Amyloidosis. Rajkumar SV, Dispenzieri A, Kyle RA. Mayo Clin Proc 2006;81:

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1 Advances in AL amyloidosis Yonsei University College of Medicine i Jin Seok Kim

2 Amyloidosis Amyloidosis results from a sequence of changes in protein folding that leads to the deposition of insoluble amyloid fibrils, mainly in the extracellular spaces of organs and dtissues. Classified according to the identity of the fibril-forming protein. Acquired amyloidosis: 79% (AL 71%, AA: 8%) Hereditary amyloidosis: 21% Rajkumar SV, Dispenzieri A, Kyle RA. Mayo Clin Proc 2006;81:

3 Amyloidosis: protein misfolding disease AL Amyloidosis N Engl J Med. 2003;349:

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6 Clinical characteristics of AL Amyloidosis ; 10/million person-year Peripheral nervous system Autonomic nervous system N Engl J Med. 2003;349:

7 Clinical manifestations of AL Amyloidosis Vague symptoms. Fatigue, edema, and weight loss ; generally not helpful in the formulation of an appropriate p differential diagnosis. the education program for the annual congress of the EHA 2008; 2(1)

8 1) MGUS 70/M, 평소어지러움으로건강검진과거력상특이소견없음 BP; 160/90 mmhg, PR; 100/min K, BUN/Cr; 20.0/1.0 SPEP; Monoclonal gammopathy IF; IgG & Lambda 가장가능성이높은진단명은? 2) AL amyloidosis 3) Multiple Myeloma 4) Waldenstrom s macroglobulinemia 5) POEMS Syndrome

9 When should the diagnosis of AL be considered? Nephrotic-range proteinuria Unexplained nonischemic cardiomyopathy (Rt. side Heart Failure) Peripheral neuropathy Unexplained hepatomegaly Orthostatic hypotension and other manifestations of autonomic neuropathy (pseudo-obstruction obstruction etc), Atypical multiple myeloma. If a diagnosis is under consideration, what is the appropriate diagnostic evaluation? Best non-invasive screens for AL; immunofixation of serum and 24hrs urine and the free light chain assay Positive finding can justify more invasive diagnostic studies to confirm the diagnosis. > 25% of patients do not have an intact immunoglobulin protein in the serum.

10 Free light chain assay Reference range Kappa FLC; mg/l Lambda FLC; mg/l / ratio; Median = 0.6 (Range = )

11 AL amyloidosis- FLC Ser rum Lam mbda FL LC (mg/ /L) Normal sera Kappa LCMM Lambda LCMM AL amyloid Serum Kappa FLC (mg/l) Lachmann H. et al. BJH 2003; 122 :78-84

12 70세남자, 피로, 체중감소, 부종으로내원. WBC 5400/ L, Hb 7.6 g/dl, Platelet 117,000/ L 골수생검 (Congo red stain) 및편광현미경소견 ; apple green birefringence Amyloid light chain amyloidosis (AL amyloidosis) i 확진을위하여추가로필요한혈액검사항목은? 1) Serum Protein electrophoresis (SPEP) 2) Serum Immunofixation 3) Serum Immunoglobulin Quantitation 4) Serum Kappa/Lambda light chain level 5) Serum Amyloid A

13 If there is a strong suspicion, how is the diagnosis i confirmed? 1) Immunoglobulin light chain abnormality by immunofixation of serum and 24hrs urine and dthe free light chain assay 2) Biopsy verification of the amyloid; apple green birefringence under polarized light after Congo red staining. Visceral biopsy is not usually necessary. (renal, cardiac, liver, or nerve biopsy) BM biopsy; amyloid (+) in 50 60% of patients. (median BM plasma cell 7%) Subcutaneous fat aspirate (? Bx); amyloid (+) in70 80% of patients (Not thin preparation Classical method) Biopsies of the minor salivary glands, gingiva, rectum, and skin. 3) Histologically confirm; the amyloid is the AL type - immunohistochemical verification with kappa and lambda antisera. - immunoelectron microscopy, mass spectrometry-based methods, DNA analysis. - for rule out of MGUS & other form of amyloidosis Mutant transthyretin; Any African American > 70 years with cardiac amyloidosis should be screened for a mutant transthyretin (3.9% of African Americans). Education program for the annual congress of the ASH 2004

