Upload
others
View
5
Download
0
Embed Size (px)
Citation preview
©2016 MFMER | slide-1
Beyond Plasma Exchange: Targeted Therapy for Thrombotic Thrombocytopenic Purpura Kristen Knoph, PharmD, BCPSPGY2 Pharmacotherapy ResidentPharmacy Grand RoundsApril 25, 2017
©2016 MFMER | slide-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-3
Thrombotic Microangiopathy Syndromes
TMA Syndromes
Microangiopathic hemolytic anemia
ThrombocytopeniaOrgan injury
Arteriolar and capillary
thrombosis
George JN et al. N Engl J Med. 2014;371(7):654-66
©2016 MFMER | slide-4
Thrombotic Microangiopathy Syndromes
George JN et al. N Engl J Med. 2014;371(7):654-66
Hereditary disorders Acquired disorders
ADAMTS13 deficiency-mediated TMA (TTP)
(Upshaw-Schulman syndrome)
ADAMTS13 deficiency-mediated TMA (TTP)
Complement-mediated TMA(Atypical HUS)
Complement-mediated TMA(Atypical HUS)
Metabolism-mediated TMA Shiga toxin-mediated TMA (Shiga toxin-HUS)
Coagulation-mediated TMA Drug-mediated TMA (immune reaction)
Drug-mediated TMA (toxic dose-related reaction)
TMA: Thrombotic microangiopathyTTP: Thrombotic thrombocytopenic purpuraHUS: Hemolytic uremic syndrome
©2016 MFMER | slide-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
Scully M et al. Br J Haematol. 2012;158(3):323-35George JN. N Engl J Med. 2006;354(18):1927-35
VWF: Von Willebrand factor
©2016 MFMER | slide-6
Pathophysiology
©2016 MFMER | slide-7
Pathophysiology
©2016 MFMER | slide-8
George JN. N Engl J Med. 2006;354(18):1927-35Scully M et al. Br J Haematol. 2012;158(3):323-35
Pentad of Clinical Features
Neurologic abnormalities
Renal abnormalities
Fever
Microangiopathic hemolytic anemia
Thrombocytopenia
Diagnosis
ADAMTS13 activity < 10%
Schistocytes↓ Hemoglobin↓ Haptoglobin↑ LDH
Platelets < 150,000/uL
LDH: lactate dehydrogenase
©2016 MFMER | slide-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-10
Treatment for Acquired TTP
Veyradier A. N Engl J Med. 2016;374(6):583-5.
First line: plasma exchange/steroids
Refractory: rituximab
Salvage: splenectomy, cyclosporine, cyclophosphamide/vincristine
New agents: caplacizumab, bortezomib
©2016 MFMER | slide-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):654-66Veyradier A. N Engl J Med. 2016 Feb 11;374(6):583-5
Rock GA et al. N Engl J Med. 1991;325(6):393-7
©2016 MFMER | slide-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):1529-49Kale-Pradhan PB et al. Pharmacotherapy. 1997;17(4):684-95
©2016 MFMER | slide-13
Steroids• Immunosuppression may produce a more
durable response• High dose vs. standard dose steroids
• No difference in response at day 9• 76.6% vs. 56.7%, p=0.17
• Improved remission rates at day 23 • 76.6% vs. 46.6%, p=0.03
Balduini CL et a. Ann Hematol. 2010;89(6):591-6Scully M et al. Br J Haematol. 2012;158(3):323-35
Sayani FA et al. Blood. 2015; 125(25):3860-7
Initial treatment Refractory, unstable, neurologic symptoms
Prednisone 1 mg/kg/day Methylprednisolone 1 g/dayx 3 days
©2016 MFMER | slide-14
Goals of Therapy• Platelet recovery
• > 150 x 109/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):1927-35Willis MS et al. Semin Thromb Hemost. 2005;31(6):700-8
©2016 MFMER | slide-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):1526-31Coppo P et al. Hematology Am Soc Hematol Educ Program. 2015;2015:637-43
©2016 MFMER | slide-16
Initial Treatment Refractory Episodes
RelapsePrevention
Trial Scully et al. 2011 Froissart et al. 2012 Hie et al. 2014
Design Phase 2, non-randomized
Prospective, open-label
Observational, cross-sectional
InterventionRTX (n=40) vs. historical control (n=40)
RTX (n=21) vs. historical control (n=53)
RTX (n=30) vs. historical control (n=18)
Results
Remission rates• RTX: 93%• Control: 95%
Relapse rates• RTX: 11%• Control: 55%• P= 0.0011
Durable remission by day 35 (p< 0.02)• RTX: 100%• Control: 58%
Relapse at 1 year• No difference
between groups
Longer relapse-free survival in RTX group (p=0.049)
Scully M et al. Blood. 2011;118(7):1746-53 Froissart A et al. Crit Care Med. 2012;40(1):104-11
Hie M et al. Blood. 2014;124(2):204-10RTX: rituximab
©2016 MFMER | slide-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):1526-31
©2016 MFMER | slide-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):1526-31
