TMA CASE STUDY. Pamela Harmon, RN & Keturah Tomlin, RN Toronto General Hospital Apheresis Unit

Transcription

1 TMA CASE STUDY Pamela Harmon, RN & Keturah Tomlin, RN Toronto General Hospital Apheresis Unit

2 Cumulative fraction of patients free of events ahus is a catastrophic disease that can result in sudden & progressive vital organ failure and premature death 33 40% of patients die or progress to end-stage renal disease (ESRD) at 30 days, despite PE or PI 2, % of all patients die, require dialysis, or have permanent renal damage within 1 year after diagnosis despite plasma exchange or plasma infusion Follow-up (months) Modified from Caprioli J et al CFH mutation depicted. 1. Sallee M et al. Nephrol Dial Transplant 2010;25: ; 2. Caprioli J et al. Blood 2006;108: ; 3. Noris M et al. CJASN 2010;10: ; 4. Noris M et al. N Engl J Med 2009;361:

3 Recap of Patient s Organs affected by ahus Renal More than 50% of patients progress to ESRD 7 Elevated creatinine Proteinuria 2 Edema, 3 malignant hypertension 4 Decreased egfr 5 CNS Up to 48% of patients experience neurological symptoms 2 Confusion 6 Stroke 6 Encephalopathy 4 Seizure 2 Blood Thrombocytopenia 7 Decreased haptoglobin 7 Elevated LDH 7 Decreased hemoglobin 7 Schistocytes 7 Organs Effected in Patient Case Visual Ocular occlusion 14 Cardiovascular Up to 43% of patients experience cardiovascular symptoms 2 Myocardial infarction 8 Hypertension 9 Diffuse vasculopathy 5 Peripheral gangrene 10 Gastrointestinal Up to 30% of patients present with diarrhea 11 Colitis 6 Nausea/Vomiting 12 Pancreatitis 12 Abdominal pain 6 Gastroenteritis 2 Liver necrosis 2 Pulmonary Dyspnea 8 Pulmonary hemorrhage 13 Pulmonary edema 8 egfr = estimated glomerular filtration rate; LDH = Lactate dehydrogenase. 1. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol 2009;24: ; 2. Neuhaus TJ et al. Arch Dis Child 1997;76: Ståhl A-L et al. Blood 2008;111: Noris M et al. Clin J Am Soc Nephrol 2010;5: ; 5. Loirat C et al. Pediatr Nephrol 2008;23: ; 6. Ohanian M et al. Clin Pharmacol 2011;3:5 12 ; 7. Caprioli J et al. Blood 2006;108: ; 8. Sallée M et al. Nephrol Dial Transplant 2010;25: ; 9.Kavanagh D et al. Med Bull 2006;77 78:5 22; 10. Malina M et al. Pediatr Nephrol 2011;26:1678; 11. Zuber J et al. Nat Rev Nephrol 2011;7:23 35; 12. Dragon-Durey M-A et al. J Am Soc Nephrol 2010;21: ; 13.Sellier-Leclerc A-L al; French Society of Pediatric Nephrology. J Am Soc Nephrol 2007;18: ; 14. Larakeb A et al. Pediatr Nephrol 2007;22:

4 ahus Genetic mutations cannot be identified in 30%-50% of patients with ahus.2 No requirement for identification of a complement mutation in the diagnosis of ahus. Patients with more than one mutation has been detected in 4% of families.1 1. Fremeaux-Bacchi et al, CJASN, Noris M et al. Clin J Am Soc Nephrol, 2010;5:

5 Proximal Terminal In ahus, Chronic Dysregulation of the Alternative Pathway of the Complement System Leads Systemic End Organ Damage Lectin pathway Classical pathway Alternative pathway C3 Ba + Gain of Function Mutations: C3, CFB C3b C3-Convertase - Loss of function Mutations: CFH, CFI, MCP, THBD, anti-fh antibodies C5-Convertase C5 Platelets PMP Coagulation Platelet activation C5b-9 deposition on endothelial cell Adapted from Noris et al. NEJM, 2009 C5b Subendothelial matrix Endothelial cell C5b-9 Proteinases Oxygen radicals Endothelial-cell damage and retraction Thrombus formation Endothelial injury = TMA 1. Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67-I74. 2.Figueroa JE, Densen P. Clin Microbiol Rev. 1991;4: Walport MJ. N Engl J Med. 2001;344: Rother RP et al. Nat Biotechnol. 2007;25: Meyers G et al. Blood. 2007;110:abs Hill A et al. Br J Haematol. 2010;149: Hillmen P et al. Am J Hematol. 2010;85: Parker C et al. Blood. 2005;106: Hillmen P et al. N Engl J Med. 1995;333: Nishimura J et al. Medicine. (Baltimore) 2004;83: Caprioli J et al. Blood. 2006;108: Noris M et al. Clin J Am Soc Nephrol. 2010;5: George JN. Blood. 2010;116: Loirat C et al. Pediatr Nephrol. 2008;23: Ståhl AL et al. Blood. 008;111: Hosler GA et al. Arch Pathol Lab Med. 2003;127; Ariceta G et al. Pediatr Nephrol. 2009;24:

6 TMA Case PMHx 57 yrs. female Mother to three sons active community volunteer and passionate skier Gall bladder removed 2008/2009 Routine knee surgery in 2014 Patient had pancreatitis post ERCP at the age of 19 Sister has a history of pancreatitis Middle son has shown symptoms of ahus (pancreatitis) and received a kidney transplant several years ago.

7 Clinical History July Patient was transferred from Centenary Hospital to UHN, post total right knee replacement. Dx: anemia/thrombocytopenia & jaundice Platelet Count of 82 Hgb 82 ( 8% fragmentation) LDH 2149 Haptoglobin 0.50 Renal Function Cr 402 Ferritin 2829 TBili 50, C3-1.14, C Hypertensive 148/93

8 TREATMENT PLAN July 24, 2014 Prior to PLEX blood work done to confirm: - ADAMTS-13 Activity >50% - Complement System Activity - CH50 - Genetics sent to Sick Kids Lab - Antibody testing: Anti-GBM (Anti-Glomerular Basement Membrane ), APLA (Antiphospholipid Antibodies), ANA (anti-nuclear antibodies) - Cryoglobulin: rule out infectious/autoimmune causes of TMA (HIV, Lupus, etc) Patient initiated on daily PLEX - FFP as replacement fluid 1.5 PV Daily hemodialysis started, for clearance and fluid overload. Antihypertensive medications initiated August 2 nd, 2014 Prednisone added to treatment Ongoing hemolysis despite daily apheresis

9 Clinical History Cont d Course in Hospital No significant response to daily PLEX Status of kidney function unchanged, now dialysis 3xper week. Feeding Tube inserted in response to ongoing bouts of pancreatitis Platelets increased from 85 to 175 LDH improved from 2149 U/L to 205 U/L Creatinine continued to increase despite PLEX 402 to 613

10 Clinical History Cont d Dx: Atypical Hemolytic Uremic Syndrome (ahus) Submitted request to the Exceptional Access Program (EAP) for coverage of Soliris EAP declined coverage of Soliris- 25/8/14 Genetic testing received after one month - Heterozygeous Pathogenic mutations in MCP gene - Uncertain variant in CFI gene

11 Markham woman, family struggle for lifesaving drug

12 Emotional Journey Patient: They had me hooked up to dialysis and plasma exchange, and my life was turned upside down 1 1. Toronto Star, Nov

13 Clinical History Continued October 2014 Discharged Home Patient spends 15 hours a week in hospital undergoing dialysis Frequency of PLEX continued 3 x per week Further weaned to PLEX - 2 x per week. Several recurrent hospitalizations for bouts of pancreatitis.

