Beyond Plasma Exchange: Targeted Therapy for Thrombotic ... PGR TTP.pdf©2016 MFMER | slide-4...

Beyond Plasma Exchange: Targeted Therapy for Thrombotic Thrombocytopenic Purpura Kristen Knoph, PharmD, BCPSPGY2 Pharmacotherapy ResidentPharmacy Grand RoundsApril 25, 2017

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

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

Hereditary disorders Acquired disorders

ADAMTS13 deficiency-mediated TMA (TTP)

(Upshaw-Schulman syndrome)

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

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

Pathophysiology

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

Thrombocytopenia

Diagnosis

ADAMTS13 activity < 10%

Schistocytes↓ Hemoglobin↓ Haptoglobin↑ LDH

Platelets < 150,000/uL

LDH: lactate dehydrogenase

Question 1• Which of the following findings support the

diagnosis of TPP?• Schistocytes• Thrombocytopenia• DVT/PE• A and B• All of the above

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

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

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

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

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

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

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

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

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

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

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%

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

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

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

Hereditary disorders Acquired disorders

(Upshaw-Schulman syndrome)

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

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

Diagnosis

• Platelet < 150,000/uL or 25% reduction from baselineThrombocytopenia

• Hemoglobin < 10 g/dL, schistocytes, decreased haptoglobin, increased LDH

• 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

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

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

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

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

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

*p=<0.001

Results

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%)

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

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

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

SummaryAcquired

TTPAtypical

HUSThrombocytopenia ✓ ✓

MAHA ✓ ✓

Neurologic symptoms ✓ ✓

Severe renal impairment ✓

ADAMTS13 <10% ✓

PLEX ✓ ✓

Steroids ✓

Rituximab, caplacizumab,bortezomib ✓

Eculizumab ✓

MAHA: microangiopathic hemolytic anemia

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.

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

Questions & Discussion

Beyond Plasma Exchange: Targeted Therapy for Thrombotic ... PGR TTP.pdf©2016 MFMER | slide-4...

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