Amyloidosis for Practicing Hematologists

Transcription

1 Amyloidosis for Practicing Hematologists Vishal Kukreti, MD Princess Margaret Cancer Centre October 2, 2015

2 Disclosures Honoraria Celgene, Janssen Ortho, Amgen, Lundbeck

3 Objectives Case Approach subtyping, staging, prognosis Treatment Princess Margaret Cancer Centre Approach

4 Case 67 yo F PMHx hypertension, irritable bowel syndrome HPI several month history of abdominal pain upper and lower endoscopy were normal (but no biopsies taken) Presented to ER with acute abdomen with a perforation of her colon To OR with partial resection of her colon and colostomy Biopsy amyloid deposition in submucosa, muscularis propria and pericolonic fat What is the initial approach?

5 Amyloidosis Disease of misfolded proteins Peptides/proteins are converted from soluble state into an organized fibrillar structure ( amyloid ) Involves interaction of Intracellular protein control system Extracellular chaperones Matrix proteins, proteases, other cofactors 28+ causative proteins identified to date

6 Subtyping - Clinical Presentation Helpful but Not Sufficient Type Precursor protein Site of synthesis Syndrome Organs involved Immunoglobulin light chain (AL) Reactive amyloidosis (AA) Senile systemic amyloidosis (SSA) Transthyretin (ATTR) Fibrinogen amyloidosis (Afib) Apolipoprotein A1 amyloidosis Monoclonal light chains Bone marrow plasma cells Primary Myeloma (10-15% of patients) SAA1 Liver Secondary to chronic inflammation, infection, certain cancers Transthyretin wild type Variant transthyretin, > 100 mutations Variant fibrinogen α-chain Liver (>90%) Age-related, usually males > 65 years Heart, liver, kidneys, GI tract, PN, AN, tissues Kidney, GI tract, spleen, liver, AN Heart Liver (>90%) Hereditary PN, AN, heart, eye, leptomeningeal, rarely kidney Liver Hereditary Kidney Variant Apo A-1 Liver, intestine Hereditary Heart, liver, kidney, skin, larynx, testis

7 Tissue Diagnosis of Affected Organ Congo Red Staining Apple Green Birefringence Fibrillar Deposits on EM Immunohistochemical staining Can be unreliable and inaccurate Immunogold electron microscopy Mass spectrometry with laser dissection Gold standard UHN Pathology Department (Dr. Rohan John/Dr. Vathany Kulasingam) NOTE: Surrogate site fat pad biopsy sensitivity 19-58%; specificity up to 100%

8 Light Chain Amyloidosis Incidence 8/10 5 Median age of 63 yrs Equal M:F ratio Occurs in up to 15% of patients with myeloma and rarely with other B-cell malignancies More commonly lambda light chain

9 Amyloidosis is a Great Mimicker Weakness or fatigue Loss of weight Autonomic disturbances: Syncope/Presyncope Numbness/Tingling Hoarseness of voice Enlarged Tongue Swelling, due to: Congestive heart failure Nephrotic syndrome Protein-losing enteropathy Shortness of Breadth Arthritis & Rheumatism Volume 56, Issue 11, pages Skin manifestations Bleeding Carpal tunnel syndrome Enlarged liver/spleen Lymphadenopathy Joint Symptoms

10 Staging of Primary Amyloidosis Evaluation of organ involvement Physical exam (blood pressure, cardiac and neuro exam) 24 hr urine protein for protein Heart - Echocardiogram, ECG and cardiac MRI Liver assessment (biopsy, hepatomegaly + alk phos) Gastrointestinal Tract - endoscopy + biopsy Neurological System - EMG/NCS Other tests Troponin I (or T), hs Troponin T and NT-proBNP (BNP) Beta 2 microglobulin level Factor X level Definition of Organ Involvement and Treatment Response in AL Amyloidosis Gertz et al., American J of Hematology 2005

11 Immunological Testing in AL Amyloidosis Bloodwork 98% had FLC detected in serum Immunofixation can detect urine LC in up to 80-90% but not quantitative

12 Prognostic Factors in AL Amyloidosis Sites of organ involvement (number of organs) Biochemical markers of cardiac function Troponin I or T; hs Troponin T NT-proBNP; BNP Renal Markers for Predicting Dialysis based on egfr and 24 Hr Urine (Dispenzieri Blood 2014) If egfr<50ml/min and 24 Hr Urine 5g/24Hr (stage III) 2 yr risk for dialysis 60-75%

13 Overall survival (OS) 583 patients based on revised Mayo staging system High early Death rate of up to 33% from starting therapy Combination of cardiac markers and clonal plasma cell characteristics (1 point each) FLC diff (inv-uninv) 18mg/dL Troponin T ng/ml NT-proBNP 1800 pg/ml 2012 by American Society of Clinical Oncology Kumar S et al. JCO 2012;30:

