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 with oral metronidazole and tetracycline for 6 months; treat non- responders and stage B or C with RCHOP-type regimen. Variable clinical course; some die within 1 \200\2232 years, others have long remissions lasting many years. \235\233\204-HCD (Franklin disease) \200 Usually elderly \231\202, associated with RA, Sj gren \200\231s, SLE, hypereosinophilic syndrome and autoimmune haemolytic anemia. \200 Present with palatal oe dema, lymphadenopathy, hepatosplenomegaly, fever and recurrent infection; pancytopenia; eos inophilia and atypical lymphocytes/plasma cells in blood BM; monoclonal chain in seru m and/or urine on immunofi xation confi rms diagnosis. Usually behaves as aggressive lymphoma; survival 71 year. \235\233\215-HCD \200 Rare LPD , resembles CLL; presents with weight loss, fever, anemia, and recurrent infection. Hepatosplenomegaly; abdominal nodes generally involved; osteolytic lesions and pathological fractures in 40%. Vacuolated BM plasma cells in 66%; serum protein electrophoresis generally n or shows hypog ammaglobulinaemia; BJP 10 \200\22315%. \200 Variable clinical course; some develop AL; no specifi c treatment: observation or alkylating agents according to course. 379 HEAVY CHAIN DISEASE 380 CHAPTER 8 Paraproteinaemias AL (1 systemic) amyloidosis AL (1 systemic) amyloidosis is a clonal plasma cell disorde r in which systemic disease results from organ dysfunction due to extracellular deposition of a fi brillar protein. It can be associated with and complicate most clonal B-cell lympho plasmacytic disorders, notably myeloma, WM, MGUS, and lymphoma. Incidence Estimated incidence 0.5 \200\2231 per 100,000 per annum; \231\202: \231\200 rati o 2:1; most cases aged 50 \200\22370 years; <10% <50 years; 71% <40 years; 15% of patients with MM develop amyloid (lower % for MGUS and WM). Pathophysiology In AL amyloidosis the fi brillar deposits are composed of the variable regi ons of immunoglobulin light-chains (VL) in association with glycosa- minoglycans and amyloi d P component derived from the n plasma protein serum amyloid P (SAP) component. More commo nly derived from LCs. Unique amino acid insertions may render the proteins amy- loidogen ic and lead to deposits. The underlying clonal neoplasm (pro- ducing the Ig/LC) is usually small and <20% of patients meet diagnostic criteria for MM at diagnosis. Subsequent progres sion to MM is rare but may refl ect short survival. The t(11;14) IgH translocation occurs m ore frequently in AL amyloidosis than in MM or MGUS. Without treatment, amyloid deposition progressively accumulates in viscera, notably kidneys , heart, liver, and peripheral nervous system causing increasingly severe dysfunction. Unde r favorable circum- stances, further amyloid deposition can be prevented, deposits possibly regress, and improvement in organ dysfunction can occur. Clinical features and presentation \200 Renal involvement is the predominant feature in 3 3% with nephrotic syndrome (oedema, fatigue, and lethargy) renal impairment (usually mild). Cardiac symptoms predominate in 20 \200\22330%: CCF due to restrictive cardiomyopathy notab ly with right-sided features (i JVP, peripheral oedema, and hepatomegaly). Peripheral neuropathy occurs in 20%; 10 \200\22315% present with isolated neuropathic sympt oms; typically painful sensory polyneuropathy; autonomic neuropathy may cause postural hypo tension, impotence and disturbed GI motility in 710%. \200 Carpal tunnel syndrome in 720% . \200 GI involvement may be focal or diff use: malabsorption, perforation, hemorrhage, and obstruction may occur; hepatomegaly 25%. Hemorrhage occurs at some time in up to 33% of patients; usually non-thrombocytopenic purpura, often periorbital causing characteristic \200\230rac coon eyes \200\231 appearance. Vocal cord infi ltration may cause dysphonia; large joint arthropathy; adrenal and thyroid infi ltration may cause endocrine dysfunction; cutaneous plaques and nodules usually on fac e or upper trunk; pulmonary infi ltration rarely symptomatic. Macroglossia 10%. 