2 Thalidomide (50 \200\223400mg/day) as a single agent achieves up to 30% 280 responses in chemotherapy-resistant myeloma; addition of dexametha- sone (20 \200\22340mg/d ay 4 days/month) 4 response rates (up to 70%); side effects constipation, tremor, headac he, oedema, somnolence; thromboembolism risk esp. in combination with anthracyclines (full dose warfarin or LMW heparin prophylaxis advised). 2 Patients who relapse after prolonged response to HDM (>18 months) with a PBSC harvest suf ficient for 2 procedures or with a further suc- cessful harvest may benefit from second HDM re-induction with VAD. 2 There is evidence of a graft-versus-myeloma effect and DLI has re- induced responses in p atients with recurrence after allogeneic SCT. 2 The immunomodulatory drug Revimid and the p roteosome inhibitor Velcade are both active in refractory and resistant myeloma; studies to define the role of these agents are in progress. 2 Cyclophosphamide (50 \200\223100mg/day PO) is well tolerated palliative therapy for patie nts with advanced refractory disease or cytopenia who are intolerant of thalidomide or dexa methasone. 1 Child, J.A. et al. (2003) High-dose chemotherapy with hematopoietic stem-cell rescue for mul- tiple myeloma. N Engl J Med, 348, 1875 \200\2231883. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 281 Paraproteinaemias Variant forms of myeloma Non-secretory myeloma 2 1% of MM cases; no detectable serum or urine paraprotein by immunofixation; (Note: serum free light chain ratio abnormal in 70%); clonal plasma cells \211 5% in BM or plasmacytoma on biopsy; myeloma- related end-organ damage. 2 Treat as above; response rates comparable to secretory MM; response more difficult to assess in absence of paraprotein; serum free light chain assay provides a lternative to surrogate markers (b2-M, CRP) and BM assessment. IgD myeloma 2 1% of cases of MM; younger mean age; high rate of Bence Jones pro- teinuria and associated higher frequency of acute and chronic renal failure; tendency to present wit h other poor prognostic features (high b2-M; low Hb). 281 2 Treat aggressively when possible. IgM myeloma 2 Very rare; <0.5% of MM; 1% of all IgM gammopathies; plasma cell infil- trate in BM associated with osteolytic lesions as opposed to lympho- plasmacytoid infiltrate char acteristic of WM; response and survival equivalent to MM. IgE myeloma 2 Rarest form of MM; younger age; high incidence of plasma cell leukemia. 2 ?shorter survival. Plasma cell leukemia 2 Defined as PB plasma cells >2 109/L or 20% of differential count; may occur de novo at presentation or in the terminal stages of other- wise typical MM. 2 Aggressive disease associated with BM failure and organomegaly; poor response to conventi onal dose therapy; few survive >6 months; better responses to HDM. Cryoglobulinaemia 2 Rare complication of paraprotein precipitation at low temperature; 2 Le g ulcers, Raynaud \200\231s phenomenon, renal impairment, gangrene, CNS and GI symptoms; biopsy usually shows vasculitis. 2 Treat myeloma and avoid cold. POEMS syndrome 2 Polyneuropathy, Osteosclerosis, Endocrinopathy, M-protein, Skin changes. 2 Association of plasmacytoma with chronic inflammatory demyelinating polyneuropathy causing predominantly motor disability. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 282 2 Confirm diagnosis by demonstrating monoclonal plasma cells in osteosclerotic bone lesion (plasmacytoma). 2 BM usually <5% plasma cells; low level paraprotein; hypercalcaemia and renal impairment rare. 2 Other features: lymphadenopathy, organomegaly, diabetes mellitus, male gynaecomastia and impotence, female amenorrhoea, hypertri- chosis and hyperpigmentation. 2 Treat solitary bone lesions with aggressive radiotherapy (45Gy) surgery. Solitary plasmacytoma of bone (SPB): Diagnostic criteria 2 Generally no paraprotein in seru m or urine though small band may be present. 2 Single area of bone destruction due to clonal plasma cells. 2 BM not consistent with MM. 2 Otherwise normal skeletal survey (and MRI of spine and pelvis). 2 No myeloma-related orga n or tissue impairment (end-organ damage). 2 Represents 5% plasma cell neoplasia: 9 : 3 ra tio 2:1; median age 55. 2 Lesion usually in axial skeleton; 66% in spine. 2 Generally prese nts with bony pain; may cause cord/root compression. 2 Diagnosis requires biopsy or FNA, ex clusion of MM (p273) and exclu- sion of other bone lesions with MRI (FDG-PET/99Tc-MIBI unde r exami- nation). 282 2 Serum or urine paraprotein detected in 24 \200\22372%; generally low level. 2 Adverse pro gnostic factors for progression to MM include persistence of paraprotein >1 year after radi otherapy, immuneparesis and lesion >5cm. 2 Negative MRI of spine is good prognostic feature. 