14 Primary Amyloidosis (Light Chain Amyloidosis, i AL Amyloidosis) i The most common form of systemic amyloidosis Median age; 62 < 20% of patients with AL amyloidosis have MM. About 15 to 20% of patients with MM have amyloidosis. Lambda chain class predominates over kappa in AL by a 2:1 ratio, whereas in MM and normal immunoglobulin synthesis; the reverse is true. Diagnosis of systemic AL amyloidosis (presence of all of the followings) Amyloid-related systemic syndrome (renal, liver, heart, G-I tract, or peripheral nerve involvement) Positive amyloid staining by Congo red in any tissue (fat aspirate, BM, or organ biopsy) Evidence that t amyloid is light chain related established by direct examination of the amyloid (immunoperoxidase staining, direct sequencing) Evidence of a monoclonal plasma cell proliferative disorder (serum or urine M protein, abnormal FLC ratio, or clonal plasma cells in BM) Note: Approximately 2%-3% of patients with AL amyloidosis will not meet the requirement for evidence of a monoclonal plasma cell disorder; the diagnosis of AL amyloidosis must be made with caution in these patients.

15 Amyloid staining with Congo red. Under polarized light to demonstrate the characteristic apple green birefringence i

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17 Definition of Organ involvement Kidney: 24-hr urinary protein > 0.5 g/day, predominantly albumin 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, or alkaline phosphatase level >1.5 times upper limit of normal Nerve: Symmetric sensorimotor peripheral neuropathy in the legs and autonomic neuropathy (gastric-emptying disorder, pseudo-obstruction, voiding dysfunction), not related to direct organ infiltration Gastrointestinal tract: Symptoms and verification by means of biopsy Lung: Symptoms and verification by means of biopsy, interstitial pattern Soft tissue: Tongue enlargement, arthropathy, skin purpura, myopathy (pseudohypertrophy or detected by means of biopsy), lymph node involvement, carpal tunnel syndrome Gertz MA, et al. Am J Hematol 2005;79:

18 M/70, AL amyloidosis Kidney and cardiac involvement 예후예측을위하여중요한검사항목은? 1) Serum M protein levell 2) 24hrs urine M protein level 3) Serum calcium level 4) Serum albumin level 5) Serum free light chain concentration

19 Cardiotoxicity of amyloidogenic light chains Infusion of amyloidogenic light chains causes immediate diastolic dysfunction in isolated mouse hearts; Liao et al Circulation 2001;104; Purification of light chains from patients with severe cardiac involvement Cardiac involvement is causing the death of ~ 80% of AL patients Cardiac biomarkers: N-terminal of natriuretic ti peptide type B (NTproBNP - BNP) and troponins (ctni or ctnt)

20 Systemic AL amyloidosis-prognosis The prognosis of AL amyloidosis has significantly improved in the last decade, due to earlier diagnosis & more effective specific and supportive treatments. t t Of 868 AL amyloidosis 394 died (median survival 3.8 yrs, Italy data) Die of cardiac complications, either congestive heart failure (50%) or sudden death (25%). 2 significant independent prognostic factors ; Response to therapy (protective) and cardiac involvement (p<0.001). Hematological response to CTx survived longer than other patients (median 108 vs. 21 months, p<0.001). 001) Median survival of patients with heart involvement was significantly shorter than that of patients without cardiac amyloidosis (21 vs. 82 months, p<0.001), Serial concurrent quantification of the serum FLC and NT-proBNP is important. the education program for the annual congress of the EHA 2008; 2(1)