381 AL (1 SYSTEMIC) AMYLOIDOSIS Investigations and diagnosis \200 High index of suspicion required; consider in patient w ith nephrotic syndrome, cardiomyopathy, peripheral neuropathy, hepatomegaly, autonomic neur opathy, or macroglossia. Confi rm diagnosis by histological examination of biopsy of aff ected organ (Table 8.22) or subcutaneous fat aspirate, rectal biopsy, or labial salivary gland biopsy stained with Con go red for red \200\223green birefringence under polarized light; confi rm AL amyloidosis b y immunochemistry for or LCs (50% are \210\222ve). Assess severity of organ involvement: FBC: d Hb suggests probable myeloma. \200 Serum chemistry: to evaluate renal and hepatic function. \200 2-microglobulin: prognostic indicator in MM. \200 Coagulation screen: may be coagulopathy due to absorption of factor X and sometimes FIX by the amyloid-fi brils. Serum protein electrophoresis, immuno \201 xation and densitometry: to detect, type, and q uantitate any paraprotein (770%; usually only modest quantity). Serum immunoglobulins: immuneparesis suggests MM. \200 SFLC assay: identifi es excess of or LC in >95%; provides best assessment of response to therapy in most patients. Creatinine clearance and 24h quantitative proteinuria: to assess renal dysfunction and severity of albuminuria. Urine electrophoresis: to detect, type and quantify paraprotein (85%; 90% have albuminuria). BM aspirate and trephine biopsy: usually only mild i in % plasma cells; overt MM in <20%; immunohistochemistry for and LCs; Congo red for amyloid. CXR, ECG, and echocardiography: low-voltage ECG; echo shows concentrically thickened ventricles, normal-to-small cavities, and a normal or mild reducti on in ejection fraction. SAP (serum amyloid protein) scan: radiolabelled serum amyloid P component allows detection and quantifi cation of amyloid deposition and assessment of extent of organ involvement by scintigraphy (done at amyloidosis diagnostic and treatment centers). Skeletal survey: only if MM suspected. Diff erential diagnosis Exclude plasma cell dyscrasia (MM, WM), reactive (AA) amyloidosis ( history of chronic infl ammatory disorder), and familial amyloidosis (family history). Prognostic factors Poor prognostic features \200 CCF. \200 Multisystem involvement. \200 Renal failure. \200 Jaundice. \200 High total body amyloid load on SAP scan. 382 CHAPTER 8 Paraproteinaemias Table 8.22 Organ involvement: biopsy of aff ected organ or an alternate sitea 24h urine protein >0.5g/d, predominantly albumin \200 Echo: mean wall thickness >12mm, no other cardiac cause \200 NT-proBNP > 332 ng/L in absence of RF or atrial fi brillation \200 Total liver span >15cm in the absence of heart failure or ALP Kidney Heart Liver >1.5 \227 ULN Peripheral: clinical; symmetrical lower extremity sensorimotor Nerve peripheral neuropathy Autonomic: gastric emptying disorder, pseudo-obstruction, voiding dysfunction not related t o direct organ infi ltration Direct biopsy verifi cation with symptoms \200 Direct biopsy verifi cation with symptoms \200 Interstitial radiographic pattern \200 Tongue enlargement \200 Clinical arthropa thy \200 Claudication, presumed vascular amyloid \200 Skin \200 Myopathy by biopsy or pseudohypertrophy \200 Lymph node (may be localized) \200 Carpal tunnel syndrome GI tract Lung Soft tissue a Alternate sites available to confi rm histological diagnosis of amyloidosis: fi ne needle abdominal fat aspirate and/or biopsy of the minor salivary glands, rectum or gingiva. Revised consensus criteria for amyloidosis involvement from the XII International Symposium on