Immune Thrombocytopenic Purpura

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Immune Thrombocytopenic Purpura

• Kenny Aristide, Pharm.D.
• PGY-1 Pharmacy Resident
• Thursday, October 4, 2012

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Pharmacist Objectives

• Discuss the etiologies associated with immune
  thrombocytopenic purpura
• Describe the pathophysiologic processes of immune
  thrombocytopenic purpura
• Define the diagnostic criteria for immune
  thrombocytopenic purpura
• Differentiate between the various pharmacologic
  agents utilized to treat immune thrombocytopenic
  purpura
• Critique the clinical trials of the pharmacologic
  agents utilized to treat immune thrombocytopenic
  purpura

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Pharmacy Technician Objectives

• Identify patients with immune thrombocytopenic
  purpura
• Identify the pharmacologic agents utilized to
  treat immune thrombocytopenic purpura
• List the generic names of the medications that
  are utilized to treat immune thrombocytopenic
  purpura

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Definition Immune (Idiopathic) Thrombocytopenic
Purpura (ITP)

• Disorder of exclusion
• Clinical syndrome of diverse disorders1
• Differentiated from non-autoimmune etiologies of
  thrombocytopenia2

1. Stasi R. Semin Thromb Hemost.201238(5)454-62.
2. Cuker A. et al. Hematology. 201033377-383.

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Epidemiology of ITP

• Incidence
• Children 5 per 100,000
• Adults 2 per 100,000
• Gender
• Children and elderly affects both equally
• Adults more common in females
• Age
• Prevalence peaks in childhood
• Peak age 2 5

Lakshmanan S, Cuker A. J Thromb Haemost. 2012.
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Epidemiology of ITP Age and sex distribution
Beutler et al. Williams Hematology. 1995.
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Etiology of ITP

• Often following infection (viral or bacterial)
• Postulated theories
• Molecular Mimicry
• Viral infection (HIV, HCV)
• H. pylori infection
• Autoantibodies

Autoimmunity
Chong BH. J Thromb Haemost. 20097(2)319-21.
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Classification of ITP

• Primary ITP
• Idiopathic no known etiology
• No clinically evident secondary form
• Secondary ITP
• Associated with infections, immunizations/vaccines

Stasi R. Semin Thromb Hemost. 201238(5)454-62.
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Classification of ITP

• Secondary ITP
• Antiphospholipid syndrome
• Autoimmune thrombocytopenia (e.g., Evans
  syndrome)
• Common variable immune deficiency
• Infection with cytomegalovirus, Helicobacter
  pylori, hepatitis C (HCV), human immunodeficiency
  virus (HIV), varicella zoster
• Lymphoproliferative disorders
• Bone marrow transplantation side effect
• Vaccination side effect (i.e. MMR)
• Systemic lupus erythematosus

Stasi R. Semin Thromb Hemost. 201238(5)454-62.
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Classification of ITP
Estimated Prevalence of Secondary ITP in the US
SLE 5
APS 2
CVID 1
CLL 2
Primary80
Evans 2
ALPS, post-tx 1
HIV 1
Hep C 2
H. pylori 1
Postvaccine 1
Misc systemic infection 2
Adapted from Cines DB, et al. Blood.
20091136511-6521.
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Classification of ITPDisease phases

• Newly diagnosed ITP
• Less than 3 months
• Persistent ITP
• 3 12 months
• Chronic ITP
• Greater than 12 months
• Refractory ITP
• Treatment failure of splenectomy

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Pathophysiology of ITP

• Harrington-Hollingsworth experiment1
• Established the autoimmune nature of ITP
• Autoimmune response2
• IgG mediated response to platelet glycoproteins
  (GP IIb/IIIa and Ib/IX)
• Platelet destruction Decreased platelet
  production

1. Stasi R. Semin Thromb Hemost. 201238(5)454-62.
2. Chong BH. J Thromb Haemost. 20097(2)319-21

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Pathophysiology of ITP

• Cines DB, et al. N Engl J Med. 2002346995-1008.
  

