1/26/12. Selected Topics in Pediatric Hematology/Oncology COMPLEMENTOLOGY OBJECTIVES. Classically Different Topics but not so much

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1 1/26/12 OBJECTIVES Selected Topics in Pediatric Hematology/Oncology COMPLEMENTOLOGY Chatchawin Assanasen MD Recognize implications of complement pathway diseases Signs and symptoms of PNH and ahus Complications of PNH and ahus Recognized appropriate diagnostic testing for PNH and ahus Understand treatment options in PNH and ahus Grand Rounds Provide a little entertainment January 27, 2012 Shamelessly plug the UTHSCSA Pediatric Hematology Consultation Service Classically Different Topics but not so much I can live for two months on a good compliment Both are diseases of complement dysfunction PNH ahus rare, acquired, disease of the blood in children and young adults Rare disease of the kidney in children and young adults characterized by hemolytic anemia, thrombosis, impaired bone marrow function, and a 3 to 5% risk of developing leukemia characterized by hemolytic anemia, thrombocytopenia and acute renal failure distinctly different illness from HUS caused by particular strains of the bacterium 0157:7 E.coli producing Shiga toxins PNH is closely related to aplastic anemia 30% of newly diagnosed cases of PNH evolve from aplastic anemia the risk developing PNH after treatment for aplastic anemia with immunosuppressive therapy (antithymocyte globulin and cyclosporine) is approximately 20 to 30%. evidence that ahus is a genetic disorder chronic condition with predilection for repeated attacks of the disorder. develop chronic serious complications such as kidney failure The median survival after diagnosis is 10 years Complement Function The Good The Bad Part of the humoral immune system guarding the intravascular space against bacterial invasion Dysregulation of the complement system can lead to wide spread cellular injury often associated with hematologic and renal disease. (ahus dense deposit disease) 3 pathways Classical Pathway Lectin Pathway Alternative Pathway Always on The Complement Pathway Infections HIV, Streptococcus pneumoniae Chemotherapeutic agents Autoimmune disorders SLE, scleroderma Pregnancy Preeclampsia, HELLP Regulatory proteins 1

2 The Complement System: Always On, Strongly Amplified, Dependent on Natural Regulators A vital component of the natural protective immune system 1 Always on to allow rapid immune response 1 Simple triggers, including common infections and trauma, lead to rapid complement amplification 1,2 Rapid amplification leads to powerful and destructive immune reactions 2 Natural inhibitors of complement keep amplification in check and prevent uncontrolled complement activation 2 PNH Discoveries began with the work of Thomas Hale Ham and Louis Pillemer in the late 1930 s suggesting a novel antibody independent mechanism for complement activation. The Ham acid hemolysis test was the up until recently the standard by which PNH was diagnosed. 1. Holers VM et al. Immunol Rev. 2008;223: Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;4: Paroxysmal Nocturnal Hemoglobinuria Prevalence: 15.9 / million 1 Diagnosed at all Ages Median age early 30 s 3,4 Aquired disease of hematopoetic stem cell Progressive disease 2-4 Uncontrolled complement activation underlies the morbidities and mortality 5 year mortality: 35% 2 Patients Surviving (%) Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH Years After Diagnosis The expected survival of an age- and gender-matched control group is shown for comparison (Hillmen et al. 1995). In a patient population where ½ the patients have <30% clone, 1 in 7 patients died by 5 years. de Latour et al. Blood. 2008;112: Age- and Gender- Matched Controls Patients with PNH Paroxysmal Nocturnal Hemoglobinuria myths and legends It s not paroxysmal Even in the absence of symptoms, destructive progression of hemolysis is ongoing It s not nocturnal Hemolysis in PNH is subtle and constant, 24 hours a day Hemoglobinuria is a less commonly seen complication ¾ patients present without hemoglobinuria 1 1. Hill A et al. Blood. 