Beyond Plasma Exchange: Targeted Therapy for Thrombotic Thrombocytopenic Purpura

Transcription

1 Beyond Plasma Exchange: Targeted Therapy for Thrombotic Thrombocytopenic Purpura Kristen Knoph, PharmD, BCPS PGY2 Pharmacotherapy Resident Pharmacy Grand Rounds April 25, MFMER slide-1

2 Objectives Describe the pathophysiology of thrombotic thrombocytopenic purpura (TTP) Review the current management of TTP Analyze literature supporting new targets for the treatment of TTP 2016 MFMER slide-2

3 Thrombotic Microangiopathy Syndromes TMA Syndromes Thrombocytopenia Organ injury Microangiopathic hemolytic anemia Arteriolar and capillary thrombosis George JN et al. N Engl J Med. 2014;371(7): MFMER slide-3

4 Thrombotic Microangiopathy Syndromes Hereditary disorders ADAMTS13 deficiency-mediated TMA (TTP) (Upshaw-Schulman syndrome) Complement-mediated TMA (Atypical HUS) Metabolism-mediated TMA Coagulation-mediated TMA Acquired disorders ADAMTS13 deficiency-mediated TMA (TTP) Complement-mediated TMA (Atypical HUS) Shiga toxin-mediated TMA (Shiga toxin-hus) Drug-mediated TMA (immune reaction) Drug-mediated TMA (toxic dose-related reaction) TMA: Thrombotic microangiopathy TTP: Thrombotic thrombocytopenic purpura HUS: Hemolytic uremic syndrome George JN et al. N Engl J Med. 2014;371(7): MFMER slide-4

5 Acquired TTP Incidence is 4-11 cases per 1 million per year Increased association Female sex Black race Obesity Severe functional deficiency in ADAMTS13, VWF-cleaving serine metalloprotease Autoantibody inhibition of ADAMTS13 activity VWF: Von Willebrand factor Scully M et al. Br J Haematol. 2012;158(3): George JN. N Engl J Med. 2006;354(18): MFMER slide-5

6 Pathophysiology 2016 MFMER slide-6

7 Pathophysiology 2016 MFMER slide-7

8 Diagnosis Pentad of Clinical Features Neurologic abnormalities Renal abnormalities Fever Microangiopathic hemolytic anemia Thrombocytopenia ADAMTS13 activity < 10% Schistocytes Hemoglobin Haptoglobin LDH Platelets < 150,000/uL LDH: lactate dehydrogenase George JN. N Engl J Med. 2006;354(18): Scully M et al. Br J Haematol. 2012;158(3): MFMER slide-8

9 Question 1 Which of the following findings support the diagnosis of TPP? Schistocytes Thrombocytopenia DVT/PE A and B All of the above 2016 MFMER slide-9

10 Treatment for Acquired TTP First line: plasma exchange/steroids Refractory: rituximab Salvage: splenectomy, cyclosporine, cyclophosphamide/vincristine New agents: caplacizumab, bortezomib Veyradier A. N Engl J Med. 2016;374(6): MFMER slide-10

11 Plasma Exchange (PLEX) First line for all patients with suspected TTP Canadian Apheresis Study (1991) PLEX is superior to plasma infusion Plasma: source of replacement ADAMTS13 Exchange: removes anti-adamts13 autoantibodies Continue daily PLEX for 2 days after platelet normalization George JN et al. N Engl J Med. 2014;371(7): Veyradier A. N Engl J Med Feb 11;374(6):583-5 Rock GA et al. N Engl J Med. 1991;325(6): MFMER slide-11

12 Pharmacist Considerations with PLEX Medication removal Low volume of distribution High protein binding Schedule medications after PLEX ACE-inhibitors are contraindicated Unopposed bradykinin Ibrahim RB et al. Pharmacotherapy. 2007;27(11): Kale-Pradhan PB et al. Pharmacotherapy. 1997;17(4): MFMER slide-12

13 Steroids Immunosuppression may produce a more durable response High dose vs. standard dose steroids No difference in response at day % vs. 56.7%, p=0.17 Improved remission rates at day % vs. 46.6%, p=0.03 Initial treatment Prednisone 1 mg/kg/day Refractory, unstable, neurologic symptoms Methylprednisolone 1 g/day x 3 days Balduini CL et a. Ann Hematol. 2010;89(6):591-6 Scully M et al. Br J Haematol. 2012;158(3): Sayani FA et al. Blood. 2015; 125(25): MFMER slide-13

14 Goals of Therapy Platelet recovery > 150 x 10 9 /L Refractory if no response after 4-7 days Prevention of relapse Risk of relapse is 20-50% George JN. N Engl J Med. 2006;354(18): Willis MS et al. Semin Thromb Hemost. 2005;31(6): MFMER slide-14