14 Patients Journey Ontario Agrees to Fund Life-Saving Drug for 6 months

15 Starting Soliris Received immunization (Menactra & Bexsero) prior to start of Solaris. PLEX discontinued and Soliris initiated on October 23 rd, 2014 Dose 900 mg weekly for 4 weeks, then 1200mg on 5 th week, and every other week, thereafter.

16 SOLIRIS ECULIZUMAB

17 Soliris works on the bottom half of the Complement Pathway, preventing Endothelial Injury and Organ Damage Defective regulation of the alternative pathway of complement Continuous complement activation Lectin Classical Alternative C3 C5 TMA C5b-9 Formation on endothelium Platelet activation Adapted from Noris et al Nat Rev Neph Zipfel PF et al. Vaccine 2008;26(Suppl 8):I67 74; 2. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4: ; 3. Walport MJ. N Engl J Med 2001;344: ; 4. Rother RP et al. Nat Biotechnol 2007;25: ; 5. Meyers G et al. Blood 2007;110:abs 3683; 6. Hill A et al. Br J Haematol 2010;149: ; 7. Hillmen P et al. Am J Hematol. 2010;85: ; 8. Parker C et al. Blood 2005;106: ; 9. Hillmen P et al. N Engl J Med 1995;333: ; 10. Nishimura J et al. Medicine (Baltimore) 2004;83: ; 11. Caprioli J et al. Blood 2006;108: ; 12. Noris M et al. Clin J Am Soc Nephrol 2010;5: ; 13. George JN. Blood 2010;116: ; 14. Loirat C et al. Pediatr Nephrol 2008;23: ; 15. Ståhl AL et al. Blood 2008;111: ; 16. Hosler GA et al. Arch Pathol Lab Med 2003;127; ; 17. Ariceta G et al. Pediatr Nephrol. 2009;24:

18 Some benefits of SOLIRIS occur rapidly and are sustained, while others continue to improve over time egfr estimated glomerular filtration ratio Hematologic Normalization = Platelet count >150,000, normal LDH Hematological Parameters (Platelet Count and LDH) improve quickly with Soliris, while kidney function continues to improve over time. Legendre CM et al. N Engl J Med. 2013;368: ; Greenbaum L et al. ASH 2012.

19 Renal Response is dependent on Time from Initial TMA to Soliris In the clinical studies, dialysis was discontinued in 4/5 (80%) patients in who required dialysis at the time of initiation of Soliris1 The duration of dialysis before the initiation of Soliris treatment, ranged from 6 to 26 days.1 Shorter interval between the ahus TMA and initiation of Soliris is associated with significantly greater improvement in renal function.1 Our patient was on dialysis for 3 months prior to initiation of Soliris 1. Legendre et al, NEJM 2013;368:

20 Hematological response to plasma therapy is a poor indicator of long-term outcomes Affected Protein Short-term Hematological Response to Plasma Therapy* Long-Term Outcome at 3 years Factor H 50% Death or ESRD: 77% MCP 94% Death or ESRD: 6% Factor I (CFI) 40% Death or ESRD: 60% Factor B 30% Death or ESRD: 70% C3 42% Death or ESRD: 67% THBD 54% Death or ESRD: 54% CFH autoantibodies 63% No mutation identified 63% *Includes partial and complete responses Death or ESRD: 63% Death or ESRD: 50% Noris M et al. CJASN :

21 Patient Case October 23 rd, Patient receives her first infusion of Soliris Clinical Parameters Initial TMA (July 2014) Prior to Tx with Soliris (October 2014) Post Tx with Soliris (July 2015) Hgb (g/l) Platelets SrCr LDH BP 148/93 109/71* Haptoglobin Urine Output Anuric Anuric Now producing Urine * Hypertensive medications decreasing doses

22 Patient Case As of July 2015 Nocturnal Dialysis 5 nights per week Patient is feeling more energized Patient has started producing urine BP low, medication decreased. Soliris treatment at home Q 2WEEKS Feeling well, good appetite and good energy levels No further TMA or Pancreatitis episodes I m staying positive, and hoping that this will eventually be just a distant nightmare

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