2 Treat with fractionated radical radio therapy 40Gy (50Gy for lesions >5cm); local control 80 \200\22395%; curative in 50% if soli tary lesion; DFS 40% at 5 years. 2 Treat non-responders with chemotherapy as for myeloma (p278). 2 Regular follow-up to moni tor paraprotein; disappears in 25 \200\22350% (often slowly over several years). 2 75% progress to MM; treat as de novo MM (p278); high response rate. 2 Some patients deve lop multiple solitary recurrences; treat each with local radiotherapy. 2 Median survival 10 years. Extramedullary plasmacytoma (SEP) Diagnostic criteria 2 Generally no paraprotein in serum o r urine though small band may be present. 2 Extramedullary tumor of clonal plasma cells. 2 BM not consistent with MM. 2 Normal skelet al survey (and MRI of spine and pelvis). 2 No myeloma-related organ or tissue impairment (e nd-organ damage). 2 Rare; may occur anywhere but 90% in head and neck; most in upper airways. 2 Diagnosis requires biopsy or FNA of the lesion; exclusion of MM and other lesions. 2 <25% have serum or urine paraprotein. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 283 Paraproteinaemias 2 Treat with radical radiotherapy (40Gy; 50Gy if lesion >5cm) including cervical lymph nodes when involved; radical surgery only for SEP outside head and neck. 2 Most cured; <5% local recurrence; relapse <30%; MM, SBP or soft tissue involvement: chemotherapy for refractory or relapsed disease (p278). 2 >70% survival at 10 years. 283 Criteria for the classification of monoclonal gammopathies, multiple myeloma and related di sor- ders: a report of the International Myeloma Working Group (2003) Br J Haematol, 121, 7 49 \200\223757; BCSH UKMF Guidelines Diagnosis and management of solitary plasmacytoma of b one (SBP) and solitary extramedullary plasmacytoma (SEP). www.bcshguidelines.com 08-plasma cell.qxd 10.12.2003 04.21 PM Page 284 Waldenstr m \200\231s macroglobulinaemia (WM) WM is an uncommon indolent chronic B-cell lymphoproliferative disorder characterized by bon e marrow infiltration by lymphoplasmacytic cells and an IgM paraproteinaemia. It is classif ied as a lymphoplasmacytic lymphoma in the REAL and WHO classifications (p195). Epidemiology 2 Incidence <0.5 per 100,000 per annum; mean age 65; rare <40; M:F 2:1. 2 Cause unknown; several familial clusters described; 23% of patients have 1st degree relative with B-cell disorder. Pathophysiology WM appears to arise from IgM+ memory B lymphocytes (suggested by the immuno phenotype and Ig somatic hypermutation without intraclonal variation); slowly progressive; symptoms may be due to infiltration of BM (BM failure) spleen (splenomegaly) or liver (hepa tomegaly) or to hypervis- cosity due increased serum levels of pentavalent monoclonal IgM ( when IgM >30g/L). Autoimmune disorders may also develop due to the para- protein: neuropath y, cold agglutinin disease 284 Clinical features and presentation 2 Occasional diagnosis following routine ESR/PV/FBC/bloo d movie. 2 Usually insidious onset of weakness and fatigue. 2 Often present with symptoms o f anemia, epistaxis, recurrent infec- tion, dyspnoea, CCF and weight loss. 2 Usually no bone pain and no evidence of destructive bone disease. 2 Symptoms of hypervisc osity (headache, dizziness, visual upset, bleeding, ataxia, CCF and somnolence, stupor and coma) 15 \200\22320%. 2 Peripheral neuropathy \200\224usually sensory or sensorimotor ( 20%): distal, symmetrical , slowly progressive, usually lower extremities. 2 Hepatomegaly ( 25%); splenomegaly and ly mphadenopathy less fre- quent. 2 Fundoscopy reveals distended sausage-shaped veins, retinal haemor- rhage papilloedema. 2 Cryoglobulinaemia (<5%) may cause Raynaud \200\231s syndrome, arthralgia, purpura, periph eral neuropathy, liver dysfunction and renal failure. 2 Haemorrhagic symptoms (e.g. epistax is or easy bruising) may develop as a result of abnormalities of platelet function or coagu lation due to the paraprotein. 2 Amyloidosis may occur (<5%) causing cardiac, renal, hepatic or pul- monary dysfunction or macroglossia. Investigation and diagnosis 2 FBC and movie: normochromic normocytic anemia 80% (often spur i- ously low due to increased plasma volume); rarely lymphocytosis or pancytopenia; blood m ovie shows rouleaux or agglutination (cold agglu- tinins 5%); may contain circulating lymp hoplasmacytic cells. 2 ESR/plasma viscosity: 4 in almost all patients ( 70% PV >1.8cP), often markedly (ESR commonly >100mm/h); risk of hyperviscosity symptoms 08-plasma cell.qxd 10.12.2003 04.21 PM Page 285 Paraproteinaemias when PV >4cP (5 \200\22310% at diagnosis); most have symptoms when PV >6cP; PV often correl ates well for symptoms in an individual though not between patients. 2 Biochemistry: renal impairment unusual; LFTs may be abnormal in advanced disease or cryoglobulinaemia; uric acid may be 4. 