Amyloidosis. Management The current aim of treatment is to suppress underlying plasma cell neo- plasia a nd paraprotein production to reduce further deposition of amyloid and permit regression res ulting in improvement in organ dysfunction. Most treatment regimens have been adapted from those used in MM but patients with AL amyloidosis often experience greater toxicity. In con trast to MM where CR is the goal, a partial clonal response may halt amyloid deposi- tion a nd even lead to its regression. Thus treatments with a signifi cant risk of severe toxicity or death may be inappropriate. Many patients with AL amy- loidosis may not require prolong ed treatment schedules and a risk-adapted approach should be adopted. Good supportive care is essential. Where possible, patients should be treated within a clinical trial. Supportive care \200 Nephrotic syndrome: loop diuretic + salt fl uid restriction. \200 Renal failure: peritoneal or haemodialysis if required; rigorous control of hypertension. CCF: diuretic + ACE inhibitors if tolerated; digoxin hypersensitivity common; Ca2+ channel blockers and -blockers contraindicated; cardiac transplantation should be considered in a ppropriate patients. 383 AL (1 SYSTEMIC) AMYLOIDOSIS Chemotherapy There is insuffi cient data to indicate the optimal treatment for amyloi- dosi s. Treatment will depend on patient-specifi c factors, underlying disease and disease local ization. Table 8.23 lists the therapeutic options. Table 8.23 Therapeutic options in AL amyloidosis Oral melphalan + dexamethasone (M-Dex) Cyclophosphamide, thalidomide and dexamethasone (CTD) Bortezomib dexamethasone Bortezomib, melphalan, and dexamethasone Cyclophosphamide, bortezomib, and dexamethasone (CVD) Thalidomide + dexamethasone Lenalidomide + dexamethasone Interferon alfa + dexamethasone Modifi ed-dose or high-dose melphalan + ASCT Best supportive care Intermediate dose: 1st line treatment with combination treatment for most patients. Commonl y used drug combinations include CTD (cyclo- phosphamide, thalidomide, and dexamethasone) a nd CVD (cyclophos- phamide, bortezomib (Velcade) and dexamethasone), or melphalan, bortezom ib (Velcade) and dexamethasone. Low dose: melphalan/dexamethasone; thalidomide or lenalidom ide with dexamethasone; rarely IFN. High dose: high-dose melphalan + auto-SCT. Rarely recom mended as 1st line treatment. Sometimes only treatment required, but can be pre- ceded by i ntermediate dose treatment. The most used schedules are discussed here. \200 Melphalan/De x: melphalan + high-dose dexamethasone (M 0.22mg/ kg/d and Dex 40mg/d d1 \200\2234, every 28d); 67% hematological responses (33% CR) in media n 4.5 months; improved organ function in 48% responsive patients; well tolerated; long-term follow-up reported 4.9 year median clonal remission in 9/15 CRs. CTD: thalidomide is poorly tolerated in doses used in MM; combination with cyclophosphamide and dexamethasone in risk-adapted CTD achieved 74% hematological resp onses (21% CR) and median OS 41 months; organ responses 31%; 3-year estimated OS 100% in CR s and 82% in PRs; TRM 4%. Thalidomide dose not to exceed 50 mg ON. CVD: bortezomib active in AL amyloid with 77% responses \211 PR. High discontinuation for toxicity; lower doses may be more tolerable. \200 Lenalidomide/Dex: 6 7% \211 hematological PR; myelosuppression occurred in 35% and VTE in 9%; lower doses required. High-dose melphalan and autologous SCT: limited availability as <20% are genuinely low risk for treatment-related mortality (TRM); 41% achieve hematological CR (superior to 20% achie ved by best intermediate dose regimen); procedure-related mortality 10 \200\22312%; improve s organ 384 CHAPTER 8 Paraproteinaemias function in up to 60%; long-term follow-up in 80 patients reported median OS 57 months; med ian OS exceeds 10 years if in CR