A Problem with Cardiac Amyloidosis. Defining Amyloidosis. Typical Amyloid Heart. Definition of a double-blind study:

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1 A disease caused by the deposition of a proteinaceous material, derived from the misfolded breakdown products of a normal or abnormal protein. Typical Amyloid Heart Defining Amyloidosis TYPEOF AMYLOID AL TTRm PRECURSOR PROTEIN Immunoglobulin light chain Variant transthyretin MAJOR ORGANS INVOLVED Heart, kidney, liver, nerves, skin, bowel Nerve Heart Major Forms of Systemic Amyloidosis Isolated atrial COMMENT Rapidly Progressive. Related to multiple myeloma Autosomal dominant with variable penetrance. High gene prevalence in African Americans TTRwt Wild-type TTR Heart Slowly progressive. Rapidlyincreasing amyloidosis prevalence. Disease of men. ANP Atrium Littleclinical significance From Patel and Hawkins J. Internal Med : A Problem with Cardiac Amyloidosis Definition of a double-blind study: Two orthopedic surgeons trying to interpret an electrocardiogram A RARE DISEASE WITHOUT DOUBLE BLIND RANDOMIZED TREATMENT STUDIES

2 30 years ago What's past is prologue. -William Shakespeare, The Tempest From: Cancer and the Heart, Amar S. Kapoor, Ralph D. Reynolds There is no specific treatment for primary cardiac amyloidosis, secondary amyloidosis involving the heart, heredofamilial amyloidosis---- Study the past if you would define the future. Confucius Cardiac Amyloidosis in 2016: What is new in the last decade? A Decade of Progress WHERE WE WERE A DECADE AGO: Light-chain (AL) amyloidosis diagnosed by paraprotein/bone marrow abnormalities and treated with melphalan (oral or IV plus autologous stem cell transplant) Transthyretin amyloidosis treated with liver transplant (familial form), or symptomatically ( rare senile systemic amyloidosis.) Main diagnostic tool echocardiography: cardiac MR beginning to show promise of promise. Basic Science UNDERSTANDING OF MECHANISMS OF CELLULAR DYSFUNCTION Molecular Manipulation FOCUS ON STABILIZATION AND SUPPRESSION OF TTR Epidemiology NEW INSIGHTS INTO MUTANT TTR PENETRANCE AND HEART FAILURE MECHANISMS A Decade of Progress Skinner M et al. Randomized trial of melphalan, prednisone and colchicine versus colchicine alone. Am. J. Med. 1996: 200, More sophisticated imaging techniques Overall survival Survival by organ involved Better diagnostics PROTEOMICS Safer and more effective AL therapies PROTEOSOME INHIBITORS IMIBS PYROPHOSPHATE SCANNING MOLECULAR IMAGING CARDIAC MR MPC

3 High-Dose Melphalan and Autologous Stem-Cell Transplantation in Patients with AL Amyloidosis: An 8-Year Study Skinner M et al. Ann. Intern. Med 2004 All patients (n=312) Cardiac v non-cardiac involvement The negative effect of cardiac involvement but the importance of a hematologic response. Data from Pavia Amyloidosis Center. From: Merlini and PalladiniG. Ann Oncol.2008 : 19 Suppl 4:iv63-6 Adverse risk factors: NT-proBNP >1800 pg/ml Troponin T >0.025 ng/ml Free light chain difference >180 mg/l 75year old woman, previously well other than treated breast cancer. Mild dyspnea 6 months earlier in Paris, with considerable leg swelling on arrival back in USA. Increasing dyspnea over several months and 15 lb weight gain. Physical exam shows cm JVP, mild cardiomegaly, and congested hepatomegaly. Edema to knees. Echo showed 14 mm concentric thickening and restrictive filling pattern. ECG low voltage. Each risk factor gets 1 point. Stage 1 =0 points Stage 4= 3 points Revised prognostic system for light-chain amyloidosis From Kumar S et al.2012 CASE 1:CHF in a 75 year old woman Normal electrolytes. NTproBNP Troponin T 0.15.Monoclonal spike in serum. Free kappa 10.4 mg/l, free lambda 279 (10X normal), trace proteinuria. Bone marrow biopsy 30% plasma cells. No bone lesions. Cardiac biopsy: Amyloid deposition, staining for lambda light chains. DIAGNOSIS: Class 3 CHF due to light chain amyloidosis Adverse risk factors: NT-proBNP >1800 pg/ml (9053) Troponin T >0.025 ng/ml (o.15) Free light chain difference >180 mg/l (269) Each risk factor gets 1 point. Stage 1 =0 points Stage 4= 3 points Revised prognostic system for light-chain amyloidosis From Kumar S et al.2012

