Review of Systemic Amyloidosis 김기현 성균관의대삼성서울병원

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1 Review of Systemic Amyloidosis 김기현 성균관의대삼성서울병원 김기현

2 Amyloidosis A heterogeneous group of diseases bound by the characteristic deposition of amyloid fibrils in soft tissues

3 Amyloid fibril protein nomenclature: 2012 recommendations Amyloid, 2012; 19(4):

4 Amyloid fibril protein nomenclature: 2012 recommendations Amyloid, 2012; 19(4):

5 Localized amyloidosis Amyloid, September 2006; 13(3):

6 Systemic Amyloidosis A group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage. N Engl J Med 2003;349:583-96

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8 Most Common Types of Systemic Amyloidoses Type Abbr. Precursor Site of Synthesis Syndrome and Organs Involved Immunoglobulin light chain amyloidosis Reactive amyloidosis Senile systemic amyloidosis Transthyretin amyloidosis AL Monoclonal light chain BM plasma cells AA Serum amyloid A Liver ATTR ATTR Transthyretin wild type Variant TTR >100 mutations Liver > 90% Liver > 90% Primary, in 10%-15% of patients with MM H, K, L, GI, PNS, ANS, ST Secondary to chr. inflammation, infection, or certain neoplasia K, GI, L, ANS, spleen, Age-related, usually males (age > 65 years) Primarily cardiac involvement Hereditary H, PNS, ANS, eye, leptomeninges, rarely kidneys Fibrinogen amyloidosis AFib Variant fibrinogen -chain Liver Hereditary Involvement of kidneys Apolipoprotein A-I amyloidosis AApoAI Variant apolipoprotein AI Liver, intestine Hereditary H, K, L, skin, larynx, testes J Clin Oncol 29:

9 66/M Case 2010년 diarrhea 시작됨 : dry cough, 심장커져있다고들음 : HCMP 진단 : heart biopsy-amyloidosis 진단 전원 Dizziness, syncope, diarrhea, Fatigue Dyspnea: : NYHA Fc III FHx: 형이같은증상으로사망함

10 NT-proBNP : pg/ml IF (s,u): no abnormal band kappa free light chain : mg/l lambda free light chain : mg/l AFT, NCS ( ) 신경전도검사상 Sensorimotor polyneuropathy (axonal>) 를시사하는전기생리학적이상소견이관찰됨. 자율신경검사상 sympathetic and parasympathetic dysfunction 을시사하는전기생리학적이상소견이관찰됨.(mCASS = 9) Heart, IHC Amyloid P: Positive Amyloid A: Negative TTR: Weak positive Kappa: negative Lambda: negative TTR Gene Mutation : Detected Identified Mutation(s) : TTR c.173a>c (p.asp58ala)

11 Transthyretin-related Hereditary Transthyretin (TTR) Amyloidosis a plasma transport protein for thyroxine and vitamin A produced predominantly by the liver TTR amyloidosis Hereditary (familial) amyloidosis mutations that destabilize the TTR protein Senile systemic amyloidosis an acquired disorder mainly affecting men after the age of 60 years deposition of wild-type TTR amyloid Ando et al. Orphanet Journal of Rare Diseases 2013, 8:31

12 Transthyretin-related Hereditary Amyloidosis TTR-FAP (Familial amyloidotic polyneuropathy) Val30Met First reported and most common Portugal, Japan, Sweden TTR-FAC (familial amyloid cardiomyopathy) Val122Ile, Ile68Leu, Thr60Ala, Leu111Met vitreous opacities, renal disease, and meningeal involvement About 120 different single or double mutations, or a deletion in the TTR gene Autosomal dominant inheritance with variable penetrance. Ando et al. Orphanet Journal of Rare Diseases 2013, 8:31