2006;108(11): 290a. Abstract Hillmen P et al. N Engl J Med. 1995;333: Nishimura JI, et al. Medicine. 2004;83: Socié G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 2007;137: International PNH Interest Group. Blood. 2005;106: The Defect in PNH The Somatic Mutation of the PIG A Gene Prevents All GPI Anchored Proteins from Binding to Cell Surface Clonal expansion of these PNH stem cells leads to affected progeny CD59 Forms a defensive shield for RBCs from complement-mediated lysis Inhibits the assembly of the membrane attack complex CD55 Prevents formation and augments instability of the C3 convertases, attenuating the complement cascade CD59 GPI-anchor CD55 1. Adapted from: Johnson RJ et al. J Clin Pathol: Mol Pathol. 2002;55: Brodsky R. Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005;

3 Historically Viewed as a Hemolytic Anemia Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Complement Without this protective complement inhibitor shield, PNH red blood cells are destroyed The peripheral blood of patients with PNH is a mosaic of normal and abnormal cells PNH III cells are completely deficient in GPI-APs PNH II cells are partially ( 90%) deficient Intact RBC Reduced Free Hemoglobin Red Cell Mass Anemia PNH I cells express GPI-APs at normal density 1. International PNH Interest Group. Blood. 2005;106: Brodsky R Paroxysmal Nocturnal Hemoglobinuria. In: Hematology - Basic Principles and Practices. 4th ed. R Hoffman; EJ Benz; S Shattil et al, eds. Philadelphia, PA: Elsevier Churchill Livingstone; 2005; Rother RP et al. JAMA. 2005;293: Socie G et al. Lancet. 1996;348: Hill A et al. Br J Haematol. 2007;137: Parker C. Management of Paroxysmal Nocturnal Hemoglobinuria in the era of complement inhibitory therapy. ASH Education Program % of Patients With PNH Have Peripheral Blood Abnormalities Other combinations* Anemia and neutropenia Anemia and thrombocytopenia Socie et al. Lancet. 1996;348: % 7% 4% No concomitant cytopenias 7% Pancytopenia 32% 33% Anemia Anemia: Hemoglobin <12.0 g/l Neutropenia: ANC <1.5x10 9 /L Thrombocytopenia: count <1.5x10 11 /L *Other combinations: Thrombocytopenia alone, neutropenia alone, both thrombocytopenia and neutropenia Signs and Symptoms Delays in diagnosis range from 1 to more than 10 years 1 Clinical Signs or Symptoms Incidence Rate (%) Thrombosis 40% 1 Dyspnea 66% 2 Pulmonary Hypertension 47% 6 Chronic Kidney Disease 64% 3 Abdominal Pain 57% 2 Anemia 88% 4 Fatigue, impaired QOL 96% 2 Hemoglobinuria (at presentation) 26% 5 Dysphagia 41% 2 Erectile Dysfunction 47% 2 1. Hillmen P et al. N Engl J Med. 1995;333: Meyers G et al. Blood. 2007;110(11):Abstract Hillmen P et al. Am. J. Hematol. 2010; 85: Nishimura J et al. Medicine. 2004;83(3): International PNH Interest Group. Blood. 2005;106(12): Hill A et al. BJH. 2010; 149(3): Characteristics of Thrombosis in PNH Classification and Testing for PNH Can occur at typical and atypical sites DVT or PE most common 1 Budd-Chiari and dermal 2,3 Both venous and arterial sites 39% of TE events occur at arterial sites 4 Abdominal pain is a predictor of TE fold increased risk Incidence of TE is elevated even in patients receiving anticoagulant therapy 1 Clinical thrombosis evident in PNH patients with 1 Minimal hemolysis No transfusion history Smaller clone size 4 Odds Ratio In patients with history of TE, there is a 7- fold increased risk of mortality 4 South Korean National Registry. n=9/43 1. Hillmen et al. Blood. 2007;110:12: Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: Parker C et al. Blood. 2005; 106(12): Lee JW et al. Hematologica (s2): Abstract #505. Borowitz MJ et al. International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: ; International PNH Interest Group. Blood. 2005;106(12):