2 Serum immunoglobulins: 4 IgM; may be mild immuneparesis of IgG (60%) and IgA (20%). 2 Serum protein electrophoresis, immunofixation and densitometry: con- firms and quantifies IgM paraprotein. 2 Urine electrophoresis: scanty Bence Jones protein present in 50%. 2 b2-microglobulin: 4 in 33%. 2 C-reactive protein: 4 in 66%. 2 BM aspirate: often hypocellular; may show infilt ration by lymphoplas- macytic cells of variable degrees of differentiation; mast cells may be increased. 285 2 BM trephine biopsy \200\224essential \200\224usually hypercellular; demonstrates intertrabecular infiltrate (diffuse, interstitial or nodular) of lymphoplas- macytic cells (Note: paratrabecular infiltrate suggests follicular NHL); immunochemistry demonstrates lig ht chain restriction. 2 BM immunophenotyping: useful in differentiating WM from other B- cell disorders; characte ristically pan B-cell marker (CD19, CD20, CD22, CD79) positive (cf. myeloma plasma cells); light chain restricted surface IgM; CD10 negative (cf. FL), CD23 negative (cf. CLL); 5 \200 \22320% express CD5 (must differentiate from CLL and MCL); CD103 and CD138 rarely positive. 2 Cytogenetics: no disease defining abnormality described; many normal; presence of IgH translocations (14q) suggests myeloma. Proposed diagnostic criteria 2 IgM monoclonal gammopathy of any concentration. 2 BM infiltr ation by small lymphocytes, plasmacytoid cells and plasma cells. 2 Intertrabecular pattern of BM infiltration. 2 Immunophenotype: surface IgM+, CD5 , CD10 \200\223, CD19+, CD20+, CD22+, CD23 \200\223, CD25+, CD27+, FMC7+, CD103 \200\223, CD138 \200\223. 2 WM may be divided into symptomatic WM and asymptomatic (smoul- dering) WM ( 25%) by the p resence or absence of symptoms attribut- able to either the IgM paraprotein (e.g. hypervisc osity or neuropathy) or tumor infiltration (BM failure or symptomatic organomegaly). Differential diagnosis 2 IgM MGUS: IgM monoclonal protein <30g/L; Hb >12g/dL; no BM infil- trate; no organomegaly or lymphadenopathy; no end-organ symptoms. 2 IgM-related disorders: IgM monoclonal protein; no overt evidence of lymphoma; symptomatic cryoglobulinaemia, peripheral neuropathy, cold agglutinin disease or amyloidosis. (Owen, R.G. et al. (2003) Clinicopathological definition of Waldenstr m \200\231s macroglo bulinaemia. Semin Oncol 30:110 \200\223115) 08-plasma cell.qxd 10.12.2003 04.21 PM Page 286 2 Other B-cell lymphoproliferative disorders: IgM monoclonal protein can be demonstrated in most B-cell lymphoproliferative disorders e.g. CLL, NHL; generally very low levels; no lym phoplasmacytic BM infiltration; hyperviscosity rare; features of other lymphoproliferative disorder e.g. phenotype. 2 IgM myeloma: very rare; BM contains plasma cells (cytoplasmic IgM+, CD20 \200\223, CD138+ ) not lymphoplasmacytic cells; myeloma associated cytogenetic abnormalities (esp. 14q trans locations) and lytic bone lesions frequent. Prognostic factors Predictors of early progression in asymptomatic WM: 2 Hb <11.5g/dL. 2 b2 -microglobulin \211 3.0mg/L. 2 IgM >30g/L. Predictors of shorter survival in WM: 2 Age \211 60. 2 Hb <10g/dL. 2 High b2-microglobulin . 2 Other less consistently identified factors: cytopenias: WBC <4.0 109/L; neu- trophil s <1.8 109/L; platelets <150 109/L; 5 serum albumin; 9 sex; con- stitutional symptoms ; plasmacytic and polymorphous morphology in BM. 286 Management 2 Therapeutic principles as for CLL and FL; no indication for therapy in asympto matic WM; regular review (3 \200\2236 monthly) of clinical and labo- ratory features requir ed: consistently monitor paraprotein by densito- metry (more reliable than IgM nephelometry ). 2 Initiation of therapy should not be based simply on IgM level alone as this does not corr elate directly with clinical manifestations of WM but for: \200\223 Constitutional symptom s: recurrent fever, night sweats, fatigue due to anemia, weight loss. \200\223 Progressive symptomatic lymphadenopathy or splenomegaly. \200\223 Hb \211 10g/d L and/or platelets <100 109/L due to BM infiltration. \200\223 Hyperviscosity syndrome, symptomatic peripheral neuropathy, sys- temic amyloidosis, symptomatic cryoglobulinaemia, renal failure. \200\223 Note: avoid red cell transfusion simply to correct low Hb (plasma volume 4 causing spuriously low Hb; low Hb protects against clin- ical effects of hypervisc osity). 2 Plasmapheresis may be necessary as urgent initial therapy for patients with symptoms of h yperviscosity; 3L exchange efficiently reduces plasma viscosity (80% of large IgM molecule is intravascular); may rarely be required regularly in treatment of neuropathic or chemo- i ntolerant patients; in an emergency venesection and exchange transfu- sion will 5 plasma vi scosity. 