15 Rituximab Monoclonal antibody targets the CD20 antigen on B lymphocytes Suppresses production of the anti- ADAMTS13 antibody Lim W et al. Blood. 2015;125(10): Coppo P et al. Hematology Am Soc Hematol Educ Program. 2015;2015: MFMER slide-15

16 Initial Treatment Refractory Episodes Relapse Prevention Trial Scully et al Froissart et al Hie et al Design Intervention Results Phase 2, nonrandomized RTX (n=40) vs. historical control (n=40) Remission rates RTX: 93% Control: 95% Relapse rates RTX: 11% Control: 55% P= Prospective, openlabel RTX (n=21) vs. historical control (n=53) Durable remission by day 35 (p< 0.02) RTX: 100% Control: 58% Relapse at 1 year No difference between groups Observational, cross-sectional RTX (n=30) vs. historical control (n=18) Longer relapse-free survival in RTX group (p=0.049) RTX: rituximab Scully M et al. Blood. 2011;118(7): Froissart A et al. Crit Care Med. 2012;40(1): Hie M et al. Blood. 2014;124(2): MFMER slide-16

17 Limitations Observational studies matched with historical controls Steroid and other salvage therapy use not controlled Shorter follow up duration in treatment groups Rituximab produces B-cell depletion for 9-18 months Lim W et al. Blood. 2015;125(10): MFMER slide-17

18 Rituximab Initial Treatment Maybe RTX may decrease time to remission and may delay relapse Refractory Episodes Yes RTX appears to be effective for patients unresponsive to PLEX/ steroids Prevention of Relapse No Benefit does not appear to outweigh risks and more evidence is needed Lim W et al. Blood. 2015;125(10): MFMER slide-18

19 Caplacizumab Anti-VWF single-variable domain immunoglobulin Targets the A1 domain of VWF Prevents interaction with platelet receptor Peyvandi F et al. N Engl J Med. 2016;374(6): MFMER slide-19

20 Caplacizumab for Acquired TTP Objective Design Intervention Results Evaluate caplacizumab for treatment of acquired TTP Phase II, randomized, controlled trial Caplacizumab 10 mg SC daily (n=36) vs. placebo (n=39) during PLEX and 30 days afterward PLUS standard of care Median time to a response Caplicizumab: 3.0 days (95% CI ) Placebo:4.9 days (95% CI ) Event rate ratio 2.20 (95% CI, , p = 0.005) Exacerbations Caplicizumab: 8% Placebo: 28% Relapses Caplicizumab: 22% Placebo: 0% Peyvandi F et al. N Engl J Med. 2016;374(6): MFMER slide-20

21 Conclusion and Role in Therapy Resulted in a more rapid resolution of TTP episodes May be effective for initial or refractory TTP Not effective for preventing relapse Not available outside of clinical trials Peyvandi F et al. N Engl J Med. 2016;374(6): MFMER slide-21

22 Bortezomib Proteasome inhibitor Apoptosis of autoreactive plasma and B cells Rituximab targets CD20+ B cells only Case reports and series (n=12) Survival and clinical remission in 11/12 cases Place in therapy Refractory TTP after lack of response to PLEX/steroids and rituximab Eskazan AE. Ann Hematol. 2016;95(11): Patriquin CJ et al. Br J Haematol. 2016;173(5): MFMER slide-22

23 Question 2 What is the recommended agent for patients with TTP who do not have a response to PLEX/steroids after 4-7 days? Caplacizumab Bortezomib Rituximab Eculizumab 2016 MFMER slide-23

24 Thrombotic Microangiopathy Syndromes Hereditary disorders ADAMTS13 deficiency-mediated TMA (TTP) (Upshaw-Schulman syndrome) Complement-mediated TMA (Atypical HUS) Metabolism-mediated TMA Coagulation-mediated TMA Acquired disorders ADAMTS13 deficiency-mediated TMA (TTP) Complement-mediated TMA (Atypical HUS) Shiga toxin-mediated TMA (Shiga toxin-hus) Drug-mediated TMA (immune reaction) Drug-mediated TMA (toxic dose-related reaction) TMA: Thrombotic microangiopathy TTP: Thrombotic thrombocytopenic purpura HUS: Hemolytic uremic syndrome George JN et al. N Engl J Med. 2014;371(7): MFMER slide-24

25 Hemolytic Uremic Syndrome (HUS) Typical HUS (90%) Shiga-toxin producing E. coli (STEC-HUS) Serotypes 0157:H7 and 0104:H4 Atypical HUS (10%) Genetic and acquired Uncontrolled complement activation Nayer A et al. Am J Ther. 2016;23(1):e MFMER slide-25