4 1/26/12 Suggestions for PNH Testing by ICCS PNH Guidelines Why Look Beyond RBCs for PNH? Granulocytes provide more accurate representation of PNH clone size PNH population in marrow failure syndromes may not otherwise be identified 40% of the MDS and AA in children1 Percentages of PNH RBCs may be affected by Hemolysis Blood transfusion Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. Borowitz MJ, Craig FE, DiGiuseppe JA, Illingworth AJ, Rosse W, Sutherland DR, Wittwer CT, Richards SJ. Cytometry. Part B 2010;00B: Important to Monitor Granulocytes and RBCs Over Time Mar 09 May 09 Gran clone: 3.8% Gran clone: 7.6% Gran clone: 14.2% Gran clone: 23.3% RBC clone: 0.8% RBC clone: 1.6% RBC clone: 1.8% RBC clone: 2.4% CD59 GPI Anchor Protein CD59 GPI Anchor Protein 3 Months Treatment options CD14-Granulocytes Dec 08 Sept 08 1.Curry C et al. High sensitivity flow cytometry testing for paroxysmal nocturnal hemoglobinuria in children with cytopenia: asingle center study ASH abstracts Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: CD59 GPI Anchor Protein CD59 GPI Anchor Protein 6 Months 9 Months PNH Clone Expanded in <1 Year Parker C. Management of Paroxysmal Nocturnal Hemoglobinuria in the era of complement inhibitory therapy. ASH Education Program 2011 Summary PNH may be more common than you might think Delays in diagnosis range from 1 to more than 10 years1 Test high-risk patients for PNH2 PNH illustrates a model of disease states related to targets of complement. What about true regulatory dysfunction of the complement system? Reliable testing and reporting procedures matter2 Granulocyte analysis in all cases PNH testing on RBCs alone is not adequate Adding quantitative results to report forms is essential With the advent of treatment options for PNH, there is a compelling reason to identify patients3 1. Hillmen P et al. N Engl J Med. 1995;333: Borowitz MJ et al. for International Clinical Cytometry Society. Part B Clin Cytometry. 2010;78B: Brodsky R et al. Blood. 2008;111(4):

5 Atypical Hemolytic Uremic Syndrome Dysregulation and/or excessive activation of the alternative pathway of complement plays a pivotal role in the pathogenesis of ahus can be both familial (<20%) and sporadic 1 Inactivating mutations in genes encoding complement regulators (factor H, factor I, and membrane cofactor protein) 2 Gain-of-function mutations in genes encoding the complement activators (C3 and factor B) have been described 2 Mutations in the gene encoding thrombomodulin have also been described in ahus. 3 membrane-bound glycoprotein with anticoagulant properties that modulates complement activation on cell surfaces Proximal Terminal Anaphylaxis Inflammation Thrombosis Genetic Loss of Natural Inhibitors Leads to Chronic Uncontrolled Complement Lectin Pathway Immune Complex Clearance Microbial Opsonization Consequences C5a Potent Anaphylatoxin Chemotaxis Proinflammatory Leukocyte/Monocyte Endothelial Prothrombotic Classical Pathway C3 C5 Natural Inhibitors C5b-9 Membrane Attack Complex Cell Lysis Proinflammatory Leukocyte/Monocyte Endothelial Prothrombotic Alternative Pathway C3 + H 2 O - ALWAYS ACTIVE (Chronic) Amplification Consequences Cell Destruction Inflammation Thrombosis 1. Noris M and Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361(17): Kavanagh D and Goodship T (2010) Genetics and complement in atypical HUS. Pediatr Nephrol 25(12): Noris M, Caprioli J, Bresin E, et al. (2010) Relative role of genetic complement abnormalities in sporadic and familial ahus and their impact on clinical phenotype. Clin J Am Soc Nephrol 5(10): Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: ; Walport MJ. N Engl J Med. 2001;344: ; Rother RP et al. Nature Biotech. 2007;25: ; Meyers G et al. Blood. 2007;110:Abstract 3683; Hill A et al. Br. J. Hematol. 2010;149: ; Hillmen P et al. Am J Hematol 2010; 85: , International PNH Interest Group. Blood. 2005;106: ; Hillmen P et al. N Engl J Med. 1995;333:1253; Nishimura J et al. Medicine.2004;83: ; Caprioli J et al. Blood 2006;108: ; Noris M, et al. Clin J Am Soc Nephrol. 2010;5: ; George JN et al. Blood. 