2 Chlorambucil at a dose of 6 \200\22310mg/d for 7 \200\22314 days prednisolone in a 28d cycle is widely used initial therapy; continue to maximum response; up to 75% achieve \211 50% reduction in paraprotein; duration of response 2 \200\2234 years; <10% achieve CR; reinstitute treatment when paraprotein approaches previously symptomatic levels; often eff ective on several occasions; resistance ultimately develops; side effects; myelosuppression ; cyclophosphamide may achieve comparable results. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 287 Paraproteinaemias 2 Purine analogs: fludarabine (40mg/m2 PO 5d or 25mg/m2 IV 5d repeated monthly for 4 \200\2236 cycles) has a response rate of 40 \200\22380% in untreated patients and achieves 33% response rate even after chlo- rambucil resistance; response duration 30 \200\22340 mo nths; similar results with cladribine (0.1mg/kg continuous infusion 7d); both agents ach ieve more rapid responses than chlorambucil; side effects: myelo- suppression; profound imm unosuppression (see p558); need P carinii prophylaxis and irradiated blood products; additi on of cyclophos- phamide to a purine analog increases response rates. 2 Rituximab: monoclonal anti-CD20 antibody administered on 4 occa- sions achieves 60% respo nses \211 25% 5 in WM and useful in patients with marked cytopenia; abrupt elevation in se rum paraprotein and PV may occur after rituximab therapy and patients should be closely mon - itored; may be of benefit for symptomatic neuropathy; administration of 4 further doses o ver 12 months extends the response from 9 months to up to 3 years; under examination in cl inical trials in combi- nation with purine analog therapy. 287 2 High dose therapy and autologous or allogeneic SCT: has been under- taken in a small number of younger patients; high response rates ( 80%; up to 40% CR) are a chieved but relapse rate is high after auto- graft and treatment related mortality of 40% occurs after allograft; the latter does offer survivors the prospect of long-term disease c ontrol; HDT should be performed in a trial context where possible and patients in whom this treatment is planned should have limited prior exposure to alkylator and purine analog the rapy. 2 Treatment of relapse: if a response of >1year has been achieved most patients will respon d to the same therapy; refractory patients or those relapsing shortly after prior therapy m ay respond to an alternative listed above; 33% of patients with refractory WM respond to t halido- mide (50 \200\223200mg) in combination with dexamethasone (20 \200\22340mg once wee kly) and/or clarithromycin (250 \200\223500mg bd). Prognosis 2 Median time to progression of asymptomatic WM 7 years. 2 Median survival of pa tients with WM 5 years; patients who achieve CR with chlorambucil have median survival of 11 years. 2 Up to 20% die of unrelated causes and 33% from infection; others from disease progression, transformation and bleeding. 2 Indolent course may be interrupted by transformation into aggressive high grade NHL which is often poorly responsive to treatment; poor tolerance of aggressive treatment due to poo r marrow reserve. Gertz, M.A. et al. (2003) Treatment recommendations in Waldenstrom s macroglobulinemia: con - sensus panel recommendations from the Second International Workshop on Waldenstrom s Macr oglobulinemia. Semin Oncol, 30, 121 \200\223126; Kyle, R.A. et al. (2003) Prognostic marker s and cri- teria to initiate therapy in Waldenstrom s macroglobulinemia: consensus panel re commendations from the Second International Workshop on Waldenstrom s Macroglobulinemia. Se min Oncol, 30, 116 \200\223120; Weber, D. et al. (2003) Uniform response criteria in Walden strom s macroglobu- linemia: consensus panel recommendations from the Second International Workshop on Waldenstrom s Macroglobulinemia. Semin Oncol, 30, 127 \200\223131. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 288 Heavy chain disease (HCD) Uncommon lymphoplasmacytic cell proliferative disorder characterized by production of incom plete immunoglobulins comprising heavy chains without light chains. Alpha (a) HCD is most f requent, g and m HCD also described but rare. a-HCD 2 Usually occurs in residents or immigrants from Mediterranean or Middle East; associated with low socio-economic group, poor hygiene, recurrent infectious d iarrhea and chronic parasitic infection. 