after HDT. Not clearly superior to intermediate regimens s uch as M-Dex or CTD; HDT better tolerated if \211 2 organ systems involved; younger patien ts with good performance status and good renal and cardiac function do best; cardiac involv ement or elevated creatinine are adverse prognostic indicators; d melphalan dose to 100 \200\223140mg/m2 in high-risk patients; GI hemorrhage a frequent complication. HDT should i deally be undertaken in context of a clinical trial. \200 Note: stem cell mobilization as sociated with mortality and morbidity due to cardiac complications (avoid cyclophosphamide), oedema and splenic rupture (low doses of G-CSF recommended). \200 Careful selection criteria recommended: see Table s 8.24 and 8.25. \200 Allogeneic SCT: isolated reports of small numbers of patients treat ed with allografts with high TRM (40%); reduced-intensity conditioning reduces this fi gure ; should be restricted to clinical trials in highly selected patients in experienced center s. Table 8.24 Mayo Clinic risk stratifi cation model to predict progres- sion of primary amylo idosis1 Median survival of patients not undergoing SCT (months) Risk group Median survival of patients undergoing SCT (months) Not reached at 40 months 26.4 Low risk (cardiac troponin <0.035mcg/L and NT-proBNP <332ng/L) Not reached at 40 months 10.5 Intermediate risk (any 1 factor abnormal) 8.4 3.5 High risk (cardiac troponin \211 0.035mcg/L and NT-proBNP \211 332ng/L) Adapted from Rajkumar, S.V. et al. (2006) Monoclonal gammopathy of undetermined signifi can ce, Walden-str m macroglobulinemia, AL amyloidosis and related plasma cell disorders: diag nosis and treatment. Mayo Clin Proc, 81, 693 \200\223703., with permission of Elsevier. Table 8.25 Criteria for eligibility for ASCT in UK amyloidosis treatment trial2 ECOG performance status 0 or 1 No greater than NYHA class I or II heart failure No more tha n 2 organs involved by amyloid by consensus guidelines Age \211 65 years Creatinine cleara nce \211 0.8mL/sec (50mL/min) Bilirubin \211 1.5 \227 and alkaline phosphatase \211 2 \227 ULN Inter-ventricular and left ventricular posterior wall thicknesses \211 15mm by ec hocardiography Absence of clinically important amyloid related autonomic neuropathy Absence of clinically important amyloid related gastrointestinal hemorrhage 385 AL (1 SYSTEMIC) AMYLOIDOSIS Response assessment Consensus response criteria have been published.3,4 Separate haemato- l ogical and organ responses have been defi ned. The latter occur slowly and are generally de pendent on the former which is a strong predictor of survival. (See Tables 8.26 and 8.27.) Table 8.26 Hematological response criteria3,4 Serum and urine \210\222ve for paraprotein by immunofi xation \200 Free LC ratio n \200 BM plasma cells <5% \200 Free LC< 40mg/L Complete response (CR) Very good partial response (VGPR) LC decrease \211 50% Partial response (PR) From CR, any detectable paraprotein or abnormal free LC Progression ratio (LC must double) From PR or stable response, 50% i in serum paraprotein to >5g/L or 50% i in urine paraprote in to >200mg/d; a visible peak must be present \200 Free LC i of 50% to >100mg/L \200 N o CR, no PR, no progression Stable Table 8.27 Organ response criteria3,4 Response Progression Heart Mean interventricular septal thickness d by 2mm, 20% i in ejection fraction, improvement by 2 NYHA classes without i diuretic use and no i in wall thickness, decrease of NT-proBNP of \211 30% Interventricular septal thickness i by 2mm compared with baseline, i in NYHA class by 1 gra de with a d in ejection fraction \211 10% Kidney 50% i ( \211 1g/d) of 24h urine protein to >1g/d or 25% worsening of serum creatinine or cr eatinine clearance 50% d ( \211 0.5g/d) of 24h urine protein (must be >0.5g/d pretreatment) Liver 50% i of alk phos above the lowest value 50% d in abnormal alk phos; \211 2cm d in liver size radiographically Nerve Improvement in EMG nerve conduction (rare) Progressive neuropathy by EMG or nerve conduction velocity Follow-up Response to therapy should be monitored by quantitation of the SFLCs or in the mi nority with measurable levels, the serum paraprotein; SAP scintigraphy; ECG, echocardiograp hy, and assessment of other organ dysfunction should be reviewed every 6 months. 