21 Evaluation of the cytogenetic aberration - At least one CA using FISH in 89% of the AL Amyloidosis (n=75); German data - t(11;14) - the most frequent aberration in AL (47%) vs. 26% in MGUS (P =.03). - t(11;14); associated with a lack of intact immunoglobulin in immunofixation. - Low frequencies of t(4;14) & deletion of 17p13 (rapid progression markers) - Gain of 1q21 -higher frequencies in MM I both with & without AL (50% and 53%) - suggest that the concept of gain of 1q21 as a progression marker Blood. 2008;111:

22 Translocation t(11;14) and OS- Mayo data 56 AL Amyloidosis, cytoplasmic staining of specific Ig (cig-fish) IgH translocations [48%] including t(11;14) [39%], and t(14;16) [2%] del13/del13q [30%] No t(4;14) or deletions of 17p (p53) were observed. Patients with t(11;14) had the lowest levels of clonal plasma cells, and those with del13 had the highest. Bryce AH et al. Haematologica. 2009;94(3):380-6.

23 Serum-free light chain (FLC) German data Higher FLC levels; associated with higher BM plasmocytosis, poorer Karnofsky index & heart involvement reflected disease severity. Patients with cardiac involvement had higher involved FLC concentrations (p=0.002) Statistically significant effect on FLC concentrations for the cardiac biomarkers ctnt (p=0.007) and NT-proBNP (p<0.001). 001) FLC concentration also reflects the expansion of the aberrant clone and, to some extent, the severity of organ involvement. Haematologica. 2008;93(3):

24 Prognostic factors in AL amyloidosis Dominant organ involved (with cardiac amyloid having the worst outcome) important role of echocardiography with Doppler Cardiac troponins and NT-proBNP The number of affective major organs. Serum uric acid; ; Mayo Clin Proc. 2008;83:297 Serum b2-microglobulin CA in FISH; t(11;14) Serum level of FLC Hematological response to CTx; A hematologic response to therapy correlates well with subsequent organ response. Rajkumar SV, Dispenzieri A, Kyle RA. Mayo Clin Proc 2006;81:

25 M/70, AL amyloidosis Kidney and cardiac involvement Kappa FLC; 10 mg/l Lambda FLC; 200 mg/l FLC / ratio; 0.05 (Range = ) NT-proBNP Elevation 24hrs urine protein; 1,500 mg/24hrs Most appropriate initial treatment for this patients 1) M l h l P d i l 1) Melphalan Prednisolone 2) Melphalan-dexa 3) VAD chemotherapy 4) VAD chemotherapy followed by Autologous HSCT 5) Initial Autologous HSCT

26 Treatment of Systemic Amyloidosis Rajkumar N Engl J Med 2007;356:2413

27 Colchicine Alone vs MP vs MP-Colchicine; Mayo data 220 AL amyloidosis Colchicine (0.6 mg twice daily) Melphalan (0.15 mg/kg) and PL (0.8 mg/kg) daily for 7 days once every 6 weeks Melphalan l (0.15 mg/kg) and PL (0.8 mg/kg) daily for 7 days once every 6 weeks plus colchicine (0.6 mg twice daily). Survival from the Date of Randomization N Engl J Med 1997;336:1202-7

28 High-Dose Dexamethasone; SWOG trial 93 AL Amyloidosis Induction therapy (HD Dexa) followed by maintenance therapy (Dexa + α-inf) Induction therapy; Dexa, 40 mg/d po (d 1-4, 9-12, 17-20) every 35 d for 3 cycles. Maintenance therapy; begin 5 weeks from day 1 of cycle 3 of induction therapy. oral Dexa 40 mg/d for 4 days every 4 weeks, + α-inf at 5 million units SQ 3 times/week for the first 2 years, followed by α-inf alone for the next 3 years. Dexa alone achieves a 53% HR (median time 3.4 mos) with 24% CR & 7% TRM OS Median OS; 31 Mo PFS Median PFS; 27 Mo Blood Dec 1;104(12):

29 Melphalan & High-Dose Dexamethasone N=46, Italy data Melphalan (0.22 mg/kg/day orally) on days 1-4 & HD dexa (40 mg/day orally) on the same 4 days. Repeated every 28 days for approximately 9 mos. 67% HR (hematologic response) with 33% CR Median survival; 5.1 years OS Palladini G, Blood. 2007;110:787

