AMYLOIDOSIS Corporation and Millennium Pharmaceuticals Speakers - PDF document

2/27/2014 Disclosures for Ann McNeill  Consultant / Advisor for Celgene AMYLOIDOSIS Corporation and Millennium Pharmaceuticals  Speaker’s Bureau for Celgen Ann McNeill, MSN, APN Corporation, Millennium Nurse Practitioner Pharmaceuticals and Onyx John Theurer Cancer Center at Pharmaceuticals Hackensack University Medical Center Hackensack, New Jersey Learning Objectives Incidence and Prevalence  “Rare” disease: each year, about  Understand the epidemiology of 50,000 people worldwide will be amyloidosis diagnosed  Describe the clinical presentation of  More than 3,000 cases diagnosed patients with amyloidosis each year in North America  Identify the pathophysiologic  2:1 ratio of males to females mechanisms involved in amyloidosis  Peaks between the ages of 60 and  Delineate treatment options for 67; only 1% are under age 40 in the amyloidosis and the efficacy of each U.S. Rosenzweig and Landau Journal of Hematology & Oncology 2011, 4:47 Definition  Amyloidosis is a rare, systemic WHAT IS THE ORIGIN OF disorder of protein metabolism THIS ABNORMAL  Progressive, extracellular deposition of insoluble fibrillary protein PROTEIN?  Disorganization of tissue architecture ??  Organ dysfunction  Death – particularly as a result of cardiac involvement Chaulagain & Comenzo Curr Hematol Malig Rep 2013 8: 291-298 1

2/27/2014 Pathophysiology of Amyloidosis Distribution of Monoclonal Gammopathies In amyloidosis, plasma cells in the bone marrow produce too many “free light chain” antibodies. These proteins misfold into amyloid, accumulate in the blood, and deposit in many organ systems. Pathophysiology of Amyloidosis Pathophysiology of Amyloidosis http://www.amyloidosissupport.com/AmyloidAware_Booklet.pdf http://www.amyloidosissupport.com/AmyloidAware_Booklet.pdf Common Presenting Symptoms of Symptoms (cont’d) Amyloidosis Symptoms tend to be vague and  Abnormal heart rhythm include  Numbness of hands or feet  Unexplained fatigue  Shortness of breath  Unintentional weight loss  Difficulty swallowing  Periorbital purpura  Weak hand grip  Edema  Macroglossia Rosenzweig and Landau J of Hem & Onc 2011, 4:47 Rosenzweig & Landau Journal of Hematology & Oncology 2011, 4:47 2

2/27/2014 Diagnosis of Primary Revised Prognostic Staging System for Light Chain Amyloidosis Amyloidosis Amyloidosis should be suspected when a Points patient presents with:  Renal disease – proteinuria, renal dFLC ≥ 18 mg/dL insufficiency, nephrotic syndrome  Infiltrative cardiomyopathy cTnT ≥ 0.025 ng/mL  Peripheral neuropathy  Hepatomegaly NT-ProBNP ≥ 1,800 pg/mL  Pseudo-obstruction of the bowel  Multiple Myeloma – 10-15% of MM patients Creates score from 0, 1, 2, and 3 points reflecting Stage I, II, III, and IV have amyloidosis dFLC=difference in free light chains; cTnT= cardiac troponin T NT-ProBNP=N terminal prohormone of brain natriuretic peptide McGowan, N Dim of Crit Care Nrsing 2006, 25 (4) 162-165 Kumar et al J Clin Oncology 2012; 30(9) 989-995 Diagnostic Screening Tests Diagnostic Screening Tests (cont’d)  Once considered, the evaluation for amyloidosis includes testing to identify  Cardiac – EKG and an underlying plasma cell disorder echocardiogram  Renal – 24 hr urine total protein  Serum and Urine protein electrophoresis assessment  Immunofixation  GI – abdominal ultrasound  Serum Free Light Chain Assay  Bone Marrow Aspirate/Biopsy  NS – nerve conduction studies Rosenzweig and Landau Journal of Hem & Onc 2011, 4: 47 Rosenzweig and Landau Journal of Hem & Onc 2011, 4:47 Diagnostic Confirmation of Diagnostic Confirmation of Amyloidosis Amyloidosis (cont’d)  In some patients, amyloid deposition will be identified on bone marrow Tissue sampling is required! biopsy or by fat pad aspirate (85% of  Demonstrate the presence of patients) congophilic amyloid deposits (“Congo  But amyloid can be present when both Red positive”) OR are negative! Direct biopsy of  Fibrils that are 7-10 nm in diameter by involved organ should be performed if Electron Microscopy index of suspicion is high Rosenzweig and Landau J of Hem & Onc 2011, 4:47 Rosenzweig and Landau J of Hem & Onc 2011, 4:47 3