©2016 MFMER | slide-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):511-22
©2016 MFMER | slide-20
Caplacizumab for Acquired TTPObjective Evaluate caplacizumab for treatment of acquired TTP
Design Phase II, randomized, controlled trial
Intervention Caplacizumab 10 mg SC daily (n=36) vs. placebo (n=39) during PLEX and 30 days afterward PLUS standard of care
Results
Median time to a response• Caplicizumab: 3.0 days (95% CI 2.7-3.9)• Placebo:4.9 days (95% CI 3.2-6.6)• Event rate ratio 2.20 (95% CI, 1.28-3.78, p = 0.005)
Exacerbations• Caplicizumab: 8%• Placebo: 28%
Relapses• Caplicizumab: 22%• Placebo: 0%
Peyvandi F et al. N Engl J Med. 2016;374(6):511-22
©2016 MFMER | slide-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):511-22
©2016 MFMER | slide-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):1751-6Patriquin CJ et al. Br J Haematol. 2016;173(5):779-85
©2016 MFMER | slide-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-24
Thrombotic Microangiopathy Syndromes
George JN et al. N Engl J Med. 2014;371(7):654-66
Hereditary disorders Acquired disorders
ADAMTS13 deficiency-mediated TMA (TTP)
(Upshaw-Schulman syndrome)
ADAMTS13 deficiency-mediated TMA (TTP)
Complement-mediated TMA(Atypical HUS)
Complement-mediated TMA(Atypical HUS)
Metabolism-mediated TMA Shiga toxin-mediated TMA (Shiga toxin-HUS)
Coagulation-mediated TMA Drug-mediated TMA (immune reaction)
Drug-mediated TMA (toxic dose-related reaction)
TMA: Thrombotic microangiopathyTTP: Thrombotic thrombocytopenic purpuraHUS: Hemolytic uremic syndrome
©2016 MFMER | slide-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):e151-8
©2016 MFMER | slide-26
Diagnosis
• Platelet < 150,000/uL or 25% reduction from baselineThrombocytopenia
• Hemoglobin < 10 g/dL, schistocytes, decreased haptoglobin, increased LDH
Microangiopathic hemolytic anemia
• Kidney, CNS, GI tractOrgan injury
• ADAMTS13 >5%• Toxin-producing bacteria negative
Exclusion of other TMA
Nayer A et al. Am J Ther. 2016;23(1):e151-8LDH: lactate dehydrogenase CNS: central nervous systemGI: gastrointestinal
©2016 MFMER | slide-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)
Nayer A et al. Am J Ther. 2016;23(1):e151-8ESRD: end-stage renal disease
©2016 MFMER | slide-28
Treatment of Atypical HUS
Nayer A et al. Am J Ther. 2016;23(1):e151-8
First line: plasma infusion or exchange
New agent: eculizumab
©2016 MFMER | slide-29
Eculizumab• Complement over-activation atypical HUS• Eculizumab binds to C5 complement protein
and blocks production of MAC
Legendre CM et al. N Engl J Med. 2016;368(23):2169-81Nayer A et al. Am J Ther. 2016;23(1):e151-8MAC: membrane attack complex
©2016 MFMER | slide-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):2169-81
©2016 MFMER | slide-31
Results
End point (at week 26) Trial 1 (n=17) Trial 2 (n=20)
Change in platelet count from baseline, x109/L 73* 5
Thrombotic microangiopathyevent-free status, % 88 80
Normalization of hematologicvalues, % 76 90
Legendre CM et al. N Engl J Med. 2016;368(23):2169-81
*p=<0.001
©2016 MFMER | slide-32
Results
Legendre CM et al. N Engl J Med. 2016;368(23):2169-81
End point Trial 1 (n=17) Trial 2 (n=20)
Increase in eGFR from baseline to week 26
32 mL/min/1.73 m2
95% CI 14-49, p=0.0016 mL/min/1.73 m2
95% CI 3-9, p<0.001
Increase in eGFR from baseline to week 60
32 mL/min/1.73 m2
95% CI 16-47, p<0.0019 mL/min/1.73 m2
95% CI 4-14, p=0.003
Discontinued dialysis 4/5 (80%)
©2016 MFMER | slide-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):2169-81
©2016 MFMER | slide-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):2169-81Cohn AC et al. MMWR Recomm Rep. 2013;62(RR-2):1-28
©2016 MFMER | slide-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-36
SummaryAcquired
TTPAtypical
HUSThrombocytopenia ✓ ✓
MAHA ✓ ✓
Neurologic symptoms ✓ ✓
Severe renal impairment ✓
ADAMTS13 <10% ✓
PLEX ✓ ✓
Steroids ✓
Rituximab, caplacizumab,bortezomib ✓
Eculizumab ✓
MAHA: microangiopathic hemolytic anemia
©2016 MFMER | slide-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):3860-7Veyradier A. N Engl J Med. 2016;374(6):583-5.
©2016 MFMER | slide-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-39
Questions & Discussion