386 CHAPTER 8 Paraproteinaemias Prognosis \200 Median survival 1 \200\2232 years; 4 \200\2236 months if CCF at diagnosis. \200 Most common cause of death cardiac, progressive congestive cardiomyopathy, or sudden death due to VF or asystole. Others succumb to uraemia or other complications. Other causes of amyloid5 Acquired \200 AA amyloidosis: reactive systemic amyloidosis asso ciated with chronic infl ammatory diseases, e.g. rheumatoid arthritis, TB; due to AA fi brils derived f rom serum amyloid A protein (SAA); treat underlying condition. Senile systemic amyloidosis due to transthyretin deposition; no therapy. Endocrine amyloidosis, associated with APUD-omas. \200 Haemodialysis associated amyloidos is, localized to osteoarticular tissues or systemic due to 2-microglobulin deposition. Non-familial Alzheimer disease, Down syndrome due to -protein. \200 Sporadic Creutzfeld t \200\223Jakob disease, due to prion protein deposition. \200 Type 2 diabetes mellitus d ue to islet amyloid polypeptide. Hereditary \200 Numerous syndromes with characteristic patterns of peripheral or cranial neurological involvement or visceral or cardiac involvement due to a variety of proteins. Familial mutant ATTR due to mutant transthyretin. \200 Familial Alzheimer disease due to a -protein. \200 Familial Mediterranean fever due to AA derived from SAA; treat with colchicine. References 1. Rajkumar, S.V. et al. (2006) Monoclonal gammopathy of undetermined signifi ca nce, Waldenstr m macroglobulinemia, AL amyloidosis and related plasma cell disorders: diag nosis and treatment. Mayo Clin Proc, 81, 693 \200\223703. 2. Wechalekar, A.D. et al. (2008). Perspectives in treatment of AL amyloidosis. Br J Haemat ol 140, 365 \200\22377. 3. Gertz, M.A. et al. (2005). Defi nition of organ involvement and treatment response in im munoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematol, 79, 319 \200\22328. 4. Gertz, M.A. et al. (2010). Defi nition of organ involvement and response to treatment in AL amyloidosis: an updated consensus opinion. Amyloid, 17(s1), 48. 5. Rajkumar, S.V. and Gertz, M.A. (2007). Advances in the treatment of amyloidosis. N Engl J Med, 356, 2413 \200\22315. Further reading Cohen, A.D. and Comenzo, R.L. (2010). Systemic light-chain amyloidosis: adv ances in diagnosis, prognosis, and therapy. Hematology Am Soc Hematol Educ Program, 2010, 2 87 \200\22394. Gertz, M.A. et al. (2009). Treatment of immunoglobulin light chain amyloidos is. Curr Hematol Malig Rep, 4, 91 \200\2238. Gertz, M.A. (2011) Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk- stratifi cation, and management. Am J Hematol, 86, 180-6. NCCN Guidelines on Amyloidosis. Version 1.2013. M www.NCCN.org. 387 Chapter 9 Haematopoietic stem cell transplantation Haemopoietic stem cell transplantation (SCT) 388 Indications for haemopoietic SCT 392 Allog eneic SCT 398 Autologous STC 402 Investigations for BMT/PBSCT 404 Pretransplant investigati on of donors 406 Bone marrow harvesting 408 Peripheral blood stem cell mobilization and har vesting 410 Microbiological screening for stem cell cryopreservation 412 Stem cell transpla nt conditioning regimens 414 Infusion of cryopreserved stem cells 416 Infusion of fresh non -cryopreserved stem cells 418 Blood product support for SCT 420 Graft-versus-host disease ( GvHD) prophylaxis 424 Acute GvHD 428 Chronic GvHD 432 Veno-occlusive disease (syn. sinusoid al