30 Treatments for AL amyloidosis education program for the annual congress of the ASH 2004

31 Autologous stem cell transplant Boston data (n=312) Mayo clinic; case control study (n=63) Median survival; 4.6 years Skinner et al, Ann Intern Med. 2004;140:85c Dispenzieri et al, Blood. 2004;103:3960

32 VAD Induction Tx + ASCT; phase II German data N=28, 2 to 5 cycles of VAD, repeated every 28 d. HD Melphalan l ASCT VAD CTx; WHO grade III IV toxicity (25%) and 7% TRM (2/28). ; did not interfere with stem cell mobilization and HDM with ASCT was possible in 86% of patients. 13% (3/24) TRM after ASCT. OS Additional VAD CTx did not increase the HR and clinical remission compared with the results of HDM + ASCT without induction CTx. Mortality and response rates ; seem to be comparable with previously reported data on HDM + ASCT without induction CTx. Perez et al. Br J Haematol 2004;127:

33 Initial ASCT vs. 2th MP induction + ASCT ; prospective randomized Trial, Boston data Initial ASCT (Arm-1) vs. 2 cycles of oral melphalan (0.2 mg/kg/d for 4 days) & prednisone (1.0 mg/kg/d for 4 days) followed by ASCT (Arm-2) Median f/u; 45 mos (range 24 70), no different OS (P= 0.39). Hematologic response (32% vs. 30%) & organ improvements; no different. Fewer patients received ASCT in Arm-2 (43 vs. 32) ; Because of disease progression during MP CTx phase (mortality; 6/48, 13%), ineligible for subsequent ASCT. The patients with cardiac involvement; early survival disadvantage in Arm-2. OS N=52 N=48 Newly diagnosed AL amyloidosis eligible for ASCT did not benefit from initial treatment with oral MP. In patients t who proceed to early transplantation, there does not appear to be any need for induction therapy. Sanchorawala V, BMT 2004;33:381

34 HD Melphalan-ASCT vs. Melphalan + HD Dexa for AL Amyloidosis; i IFM & MAG randomized d trial median OS 56.9 months N=50 median OS months N=50 OS may not be superior with ASCT compared with melphalan + HD Dexa. Among high-risk disease; similar OS in the two groups. Among low-risk disease; non-significant difference in 3 yr OS (58% in HD melphalan-asct vs. 80% in melphalan + HD Dexa; P = 0.13). However, interpretation of this trial is confounded by very high TRM in ASCT arm (24%). (vs. 9% from Boston results) Mayo Clinic-ongoing randomized phase 3 trial; ASCT vs. melphalan + HD Dexa. N Engl J Med 2007;357:

35 New agents for AL Amyloidosis Thalidomide; poorly tolerated in AL amyloidosis patients Thal+dexa as 2nd-line Tx; 48% HR with 19% CR. ; > 60% developing > grade 3 toxicity. (Blood. 2005;105:2949) Cyclophosphamide, thalidomide, and dexa (CTD), (Blood. 2007;109:457) ; Thal mg/day (starting dose, 100 mg/d, increased after 4 weeks if tolerated) ; 74% HR with 21% CR (15% IF(-) CR), ; Toxicity grade 3-32%, 8% cessation of therapy, 4% TRM. Lenalidomide + dexa, (Blood. 2007;109: ) 34 patients (Boston data); 25 mg/d reduced dose of 15 mg/d, 67% HR with 29% CR Fatigue and myelosuppression were the most common (35%) Thromboembolic complications (9%) were the most serious. Proteasome inhibitor, bortezomib Phase I-II dose escalating trial - 31 relapsed AL Amyloidosis, (Blood. 2009) - MTD was not defined - Maximum doses; 1.6 mg/m 2 (weekly) & 1.3 mg/m 2 (twice weekly) - HR 15/30 (50%) with 6 (20%) CR, 30% PR. - Median time to first response; 1.2 mos - 12 (39%) discontinuations - 4 (13%) dose reductions for toxicity. -No TRM.