13 Treatment for clinical symptoms Symptom Arrhythmias Cardiac failure Orthostatic hypotension Treatment Pacemaker implantation, pharmacotherapy Diuretics, angiotensin converting enzyme inhibitors Droxidopa, midodrine, amezinium metisulfate, fludrocortisone, Gastrointestinal disorders (not severe) Polycarbophil calcium, metoclopramide Severe diarrhea Neuropathic pain Carpal tunnel syndrome Dry mouth Hypoglycemia Renal failure Urinary incontinence Anemia Hypothyroidism Ocular amyloidosis Loperamide Pregabalin, gabapentin, amitriptyline, duloxetine Surgery Potassium dihydrogen phosphate, cevimeline Glucose loading Hemodialysis Distigmine Erythropoietin, iron Levothyroxine Vitrectomy, trabeculectomy

14 Stage 0 Stage asymptomatic but have both a variant form of the TTR gene and evidence of amyloid deposits. Stage I (mild) disease Ambulatory Stage II (moderate) disease ambulatory but require assistance Stage III (severe) disease bedridden or wheelchair-bound Ando et al. Orphanet Journal of Rare Diseases 2013, 8:31

15 Treatment Liver transplantation Combined heart and liver transplant MUSCLE & NERVE February

16 Treatment Pharmacotherapy Tafamidis (Vyndaqel; Pfizer Inc) limits dissociation of the native TTR tetramer into monomers could slow progression in patients with stage I disease Diflunisal (Dolobid; Merck and Co, Inc) Commercially available NSAID stabilizes TTR tetramers in vitro ALN-TTR01 and ALN-TTR02 RNA interference therapeutics that employs a first-generation lipid nanoparticle formulation. ISIS-TTRRx an antisense therapy that suppresses TTR mrna expression. Doxycycline/tauroursodeoxycholic acid (Doxy-TUDCA) Ando et al. Orphanet Journal of Rare Diseases 2013, 8:31

17 Primary Amyloidosis The most common form of systemic amyloidosis incidence of 8.9 per million person-years by a clonal population of bone marrow plasma cells a monoclonal light chain of kappa or lambda type misfolds and forms a beta-pleated sheet deposits in tissues and interferes with organ function.

18 When should the diagnosis of AL be considered? Non-diabetic nephrotic syndrome Non-ischemic cardiomyopathy with hypertrophy on echocardiography Hepatomegaly or increased alkaline phosphatase value with no imaging abnormalities of the liver Peripheral and/or autonomic neuropathy with a monoclonal protein a monoclonal gammopathy in a patient with unexplained fatigue, edema, weight loss, or paresthesia unexplained facial or neck purpura macroglossia Am. J. Hematol. 88: , 2013

19 Merlini et al. Annals of Oncology 19 (Supplement 4): iv63 iv66, 2008 Jun et al. Am. J. Hematol. 88:52 55, 2013.

20 Merlini et al. Annals of Oncology 19 (Supplement 4): iv63 iv66, 2008 Jun et al. Am. J. Hematol. 88:52 55, 2013.

21 Screening of a patient with a clinical syndrome compatible with AL amyloidosis Mayo Clin Proc 2006; 81:

22 Diagnostic algorithm for systemic amyloidosis. Immunohistochemistry immunogold assay. Laser microdissection with mass spectrometry (LMD/MS) Kappa Lambda Amyloid A J Clin Oncol 29:

23 MISDIAGNOSIS OF HEREDITARY AMYLOIDOSIS AS AL (PRIMARY) AMYLOIDOSIS N Engl J Med 2002; 346:

24 Laser microdissection with mass spectrometry (LMD/MS) Vrana, J. A. et al. Blood 2009;114:

25 2010 ASH education

26 Durie et al. Leukemia (2006) 20,

27 British Journal of Haematology, 2013, 161,

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31 Response category Complete Very good partial Partial No response (Stable 2005) Progression Hematologic Response Serum and urine negative for a monoclonal protein by immunofixation Free light chain ratio normal Marrow<5% plasma cells If serum M component>0.5 g/dl, a 50% reduction If light chain in the urine with a visible peak and>100 mg/day and 50% reduction If free light chain >100 mg/l and 50% reduction No CR, no PR, no progression From CR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must double) From PR or SD, 50% increase in serum M protein to>0.5 g/dl or 50% increase in urine M protein to>200 mg/day; a visible peak must be present Free light chain increase of 50% to>100 mg/l Normalization of the free light chain levels an d ratio, negative serum and urine immunofixat ion Reduction in the dflc to <40 mg/l A greater than 50% reduction in the dflc Less than a PR From CR, any detectable monoclonal protein or abnormal free light chain ratio (light chain must double) From PR, 50% increase in serum M protein to >0.5 g/dl or 50% increase in urine M protein to >200 mg/day (a visible peak must be prese nt) Free light chain increase of 50% to >100 mg/l Leukemia Nov;26(11):

32 Organ Response Organ Heart Kidney Liver Peripheral nervous system Mean interventricular septal thickness decreased by 2 mm 20% improvement in ejection fraction improvement by 2 New York Heart Association classes without an increase in diuretic use, and no increase in wall thickness 50% decrease (at least 0.5 g/day) of 24-hr urine protein (urine protein must be>0.5 g/day pretreatment) Creatinine and creatinine clearance must not worsen by 25% over baseline 50% decrease in abnormal alkaline phosphatase value Decrease in liver size radiographically at least 2 cm Improvement in electromyogram nerve conduction velocity (rare) NT-proBNP response (>30% and >300 ng/l decrease in patients with baseline NTproBNP 650 ng/l) or NYHA class response (2 class decrease in subjects with baseline NYHA class 3 or 4) 50% decrease (at least 0.5 g/day) of 24-h urine protein (urine protein must be >0.5 g/day pretreatment). Creatinine and creatinine clearance must not worsen by 25% over baseline 50% decrease in abnormal alkaline phosphatase value Decrease in liver size radiographically at least 2 cm Improvement in electromyogram nerve conduction velocity (rare) Leukemia Nov;26(11):

33 Organ Progression Organ Heart Kidney Interventricular septal thickness increased by 2 mm compared with baseline An increase in New York Heart Association class by 1 grade with a decreasing ejection fraction of 10% 50% increase (at least 1 g/day) of urine protein to greater than 1 g/day or 25% worsening of serum creatinine or creatinine clearance NT-proBNP progression (>30% and >300 ng/l increase) # or ctn progression (33% inc rease) or Ejection fraction progression (10 % decrease) 50% increase (at least 1 g/day) of 24-h uri ne protein to >1 g/day or 25% worsening of serum creatinine or creatinine clearance Liver 50% increase of alkaline phosphatase above t he lowest value 50% increase of alkaline phosphatase abov e the lowest value Peripheral nervous system Progressive neuropathy by electromyography or nerve conduction velocity Progressive neuropathy by electromyograp hy or nerve conduction velocity # Patients with progressively worsening renal function cannot be scored for NT-proBNP progression. Leukemia Nov;26(11):

34 J Clin Oncol 30: , 2012

35 Survival Median 3.8 years median 22.6 months Merlini et al. Annals of Oncology 19 (Supplement 4): iv63 iv66, 2008 Jun et al. Am. J. Hematol. 88:52 55, 2013.

36 Proportion surviving 1 Stage I-t Stage II-t Stage III-t NT-proBNP ( 332 ng/l) ctnt ( ng/ml) N Deaths MS, months Stage I-t Stage II-t Stage III-t P < Time (months)

37 New Mayo Staging for AL amyloidosis ctnt ng/ml NT-ProBNP 1,800 pg/ml FLC-diff 180 mg/l Stage N Median OS (months) I II III IV J Clin Oncol 2012, 30:

38 Wechalekar et al. Blood. 2013;121(17):

39 Evaluation of the cytogenetic aberration Blood. 2008;111: Bryce AH et al. Haematologica. 2009;94(3):380-6.

40 Stem cell transplantation: BUMC Blood May 15;91(10): Blood. 2011;118(16):

41 Stem cell transplantation: BUMC Blood. 2011;118(16):

42 Improvement of TRM Tsai et al, Blood Nov 22;120(22):4445-6

43 Stem cell transplantation: Mayo clinic Patients with cardiac involvements (N=187), D100 mortality (N=30) Dispenzieri et al. Blood. 2004;103: Madan et al.blood. 2012;119(5): Cordes et al. Cancer Dec 15;118(24):6105-9