2010;116: ; Loirat C, et al. Pediatr Nephrol. 2008;23: ; Stahl A, et al Blood. 2008;111: ; Hosler GA, et al Arch Pathol Lab Med. 2003; 127; ; Ariceta G et al. Pediatr Nephrol. 2009; 24: Chronic Uncontrolled Complement Causes, Endothelial, Leukocyte/Monocyte Leading to Inflammation and Systemic Small Vessel Occlusion Atypical Hemolytic Uremic Syndrome Neutrophil Uncontrolled Complement Neutrophil Endothelium Endothelial Swelling and Disruption Aggregation Consumption Mechanical Hemolysis (Schistocytes) Blood Clots Inflammation Occlusion Ischemia Hypoxia Complement-mediated thrombotic microangiopathy (TMA) 1 Sudden death with vital organ damage 2 Chronic progressive course with premature mortality 1,3,4 1 year mortality/dialysis/ permanent renal damage: >50% 3 despite PE/PI Manifests at all ages 4 Cumulative Fraction of Patients Free of Events Follow-up (months) 70% of patients with ahus with the most common mutation (CFH) die, require dialysis, or have permanent renal damage 1 No. at Risk Modified from Caprioli et al Modified from Desch K et al. JASN. 2007;18: Modified from Licht C et al. Blood. 2009;114: Modified from Noris M et al. NEJM. 2009; 361: Modified from Stahl A, et al. Blood 2008;111: Modified from Camous L et al. Blood. 2011;117: Noris M, et al. N Engl J Med. 2009;361: Sallee M, et al. Nephrol Dial Transplant. 2010;25: Caprioli et al Blood. 2006; 108: Noris M, et al. CJASN. 2010;10: Early Diagnosis of ahus: Challenges ahus can manifest with early signs and symptoms that are non-specific Often diagnosed late when organ damage already occurred Clinical presentation can be similar to other systemic thrombotic microangiopathies (TMA) Historically limited interest to differentiate ahus from severe ADAMTS13 deficiency (TTP) as no specific management for ahus ahus is a rare disease and thus unfamiliar to many care takers: Leads to lack of clinical suspicion Perception that diagnosis requires identification of genetic mutation Differential Diagnosis for Thrombotic Microangiopathies (TMAs) Thrombocytopenia 1,7 count <150,000 Or >25% Decrease from baseline Neurological Symptoms 3,4,9,12 5% ADAMTS13 Activity >5% ADAMTS13 Activity Shiga-toxin/EHEC Positive TTP ± Plus One or More of the Following: Renal Impairment 5,6,7 Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC*Test 10,11 ahus Microangiopathic Hemolysis 2,7 Elevated LDH and/or Decreased Haptoglobin and/or Schistocytes and/or Decreased Hemoglobin Gastrointestinal Symptoms 7,8,9 STEC-HUS *Shiga-toxin/EHEC test is warranted in history/presence of GI symptoms. 1. Alexion Pharmaceuticals, Inc. 2. Noris et al. NEJM. 2009;361: Neuhaus et al. Arch Dis Chilid. 1997;76: Noris et al. JASN. 2005;16: Al-Akash et al. Pediatr Nephrol. 2011;26: Sellier-Leclerc AL. JASN. 2007;18: Caprioli et al Blood. 2006; 108(4) Noris M et al. Clin J Am Soc Nephrol. 2010;5: Dragon-Durey et al. J Am Soc Nephrol. 2010;21: Tsai H-M. Int J Hematol. 2010;91: Bitzan M. Semin Thromb Hemost. 2010;36: Davin et al. Am J Kid Dis. 2010;55:

6 Diagnostic Testing Recommended in patients presenting with clinical features of ahus 1 Current Therapeutic Options Plasma exchange and/or plasma infusions removal/replacement of bad humors ahus: Diagnosis Does Not Require Identification of a Genetic Mutation Genetic mutation cannot be identified in 30%-50% of patients with ahus 2 Absence of identifiable genetic mutations should not rule out ahus 2 1. Kavanagh D, Goodship T. Atypical hemolytic uremic syndrome genetic basis and clinical manifestations. ASH Education Program Noris M et al. Clin J Am Soc Nephrol. 2010;5: Immunosuppressive agents +/- plasma exchange Corticosteroids, azathioprine, mycophenolate mofentil Rituximab (anti-cd20) Renal Transplantation Anti-C5 monoclonal antibody (eculizumab).but do they truly affect the underlying physiology? 