obstruction syndrome) 438 Invasive fungal infections and antifungal therapy 442 CMV prophylaxis and treatment 446 Pos t-transplant vaccination program and foreign travel 448 Longer term eff ect post-transplant 450 Treatment of relapse post-allogeneic SCT 451 Discharge and follow-up 452 388 CHAPTER 9 Haematopoietic stem cell transplantation Haemopoietic stem cell transplantation (SCT) Haemopoietic SCT achieves reconstitution of ha ematopoiesis by the transfer of pluripotent haemopoietic stem cells. In allogeneic SCT stem cells are obtained from a donor, e.g. a matched sibling or normal matched volunteer unrela ted donor (VUD); in syngeneic SCT the donor is a monozygotic (identical) twin. For autologo us SCT the patient acts as his/her own source of stem cells. Umbilical cord stem cells have become a useful source of stem cells for some patients where no HLA- identical donor is fo und/available. Note that stem cell transplants/bone marrow transplants should only be performed in special ized and accredited centers under supervision by transplant physicians. Centers in Europe a re accredited by JACIE, the Joint Accreditation Committee of the ISCT (International Societ y for Cellular therapy) and the EBMT (European Society for Blood and Marrow Transplantation ). This regulatory body mandates standards and inspection programs to assure appropriate fa cilities, staff , experience, and protocols are in place. Outcome measures such as d100 out come/ mortality, 1-year survival, and relapse rates are also monitored. The decision for referral for a patient to a transplant center is based on indications (dis cussed on E pp.392 \200\223396), patient-specifi c features, and multidisciplinary team dis cussions. The aim of SCT is: \200 To permit haemopoietic reconstitution after potentially curative but myeloablative doses of chemotherapy or chemoradiotherapy (high- dose therapy (HDT)) in the treatment of malignant disease; or \200 To replace congenital or acquired life-threatening abnormal BM or immune function with a normal haematopoietic and immune system. The therapeutic eff ect of allogeneic SCT is not restricted to the con- ditioning as there can be an additional graft-versus-disease eff ect (e.g. graft-versus-leukemia (GvL)), media ted by the incoming donor immune system that contributes signifi cantly to the curative pot ential of the procedure, though this is linked to its major toxicity, graft-versus-host dis ease (GvHD). No GvL eff ect occurs in syngeneic or autologous SCT and in allogeneic SCT it can be abrogated by intensive eff orts to prevent GvHD (see Tables 9.1 and 9.2). Stem cells may be obtained from BM (bone marrow transplant (BMT)) by multiple aspirations u nder general anesthesia (BM harvest), or obtained from peripheral blood after \200\230mobi lization \200\231 and collection by apheresis (peripheral blood stem cell harvest and trans plant (PBSCH and PBSCT)). Whether used fresh from donor harvest or thawed after cryopreserv ation, stem cells are re-infused IV. PBSCT carries the advantages of avoiding general anest hesia for the donor and more rapid engraftment (77d) but may be associated with a higher in cidence of chronic GvHD (cGvHD). In the autologous setting not all previously treated patie nts will mobilize adequate numbers of stem cells. 