Understanding and Managing Long- Term and Late Issues in PNH. Outline

Transcription

1 Understanding and Managing Long- Term and Late Issues in PNH AA & MDS International Foundation Regional Patient and Family Conference Cleveland, Ohio Ramon V. Tiu, MD Cleveland Clinic Taussig Cancer Institute Dept. of Translational Hematology and Oncology Research Minneapolis, Minnesota September 24, Outline Overview on long term outcomes Problems that can develop in patients with PNH Blood clots or, Kidney Damage, Hemolysisassociated pulmonary HTN, Pain symptoms/ fatigue Development of AA or MDS Potential complications of Therapy Eculizumab, ATG-CsA, BMT Special Situations Pregnancy Surgery Updates from 52nd American Society of Hematology Meeting 2 1

2 Patients Surviving (%) Paroxysmal Nocturnal Hemoglobinuria: Estimated 4,000 6,000 patients in U.S Actuarial Survival From the Time of Diagnosis in 80 Patients With PNH 2 5 year mortality: 35% 2 Diagnosed at all Ages Median age early 30 s 3,4 Quality of life diminished 5 Progressive disease Years After Diagnosis Age- and Gender- Matched Controls Patients with PNH The expected survival of an age- and sex-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: 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: Paroxysmal Nocturnal Hemoglobinuria 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. International PNH Interest Group. Blood. 2005;106:

3 Consequences of Chronic Hemolysis and Free Hemoglobin Normal red blood cells are protected from complement attack by a shield of terminal complement inhibitors Without this protective complement inhibitor shield, PNH red blood cells are destroyed Renal Failure Pulmonary Hypertension Significant Impact on Survival Complement Activation Abdominal Pain Dyspnea Dysphagia Intact RBC Free Hgb/Anemia Fatigue Hemoglobinuria Significant Impact on Morbidity NO Erectile Dysfunction 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: Lee JW et al. Hematologica 2010;95 (s2):abstract #505 and Hill A et al. Br J Haematol. 2010; May;149(3): Hillmen P et al. Am. J. Hematol. 2010;85: in PNH A common complication in patients with PNH Can occur in common and not so common locations Patients with PNH are at risk for thrombosis 6 3

4 % TE TE Can Occur Regardless of Clone Size (n=43) PNH Granulocyte Clone Size (%) South Korean National Registry. Lee JW et al. Hematologica. 2010;95(s2):Abstract # in PNH DVT and Pulmonary embolism most common types of blot clots in PNH But can occur anywhere in PNH 1. Medscape reference website: 2. Mynyp.org website: 8 4

5 Common Sites of Occur Frequently in PNH TE Type Hillmen P et al (N=80) Hillmen P et al (N=195) DVT or PE 33% 40% CVA/MI 16% 15% Typical VTE most common VTE in PNH Atypical VTE more common in PNH than in the general population 3 Higher proportion of PE and/or DVT sites of thrombosis consistently found in PNH patients Socie et al (29%) 4 and Nishimura and Rosse (27%) 5 1. Hillmen P et al. N Engl J Med. 1995;333: Hillmen P et al. Blood. 2007; 100: Fowkes FJI et al. Eur J Vasc Endovasc Surg. 2003;25: Socie G et al. Lancet. 1996;348: Nishimura J et al. Medicine. 2004;83(3): in PNH Symptoms associated with blood clots (depends on the location) Limbs Lungs Deep Vein Swelling of the leg most of the time just one leg or one limb Pain in one leg or one limb Painful swelling of one leg or one limb Pulmonary embolism sudden onset of difficulty breathing chest pain coughing up blood pain when taking a deep breath 10 5

6 in PNH Symptoms associated with blood clots (depends on the location) Cerebral Vein difficulty speaking difficulty in moving your limbs weakness on one side of the body blurring of vision Abdominal venous thrombosis sudden onset of abdominal pain abdominal bloating rapid weight gain an enlarged spleen can indicate portal vein thrombosis headaches 11 / Blood Clots in PNH: 40% of patients experience clinical thrombotic events 1 Leading cause of death 2 Accounts for 40-67% of deaths 1 First thrombotic event can be fatal 1,3 Median time to TE was years from diagnosis 4 First TE increases risk for death 5- to 10-fold 1 1. Hillmen et al. Blood. 2007;110: International PNH Group et al. Blood. 2005;106(12): Audebert HJ et al. J Neurol. 2005;252: De Latour. Blood. 2008;112:

7 How to manage blood clots in PNH (Treatment): If a blood clot were to occur, it is treated in the same way as one will be treated if the blood clot occurred from another cause blood thinners. Blood thinners usually used to treat blood clots Heparin Unfractionated heparin Low molecular weight heparin: Enoxaparin (commonly called Lovenox) Fondaparinux (Arixtra) Warfarin (commonly called coumadin) Many others: Dabigatran 1. Brodsky R. Blood. 2009;113(26): Elevated Thrombotic Rate in Anticoagulation-Treated Patients (n=91) Hillmen et al. Blood. 2007;110:

8 How to manage blood clots in PNH (Prevention): For patients not on eculizumab for their PNH, eculizumab may help prevent future blood clots from happening. Remember that blood clots still occur even in patients on long term anticoagulation. However there are several controversial issues: Patient not on eculizumab role for long term anticoagulation (no clear consensus) Patients on eculizumab and had prior blood clots role for long term anticoagulation (no clear consensus) 1. Brodsky R. Blood. 2009;113(26): How to manage blood clots in PNH (Important Reminder): Although, beneficial in certain specific circumstances, the use of blood thinners whether for treatment or prevention of blood clots in PNH and any other diseases carry many potential short term and long term risks. It is therefore important that treatment is individualized according to the patient s clinical scenario after careful discussion and consideration of the risks and benefits with a specially trained medical professional in this disorder. 16 8

9 in PNH Conclusions 40-67% mortality in PNH results from thrombosis 1 is the leading cause of death in PNH 2 First TE increases risk for death 5- to 10-fold 1 DVT or PE most common clinical presentation 1 Arterial thromboses are also common 3 39% of TE events occur at arterial sites Anticoagulant therapy may not be adequate to control thrombosis in PNH 1 Anticoagulant therapy also associated with higher risk of fatal hemorrhage in PNH 4 1. Hillmen P et al. Blood. 2007;110:12: International PNH Group et al. Blood. 2005;106(12): Lee JW et al. Hematologica 2010;95(s2):Abstract # Hall C et al. Blood. 2003;102: Kidney Problems in PNH Chronic hemolysis and cell-free plasma hemoglobin lead to chronic kidney disease in PNH 1-4 Repetitive exposure of tissue to cell-free hemoglobin may lead to kidney damage in PNH 3,4 80% of PNH patients (median age of 31.5 years) had MRI evidence of significant deposition of iron material called hemosiderin renal hemosiderosis 1,5 Marked hemosiderin deposits in the proximal renal tubule are a common feature in all autopsy and biopsy reports dealing with PNH Demonstrable by MRI even when no overt hemoglobinuria is seen Autopsy and biopsy often show interstitial nephritis and fibrosis 3,4 1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005: Rother R et al. JAMA. 2005;293: Clark DA et al. Blood. 1981;Jan;57(1): Hillmen P et al. Am. J. Hematol. 2010; 85: Hill A et al. Blood. 2006;108:Abstract

10 What is? A slow progressive decline in kidney function Kidney function is best measured by a mathematical formula called glomerular filtration rate (GFR). The mathematical formula is based on the patient s age, sex, race, and serum creatinine There are different stages of chronic kidney disease defined based on GFR 1. Brodsky R. Hematology: Basic Principles and Practice. Churchill Livingstone; 2005: Rother R et al. JAMA. 2005;293: Clark DA et al. Blood. 1981;Jan;57(1): Hillmen P et al. Am. J. Hematol. 2010; 85: Hill A et al. Blood. 2006;108:Abstract Stage 5 Stages of GFR <15 ml/min/1.73 m 2 Stage 4 GFR ml/min/1.73 m 2 Stage 3 GFR ml/min/1.73 m 2 Stage 2 End stage chronic kidney disease Chronic chronic kidney disease Moderate chronic kidney disease Mild Chronic kidney disease GFR ml/min/1.73 m 2 and evidence of kidney damage, which may include spot urinalysis with proteinuria or by abnormal imaging findings Stage 1 Normal Kidney function but with urine findings or structural abnormalities GFR >90 ml/min/1.73 m 2 and evidence of kidney damage, which may include spot urinalysis with proteinuria or by abnormal imaging findings 20 10