44 Auto-SCT in AL versus MM Dispenzieri et al.bone Marrow Transplantation 2013 Apr 22. doi: /bmt

45 High-Dose Melphalan versus Melphalan plus Dexamethasone for AL Amyloidosis median OS 56.9 months median OS 22.2 months poor results with high-dose melphalan no selection bias d/t referral to tertiary center the delay before initiation of therapy the possible enrollment of patients with advanced disease N Engl J Med 2007;357:

46 Center Exclusion criteria for HDM in eight centers and study groups worldwide Amyloidosis Center Boston Amyloidosis Program Mayo Clinic Amyloidosis Center Pavia Memorial Sloan Kettering NY Exclusion criteria for HDM >70 years, >NYHA II, PS >2, systolic blood pressure < 90mmHg, symptomatic pleural effusions, EF 40% >70 years, PS 2, ctnt>0.06 ng/ml, CCr<30 ml/min (unless on chronic dialysis), NYHA >II, >2 organs significantly involved >2 organs involved, severe cardiac involvement, creatinine >2mg/dL, abnormal respiratory function test, >65 years 60 years 3 organs involved, advanced cardiac disease HOVON Study Group PS>, NYHA>III, EF 45%, other severe diseases French Study group National Amyloidosis Center London Amyloidosis Center Heidelberg et al. Inadequate organ function, elevated NT-ProBNP and TNT >2 organs, ECOG >1, egfr 50 ml/min, significant cardiac involvement, autonomic neuropathy or gastrointestinal involvement, TNT >70 years, >NYHA II, PS >2, systolic blood pressure<90mmhg, symptomatic pleural effusions, facto X deficiency < 10%. Since 2009: CCr<30 ml/min (unless on chronic dialysis) Schönland et al. Bone Marrow Transplantation (2012) 47,

47 Issues of transplantation in AL amyloidosis Induction chemotherapy Stem cell collection G-CSF alone vs. Cytoxan with G-CSF Tandem transplantation Consolidation or maintenance therapy End stage renal disease Treatment after relapse Organ transplantation followed by SCT Allo SC transplantation

48 Treatment Overall survival Median OS; 31 Mo Progression-free survival Median PFS; 27 Mo Blood Dec 1;104(12):

49 Melphalan and High-Dose Dexamethasone Median survival; 5.1 years Blood. 2004;103: , Blood. 2007;110:787, Blood. 2010;116(4):

50 Thalidomide N Dose HR (CR) OR Toxicity T 16 Phase I/II 25% (0) 0 G3-4 (50%) T TD 31 CTD mg D / /40 500/50-200/20 48% (19%) 26% MTD /kg/100/20 36% (5%) 18% Edema, somnolence 6 withdraw d/t toxicity Symptomatic bradycardia (26%) G3-4 (65%) Median OS (PFS) 74% (21%) G3-4 (32%), TRM 4% 41 (32) 27% early death G3-4 (27%) 5.3 Seldin et al. Clin Lymphoma Mar;3(4):241-6 Dispenzieri Amyloid Dec;10(4): Palladini et al. Blood. 2005;105: Wechalekar et al. Blood. 2007;109: Palladini et al. Ann Hematol (2009) 88:

51 Lenalidomide N Dose HR (CR) OR Toxicity Median OS (PFS) months L ± D D1-21 /40 D1-4, % 23% G3-4 (86%), neutropenia (45%), thrombocytopenia (27%), Rash (18%), fatigue (18%) 31 (18.8) L ± D >15 /10-20mg 67% (29%) 41% (renal) 3% (cardiac) G3-4 Fatigue (35%), myelosuppression (35%) Rash (18%) Thromboembolism (9%) Ld 24 15/40 38% (0%) 4% 14 LMD 26 LMD 16 CRd 37 5,10,15,20 /0.18/kg/40mg 10/5mg/m 2 / ,15/50, 100 D1-10/20 D1-4 58% (23%) 50% 43% (7%) 6% CRd 35 15/300/40 60% (11%) 29% Hematologic(31%) gastrointestinal (16%) Fatigue, asthenia (12%) G3-4 (88%) hematologic, infection, fatigue (31%) 55% (8%) 22% Fatigue, infection, rash G3-4 hematologic (46%) Fatigue, rash 2Y OS 80.8% 2Y EFS 53.8% NR (24) 2Y OS 41% TTP 10 mo 37.8 (28.3) CRd 21 15/500/40 62% (5%) 19% G3-4 (57%), neutropenia (29%) 36 Dispenzieri et al. Blood. 2007;109: , Sanchorawala et al. Blood. 2007;109: , Moreau et al. Blood : , Kastritis et al. Blood : , Kumar et al. blood : , Palladini et al. Ann Hematol. 2012;91(1): Palladini et al. Haematologica Mar;98(3): Sanchorawala et al. Haematologica May;98(5):

52 R. Specter et al. Nephrol Dial Transplant (2011) 26: Tapan et al. blood :

53 Pomalidomide AE G3-5 Hematology 45% fatigue 19% infection 27% Dispenzieri et al. Blood. 2012;119(23):

54 bortezomib N Dose HR (CR) OR Toxicity Median OS (PFS) months BD 94 Btz 1.3 mg/m2 1, 4, 8, and 11; Dex dose was variable 72% (25%) 30% G3-4 29% Neuropathy G2-4 30% Orthostatic hypotension 13% 1Y OS 76% B 34 Btz 1.3 mg/m2 1, 4, 8, and 11 67% (24%) 27% G3-5 79% 84% at 1 y B 18 Btz 1.3 mg/m2 1, 8, 15, and 22 39% (38%) 67% G3-5 50% 94% at 1 y BD 20 Btz 1.3 mg/m2 1, 4, 8, and 11 (9 pats variable doses of Dex) 80% (15%) 38% G3-5 45% BD 26 54% (31%) 12% 18.7 (5) CyBorD mg/m2 /300mg/m2 /40 weekly 94% (71%) Kidney 50% No G3-4 neurotoxicity CyBorD 43 Btz 1.0 mg/m2 1, 4, 8, and 11/350mg/m2 /20 81% (41.9) 46% 2YOS 97.7% Kastritis E et al, J Clin Oncol. 2010;28(6): Reece et al. Blood. 2011,118(4): , Lamm et al. Ann Hematol. 2011;90(2): Wechalekar et al. Haematologica. 2008;93(2): Mikhael et al. Blood ;119(19): Venner et al. Blood ;119(19):

55 msmart guideline: MAYO clinic

56 msmart guideline: MAYO clinic

57 Autologous stem cell transplant after heart transplant for AL amyloid cardiomyopathy. Heart transplantation followed by SCT is feasible in selected patients with cardiac AL amyloidosis and may confer substantial survival benefit. - In patients presenting with end-stage organ failure, sequential solid organ (kidney, heart, liver) transplant followed by stem cell transplantation (ASCT) has been successfully applied. J Heart Lung Transplant Aug;27(8):823-9.

58 Kidney transplantation American Journal of Transplantation 2013; 13: Nephrol Dial Transplant (2011) 26:

59 Supportive care Digoxin, calcium channel blocker, ACE inhibitor, beta blocker higher toxicity Amiodarone prophylaxis for complex ventricular arrhythmias detected on Holter ECG. Diuretics Alpha agonists (midodrine) Implantable cardiac difibrillator Kidney & heart transplantation Merlini et al. J Clin Oncol 29:

60 Conclusions Although systemic amyloidosis is rare and highly complicated disease entity, early diagnosis and proper treatment can improve the survival. N=117 SMC data

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