389 HAEMOPOIETIC STEM CELL TRANSPLANTATION (SCT) Stem cell collection for autologous SCT with curative intent in diseases involving the BM s hould 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 rather than with cura- tive intent, low-level BM involvement is often accepted. The patient receives \200\230conditioning \200\231 comprising of high-dose chemo- therapy or chemo-radiotherapy antibodies (e.g. alemtuzumab) which ablates the recipient \200\231 s BM and immune system. Reduced inten- sity conditioning (RIC) is now more often used, rely ing more heavily on the graft-versus-disease eff ect. After conditioning is completed, BM o r PBSC are infused IV. After a period of profound myelosuppression (7 \200\22325d), engraft ment occurs with production of WBCs, platelets, and RBCs. Immunosuppression is required aft er allogeneic transplantation to prevent graft failure, GvHD, and graft rejection. Table 9.1 Comparison of autologous and allogeneic SCT Autologous Allogeneic Wide age range, generally \211 70 years Age range generally \211 60 years, though higher age limit now that RIC is used No need for donor search if BM clear Sibs have 71 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-disease eff ect (e.g. GvL) Low early treatment related mortality (2 \200\2235%) Higher early treatment-related mortality from GvHD and infection (10 \200\22320%) Risk of long-term MDS from BM injury Lower risk of late MDS 390 CHAPTER 9 Haematopoietic stem cell transplantation Table 9.2 Factors infl uencing outcome of haemopoietic SCT Time Patient Donor Pre-transplant Disease Diagnosis, subtype, stage Age, sex, sex-mismatch, ethnicity, viral status, histocompatibility Major histocompatibilit y antigens Minor histocompatibility antigens ABO Cytokine polymorphisms Individual Age, sex, ethnicity, organ status, viral status, Performance status Environment Geography Economic status Peri-transplant Conditioning GvHD prevention Graft product Intensity: RIC? Prevention method Stem cell source, graft composition Post-transplant Disease Individual Environment Relapse Immune reconstitution Retreatment possibilities Availability for DLI or retransplant Reproduced from Gratwohl, A. (2007). Risk assessment in haemopoietic stem cell transplantat ion. Best Pract Res Clin Haematol, 20, 119 \200\22324, with permission from Elsevier 200 7. Early complications of the transplant procedure Chemo-radiotherapy \200 Nausea/vomiting. \200 Reversible alopecia. \200 Fatigue. \200 Dry skin. \200 Mucositis. \200 Organ failure. \200 VOD (veno-occlusive disease). Infection \200 Bacterial (Gram \210\222ve and +ve). \200 Viral \200\224HZV. \200 CMV (particularly pneumonitis).* \200 Fungal \200\224Candida, Aspergillus*, Mucor*. \200 A typical organisms \200\224Pneumocystis (PCP)*, Toxoplasma*, Mycoplasma*, Legionella*. (*Low risk in autologous SCT; signifi cant to high risk in allogeneic SCT.) 391 HAEMOPOIETIC STEM CELL TRANSPLANTATION (SCT) GvHD May occur in recipients of allogeneic SCT due to tissue incompatibility between donor and recipient undetected by standard tissue-typing tests. Acute and chronic forms. Higher i ncidence of severe GvHD following VUD SCT, and mismatched or haploidentical grafts. Acute o r chronic. Late complications of transplantation \200 Complications of chronic GvHD. \200 Infertil ity (both sexes). \200 Hypothyroidism. \200 2 malignancy. \200 Late sepsis due to h yposplenism (in myeloablative regimens). \200 Cataracts (where TBI used). \200 Psycholo gical disturbance. Follow up and post-transplant surveillance Lifelong follow-up is required. The particular r isks and monitoring required depend on the type of graft and whether TBI was used. Suitable conditioning regimens are outlined in E Stem cell transplant conditioning regimens, p.414. Further reading Apperley, J. et al. (eds.) (2012). The EBMT-ESH Handbook on Haemopoietic St em Cell Transplantation, revised ed. Paris: EBMT. Cant, A.J. et al. (eds.) (2007). Practica l Haematopoietic Stem Cell Transplantation. Oxford: Blackwell Publishing. Gratwohl, A. (ed. ) (2007). Risk assessment in haematopoietic stem cell transpantation. Best Pract Res Clin H aematol, 20(2), 119 \200\22324. 392 CHAPTER 9 Haematopoietic stem cell transplantation Indications for haemopoietic SCT The Accreditation Subcommittee of the European Group for B lood & Marrow Transplantation (EBMT) reports current practice for HSCT in Europe (Tables 9. 