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Two Processes Involved in Immune Thromcytopenic
Purpura
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Two Processes Involved in Immune Thromcytopenic
Purpura
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Two Processes Involved in Immune Thromcytopenic
Purpura
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Two Processes Involved in Immune Thromcytopenic
Purpura
Antibody
Antibody
Platelets
Bone marrow where platelets are produced

Increased platelet destruction
Inadequate platelet production
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Assessment Question

• What is the most commonly identified antigenic
  target of the ITP autoantibodies?
• VH1
• GP IIb/IIIa
• ITP IIIa
• GP IVc/IX

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Clinical Presentation of ITP

• Bleeding
• most important clinical manifestation of ITP
• Petechiae
• Ecchymoses
• Epistaxis
• Gingival bleeding
• Menorrhagia
• Major hemorrhage (GI bleed, CNS bleed) rare
• Disabling fatigue
• Withdrawal from professional and social
  activities

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Clinical Presentation of ITP
Purpura and Petechiae. Available at
http//www.nhlbi.nih.gov/health/health-topics/imag
es/itp_photo.jpg
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Diagnosis of ITP

• Platelet count
• Less than 100 x 109/L (rather than 150 x 109/L)
• Medical History
• Response to therapy
• Peripheral Smear
• Physical Exam
• Bone marrow aspiration and biopsy
• Not routinely done
• Antiplatelet Antibody Testing

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Assessment Question

• In order to make the diagnosis of ITP, a bone
  marrow biopsy must be performed.
• True
• False

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ITP Treatment Options
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Indications for Treatment

• American Society of Hematology (ASH) suggests
• Platelet counts gt 30 x 109/L usually have few or
  no symptoms and require no treatment
• Avoid treatment in patients with mild,
  asymptomatic disease
• Platelet counts lt 30 x 109/L have treatment
  recommendations based on the presence and
  severity of associated bleeding symptoms
• Hospitalization and emergent treatment is
  indicated if
• Severe bleeding occurs, regardless of platelet
  count
• Platelet count lt 20 x 109/L and signs/symptoms of
  mucocutaneous bleeding is present

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Goals of Treatment

• Obtain a hemostatic platelet count to
• prevent bleeding
• Individualized to the patient
• Minimizing toxicity associated with treatment
• Induce long-term remission

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ITP Treatment Options

• 1st line
• Corticosteroids
• Intravenous immunoglobulins (IVIG)
• 2nd Line
• Splenecotomy
• Thrombopoietin Receptor Agonists
• Rituximab
• 3rd Line
• Other immunosuppressive agents

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ITP Treatment Options Corticosteroids

• Prednisone
• Mechanism of Action
• Impair clearance of platelets in the bone marrow
  and peripherally
• Reduce antibody production
• Dose
• 1 2 mg/kg/day PO as single or divided doses
• Usually responds within 2 - 3 weeks
• Response rate 50 75
• Taper over 4 6 weeks following platelet
  response
• Side effects numerous

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Assessment Question

• All of the following are side effects of
  corticosteriods except
• Bone density loss
• Hypertension
• Weight loss
• Muscle weakness

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ITP Treatment Options IVIG

• IVIG
• Mechanism of action
• Undefined and potentially multifactorial
• Dose
• Variable regimen
• Standard dose 1 g/kg/day x 1 2 days
• Side effects
• - hypersensitivity -headache
• - renal failure -nausea/vomiting
• - alloimmune hemolysis -pulmonary edema

George JN. Am J Hematol. 201287 Suppl 1S12-5.
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ITP Treatment Options

• 1st line
• Corticosteroids
• IVIG
• Anti-D immunoglobulins
• 2nd Line
• Splenecotomy
• Rituximab
• Thrombopoietin Receptor Agonists
• 3rd Line
• Other immunosuppressive agents