4 CASE 1 NOT DIFFICULT TO DIAGNOSE. BUT WHAT ABOUT THERAPY? Bortezomib: Rapid onset proteasome inhibitor SHOULD SHE PUT HER AFFAIRS IN ORDER IMMEDIATELY? Plasma cells are proteasome-rich and highly sensitive to bortezomib High risk patient. Age and severity of heart failure preclude high-does melphalan with autologous stem cell therapy. Therapy instituted with bortezomib, dexamethasone and cyclophosphamide, modified from standard myeloma regimen. Case 1. AL amyloidosis risk assesment Tolerated triple chemotherapy regimen, with minor side-effects and careful control of CHF After 2 cycles (2 months of weekly therapy), lambda free light chain normalized. Continued for 3 more cycles and is now chemotherapy free, off diuretics and class 1 CHF. Took a trip to France followed by a winter in LA. Still working. NTproBNP fell from 9053 to 1106 and troponin T from 0.15 to below detectable. Standard echo structurally unchanged, but strain imaging improved. Case 1 Follow up. Serial strain Imaging: Effect of light chain resolution Bortezomib-based therapy in AL amyloidosis of the heart Pre-Chemotherapy 18 month Hematologic remission Apical 4 strain -7.8% Apical Strain -11.4% Global Strain -9.2% Global Strain -13.5%

5 Mayo score Previously published median survival (months) Observed median survival with bortezomib-based therapy (n=52) Not reached 3 14 Not reached Overall Survival CR PR NR(ITT) 12 months 100% 83.3% 61.1% 24 months 100% 71.8% 35.4% Putting the puzzle together correctly-- Infiltration Infiltration Light chain toxicity From Patel and Hawkins J. Internal Med : Diagnosis of cardiac amyloidosis YOU CAN DO IT ON A DESERT ISLAND Normal or Abnormal Systolic Function?

6 Check the neck A clue to the Presence and Type of Amyloidosis Did Popeye have early TTR amyloidosis? The tongue is large, but the differential diagnosis is small Ruptured biceps tendon Multimodality Imaging beyond echo Insights into amyloid cardiomyopathy mechanism and prognosis

7 Technetium Pyrophosphate Scanning AL AMYLOIDOSIS TTR AMYLOIDOSIS Val122Ile Cardiomyopathy: How big a problem? Increasing dyspnea on exertion.50% plasma cells in marrow. Negative fat pad biopsy. 3-4% of African-Americans are heterozygous for the Val122Ile gene, associated with a late-onset (7 th decade) amyloid cardiomyopathy. If penetrance is high, then >1,000,000 African Americans carry the gene and approximately 130, 000 > 65 years old are at risk of amyloid cardiomyopathy. Where are they??? Underdiagnosed, poor penetrance or both? What is the effect of V122I TTR variant on mortality? 3732 wild-type TTR African-Americans in the ARIC Study compared to 124 (3%) carriers of Ile122 variant. Median follow up 21.5 years. Effect of Val122Ile Mutation on Survival and Heart Failure SURVIVAL FREEDOM FROM HEART FAILURE Quarta CC et. al. NEJM 2015:372;21-29 From Quarta CC et al. NEJM: 2015:372; 21-29

8 Increased Extracellular Volume in Cardiac Amyloidosis Ammonia PET scan Dorbalaet al. JACC HF 2014;2: Mongeon et. al. JACC CV Imaging. 2012: 5; Florbetapir for imaging amyloid deposits Tackling TTR preventing unfolding Tackling TTR preventing unfolding Tolcapone: an approved drug for a new indication? Tafamadis Diflunisal Sant Anna et. al. Nature Communications :10787 DOI: /ncomms10787

9 Effect of doxycycline and TUDCA on progression of ATTRwt Effect of a sirna on TTR levels. NEJM 369: ; 2013 Preliminary echo-strain data on 22 patients treated for 12 months with a combination of doxycycline and TUDCA, compared to historical controls. Revusiran Phase 2 Study Preliminary Results* Serum TTR Lowering Overall and by Dose Group GSK-Ionis Antisense Oligonucleotide Mean (SEM) % Serum TTR Knockdown Rel. to Baseline Treatme nt N Individual Max KD (%) Mean ± SDMax KD (%) All ± mg/kg ± mg/kg ± 5.4 Revusiran Dose Group 5.0 mg/kg 7.5 mg/kg Similar in action to sirna for TTR Approximately 80% TTR reduction Weekly sc administration Currently in phase 3 trial for familial amyloid polyneuropathy Phase 2 open-label trial in ATTRwt? Multicenter phase 3 double-blind trial for ATTR wt and ATTrmto start late Fall? Revusiran (mg/kg), qdx5; qwx5 Days since first visit 5.0 mg/kg (N) mg/kg(n) * Results as of October 3,

10 Effect of anti-sap antibody on hepatic amyloid load Images are 6 weeks apart. CARDIAC AMYLOIDOSIS THERAPY: THE FUTURE LOOKS BRIGHT Better diagnostic and imaging tools Better discriminatory techniques for amyloid typing Better current therapies for AL amyloidosis Very promising TTR therapies BUT EARLY DIAGNOSIS REMAINS THE KEY FROM THE AMYLOID CARDIOLOGIST S PERSPECTIVE I only think of what I already know I only think of what I already know I think I have heard of amyloidosis

11 I only think of what I already know I think I have heard of amyloidosis Yes, I ve heard of it, but so what? I only think of what I already know I think I have heard of amyloidosis Yeah, I ve heard of it, but so what? ZZZZZZZZ I only think of what I already know I think I have heard of amyloidosis Yeah, I ve heard of it, but so what? ZZZZZZZZ (forget about it!)