3 and 9.4). Table 9.3 EBMT indications for HSCT for adults (recommendation from 2010, adopted and uncha nged 2012)1 Disease Disease status Allo Auto Mismatch unrelated/ >1 antigen mismatched related Sibling donor Matched unrelated /1 antigen mismatched related GNR D CO CO D GNR CO S CO CO GNR GNR D CO S S CO CO CO S S S S S AML CR1 (low risk) CR1 (int risk) CR 1 (high risk) CR2 CR3, incipient relapse APML molecular pe rsistence CO D S CO APML molecular CR2 Relapse/refractory GNR D S GNR D GNR GNR D ALL CR1 (standard/ int risk) CR1 (high risk) CR2, incipient S S S S CO CO D GNR relapse Relapse/ refractory CO D D GNR CML 1st CP, failed imatinib AP, >1st CP Blast crisis S S CO D S CO S CO CO CO D GNR Myelofi brosis 1 , 2 with high/ int Lille score S S D GNR Myelodysplastic syndrome RA, RAEB RAEBt, sAML, CR1, CR2 More advanced stages S S S S S CO CO CO D GNR CO GNR CLL High-risk disease S S D CO CO GNR GNR GNR Diff use large B-cell NHL CR1 (int/high-risk at Dx) S GNR CO CO Chemosensitive relapse; \211 CR2 GNR GNR D D Refractory (continued) 393 INDICATIONS FOR HAEMOPOIETIC SCT Table 9.3 (continued) EBMT indications for HSCT for adults (recom- mendation from 2010, ado pted and unchanged 2012)1 Disease Disease status Allo Auto Sib Matched Mismatched CO CO D D GNR GNR S S Mantle cell lymphoma CR1 Chemosensitive relapse; \211 CR2 Refractory D D GNR GNR CO CO CO CO GNR GNR CO CO CR1 Chemosensitive relapse; Lymphoblastic and Burkitt lymphoma \211 CR2 Refractory D D GNR GNR GNR CO GNR CO GNR D CO S Follicular NHL CR1 (int/high risk at dx) Chemosensitive relapse; \211 CR2 Refractory CO CO D GNR CO CO D CO GNR GNR CO D T-NHL CR1 Chemosensitive relapse; \211 CR2 Refractory D D GNR GNR GNR CO GNR CO GNR CO GNR S HL \200\224classical CR1 Chemosensitive relapse; \211 CR2 Refractory D D GNR CO GNR GNR GNR GNR GNR GNR GNR CO HL \200\224NLPHL CR1 Chemosensitive relapse; \211 CR2 Refractory GNR GNR GNR CO Myeloma CO CO GNR S Amyloidosis (primary; AL) CO CO GNR CO Severe aplastic anemia Newly diagnosed Relapsed, refractory S S CO S GNR CO GNR GNR PNH S CO CO GNR Solid tumors Germ-cell tumors Sensitive relapses 3rd line refractory GNR GNR GNR GNR GNR GNR CO S Breast ca Adjuvant high risk Metastatic respond GNR D GNR D GNR GNR CO D/CO Ovarian ca CR/PR Platinum sensitive relapse GNR D GNR GNR GNR GNR D CO Medulloblastoma Post-surgery GNR GNR GNR D Small cell lung Limited stage GNR GNR GNR D Renal cell ca Metastatic, cytokine refr CO CO GNR CO Soft cell sarcoma Metastatic responsive D GNR GNR D (continued) 394 CHAPTER 9 Haematopoietic stem cell transplantation Table 9.3 (continued) EBMT indications for HSCT for adults (recom- mendation from 2010, ado pted and unchanged 2012)1 Disease Disease status Allo Auto Sib Matched Mismatched Auto immune diseases Immune CO D D CO cytopenias Systemic sclerosis D GNR GNR CO R.A. CO GNR GNR CO Multiple D GNR GNR CO sclerosis Lupus D GNR GNR CO erythematosis Crohn \200\231s disease CO GNR GNR CO CIDP CO GNR GNR D S = standard of care, generally indicated in suitable patients; CO = clinical option, can b e carried out after careful assessment of risks and benefi ts; D = developmental, further t rials are needed; GNR = generally not recommended. NB This classifi cation does not cover patients for whom a syngeneic donor is available. A syngeneic twin donor is generally considered S for all indications except, by defi nition, congenital disorders. Donor type is divided into: HLA identical sibling donor. Matched unrelated: there is no uniformly accepted defi nition. A \211 10/10 antigen matche d donor is unequivocally considered as matched. Mismatched donor: there is no uniformly accepted defi nition. A < 8/8 antigen matched unrelated and a >1 antigen mismatched family donor is unequivocally considered mismatched. 395 INDICATIONS FOR HAEMOPOIETIC SCT