14 Case Exam normal vitals (no postural changes); ostomy infection, distended abdomen Pathology mass spectrometry c/w Dx of lambda light chain amyloidosis Staging investigations 10% plasma cells, lambda restricted Laboratory Testing Hgb 130 g/l, Lytes/Cr and LFTs normal, Troponin I normal, BNP 110, normal Ig profile with negative IFE, free kappa 17 mg/l, free lambda 440 mg/l, ratio 0.04, albumin 33g/L; 24 hr urine normal (IFE negative) 2D echo normal EF 60%, IVSD 8mm, PWD 8mm, diastolic dysfunction; EKG normal AL amyloidosis with GI only disease Optimal Therapy, goal of treatment and role for stem cell transplant

15 Treatment Substantially reduce the supply of the monoclonal immunoglobulin light chain Stabilize or reduce existing deposits of amyloidosis Preservation or improvement in organ function Borrowed from the myeloma literature Autologous stem cell transplant (High dose Melphalan) Melphalan and Dexamethasone (Palladini) 67% ORR, 33% CR, median time to response of 4.5 mo Cyclophosphamide, Thalidomide and Steroids Supportive Therapy GI/Cardiac/Renal

16 Hematological Response at 6 mo and Survival Target Heme Response Note: Organ Response is slower to occur Comenzo et al, Leukemia 2012

17 Issues with Autologous Stem Cell Transplant in Primary Amyloidosis Poor tolerance of priming procedure Fluid retention Cardiotoxicity Heart Failure Nephrotoxicity Gastrointestinal bleeding Patient ineligibility Prognostic variables number of organs involved and cardiac markers

18 Randomized Trial of ASCT vs Mel + Dex Long Term Follow up 47% had Cardiac Involvement ASCT Heme Response of 67% and CR of 40% M-Dex 68% Heme Response; 34% had CR Median f/u 3 yrs Med survival M-Dex 56.9 mo vs 22.2 mo in ASCT Jan 2010 excluding pts dying within the first 6 months no difference between ASCT vs M-Dex Jaccard A, et al. N Engl J Med 2007; 357:1083

19 Princess Margaret AL Amyloidosis ASCT Retrospective Review 78 selected transplanted patients 48% cardiac involvement, 72% renal involvement 78% overall hematological response; 56% hematological CR and 60% organ response Median PFS 72 mo (97mo if have CHR) TRM 11.5% - higher if BNP >300pg/ml or increased troponin I Zepeda BJH 2013

20 Novel Therapies Proteosome Inhibition Velcade (Bortezomib) rapid response Phase 2 studies for relapsed/refractory disease and for first line therapy weekly dosing;?sc vs IV Immunomodulatory drugs (relapsed disease) Revlimid Pomalidomide Newer agents MLN9708, Carfilzomib

21 Results of Therapy in Newly Diagnosed AL Regimen Mel + ASCT 1,2,3 High-dose Lower dose Overall heme response (CR ) 75% (33%-50%) 53% (18%) TRM 12-13% [8%] Median survival (years) Melphalan + dex 4 67%(33%) 4% 5.1 High-dose dex 5 53% (24%) 7% 2.6 Thalidomide + dex 6 48% (19%) 0* >3 Mel + prednisone 7 28% (rare) CTD 8 74% (21%) 4% NYR CyBorD 9 90% (60%) Cybor D - Projected 5 yr OS of 55% (Blood 2015) 1 Skinner M, et al. Ann Int Med 2004; 140: 85-93; 2 Gertz MA, et al. Bone Marrow Transplant 2004; 34: ; 3 Gertz MA, et al. Blood 2006; 107: ; 4 Palladini G, et al. Blood 2004; 103: ; 5 Dhodapkar MV, et al. Blood 2004; 104: ; 6 Palladini G, et al. Blood 2005; 105: ; 7 Kyle RA, et al. N Enl J Med 1997; 336: ; 8 Wechalekar AD, et al. Blood 2007; 109: ; 9 Mikhael JR, et al. Blood 2012, February 13 [Epub ahead of print] NYR=not yet reached

22 PM Risk Adapted Approach Eligible for ASCT LVEF > 45% DLCO > 50% Bilirubin < 35 mmol/l 2 organ systems Absence of advanced cardiac disease Normal troponin I + low BNP Systolic BP >90 mmhg If in CR, stop and monitor MELPHALAN mg/m 2 + ASCT CyBorD X 2-8 cycles If in CR, stop and monitor If not in CR If significant residual disease burden Novel agent-based therapy or clinical trial Ineligible for ASCT 3 organ systems High troponin + BNP Low systolic BP Alternative Mel-Dex Reassess: Consider ASCT if now eligible. If not ASCT eligible, continue therapy until CR. Consider stem cell collection for selected patients. If in CR, stop and monitor

23 NEOD001 Phase 1/2 in Patients with AL amyloidosis and Persistent Organ Dysfunction NEOD001 Neutralizes Soluble Amyloid and Clears Insoluble Amyloid Cardiac Biomarker Response<br />Best Response Analysis

24 Conclusions Better Prognostication and Response Criteria More treatment options available Risk-adapted ASCT Melphalan and dex frail pts, non-cardiac disease CyBorD - rapid response Lenalidomide + dex or combinations (CRD) Pomalidomide + dex Improved strategies needed cardiac protection Early Detection

25 Case Weighing risks/benefits felt not to be a good candidate for ASCT Choose PVD clinical trial over CyborD