11 Kidney Disease Conclusions Kidney disease in PNH is caused by hemolysis 2 Kidney disease is underappreciated in PNH 3 1. Nishimura JI et al. Medicine. 2004;83: Clark DA et al. Blood. 1981;Jan;57(1): Hillmen P et al. Am. J. Hematol. 2010; 85: Stevens LA et al. N Engl J Med. 2006;354: Hemolysis Causes Fatigue Independent of Anemia Rosse (Hoffman-Hematology) 1 Many patients note a feeling of fatigue that may be disabling during periods of hemoglobinuria. This is not related to hemoglobin level (anemia), as it disappears when the hemoglobinuria stops. Brodsky (Hoffman-Hematology) 2 PNH patients frequently complain of disabling fatigue that is often out of proportion to the degree of anemia. Multivariate analysis indicates hemolysis drives fatigue in PNH not anemia 3 1. Rosse W. Paroxysmal nocturnal hemoglobinuria In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology: Basic Principles and Practice. 3rd ed. New York: Churchill-Livingstone; 2000: Brodsky RA. Paroxysmal nocturnal hemoglobinuria. In: R Hoffman; EJ Benz; SJ Shattil et al., eds. Hematology. Basic Principles and Practice. 4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005: Hill A et al. Haematologica. 2008;93(s1):359. Abstract 0903 and Presentation at: European Hematology Association 15 th Annual Meeting; June 15 th, 2008; Copenhagen, Denmark

12 Impact of PNH on Quality of Life ~75% of Patients Reported Symptoms as Moderate to Very Severe 59% patients were transfusion-free for at least 12 mo or had never been transfused 76% were forced to modify their daily activities to manage their PNH 17% were unemployed due to PNH *Moderate to severe; N=29. Meyers G et al. Blood. 2007;110 (11): Abstract Pain is a Common Symptom in PNH Patients Pain, No treatment Medical Intervention Pain, Treatment Opioids Other No pain NSAID (n=286) Almost 3 out of 5 (58%) patients reported significant pain 47% of patients with pain required medical intervention South Korean National Registry. Lee JW et al. Hematologica. 2010;95(s2):Abstract #

13 Fatigue and Quality of Life Conclusions Common symptoms in PNH are predictive of TE 96% of patients report fatigue 1 Fatigue/QoL independent of anemia/transfusion requirements 76% of patients with PNH have disruptions in daily activities 1 17% of patients were unemployed due to PNH Abdominal pain, dyspnea, chest pain and hemoglobinuria are linked by underlying hemolysis and the threat of thrombosis 2 66% of patients report shortness of breath 57% of patients report abdominal pain PNH symptoms are independent of clone size 3 1. Meyers G et al. Blood. 2007;110(11):Abstract Lee JW et al. Hematologica. 2010;95(s2):Abstract # Urbano-Ispizua A et al. Hematologica. 2010;95(s2):Abstract # Pulmonary Arterial Hypertension and difficulty of breathing (Dyspnea) in PNH 26 13

14 What is Pulmonary Arterial Hypertension? The blood pressure in the pulmonary arteries increase above normal levels leading to persistent increase in pressure in the lung circulation. 1. Nationwide Children s hospital website 27 Evidence of Pulmonary Hypertension in PNH Study 1: 47% of patients (34/73) had elevated NT-proBNP 160 pg/ml, indicating PHT in these patients 1 Study 2: 43% of hemolytic PNH patients (12/28) had mild to moderate PHT and 7% (2/28) had severe PHT, measured by doppler echocardiography 2 Study 3: 80% of PNH patients with elevated BNP levels had reduced right ventricular ejection fraction (RVEF) 3 1. Hill A et al. Blood. 2008;112(11):Abstract Hill et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract Hill et al. Blood. 2006;108(11):Abstract

15 Odds Ratio Is difficulty breathing in PNH Linked to Pulmonary Hypertension? 66% of PNH patients report dyspnea 1 Hemolysis results in cell-free hemoglobin and NO consumption leading to pulmonary hypertension 2, Chest Pain Dyspnea Dyspnea and chest pain are significant predictors of TE (P=0.009, 0.002, respectively) Symptoms Predictive of TE in PNH Patients South Korean National Registry. 1. Meyers G et al. Blood. 2007;110(11):Abstract Rother R. et al. JAMA. 2005; 293: Hill A et al. Br J Haematol. 2010; May;149(3): Abstract #1022; 4. Lee JW et al. Hematologica. 2010;95(s2):Abstract # Difficulty breathing in PNH May be Linked to Pulmonary Hypertension Hemolysis results in cell-free hemoglobin and NO consumption leading to pulmonary hypertension 1,2 47% of PNH patients have pulmonary hypertension 3 PNH patients with pulmonary hypertension have cardiac dysfunction 3 66% of PNH patients report difficulty breathing 4 Improvement in dyspnea is associated with A reduction in LDH and NO consumption 2 No change in hemoglobin 2 A reduction in NT-proBNP 2 1. Rother R et al. JAMA. 2005;293: Hill A et al. Br J Haematol. 2010; May;149(3): Hill A et al. Br J Haematol. 2006;133 (suppl 1):119:Abstract Meyers G et al. Blood. 2007;110(11):Abstract:

16 Management of pulmonary hypertension in the setting of PNH A study shows that treatment with eculizumab may help alleviate symptoms like difficulty breathing associated with pulmonary hypertension and results in improvement of objective laboratory parameters associated with pulmonary HTN like NT-proBNP 1. Hill A et al. Br J Haematol. 2010; May;149(3): Presence of AA and development of MDS 32 16

17 PNH Aplastic anemia and MDS/leukemia A fairly sizable proportion of patients with aplastic anemia may later develop PNH (20-40%). Patients with PNH may often have bone marrow failure and some will develop aplastic anemia. Patients with PNH may develop myelodysplastic syndrome and or acute myelogenous leukemia (<5%). Patients with MDS may have a small PNH clone present and these patients may respond better to immunosuppressive therapy with ATG and/or cyclosporine. 33 Potential complications related to PNH Therapy 34 17

18 Warning WARNING: SERIOUS MENINGOCOCCAL INFECTION SOLIRIS increases the risk of meningococcal infections. Meningococcal infection may become rapidly lifethreatening or fatal if not recognized and treated early. Vaccinate patients with a meningococcal vaccine at least 2 weeks prior to receiving the first dose of SOLIRIS Revaccinate according to current medical guidelines for vaccine use Monitor patients for early signs of meningococcal infections, evaluate immediately if infection is suspected, and treat with antibiotics if necessary SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Safety: Warnings and Precautions SOLIRIS therapy increases the risk of meningococcal infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early All patients must be vaccinated against Neisseria meningitidis 2 weeks prior to receiving SOLIRIS Use caution when administering SOLIRIS to patients with any systemic infection Other infections: SOLIRIS blocks terminal complement; therefore patients may have increased susceptibility to infections, especially with encapsulated bacteria Use caution when administering SOLIRIS to patients with any systemic infection SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals;

19 Safety: Warnings and Precautions (cont.) The effect of withdrawal of anticoagulant therapy during SOLIRIS treatment has not been established. Therefore, treatment with SOLIRIS should not alter anticoagulant management Patients who discontinue SOLIRIS must be monitored closely for signs of serious hemolysis If serious hemolysis occurs after SOLIRIS discontinuation, consider the following procedures/treatments: blood transfusion (packed RBCs), or exchange transfusion if the PNH RBCs are >50% of the total RBCs by flow cytometry; anticoagulation; corticosteroids; or reinstitution of SOLIRIS In clinical trials, 16 of 196 PNH patients discontinued SOLIRIS treatment; no serious hemolysis was observed SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Safety: Warnings and Precautions (cont.) LDH levels may be used to monitor hemolysis SOLIRIS dose adjustment to every 12 days may be necessary for some patients to maintain LDH reduction Infusion reactions may occur In clinical trials, no patients experienced infusion reactions that required discontinuation SOLIRIS treatment should be interrupted in all patients experiencing severe infusion reactions and appropriate medical therapy administered SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals;

20 Adverse Reactions Reported in 5% of SOLIRIS Treated Patients in TRIUMPH Patients, n (%) Reaction SOLIRIS (n=43) Placebo (n=44) Headache 19 (44) 12 (27) Nasopharyngitis 10 (23) 8 (18) Back pain 8 (19) 4 (9) Nausea 7 (16) 5 (11) Fatigue 5 (12) 1 (2) Cough 5 (12) 4 (9) Herpes simplex virus infections 3 (7) 0 Sinusitis 3 (7) 0 Respiratory tract infection 3 (7) 1 (2) Constipation 3 (7) 2 (5) Myalgia 3 (7) 1 (2) Pain in extremity 3 (7) 1 (2) Influenza-like illness 2 (5) 1 (2) SOLIRIS (eculizumab) [package insert]. Alexion Pharmaceuticals; Other Complications of PNH Therapy ATG/Cyclosporine Hospitalization Anaphylactic reactions Serum sickness Immunosuppression / Infection Bone marrow transplantation Allogeneic bone marrow transplant Prolonged hospitalization Up to 44% mortality at 2 yrs with HLA-matched sibling donor Acute GVHD in 34%; chronic GVHD in 33% GVHD-free survival in 14% of patients 40 20

21 PNH and Pregnancy PNH is a known hypercoagulable state Pregnancy is a hypercoagulable state High estrogen levels Compression of abdominal and pelvic veins by the enlarging uterus 41 PNH and Pregnancy 23 women: 19 with PNH, 4 with AA/PNH 38 pregnancies 11 miscarriages Pregnancy: 6 hemolysis, 6 hemorrhage Labor: 5 hemolysis, 3 hemorrhage 1 thrombosis, 1 sepsis No maternal deaths Uncomplicated in one-third of pregnancies De Gramond et al., Lancet 1987;1:

22 Women with PNH, Effects on Pregnancy : 5 women 2 with previous clots (Budd-Chiari syndrome, pulmonary embolus) 1 during pregnancy (phlebitis) 2 post-partum (hepatic, intracranial) Hemolysis: 24 pregnancies (73%) 20 required PRBC transfusions Thrombocytopenia: 9 cases Obstetrical complications: 4 women Hypertension, pre-eclampsia, eclampsia Ray et al., Haemostasis 2000;30: Women with PNH: Effects on Infants Perinatal outcomes of 33 pregnancies 45% of the babies were pre-term Average birthweight 2800g Three infant deaths Two had hemolytic disease of the newborn, not related to PNH No infant thrombosis Ray et al., Haemostasis 2000;30:

23 PNH and Pregnancy Summary Pregnancy is possible for women with PNH, with or without aplastic anemia, but is potentially hazardous for mother and infant. Pregnancy leads to complications in up to 50% of women: worse cytopenia, transfusion dependency, thrombosis, and the need for anticoagulation or immunosuppressants Pregnancy for women with PNH is risky, and should be planned carefully with an experienced hematologist and high-risk OB. There is emerging data on the use of Eculizumab in pregnancy. 45 Surgical Considerations in a patient with PNH Use of blood thinners for a short period of time after completing surgeries that puts patients at high risk for blood clots (e.g. hip surgeries, knee surgeries). Certain patients with PNH accompanied by aplastic anemia may have lower ability to compensate for blood loss that occurs as part of the surgery and therefore close monitoring of counts and administration of appropriate transfusions may be necessary In a case of a patient who is undergoing cardiac surgery where extracorporeal machine is used. G-CSF administration and red blood pack transfusions, perioperative platelet substitution, fluid management, and antibiotic prophylaxis were utilized successfully. 1. Knobloch K et al. Interactive Cardiovascular and Thoracic Surgery. 2003; 2(4):

24 Updates from 52 nd Annual ASH meeting Evaluation of Paroxysmal Nocturnal Hemoglobinuria Disease Burden: The Patient's Perspective. A Report From the International PNH Registry Mean EORTC Scores PNH Patients Gen Population Global Health Physical Functioning Role Functioning Emotional Functioning PNH Scores were decreased by 10% in 4 of the 6 subscales Cognitive Functioning Social Functioning International PNH Registry Muus P. et al.52 nd Annual American Society of Hematology Meeting Abstract # Updates from 52 nd Annual ASH meeting Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry PNH Patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall However AA patients with <50% PNH clones are almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08) the proportion of patients receiving transfusions, in the prior year increased as clone size increased (p<.01). PNH clone size 29% <10% 31% 10% 69% 49% % requiring transfusions International PNH Registry Schrezenmeier H. et al.52 nd Annual American Society of Hematology Meeting Abstract #

25 Conclusions PNH patients are at risk for thrombosis Eculizumab can decrease thrombotic events. Blood thinners are use to treat blood clots and can be used to prevent blood clots in certain circumstances Other potential long term problems in PNH includes kidney damage, hemolysis-associated pulmonary HTN, pain symptoms, fatigue, development of AA or MDS It is important to discuss with your PNH specialist any plans for pregnancy and surgery. The treatment for PNH has improved significantly over the years and this has lead to better outcomes and quality of life. 49 Acknowledgements Jaroslaw P. Maciejewski, MD, PhD Manuel Afable II, MD Maciejewski Laboratory (Hadrian Szpurka, PhD, Anna Jankowska, PhD, Christine O Keefe, PhD, Hideki Makishima, MD, PhD, Andres Jerez, MD Michael Clemente, MS,) Tiu Laboratory (Fabiola Traina, MD,PhD; Valeria Visconte, PhD, Manoj Bupathi, MD) Antonio M. Risitano, MD, PhD Carlos de Castro, MD Thank you to all our patients who always serve as our inspiration in our clinic and research 50 25

26 CCF Bone Marrow Failure Program (for PNH, LGL leukemia and Aplastic Anemia) PNH Ramon V. Tiu, MD Jaroslaw P. Maciejewski, MD, PhD Large Granular Lymphocytic Leukemia and Aplastic Anemia Ramon V. Tiu, MD Jaroslaw P. Maciejewski, MD, PhD PHONE NO: PHONE NO: