Amyloidosis Nelson Leung Mayo Clinic (Rochester MN USA) - PowerPoint PPT Presentation

Amyloidosis Nelson Leung � Mayo Clinic (Rochester MN � USA) Discussant: Sonia Pasquali (Reggio Emilia � Italy)

Amyloidosis EFFECTIVE THERAPY

Amyloidoses are treatable (curable?) Palladini G, Merlini G Haematologica, 94: 1004 - 2009

Keys to effective treatment: � Early diagnosis � Accurate clinical approach � Accurate follow-up

DIAGNOSING AMYLOIDOSIS Key points: � Diagnosis relies on demonstration on tissue biopsy of fibrillar deposits which are congophilic and birefringent under polarized light, or typical, rigid, nonbranching, 7.5-10 nm wide fibrils by electron microscopy � Unequivocal identification of amyloid protein is essential for: � appropriate treatment � assess prognosis � genetic counseling (when appropriate)

DIAGNOSIS AND TYPING OF SYSTEMIC AMYLOIDOSES Abdominal fat biopsy Renal biopsy

Diagnosis of Systemic Amyloidoses Biopsy site: fine needle abdominal fat aspirate (sensitivity 80-85%, specificity 98-100%) biopsy of the labial minor salivary glands (sensitivity 85-90%, specificity 98-100%) rectal biopsy (sensitivity 70-80%, specificity 98-100%)

Diagnosis of Systemic Amyloidoses Biopsy site: fine needle abdominal fat aspirate (sensitivity 80-85%, specificity 98-100%) biopsy of the labial minor salivary glands (sensitivity 85-90%, specificity 98-100%) rectal biopsy (sensitivity 70-80%, specificity 98-100%) biopsy of the organ involved

Keys to effective treatment : Early diagnosis � Question: the role of renal biopsy ?

D.M.: AA AMYLOIDOSIS DONINI 2002 � IGS

Heart: Mean wall thickness >12 mm on echocardiogram, no other cardiac disease responsible for the increase in wall thickness Liver: Total liver span >15 cm in the absence of heart failure, oralkaline phosphatase level >1.5 times upper limit of normal Nerve: Symmetric sensorimotor peripheral neuropathy in the legs, gastric-emptying disorder, pseudo-obstruction, voiding dysfunction notrelated to direct organ infiltration Gastrointestinal tract: Symptoms and verification by means of biopsy Soft tissue: Tongue enlargement, arthropathy, skin purpura, Lymph node involvement, carpal tunnel syndrome

Kidney 24-h urinary protein >0.5 g/day, predominantly albumin with or without renal insufficiency

Kidney (patients with renal insufficiency) � reduction in proteinuria by at least 50% � in the absence of 25 % or greater reduction in renal function Heart: Mean interventricular septal thickness decreased by 2 mm, 20% improvement in ejectionf raction,improvement by two New York Heart Association classes without an increase in diuretic use, and no increase in wall thickness. Liver: 50% decrease in abnormal alkaline phosphatase value, at least 2-cm decrease in liver size on radiographic imaging Nerve: Improvement in nerve conduction velocity on electromyogram

IF anti λ Complete response: Serum and urine negative for a monoclonal protein by means of immunofixation, normal kappa:lambda free light-chain ratio Partial response: Serum M component >0.5 g/dl and 50% reduction; light chain in the urine with a visible peak >100 mg/day and 50% reduction; or free light chain>10 mg/dl and 50% reduction

Keys to effective treatment: � Early diagnosis � Accurate clinical approach Question: The differential diagnosis of AL Amyloidosis and MM with Amyloidosis ?

MULTIPLE MYELOMA AL AMYLOIDOSIS + AL AMYLOIDOSIS

PROGNOSTIC FACTORS IN AL AMYLOIDOSIS Cox multivariate analysis (705 patients): hematologic response to therapy p=9.2x10-24 heart involvement p=1.7x10-14

Cause of death (%) in 258/600 patients with AL AMYLOIDOSIS Other; 7,5 Hemorrage; 2 Liver failure; 3 Renal failure; 3,5 Cachexia; 4 Infection; 5 CHF; 46 Myocardial infarction/stroke; 7,5 Cardiac 75% Sudden death; 21,5

� AL patients developing end-stage renal failure requiring � dialysis: � 18 % (Gertz et al, Arch Intern Med 1992;152:2245-50) � AL patients with renal involvement developing end- stage � renal failure requiring dialysis: � 23% (IASG, Budapest Amyloid Symposium, 2001) � The most important predictors of renal failure requiring dialysis are: 24-h u.protein > 2 g � s. creatinine (> 1.7 mg/dL) �

Nephron 2001; 187: 333-39 Hypertens Res 2001; 24: 691-97

Responders Non responders p (6 pts) (6 pts) GFR 0% 50% 0.09 (15-29 ml/min) Proteinuria 67% 17% ns (> 5g/24h) Serum uric 0% 50% 0.09 acid (>8 mg/dl)

Responders Non responders p (6 pts) (6 pts) Duration disease 33% 100% 0.03 (>12 months) Heart 0% 33% ns involvement Hematologic 100% 50% 0.09 response

Keys to effective treatment: � Early diagnosis � Accurate clinical approach � Accurate follow-up Question: the prognostic role of serum uric acid ?