2 Commonly presents with diarrhea, steatorrhoea, weight loss, abdom- inal pain and vomiting ; a-HCD protein detectable in serum of most patients, concentration often low; mild to mode rate anemia; low serum albumin; hypokalaemia and hypocalcaemia (tetany); infiltrative lesio ns in duodenum and jejunum in most patients; histology ranges from lymphoplasmacytic infilt ration of mucosa (Stage A) to immunoblastic lymphoma invading entire intestinal wall. 288 2 Progressive course without treatment; treat Stage A initially with oral metronidazole and tetracycline for 6 months; treat non-responders and Stage B or C with CHOP-type regimen. AL (primary systemic) amyloidosis AL (primary systemic) amyloidosis is a clonal plasma cell disorder in which systemic diseas e results from organ dysfunction due to extracellular deposi- tion of fibrillar protein. It can also complicate most clonal B-cell lymphoplas- macytic disorders, notably myeloma, Wal denstr m \200\231s macroglobulinaemia, MGUS and lymphoma. Incidence Estimated incidence 0.5 \200\2231 per 100,000 per annum; 9:3 ratio 2:1; most case s aged 50 \200\22370; <10% <50 years; 1% <40 years; 15% of patients with MM develop amyloi d (lower % of MGUS and WM). Pathophysiology In AL amyloidosis the fibrillar deposits are composed of the variable regio ns of immunoglobulin light chains (VL) in association with gly- cosaminoglycans and amyloid P component derived from the normal plasma protein serum amyloid P (SAP) component. More c ommonly l light chains. Unique amino acid insertions may render the proteins amy- loidogeni c. Without treatment deposits progressively accumulate in viscera notably kidneys, heart, l iver and peripheral nervous system causing increasingly severe dysfunction. Under favorable circumstances, further amyloid deposition can be prevented, deposits can regress and impro ve- ment in organ dysfunction can occur. Clinical features and presentation 2 Renal involvement is the predominant feature in 33% wi th nephrotic syndrome (oedema, fatigue and lethargy) renal impairment (usually mild). 08-plasma cell.qxd 10.12.2003 04.21 PM Page 289 Paraproteinaemias 2 Cardiac symptoms predominate in 20 \200\22330%: CCF due to restrictive cardiomyopathy not ably with right sided features (4 JVP, peripheral oedema and hepatomegaly). 2 Peripheral neuropathy occurs in 20%; 10 \200\22315% present with isolated neuropathic symptoms; typically painful sensory polyneuropathy; carpal tunnel syndrome in 4 0%; autonomic neuropathy may cause postural hypotension, impotence and disturbed GI motilit y. 2 GI involvement may be focal or diffuse: malabsorption, perforation, hemorrhage and obstruction may occur; hepatomegaly 25%; macroglossia 10%. 2 Hemorrhage occurs at some time in up to 33% of patients; usually non-thrombocytopenic purpura, often periorbital causing characteristic \200\230raccoon eye s \200\231 appearance. 2 Vocal cord infiltration may cause dysphonia; large joint arthropathy; 289 adrenal and thyroid infiltration may cause endocrine dysfunction; cuta- neous plaques and n odules usually on face or upper trunk; pulmonary infiltration rarely symptomatic. Investigation and diagnosis 2 High index of suspicion required; consider in patient with ne phrotic syndrome, cardiomyopathy, peripheral neuropathy, hepatomegaly or autonomic neuropat hy. 2 Confirm diagnosis by histological examination of biopsy of affected organ or subcutaneous fat aspirate, rectal biopsy or labial salivary gland biopsy stained w ith Congo Red for red-green birefringence under polarized light; confirm AL amyloidosis by immunochemistry for k or l light chains (50% are negative). 2 Assess severity of organ involvement: \200\223 FBC: 5 Hb suggests probable myeloma. \200\223 Serum chemistry: to assess renal a nd hepatic function. \200\223 b2-microglobulin: prognostic indicator in MM (see p276). \200\223 Coagulation screen; may be a coagulopathy due to absorption of factor X and sometimes FIX by the amyloid. \200\223 Serum protein electrophoresis, immunofixation and densitometry: to detect, type a nd quantitate any paraprotein present ( 70%; usually only modest quantity). \200\223 Serum immunoglobulins: to identify immuneparesis (suggests MM). \200\223 Serum f ree light chain assay: useful in patients with no detectable paraprotein in serum or urine (10 \200\22315%). \200\223 Creatinine clearance and 24h quantitative proteinuria: to assess renal dysfunction. \200\223 Urine electrophoresis: to detect, type and quantify paraprotein (85%; 90% have albuminuria). \200\223 BM aspirate and trephine biopsy: usually only mild 4 in % plasma cells; overt MM in 20%. \200\223 Skeletal survey: if MM suspected. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 290 \200\223 ECG and echocardiography: low voltage ECG; echo shows concen- trically thickened ventricles, normal to small cavities and a normal or mild reduction in ejection fraction. \200\223 SAP (serum amyloid protein) scan: radiolabelled serum amyloid P component allows detection and quantification of amyloid deposits and assessment of extent of organ involvement by scintigraphy. (In UK contact National Amyloidosis Center at UCLMS R oyal Free Hospital, London Campus). Differential diagnosis Exclude MM (as above), reactive (AA) amyloidosis (history of chronic inflammatory disorder) and familial amyloidosis (family history). Prognostic factors Poor prognostic features: 2 CCF. 2 Multisystem involvement. 