1. Remuzzi G, Misiani R, Marchesi D, et al. Haemolytic-uraemic syndrome: deficiency of plasma factor(s) regulating prostacyclin activity? Lancet 1978;2: Remuzzi G, Misiani R, Marchesi D, et al. Treatment of the hemolytic uremic syndrome with plasma. Clin Nephrol 1979;12: Genetic Abnormalities and Clinical Outcomes Eculizumab Greenbaum L et al 17 pts enrolled >12 yrs despite >4 PE/PI sessions 5 pts required dialysis at baseline All pts had plt normalization at wk 26 4/5 pts became dialysis free No progression of disease to require new dialysis Licht C et al 20 pts enrolled >12 yrs 7 pts improved >1 CKD level from baseline by week 26 9 pts improved >1CKD level from baseline by week 60 No progression of disease or new dialysis requirement Noris M et al. N Engl J Med. 2009;361: Greenbaum L et al ASH abstracts # , Licht C et al ASH abstracts #3303 ahus is Not an Acute Disease ahus is Not Only a Renal Disease as it Often Results in Damage or Failure of Other Vital Organs Due to a genetic deficiency of complement regulators, ahus is a permanent, ongoing, life-long disease of systemic, complement-mediated TMA 1,3,4 Complement-mediated TMA results in organ damage: Sudden and catastrophic leads to rapid loss of vital organs and sudden death, 2 or Progressive worsening of vital organ function leads to vital organ failure and pre-mature death 1,3,4 Cardiovascular 2,3,4,6 Myocardial infarction Thromboembolism Cardiomyopathy Diffuse vasculopathy Renal 7,8,9,11,12 Elevated creatinine Edema, malignant hypertension Renal failure Dialysis, transplant Pulmonary 1 Dyspnea Pulmonary edema Pulmonary embolism Complement-Mediated Thrombotic Microangiopathy Blood 11 Hemolysis Decreased platelets Fatigue Transfusions CNS 1,2,3,4,5 Confusion Seizures Stroke Encephalopathy Gastrointestinal 2,3,5,10,11,12 Liver necrosis Pancreatitis Colitis, Diarrhea Nausea/vomiting Abdominal pain Impaired Quality of Life 1 Fatigue Pain/Anxiety Reduced mobility 1. Noris M et al. N Engl J Med. 2009;361: Sallee M et al. Nephrol Dial Transplant. 2010;25: Caprioli et al. Blood. 2006;108: Noris M et al. CJASN. 2010;10: George et al. Blood. 2010;116: Hosler et al. Arch Pathol Lab Med. 2003;127: Noris et al. CJASN. 2010;10: Neuhaus et al. Arch Dis Chilid. 1997;76: Vesely et al Blood. 2003;102: Sallee et al. Nephron Dial Trans. 2010; 25: Kose et al. Semin Thromb Hemost. 2010;36: Davin et al. Am J Kid Dis. 2010;55: Caprioli et al. Blood. 2006;108: Dragon-Durey et al. J Am Soc Nephrol. 2010;21: Loirat et al. Pediatr Nephrol. 2008;23: Stahl et al. Blood. 2008;111:

7 ahus : Advancing the Understanding of Disease Eculizumab ahus affects all ages and is not only a pediatric disease ahus is a not an acute but chronic, genetic & life-long disease Diagnosis does NOT require identifiable genetic mutation ahus is not only a renal disease but affects all organs Plasma exchange/infusion has not been proven in well-controlled trials to be safe or effective Leaves >50% of patients with death, dialysis or permanent renal damage within 1 year of diagnosis Anti-C5 monoclonal antibody binds to the complement protein C5 inhibiting its cleavage to C5a and C5b preventing the formation of the membrane attack complex (MAC), C5b-9 Biologic immunosuppressant Patients must receive meningococcal vaccine 2 weeks prior to infusion Requires infusions every 1-2 weeks Typically in ahus lifelong therapy may be indicated. PNH patients may consider tailored therapy based on symptoms and evidence of clonal population Eculizumab is expensive ( $ /year in the United States) Investigational uses in cold agglutinin disease 1 and antibody mediated kidney transplant rejection 2,3 1. Roth A, Huttmann A, Rother RP, Duhrsen U, Philipp T (2009). "Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease". Blood 113 (16): Biglarnia AR, Nilsson B, Nilsson T, von Zur-Mühlen B, Wagner M, Berne C, Wanders A, Magnusson A, Tufveson G. Prompt reversal of a severe complement activation by eculizumab in a patient undergoing intentional ABO-incompatible pancreas and kidney transplantation. Transpl Int Aug;24(8):e Study Shows New Approach to Prevent Antibody-Mediated Damage in Kidney Transplants, Mayo Clinic, June 02,