(Leung N. et al. Kidney Int 2008;73:1282-1288) � Plasma Exchange is effective at reversing Plasma Exchange is effective at reversing � renal failure if it is due to cast renal failure if it is due to cast nephropathy and if sFLC levels can be nephropathy and if sFLC levels can be reduced by at least 50% (improvement in reduced by at least 50% (improvement in 78% of cases) 78% of cases) � The diagnosis is a key factor in the The diagnosis is a key factor in the � success of therapy success of therapy

CG71 MDR3 CG161 Bead diameter 35 micron 75 micron 75 micron bead Pore diameter 250 angstrom 300 angstrom 150 angstrom Area 500 m 2 /g 700 m 2 /g 900 m 2 /g in vitro pure resins screen in vitro mixed resins screen 350 350 30 30 300 300 120 120 250 250 Lambda Lambda 200 200 150 150 Best 100 100 results 50 50 0 0 C C C C 1 2 P 1 1 1 C C C C 1 2 P 1 1 1 - - 7 6 7 - - 7 6 7 0 0 E 0 S 0 0 E 0 S M M M M G 1 G G 1 G 5 4 0 5 5 4 0 5 r G r G Toyopearl CM-650C Toyopearl HW40C Toyopearl SP-550C BEL-0406-RAM-1 BEL-0406-RAM-2 Toyopearl Super SP MDR3 (CG300) CG71 Toyopearl CM-650C CG161 Toyopearl HW40C Toyopearl SP-550C BEL-0406-RAM-1 BEL-0406-RAM-2 Toyopearl Super SP MDR3 (CG300) CG71 CG161 6 - 5 A A C C 6 - 5 A A C C Toyopearl Megacap SP-550EC Toyopearl Megacap SP-550EC W 5 e W 5 e - - - 5 R R p C - 5 R R p C M P M P + + + + H - - - u H - - - u P S 6 6 3 + 3 P S 6 6 3 + 3 C S C S l S 0 0 R 3 R l S 0 0 R 3 R r l r l l r 4 4 l R l r 4 4 l R r a a r D D r a a r D D p p a e 0 0 a D a e 0 0 a D e M M e M M e p a - - e e p a - - e p L L M p L L M c c p o p p o p a o E E a o E E o y o o y o y y g B B g B B y o y y o y e o e o o T o o T o T + + T + + T M T T M T + 3 3 + 3 3 + + + R R + + R R + 3 l 3 3 l 3 r r 3 R a D D 3 3 R a D D 3 R R R R R R D e M M D e M M D D D p D D p D M M o M o M M M M M y y o o T T + + 3 3 R R D D M M Programma di ricerca Regione-Università 2007-2010

Pore Sizes of High Cut-Off (HCO) Membranes in comparisson to HighFlux and plasmafiltration membranes HighFlux HighFlux High Cut-Off High Cut-Off HighFlux HighFlux Plasmafilter 1,0 1,0 1,0 0,8 0,8 0,8 HCO 0,6 0,6 0,6 ] ] ] - - - [ [ [ 0,4 0,4 0,4 o o o n n n / / / n 0,2 n n 0,2 0,2 Plasmafilter 0,0 0,0 0,0 0,001 0,01 0,1 1 0,001 0,001 0,01 0,01 0,1 0,1 1 1 m m m p p o o e e e e µ µ p o e s z e µ s s z z r r r [ ] [ [ ] ] i i i

Aim: Evaluate the removal of FLCs by extended HD in patients with biopsy proven cast nephropathy + dialysis dependent acute renal failure Outcomes: � Reduction in serum FLC concentrations � Recovery of renal function + patient survival � Study population compared with a case matched historical control population Of 27 multiple myeloma patients with dialysis dependent renal failure assessed, 19 meet inclusion criteria Hutchison et al. cJASN 2009

Lambda Kappa Lambda Kappa 2000 2000 Kappa: - 68% Kappa: - 68% Lambda: - 58% 1562 Lambda: - 58% 1562 1500 1500 1111 1111 1000 1000 848 848 899 899 655 655 mg/L 500 500 450,6 450,6 570,6 570,6 353 353 0 0 0 4 h 8 h Rebound 0 4 h 8 h Rebound

Removal of circulating light chains Removal of circulating light chains The role in amyloidosis treatment? The role in amyloidosis treatment?

� Early diagnosis � Accurate clinical approach � Accurate follow-up Highy individualized treatment