36 Bortezomib with or without Dexamethasone in AL Amyloidosis multicenter retrospective 94 AL Amyloidosis, median 4 th cycles of Tx 19% first line, 81% 2 nd line (median 2) (69% refractory) Symptomatic ti heart involve or elevated NT-proBNP 71% HR within median 52 days (25% CR) 47% CR in first line Tx Age 65 yrs & twice weekly use of bortezomib; associated with higher RR. 29% Cardiac response; sustained improvement HR; associated with cardiac response and NT-proBNP reduction 12 mo median F/U; 29% organ PD, 27% Hematologic PD Baseline NT-proBNP; independent prognostic factor for OS 30% NT-proBNP reduction & achieve HR; predictive factor for OS No TRM, Grade 3 toxicity; 29%. Toxicity was manageable and mostly consisted of neuropathy (grade 2; 30%), orthostasis, peripheral edema, and constipation or diarrhea. Kastritis J Clin Oncol 2010;28:

37 HD Melphalan-ASCT + Adjuvant Thal/dexa MSKCC data, n=45, Newly diagnosed AL involving 2 organ systems Risk adapted ASCT; ; MEL 100/140/200 mg/m 2 based on age, renal Fx, cardiac involve. 9 mo adjuvant thal/dex from 3 mo after ASCT (dex if DVT + or neuropathy +). Thalidomide; start t at 50 mg/d & titrated t every 2 wks up to 200 mg/d as tolerated. t Dexamethasone; given at 20 mg/m 2 /d for a 4-d pulse, with up to 3 pulses/mo 31 patients began adjuvant therapy, with 16/31 (52%) completing 9 cycles 71% Overall HR (36% CR), with 44% organ responses. 4.4% TRM. 31 mo Median f/u - 84% 2-year OS. Risk-adapted ASCT with adjuvant thal/dex is feasible and results in low TRM and high haematological and organ response rates in AL patients. Br J Haematol 2007;139:224

38 Allogeneic stem cell transplant EBMT Data (N=19, 7 patients treated with HD Melphalan-ASCT) Allogeneic (allo; n = 15) or syngeneic (syn; n = 4) HSCT 7 Full-intensity conditioning and 8 RIST. 40% Death of TRM. 8 CR after HSCT and 2 PR, 8 Organ response. 7/10 patients in remission are long-term survivors. In 5/7 evaluable patients in CR, chronic GvHD 1 Yr OS; 60% 1 Yr PFS; 53% - Main clinical problem; cardiac failure in patients with poor performance status due to amyloidosis or in combination with severe infections. - Patients could be eligible for allo-hsct if they have not achieved a CR 6 mos after HD Mel-ASCT, are still in a good PS, and have an HLA-matched donor. Blood. 2005;107:

39 Prognostic markers in AL amyloidosis undergoing ASCT Cardiac involvement Higher level of baseline FLC Ann Intern Med. 2004;140:85 Blood. 2006;107: Cardiac troponins and NT-proBNP Excessive fluid accumulation during PBSCH (>2% weight gain) ; predictive of a higher mortality rate with ASCT. Achievement of response after ASCT; Hematologic CR hematologic CR. - Boston data; 57 Mo median OS (4.75 yr). - Durable remissions and prolonged survival who achieve a hematologic CR. ; Median survival exceeds 10 yrs Blood. 2007;110:

40 ASCT after heart transplant for AL amyloid cardiomyopathy. Heart transplantation followed by ASCT 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 ASCT has been successfully applied. J Heart Lung Transplant. 2008;27(8):823-9.

