TMA in HUS and TTP: new insights

Transcription

1 TMA in HUS and TTP: new insights Daan Dierickx University Hospitals Leuven, Department of Hematology, Belgium 20th Annual Meeting Belgian Society on Thrombosis and Haemostatis Antwerpen, 22 th November 2012

2 TMA in HUS and TTP: new insights

3 TMA: terminology Neurological deficits Renal failure Thrombotic Thrombocytopenic Hemolytic Uremic Purpura (TTP) Syndrome (HUS) TTP/HUS Thrombotic Microangiopathy (TMA) è No uniform definition

4 ADAMTS13-deficiency thrombotic thrombocytopenic purpura (TTP) Acquired (auto-anti-adamts13 antibodies) Congenital (mutations in ADAMTS13 gene) Hemolytic uremic syndrome (HUS) Typical HUS (Shiga toxin producing Escherichia coli) Atypical HUS Congenital (mutations in complement regulatory proteins, thrombomodulin) Acquired (auto-anti-complement regulatory proteins antibodies) Secondary thrombotic micro-angiopathy (TMA): associated with Solid organ transplantation Hematopoietic stem cell transplantation Pregnancy Medication (clopidogrel, ticlodipin, quinine, mitomycin C, gemcitabin, calcineurin inhibitors, proliferation signaling inhibitors, ) Auto-immune disorders (antiphopsholipid syndrome, systemic lupus erythematosus, )

5 ADAMTS13-deficiency thrombotic thrombocytopenic purpura (TTP) Acquired (auto-anti-adamts13 antibodies) Congenital (mutations in ADAMTS13 gene) Hemolytic uremic syndrome (HUS) Typical HUS (Shiga toxin producing Escherichia coli) Atypical HUS Congenital (mutations in complement regulatory proteins, thrombomodulin) Acquired (auto-anti-complement regulatory proteins antibodies) Secondary thrombotic micro-angiopathy (TMA): associated with Solid organ transplantation Hematopoietic stem cell transplantation Pregnancy Medication (clopidogrel, ticlodipin, quinine, mitomycin C, gemcitabin, calcineurin inhibitors, proliferation signaling inhibitors, ) Auto-immune disorders (antiphopsholipid syndrome, systemic lupus erythematosus, )

6 Mannucci PM. Pathophysiol Haemost Thromb 2006;35:89-97

7 Mannucci PM. Pathophysiol Haemost Thromb 2006;35:89-97

8 Mannucci PM. Pathophysiol Haemost Thromb 2006;35:89-97

9 TTP: symptoms Pentade: Coombs negative hemolytic anemia Presence of schistocytes Elevated indirect bilirubin Elevated LDH (hemolysis + tissue damage) Trombocytopenia In acute fase very low (<20000/µL) Often bleeding tendency CNS abnormalities Most frequently: coma, convulsions and focal deficits Often in advanced and non-diagnosed cases Renal abnormalities Elevated serum creatinin, microscopic hematuria, proteinuria Fever Thrombocytopenic Purpura Thrombotic Thrombotic Recently: often cardiac and pancreatic involvement

10 TTP: ADAMTS13 Zheng XL. Blood 2010;115: Kreminger Hovinga, et al. Blood 2010;115:

11 TTP: treatment High mortality (>90%) without treatment Daily TPE: reduction mortality to <20% Plasma infusion: less effective but value in initial phase if TPE not immediately available Substitution fluid: FFP Plasmapheresis component: removal of auto-antibodies against ADAMTS13 Infusion of plasma: contains non-inhibited ADAMTS13 If severe ADAMTS13 deficiency: better and faster response to TPE compared to normal levels 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Rock GA, et al. N Engl J Med 1991;325:393-7

12 TTP: problems Clinical Still 10-20% mortailty: need for new treatments ADAMTS13 deficiency TTP Rare disorder (trials) Pathophysiological No good animal model Importance of vwf-platelet interaction > 20% of TTP: normal ADAMTS13

13 TTP: problems Mice: no clear model è problems ADAMTS13 KO mice: no spontaneous development of TTP! Exogenous triggers necessary, but only in subset of animals (high plasma levels of vwf) Adamts13 +/+ Adamts13 -/- Red blood cell count, /L 8.19 ± ± 0.25 Hemoglobin level, g/l 129 ± ± 4 Hematocrit concentration.426 ± ±.008 Platelet count, 10 9 /L 512 ± ± 62 Banno F, et al. Blood 2006;107: Motto DG, et al. J Clin Invest 2005;115:

14 TTP: problems Baboon model Feys HB, et al. Blood 2010;116:

15 How to improve outcome of patients with TTP? Blocking vwf-platelet binding Anti-CD20 therapy

16 Blocking vwf-platelet binding De Meyer SF, et al. Stroke 2012;43:

17 Blocking vwf-platelet binding GBR 600 ALX-0681 ARC1779 ALX-0081 (TITAN studie)

18 GBR 600 / ALX-0681 No severe bleeding Feys HB, et al. Blood 2012;120: Callewaert F et al. Blood 2012;120: Salles II & Crawley JT. Blood 2012;120:3390-2

19 ARC 1799 No severe bleeding Cataland et al. Am J Hematol 2012;87:430-2

20 TITAN trial Josefin-Beate Holz The TITAN trial? Assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura Transfusion and Apheresis Science Volume 46, Issue

21 TITAN trial 48 sites 40 patients Josefin-Beate Holz The TITAN trial? Assessing the efficacy and safety of an anti-von Willebrand factor Nanobody in patients with acquired thrombotic thrombocytopenic purpura Transfusion and Apheresis Science Volume 46, Issue