26 Diagnosis Thrombocytopenia Platelet < 150,000/uL or 25% reduction from baseline Microangiopathic hemolytic anemia Hemoglobin < 10 g/dl, schistocytes, decreased haptoglobin, increased LDH Organ injury Kidney, CNS, GI tract Exclusion of other TMA ADAMTS13 >5% Toxin-producing bacteria negative LDH: lactate dehydrogenase CNS: central nervous system GI: gastrointestinal Nayer A et al. Am J Ther. 2016;23(1):e MFMER slide-26

27 Clinical Consequences Lifelong risk of systemic thrombotic microangiopathy Organ damage to kidneys, CNS, GI tract 50% develop ESRD Poor prognosis 25% mortality High recurrence rate after transplantation (60-90% graft failure) ESRD: end-stage renal disease Nayer A et al. Am J Ther. 2016;23(1):e MFMER slide-27

28 Treatment of Atypical HUS First line: plasma infusion or exchange New agent: eculizumab Nayer A et al. Am J Ther. 2016;23(1):e MFMER slide-28

29 Eculizumab Complement over-activation atypical HUS Eculizumab binds to C5 complement protein and blocks production of MAC MAC: membrane attack complex Legendre CM et al. N Engl J Med. 2016;368(23): Nayer A et al. Am J Ther. 2016;23(1):e MFMER slide-29

30 Eculizumab for Atypical HUS Trial 1 Trial 2 Objective Evaluate safety and efficacy of eculizumab for atypical HUS Population AHUS and progressing TMA after 4 PLEX/PI (n=17) AHUS and long disease duration, CKD, prolonged PLEX/PI treatment (n=20) Intervention Eculizumab IV 900 mg weekly x 4 weeks, then 1200 mg every 2 weeks x 26 weeks Legendre CM et al. N Engl J Med. 2016;368(23): MFMER slide-30

31 Results End point (at week 26) Trial 1 (n=17) Trial 2 (n=20) Change in platelet count from baseline, x10 9 /L Thrombotic microangiopathy event-free status, % 73* Normalization of hematologic values, % *p=<0.001 Legendre CM et al. N Engl J Med. 2016;368(23): MFMER slide-31

32 Results End point Trial 1 (n=17) Trial 2 (n=20) Increase in egfr from baseline to week ml/min/1.73 m 2 95% CI 14-49, p= ml/min/1.73 m 2 95% CI 3-9, p<0.001 Increase in egfr from baseline to week ml/min/1.73 m 2 95% CI 16-47, p< ml/min/1.73 m 2 95% CI 4-14, p=0.003 Discontinued dialysis 4/5 (80%) Legendre CM et al. N Engl J Med. 2016;368(23): MFMER slide-32

33 Conclusion Inhibited complement-mediated TMA Platelet count recovery (Trial 1) Absence of TMA events (Trial 2) Improved renal function Eculizumab should be started without results of complement mutation testing Legendre CM et al. N Engl J Med. 2016;368(23): MFMER slide-33

34 Eculizumab Clinical Pearls REMS program Increased risk of meningococcal sepsis Meningococcal vaccination At least 14 days prior to dose OR Vaccination plus antimicrobial prophylaxis for 14 days Legendre CM et al. N Engl J Med. 2016;368(23): Cohn AC et al. MMWR Recomm Rep. 2013;62(RR-2): MFMER slide-34

35 Question 3 In the Phase 2 trial, eculizumab demonstrated which of the following outcomes? Platelet count recovery Prevention of TMA events Improvement in GFR All of the above 2016 MFMER slide-35

36 Summary Acquired TTP Atypical HUS Thrombocytopenia MAHA Neurologic symptoms Severe renal impairment ADAMTS13 <10% PLEX Steroids Rituximab, caplacizumab, bortezomib Eculizumab MAHA: microangiopathic hemolytic anemia 2016 MFMER slide-36

37 Future Directions Acquired TTP Role of caplacizumab and bortezomib Optimal dose, timing, and sequence of therapies Agents for prevention of relapse Atypical HUS Optimal duration of eculizumab therapy Treatment of refractory patients Sayani FA et al. Blood. 2015; 125(25): Veyradier A. N Engl J Med. 2016;374(6): MFMER slide-37

38 Conclusion Acquired TTP is caused by autoantibody inhibition of ADAMTS13 activity PLEX and steroids are recommended for first line treatment Several new agents targeted at the underlying mechanism have shown efficacy 2016 MFMER slide-38

39 Questions & Discussion 2016 MFMER slide-39