41 Treatment and Monitoring therapeutic effects Key elements Early diagnosis and correct typing Fine balance of chosen treatment regimen and patient s ability to bear toxicities Aim of therapy obtain durable improvement of AL amyloidosis-related organ function extend survival Monitoring response to therapy Chemotherapy guided by frequent assessment of FLC and cardiac biomarkers (every 2 cycles) Hematologic response Organ response: NT-proBNP, troponins, rapid Kidney markers (proteinuria, s. creatinine) may be delayed by > 3 mos up to 1 yr Gertz MA, et al. Am J Hematol 2005;79:

42 Organ Response & Hematologic response Gertz MA, et al. Am J Hematol 2005;79:

43 Role of the FLC assay in response assessment The consensus opinion from the 10 th International Symposium on Amyloid and Amyloidosis FLC response - 50% reduction in involved FLC (iflc) in AL amyloidosis patients with iflc > 100 mg/l Progression - 50% increase in iflc. Leukemia Feb;23(2):

44 NCCN Guideline

45 Treatment of AL Amyloidosis Mayo clinic protocol

46 Criteria for eligibility for ASCT in UK amyloidosis treatment trial (UKATT) Age 65 years ECOG performance status 1 NYHA class I or II heart failure 2 organs involved by amyloid by consensus guideline (Gertz, 2005) Creatinine clearance 0.8 ml/s (50 ml/min) Bilirubin 1.5 times and ALP 2 upper limit of normal Inter ventricular and LV posterior wall thicknesses of 15 mm by Echo. Absence of clinically important amyloid related autonomic neuropathy Absence of clinically important amyloid related GI hemorrhage Patients must satisfy all the above criteria to be eligible for a stem cell transplant. When analysed retrospectively, patients satisfying all the criteria had no TRM (Goodman et al, 2006).

47 Proposed criteria for patient selection and dose adaptation for high-dose melphalan. Comenzo RL, Gertz MA. Blood. 2002;99:4276. Skinner M, Ann Intern Med. 2004;140: Education program for the annual congress of the ASH 2004

48 Supportive care for AL Amyloidosis Supportive therapy is importance; sustaining the function of the target organs. Best supportive therapy; collaboration with nephrologists, cardiologists Amyloid cardiomyopathy; Diuretics with frequent monitoring, Salt restriction, permanent pacemaker implantation (for recurrent syncope) Orthostatic hypotension; fluoricortisone, midodrine. Renal amyloidosis; control of the edema by diuretics. ACE inhibitors, treatment of hypercholesterolemia, treatment of renal vein thrombosis, dialysis. Effusion/Ascites; it Paracentesis/Thoracentesis t i Diarrhea (common and incapacitating problem); Octreotide Chronic intestinal ti pseudo-obstruction; ti usually refractory to treatment. t t Neuropathic pain; difficult to control, Gabapentin Bleeding; frequent and multifactorial. Factor X deficiency dramatically improves following effective chemotherapy

49 Current clinical trials Mayo clinic phase 3; Low-Dose Melphalan + Dexa vs. High-Dose Melphalan followed by ASCT Boston Medical Center; Bortezomib + Dexa followed by ASCT, Phase 2 Memorial Sloan-Kettering Cancer Center ; HD melphalan + ASCT followed by bortezomib + dexa, Phase 2 Mayo clinic; Bortezomib, Cyclophosphamide, p and Dexa ECOG phase 3; Melphalan + Dexa With or Without Bortezomib Italy Giovanni Palladini; CLD (Lenalidomide) German-University Clinic Heidelberg & Boston Medical Center; Lenalidomide-Melphalan-Dexa

50 Summary Diagnosis of AL amyloidosis Clear evidence of a plasma cell dyscrasia (IF, FLC) Light chain derived amyloid deposit by direct examination Prognosis of AL amyloidosis Response to therapy and cardiac involvement Serial evaluation of the serum FLC and NT-proBNP is important. Treatment of AL amyloidosis No therapy is uniformly effective in the treatment of AL amyloidosis. ASCT is widely used but is applicable only to a minority. Melphalan + high-dose dexamethasone; appropriate initial regimen in the AL amyloidosis who are not eligible for ASCT Novel agents (eg, thalidomide, lenalidomide, and bortezomib) also have a significant role for treatment of AL amyloidosis Clinical trials must be considered and are preferred at every level.