22 How to improve outcome of patients with TTP? Blocking vwf-platelet binding Anti-CD20 therapy

23 Rituximab 2. ADCC ROS, IL-6, TNF, Cytolysis & Cell death B B 1. CDC Proteolytic cascade c1q MAC B NK IL- 6, TNF- y Rituximab CD 20 M Th2 Cytolysis Internalization B B Th2 B 3. Direct apoptosis Th 2 Th 1 Th 1 Th 2 Th 2 Th 1 Rituximab Y 4. Increase Th2 cells, restorement of Th1/Th2 balance Caspase- dependent pathway (Src Tyr kinase, Fas, inhibition p38, MAPK, ) & Caspase-independent pathway B 5. Enhancement of peripheral tolerance: Increase of CD4+CD25+Foxp3 regulatory T cells CD4+CD25+ Foxp3 Treg Dierickx D, Beke E, et al. Med Clin North Am 2012;96:

24 Rituximab Literature: > 150 cases; mostly because of refractory/relapsed disease è remission rates > 85% N=25: 100% complete remission, occuring within 11 days following rituximab administration UK TTP Registry: significant increase of rituximab use Scully M, et al, Br J Haematol 2007;136: Scully M, et al. Br J Haematol 2008;142:819-26

25 Rituximab Long term follow-up data (n=12): 100% initial response After mean follow-up of 49.6 months: 3 patients relapsed. Also used prophylactically in patients with relapsing TTP Use of TPE + rituximab upfront?. Chemnitz JM, et al. Ann Hematol 2010;89:

26 Rituximab STAR trial: TPE + Steroids +/- rituximab è terminated due to a low enrollment rate French Thrombotic Microangiopathies Reference Center Open label, prospective study N=22 Froissart A, et al. Crit Care Med 2012;40:104-11

27 Rituximab United Kingdom Multicentric non-randomised Phase II trial N=40 Scully M, et al. Blood 2011;118:

28 Rituximab Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies Recommendations: 1/ In acute idiopathic TTP with neurological/cardiac pathology, which are associated with a high mortality, rituximab should be considered on admission, in conjunction with PEX and steroids (1B).. 2 / Patients with refractory or relapsing immune-mediated TTP should be offered rituximab (1B). Scully M, et al. Br J Haematol 2012;158:323-35

29 ADAMTS13-deficiency thrombotic thrombocytopenic purpura (TTP) Acquired (auto-anti-adamts13 antibodies) Congenital (mutations in ADAMTS13 gene) Hemolytic uremic syndrome (HUS) Typical HUS (Shiga toxin producing Escherichia coli) Atypical HUS Congenital (mutations in complement regulatory proteins, thrombomodulin) Acquired (auto-anti-complement regulatory proteins antibodies) Secondary thrombotic micro-angiopathy (TMA): associated with Solid organ transplantation Hematopoietic stem cell transplantation Pregnancy Medication (clopidogrel, ticlodipin, quinine, mitomycin C, gemcitabin, calcineurin inhibitors, proliferation signaling inhibitors, ) Auto-immune disorders (antiphopsholipid syndrome, systemic lupus erythematosus, )

30 Atypical HUS Factor mutated Frequency Complement factor H (CFH) 20-30% Membrane cofactor protein (MCP = CD46) 5-15% Complement factor I (CFI) 4-10% Thrombomodulin (THBD) 3-5% C3 2-10% Complement factor B (CFB) 1-4% Auto-antibodies Frequency Anti-CFH 6% Loirat C, Frémeaux-Bacchi V. Orphanet J Rare Dis 2011;6:60

31 Atypical HUS Noris M, et al. Clin J Am Soc Nephrol 2010;5:

32 Atypical HUS Noris M, et al. Am J Transpl 2010;10:

33 Atypical HUS ECULIZUMAB Kavanagh D & Goodship T. Pediatr Nephrol 2010;25:

34 Case reports Eculizumab in ahus International Multicentric Prospective Phase II trials Adolescents and adults Native kidneys or posttransplant recurrence Resistant to plasmatherapy or switch from chronic plasmatherapy to eculizumab Loirat C, et al. Presse Med 2012;41:e115-35

35 Eculizumab in ahus International Multicentric Prospective Phase II trials Eculizumab able to stop the TMA process Response similar in patients with or without detectable complement mutations 2 year efficacy and safety New trials initiated in both adults and children Legendre C, et al. ASN 2012 Light C, et al. ASN 2012

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38 Eculizumab Approved Dosing Schedule in ahus For patients 18 years of age, eculizumab therapy consists of: Induction 900 mg weekly x 4 doses Maintenance 1200 mg at week 5; then 1200 mg every 2 weeks For patients <18 years of age, administer eculizumab based upon body weight, according to the following schedule: Patient Body Weight Induction Maintenance kg and over 900 mg weekly x 4 doses 30 kg to less than 40 kg 600 mg weekly x 2 doses 20 kg to less than 30 kg 600 mg weekly x 2 doses 10 kg less than 20 kg 600 mg weekly x 1 dose 5 kg to less than 10 kg 300 mg weekly x 1 dose 1200 mg at week 5; then 1200 mg every 2 weeks 900 mg at week 3; then 900 mg every 2 weeks 600 mg at week 3; then 600 mg every 2 weeks 300 mg at week 2; then 300 mg every 2 weeks 300 mg at week 2; then 300 mg every 3 weeks

39 New complement inhibitors: TT30 C3/C5 convertase inhibitor Fridkis-Hareli M, et al. Blood 2011;118:

40 Conclusion Acquired TTP Blocking vwf-bp Rituximab Plasma ADAMTS13 Transplantation Eculizumab Atypical HUS TMA Congentital TTP rhadamts13 Eculizumab (German outbreak E.coli 0104:H4) Complement Typical HUS