2 Renal fail ure. 2 Jaundice. 2 High total body amyloid load on SAP scan. 290 Management Aims: suppress underlying plasma cell neoplasia and paraprotein produc- tion to reduce further deposition of amyloid and permit regression resulting in improvement in orga n dysfunction. Supportive care 2 Nephrotic syndrome: loop diuretic + salt fluid restriction. 2 Renal fa ilure: peritoneal or haemodialysis if required; rigorous control of hypertension. 2 CCF: diuretic + ACE inhibitors if tolerated; digoxin hypersensitivity common; calcium cha nnel blockers and b-blockers contraindicated; cardiac transplantation should be considered in appropriate patients. Chemotherapy 2 Melphalan prednisolone: slow response rate; consider for patients not eligible for HDT; prolongs median survival in a randomized trial vs. colchicine (but su rvival only 12 \200\22318 months). 2 VAD: induces a more rapid response than M&P; suitable initial therapy in those patients e ligible for HDT; caution with vincristine in neuro- pathic patients and adriamycin in those with CCF; dexamethasone alone may produce responses. 2 High dose melphalan and autologous PBSCT: improves organ function in up to 60% of survivo rs; up to 40% procedure related mortality; Note: stem cell mobilization associated with mor tality and morbidity due to cardiac complications (avoid cyclophosphamide), oedema and sple nic rupture (low doses of G-CSF recommended); better tolerance of HDT if \211 2 organ syst ems involved; younger patients with good performance status and good renal and cardiac func tion do best; cardiac involve- ment or elevated creatinine poor prognostic factor; reduce m elphalan dose to 100 \200\223140mg/m2 in high risk patients; GI hemorrhage a fre- quent com plication; HDT should be undertaken in trial context. 2 Allogeneic SCT: few patients have been treated; complete resolution has been reported. 08-plasma cell.qxd 10.12.2003 04.21 PM Page 291 Paraproteinaemias Follow-up Response to therapy should be monitored by quantitation of the serum or urine par aprotein (or serum free light chains); SAP scintigraphy; ECG, echocardiography and assessme nt of other organ dysfunction should be reviewed every 6 months. Prognosis 2 Median survival 1 \200\2232 years; 4 \200\2236 months if CCF at diagnosis. 2 Mo st common cause cardiac: progressive congestive cardiomyopathy or sudden death due to VF or asystole. 2 Others succumb to uraemia or other complications. Other causes of amyloid Acquired 2 AA amyloid: reactive systemic amyloidosis associated wit h chronic 291 inflammatory diseases e.g. rheumatoid arthritis, TB; due to AA fibrils derived from serum a myloid A protein (SAA). 2 Senile systemic amyloidosis due to transthyretin deposition. 2 Endocrine amyloidosis, ass ociated with APUDomas. 2 Haemodialysis associated amyloidosis, localized to osteoarticular tissues or systemic due to b2-microglobulin deposition. 2 Non-familial Alzheimer \200\231s disease, Down syndrome due to b-protein. 2 Sporadic Creu tzfeldt \200\223Jakob disease, kuru due to prion protein deposition. 2 Type II diabetes mel litus due to islet amyloid polypeptide. Hereditary 2 Numerous syndromes with characteristic patterns of peripheral or cranial neurological involvement or visceral or cardiac involvement due to a variety of pro teins. 2 Familial Alzheimer \200\231s disease due to a b-protein. 2 Familial Mediterranean fever d ue to AA derived from SAA. BCSH/UKMF Guideline. Guidelines on the dignosis and management of AL amyloidosis. (cid:27) http://www.bcshguidelines.com 08-plasma cell.qxd 10.12.2003 04.21 PM Page 292 This page intentionally left blank 292 09-BMT.qxd 10.12.2003 04.21 PM Page 293 Transplantation 9 Stem cell transplantation 294 Allogeneic stem cell transplantation 296 Autologous stem cell transplantation 300 Investigations for BMT/PBSCT 302 Bone marrow harv esting 304 Peripheral blood stem cell mobilization and harvesting 306 Microbiological screening for stem cell cryopreservation 308 Stem cell transplant conditioning regimens 310 Infusion of cryopreserved stem cells 312 Infusion of fresh non-cryopreserved stem cells 314 Blood product support for stem cell trans plantation 316 GvHD prophylaxis 320 Acute GvHD 324 Chronic GvHD 326 Veno-occlusive disease 328 Invasive fungal infec tions and antifungal therapy 330 CMV prophy laxis and treatment 334 Post-transplant vaccination program 336 Treatment of relapse post-allegeneic SCT 338 Discharge and follow-up 