2/27/2014 AL Amyloidosis (cont’d) AL Amyloidosis The diagnosis of systemic amyloidosis  Presence of amyloid-related systemic requires the presence of all of the syndrome (renal, heart, GI, NS) following:  Evidence of a monoclonal plasma cell  Positive amyloid staining by Congo proliferative disorder [serum or urine Red or EM in any tissue M protein; abnormal free light chain ratio; clonal plasma cells identified in  Evidence that amyloid is light chain bone marrow] related by direct examination of amyloid by molecular methods Chaulagain and Comenzo Curr Hematol Malig Rep 2013, 8: 291-298 Treatment Treatment This condition is treated the same way The source of the amyloid light chains is a clone as multiple myeloma would be of plasma cells histologically identical to those approached: seen in multiple myeloma  Dexamethasone ↓  Chemotherapy (including alkylating agents, proteasome inhibitors and Treatments for amyloidosis have been derived immunomodulatory agents) from those studied for the treament of multiple myeloma  High dose therapy followed by ASCT ASCT=autologous stem cell transplant Factors that influence approach to Treatment Goal treatment  Age Eradicate the plasma cell clone to achieve a Complete Response (CR)  Performance Status or a Very Good Partial Response  Bone Marrow Reserve (VGPR) for meaningful reversal of  Renal Function organ dysfunction and for prolonged  Pre-existing Toxicities (peripheral survival neuropathy, cardiac disease, VTE’s) VTE=venous thromboembolism 4

2/27/2014 Hematologic Response Criteria in Treatment Strategies Amyloidosis Response Criteria Bortezomib based therapy (bortezomib/cyclophosphamide/dexamethasone CR Negative serum and urine IFE, or CyBorD) normal FLC levels and ratio  High response rates – rapid reduction of free VGPR Reduction of dFLC to <40 mg/L light chain levels  Favorable cardiac toxicity profile PR >50% reduction in the dFLC  Minimal toxicity  Ease of administration No response Less than a partial response Chaulagain & Comenzo Curr Hematol Malig Rep 2013 8:291-298 Treatment Approach in Treatment Approach in Amyloidosis Amyloidosis Low-Risk (standard risk) patients Intermediate-Risk patients (not high risk, not low risk)  Risk-adapted SCT with  CyBorD or MDex (oral mel/dex) bortezomib/dexamethasone  Patients who are initially ineligible for consolidation (200, 140, and 100 ASCT may become eligible if they mg/m 2 of MEL) respond to initial therapy  Clinical trials SCT = stem cell transplant; MEL = melphalan Eligibility Criteria and Treatment Approach in Schema for risk-adapted Amyloidosis Melphalan and SCT High-Risk patients [Advanced Cardiac  Age <71 years (high risk stage III) or 3 organs  ECOG performance status 0 to 2  Serum Bilirubin ≤ 2 mg/dL involved)  Pulmonary diffusion capacity ≥ 50%  CyBorD or Mel predicted (adjusted)  Left ventricular ejection fraction ≥ 45%  Clinical Trials  NYHA Class ≤ 2b  No symptomatic cardiac arrhythmia or syncope within 60 days  Systolic blood pressure ≥ 95 mm Hg supine Chaulagain and Comenzo Curr Hematol Malig Rep 2013 8, 291-298 Chaulagain and Comenzo Curr Hematol Malig Rep 2013 8, 291-298 5

2/27/2014 Eligibility Criteria and Schema for risk-adapted Transplant Eligibility Criteria Melphalan and SCT  MEL 200: For patients who are <60 yrs old with no cardiac or renal compromise  MEL 140: For patients who are 61-70 yrs Only 20% of the patients are old with no cardiac or renal compromise; for eligible for stem cell transplant! patients who are <60 yrs old with cardiac involvement or renal compromise  MEL 100: For patients who are 61-70 yrs old with cardiac involvement or renal compromise Gertz et al Am J Hematol 2013; 88: 416-425 Chaulagain and Comenzo Curr Hematol Malig Rep 2013 8, 291-298 Treatment Related Treatment Related Mortality Mortality  Average TRM in four single center  Cardiac amyloid patients can studies is 21% but has been reported as high as 39%. experience critical arrhythmias or sudden death during stem cell  Patients with cardiac involvement and autonomic dysfunction are particularly infusion presumably related to the susceptible to fluid shifts and toxicity of the DMSO preservative hypotension and should be monitored  Wash cells prior to infusion? closely during all phases of treatment including mobilization/collection Rosenzweig and Landau J of Hem & Onc 2011, 4:47 Gertz and Zeldenrust Curr Hematol Malig Rep 2009, 4: 91-98 ASCT Results ASCT Results Boston University Two large studies from  312 patients with amyloidosis were treated with HDM/SCT at 200 mg/m 2 or experienced centers confirmed 140 mg/m 2 based on age and cardiac the utility of high dose status  TRM was reduced to 14% melphalan/stem cell transplant  Median survival for those who achieved as a treatment for amyloidosis CR was >10 years compared to 50 months for those who did not achieve a CR HDM/SCT=high dose melphalan/stem cell transplant; TRM=treatment-related mortality; CR=complete response Sanchorawala et al Blood 2007, 110 3561-3563 6