Amyloidosis: What to do and how to diagnose: An Update 2017

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1 Amyloidosis: What to do and how to diagnose: An Update 2017 Jonathan L. Kaufman, MD Associate Professor Hematology & Oncology Winship Cancer Institute of Emory University

2 Amyloidosis Protein Conformation/Deposition Disorder AL Amyloidosis Hereditary Amyloidosis Transthyretin Fibrinogen Aα Apolipoprotein AI and AII Lysozyme Secondary Amyloidosis 2

3 The Cascade of Molecular Events leading to Amyloidosis Merlini G, et al. J Clin Oncol. 2011;29(14):

4 Clinical Manifestations of Amyloidosis 4

5 AL Amyloidosis Monoclonal plasma cell disorder 3,000 cases annually in the USA 10% of patients are < 50 years old Presenting symptoms are varied Delays in diagnosis are common Comenzo RL, et al. Blood. 2002;99(12):

6 Clinical Manifestations of AL Amyloidosis Merlini G, et al. N Engl J Med. 2003;349(6):

7 Merlini G, et al. Blood. 2006;108(8):

8 Establishing the Clinical Diagnosis Assay % Positive (CI) 1 FLC / ratio 91 (84 96) Serum IFE 69 (60 78) Urine IFE 83 (74 89) Serum IFE + urine IFE 95 (90 99) FLC / ratio + urine IFE 91 (84 96) FLC / ratio + serum IFE 99 (95 100) All 3 assays 99 (95 100) Katzmann JA, et al. Clin Chem. 2005;51(5):

9 Establishing the Diagnosis by non-invasive testing Fat+ Marrow+ 62% Fat+ Marrow 11% Fat Marrow+ 15% Fat Marrow 13% Gertz MA, et al. Hematology Am Soc Hematol Educ Program. 2004;2004( ). 9

10 Diagnostic Algorithm for Systemic Amyloidosis Merlini G, et al. J Clin Oncol. 2011;29(14): by American Society of Clinical Oncology 10

11 67 year old WF with presents with dyspnea on exertion 2 months, intermittent, resolves with rest EKG, Stress test, echocardiogram and CXR Stress test normal Echo- IVS 1.5 cm, EF: 55%, diastolic dysfunction Cardiac cath- no vessel disease Cardiac MRI Endomyocardial biopsy 11

12 All of the following clinical scenarios should trigger a suspicion of amyloidosis except 1. Dilated cardiomyopathy with low EF 2. Nephrotic syndrome with preserved GFR 3. Bilateral carpal tunnel syndrome 4. Purpura around the eyes and neck 12

13 Screening tests for amyloidosis in MGUS (at least annually) urine protein/creatinine ratio > 0.5 NT-proBNP >330 What monoclonal protein studies? Serum and Urine electrophoresis and immunofixation Free light chain assay Sequence of biopsy Bone marrow and fat pad aspirate Target organ 13

14 What is the next best step? 1. PET/CT scan 2. Bone marrow biopsy 3. Sub-type amyloid tissue 4. Start chemotherapy 14

15 Subtyping of amyloid is critical in any newly diagnosed amyloid patient 15

16 In a patient with MGUS, found to have cardiac amyloidosis, do you need to subtype? Prevalence of MGUS in older adults Higher prevalence in Blacks 143 cases of cardiac biopsy-proven amyloidosis 81(57%) - ATTR, 62 (43%) AL 76 (53%) had MG detected including 20 with ATTR Kyle RA, et al. N Engl J Med. 2006;354(13): Maleszewski JJ, et al. Cardiovasc Pathol. 2013;22(3):

17 Subtyping revealed AL(lambda) amyloidosis Patient was referred to Oncology Additional tests were performed 17

18 All except which of the following tests provide additional prognostic information in AL? 1. NT-proBNP 2. M-spike quantity 3. Free light chain assay 4. Troponin T 18

19 Staging of AL amyloidosis 2012 revised staging system dflc (involved-uninvolved free light chain) 180 mg/l (18 mg/dl) NT-proBNP 1800 pg/ml ctnt ng/ml Kumar S, et al. J Clin Oncol. 2012;30(9):

20 Free kappa mg/l Free lambda mg/l NT-proBNP 6,752 pg/ml ctnt 0.06 ng/ml Bone marrow biopsy revealed 13% plasma cells 20

21 Which of the following cytogenetic abnormalities is the most common in AL? 1. t(4;14) 2. t(11;14) 3. 17pdel 4. hyperdiploidy 21

22 Which of the following is the best treatment option for this patient? 1. Melphalan/dexamethasone 2. Autologous stem cell transplantation 3. Lenalidomide 4. Clinical trial 22

23 To transplant or not to transplant? High early mortality (24% in RCT) Patient selection is critical NT probnp >5000, TnT >0.06 Center experience also key Centers 4 AL transplants/year Induction treatment pre-transplant? CyBorD can convert transplant ineligible to eligible May test ability of patients to tolerate treatment BMPC >10% Jaccard A, et al. N Engl J Med. 2007;357(11): Gertz MA, et al. Bone Marrow Transplant. 2013;48(4): D Souza A, et al. J Clin Oncol. 2015;33(32): Hwa YL, et al. Am J Hematol. 2016;91(10):

24 Bone marrow plasma cell clone clonal free light chains misfolded light chains (AL) organ AL deposition leading to dysfunction Effective Chemotherapy available Needs time for endogenous clearance Chemotherapy can worsen e.g. fluid retention, cardiotoxicity, neuropathy Need for clinical trials with fibrildirected therapies 24

25 ASH 2016 (Abstract #644) 25

26 1. Palladini G, et al. Blood. 2015;126(suppl): Abstract Palladini G, et al. Blood. 2015;126(5): Comenzo RL, et al. Leukemia. 2012;26(11): Palladini G, et al. Haematologica. 2013;98(3): Gertz MA, et al. Blood. 2016;128(suppl): Abstract

27 1. Comenzo RL, et al. Leukemia. 2012;26(11): Palladini G, et al. J Clin Oncol. 2012;30(36): Gertz MA, et al. Blood. 2016;128(suppl): Abstract

28 This patient had stage IV AL amyloidosis Enrolled on a phase III clinical trial using bortzomib-based chemotherapy + NEOD001/placebo After 8 months of treatment, she achieved a hematologic CR and cardiac response She then successfully underwent autologous hematopoietic cell transplantation 28

29 Conclusions AL amyloidosis remains a challenge to diagnose and treat Amyloid subtyping is critical is establishing diagnosis Autologous transplant remains an important part of treatment in selected patients Improved plasma cell directed therapy improves outcomes Clinical trials comparing dara VCD to VCD are starting Organ directed therapy with antibodies are promising 29