-248. Clin Cancer Res, 1 3, 3320 \200\2235. 17. Dimopoulos, M.A. et al. (2003). Treatment of Waldenstr m \200\231s macroglobulinemia w ith single-agent thalidomide or with the combination of clarithromycin, thalidomide and dex amethasone. Semin Oncol, 30, 265 \200\2239. 18. Anagnostopoulos, A. et al. (2006). Autologous or allogeneic stem cell transplantation i n patients with Waldenstr m \200\231s macroglobulinemia. Biol Blood Marrow Transplant, 12, 8 45 \200\22354. 19. NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma V.2.2008. M http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf 20. Kyle, R.A. et al. (2003). Prognostic markers and criteria to initiate therapy in Walden str m \200\231s macroglobulinemia: consensus panel recommendations from the Second Interna tional Workshop on Waldenstr m \200\231s Macroglobulinemia. Semin Oncol, 30, 116 \200\2231 20. Further reading Anderson, K.C. et al. (2012). Waldenstr m \200\231s macroglobulinemia/lymp hoplasmacytic lymphoma, version 2.2013. J Natl Compr Canc Netw. 10, 1211 \200\22319. Kastri tis, E. et al. (2011). Emerging drugs for Waldenstr m \200\231s macroglobulinemia. Expert Opin Emerg Drugs, 16(1), 45 \200\22357. Varghese, A.M. et al. (2009). Assessment of bone ma rrow response in Waldenstr m \200\231s macroglobulinemia. Clin Lymph Myeloma. 9, 53 \200 \2235. 378 CHAPTER 8 Paraproteinaemias Heavy chain disease Uncommon lymphoplasmacytic cell neoplasms characterized by produc- tion of incomplete Igs comprising HCs without LCs. \235\233\202-HCD (= IPSID) \200 IPSID: im muneproliferative small intestinal disease (WHO 1978). \200 Variant of extranodal margina l zone lymphoma of MALT type. \200 Most frequent; more frequent in the Mediterranean and Middle East; generally 10 \200\22330 years; associated with low socioeconomic group, poor h ygiene, recurrent infectious diarrhea, and chronic parasitic infection. Commonly presents with diarrhea, steatorrhoea, weight loss, abdominal pain and vomiting; mild-to-moderate anemia; low serum albumin; hypokalaemia, and hypocalcaemia (tetany). -HC protein detectable in serum of most patients; SPEP normal in 50%; monoclonal -chain on immunofi xation of serum or in concentrated urine, otherwise diagnose by biopsy. Villous atrophy and infi ltrative lesions in duodenum and jejunum in most patients; histolo gy ranges from lymphoplasmacytic infi ltration of mucosa (stage A) to immunoblastic lymphom a invading entire intestinal wall. Mesenteric lymph nodes sometimes involved but peripheral lymph nodes, liver, spleen and BM rarely involved. Progressive course without treatment; early stage (A) treated