340 09-BMT.qxd 10.12.2003 04.21 PM Page 294 Stem cell transplantation Stem cell transplantation (SCT) achieves reconstitution of haematopoiesis by the transfer o f pluripotent haemopoietic stem cells. In allogeneic SCT stem cells are obtained from a don or e.g. a matched sibling or normal vol- unteer (matched unrelated donor; MUD), in syngenei c SCT the donor is a monozygotic (identical) twin. For autologous SCT the patient acts as h is/her own source of stem cells. Placental cord blood has become a useful source of stem ce lls for pediatric transplants. The aim of SCT is 1. To permit haemopoietic reconstitution after potentially curative but m yeloablative doses of chemotherapy or chemoradiotherapy (high dose therapy; HDT) in the tre atment of malignant disease. or 2. To replace congenital or acquired life threatening abnormal BM or immune function with a normal haematopoietic and immune system. Stem cells may be obtained from bone marrow (BMT) by multiple aspira- tions under general a nesthesia (BM harvest) or obtained from peripheral blood after \200\230mobilization \200 \231 by G-CSF ( chemotherapy in the case of autol- ogous SCT) and collection by apheresis (peripheral blood stem cell trans- plants; PBSCT). Whether used fresh from donor harvest o r thawed after cryopreservation, stem cells are re-infused IV. PBSCT carries the advan- tag es of avoiding general anesthesia for the donor and more rapid engraftment ( 7 days) but ma y be associated with a higher incidence of chronic graft versus host disease (cGvHD). In th e autologous setting not all previously treated patients will mobilize adequate numbers of stem cells. 294 Stem cell collection for autologous SCT with curative intent in diseases involving the bone marrow should be undertaken after a complete response has been achieved by initial therapy . In some settings e.g. myeloma where HDT is being used with the aim of disease control rat her than with curative intent, BM involvement up to 30% is often accepted. Comparison of autologous and allogeneic SCT Autologous Allogeneic Wide age range, generally \211 65 Age range generally \211 55 No need for donor search if BM clear Sibs have 1 in 4 chance of match Not feasible if BM involved May be used in patients with BM disease Risk of tumor cell re-infusion No tumor contamination of graft Not all patients can be mobilized Donor search may impose delay No GvHD GvHD mortality and morbidity No immunosuppression Graft-versus-leukemia (GvL) effect Low early treatment related mortality (2-5%) Higher early treatment related mortality from GvHD and infection (20-40%) Risk of long term MDS from BM injury Less risk of late MDS 09-BMT.qxd 10.12.2003 04.21 PM Page 295 Transplantation Patient receives high dose chemo \200\223( radio)therapy (conditioning) which ablates the BM and immune system. After conditioning is completed, BM or PBSC are infused IV. After a p eriod of profound myelosuppression (7 \200\22325d), engraftment occurs with production of W BCs, platelets and RBCs. Immunosuppression is required after allogeneic transplantation to prevent GvHD and graft rejection. Early complications of the transplant procedure Chemoradiotherapy 2 Nausea/vomiting. 2 Reve rsible alopecia. 2 Fatigue. 2 Dry skin. 2 Mucositis. 2 VOD* (p328). Infection 2 Bacterial (Gram \200\223ve and +ve). 2 Viral \200\224HZV. 2 CMV (particularly pneumonitis)*. 2 Fungal \200\224Candida, Aspergillus*, Mucor*. 2 Atypical organisms \200 \224Pneumocystis (PCP)*, Toxoplasma*, Mycoplasma*, 295 Legionella*. Low risk in autologous SCT; significant to high risk in allogeneic SCT Graft-versus-host disease (GvHD) May occur in recipients of allogeneic SCT due to tissue in compatibility between donor and recipient undetected by standard tissue-typing tests. Acute and chronic forms occur. Higher incidence of severe GvHD fol- lowing unrelated donor SCT a nd mismatched (haploidentical) grafts. Late complications of transplantation 2 Infertility (both sexes). 2 Hypothyroidism. 2 Secon dary malignancy. 2 Late sepsis due to hyposplenism. 2 Cataracts (where TBI used). 2 Psychol ogical disturbance. Follow up and post-transplant surveillance Life-long supervision required. The particular r isks and monitoring required depend on the type of graft and whether TBI was used. Suitable conditioning regimens are outlined on p310. 09-BMT.qxd 10.12.2003 04.21 PM Page 296 Allogeneic stem cell transplantation Patient selection 2 Recipients should be in good physical condition, and \211 55 years old . 2 Donor and recipient should be fully or closely HLA-matched to reduce the risk of life threatening GvHD or graft rejection. 2 Greatest chance of full HLA match is with siblings (small chance of full match with cousins); each sib has 1:4 chance of full HLA-match. 2 Matched-volunteer unrela ted donor (MUD) may be sought from donor registries e.g. in UK The National Blood Authority and Anthony Nolan panels. 2 Haploidentical sibling may considered as a donor for patients in whom no matched sibling or volunteer donor is available ( 40%) and the increased risks of the procedure are accepta ble (e.g. poor risk adult AML, Ph-positive adult ALL). Indications for allogeneic SCT 2 Adult AML (poor risk first CR or any second CR)1. 2 Adult ALL (poor risk first CR or any second CR)2. 2 Severe aplastic anemia. 2 Chronic myeloid leu kemia. 2 Myelodysplasia. 2 Multiple myeloma (stage II/III). 2 Primary immunodeficiency synd romes. 2 Thalassaemia major. 2 Sickle cell disease. 2 Inborn errors of metabolism. 2 Relaps ed aggressive histology NHL. 2 Relapsed Hodgkin \200\231s lymphoma. 1. Good risk adult AML should not receive SCT in first remission as out- comes are good for most patients with sta ndard treatment (p156) 2. Most children with ALL will be cured by standard chemotherapy alo ne \200\224transplantation is reserved for those who relapse. (p475) 296 Outline of allogeneic SCT procedure 2 Patient receives standard conditioning therapy with h igh dose chemoradiotherapy (e.g. cyclophosphamide (CTX) 120mg/kg + 14Gy fractionated total body irra diation (TBI)) or chemotherapy (e.g. cyclophosphamide 120mg/kg + busulfan 16mg/kg). 2 Non-myeloablative conditioning regimens use moderate doses of chemotherapy and immunosuppression to achieve engraftment and have a lower transplant-relat ed mortality and morbidity; utilized to increase age range for allogeneic SCT and permit th e use of adoptive immunotherapy with donor lymphocyte infusion (DLI) for residual disease p ost-transplant. 2 In patients receiving MUD or haploidentical SCT, Campath-1H (humanized anti-CD52 monoclonal antibody) is often administered daily for 5d prior to condi tioning as an immunosuppressant to 5 the risk of graft rejection. 2 For patients with aplastic anemia less intensive conditioning is used (200mg/kg CTX combined with anti-thymocyte globulin) and because 09-BMT.qxd 10.12.2003 04.21 PM Page 297 Transplantation of sensitivity to alkylating agents in Fanconi \200\231s anemia still less intensive condit ioning is used. 2 One day after completing conditioning treatment, BM or PBSC are harvested from donor and infused IV through a central line. 2 In MUD and haploidentical SCT the graft is usually depleted of T lym- phocytes prior to infusion to reduce the risk of severe GvHD. 2 After 7 \200\22321d of severe myelosuppression, haematopoietic engraftment occurs. 2 Reverse barrier nursing in a filtered air environment, prophylactic anti- infectives (cip rofloxacin, itraconazole, acyclovir) reduce the risk of infective complications. 2 Immunosuppression is required to prevent GvHD and graft rejection; generally methotrexate (in the early engraftment phase) + cyclosporin A (for 6 months). Mechanism of cure: evidence for graft versus leukemia (GvL) effect 1. Reduced risk of relap se in patients with acute and chronic GvHD. 2. Increased risk of relapse after syngeneic SC T (no GvHD). 3. Increased risk of relapse after T-lymphocyte-depleted SCT. 4. Delayed clear ance of minimal residual disease detected post-SCT. 5. Induction of remission by donor lymp hocyte infusion (DLI) after 297 relapse post-SCT. Early complications of allogeneic SCT 2 Overall transplant related mortality for matched si bling allografts is 15 \200\22330%, for volunteer unrelated donors may reach 45%. 2 Infection: severe myelosuppression together with immune dysfunction from delayed reconsti tution or GvHD predisposes to a wide variety of potentially fatal infections with bacterial (Gram +ve and \200\223ve), viral, fungal and atypical organisms. Both HSV and HZV infecti ons are common \200\224may present with fulminant extensive lesions. Main causes of infecti ve death post-transplant are: CMV pneumonitis and invasive fungal infections with molds e.g . Aspergillus. 2 Graft versus host disease (GvHD): Acute GvHD occurs \211 100d of transplant and chronic >100d. (p324 \200\223327) 2 Other complications: \200\223 Endocrine infertility (both sexes), early menopause and occasionally hypothyroidism. \200\223 Cataract (TBI induced) >12 months post-transplant. \200\223 2 malignancies (es p. skin). \200\223 EBV associated lymphoma. \200\223 Mild psychological disturbances comm on (serious psychoses rare). Follow-up treatment and post-transplant surveillance Immunosuppression requires careful mon itoring to avoid toxicity. Unlike solid organ transplant recipients, immunosuppression not required and cyclosporin is usually discontinued at about 6 months post- transplant. Prophy laxis against pneumococcal sepsis secondary to hypos- lifelong