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ITP Treatment OptionsSplenectomy

• Splenectomy
• Mechanism of action
• Removes a primary site of platelet destruction
  and increases platelet count
• Possible site of autoantibody production
• Side effects increase risk of infection,
  thrombosis, pulmonary hypertension
• Vaccination recommended
• HIB, pneumococcal, and meningococcal

George JN. Am J Hematol. 201287 Suppl 1S12-5.
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Assessment Question

• Which of the following is a recommended
  vaccination patients should receive following
  splenecotomy?
• Hepatitis C
• Hepatitis B
• Pneumovax
• Tdap

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Rituximab

• Anti-CD20 Antibody

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ITP Treatment OptionsRituximab

• Rituximab (Rituxan)
• Mechanism of action
• Hypothesis-driven use
• B-cell depletion ? antiplatelet antibodies
• Dose
• Most effective dose/schedule not known, not
  FDA-approved for ITP
• Usual dosage 375 mg/m2 IV once weekly x 4 weeks
• Response rate
• 40 at 1 year
• 20 25 at 5 years
• Side effects
• -Infusion reaction - Tumor lysis syndrome
• -Pulmonary toxicity - Hepatitis B reactivation

1. Rituxan package insert. San Francisco, CA
   Genentech, Inc. 2012.
2. Lakshmanan S, Cuker A. J Thromb Haemost. 2012.

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Thrombopoietin (TPO) Receptor Agonists
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TPO Receptor Agonists

• Romiplostim (Nplate)
• Mechanism of action
• Analog of thrombopoietin which increases the
  production of platelets
• Dose 1 10 mcg/kg SubQ weekly
• Increase dose by 1 mcg/kg qweek to effect (Plts
  50 x 109/L)
• Side effects
• Headache - Paresthesia
• Myelodysplastic Syndrome - Mylagia
• Insomnia - Pain in extremity
• Monitor CBC with differential and platelets
  continually

Nplate package insert. Thousand Oaks, CA
Amgen, Inc. 2011.
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TPO Receptor Agonists

• Eltrombopag (Promacta, Revolade)
• Mechanism of Action
• induces megakaryocyte proliferation and
  differentiation from bone marrow progenitor
  cells.
• Dose 12.5-75 mg PO daily
• Reduce dosage in patients with East Asian
  ancestry (25 mg once daily initially)
• Side effects
• - Myalgia - Paresthesia
• - Hepatotoxicity (BBW)
• Monitor
• LFTs, CBCs, and platelets

Promacta package insert. Research Triangle
Park, NC GlaxoSmithKline 2011.
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Clinical Evidence
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Romiplostim vs. Standard of Care (SOC) in
Patients with ITP
Study Design Multicentered, randomized, controlled open-label trial N 234 (Romiplostim, n 157 vs. SOC, n 77)
Primary endpoint Incidences of treatment failure and splenectomy
Secondary endpoint Rate of platelet response (Plt count gt 50 x 109/L) Safety outcomes Quality of Life (QOL)
Results Primary Endpoint Treatment failure 11 (romiplostim) vs. 30 (SOC) p lt0.001 Splenectomy 9 (romiplostim) vs. 36 (SOC) plt0.001 Secondary Endpoint Serious adverse events 23 (romiplostim) vs. 37 (SOC)
Kuter et. al. NEJM. 20101889-1899
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Romiplostim vs. Standard of Care (SOC) in
Patients with ITP
Kuter et. al. NEJM. 20101889-1899
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Assessment Question

• What type of bias is the most closely associated
  with an open-label study design?
• Participant bias
• Recall or memory bias
• Compliance bias
• Selection bias

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Eltrombopag for management of chronic immune
thrombocytopenia (RAISE) 6 month, randomized,
phase III study
Study Design Multicentered, randomized, double-blind, placebo-controlled trial N 197 (Eltrombopag, n 135 vs. Placebo, n 62)
Primary endpoint Percentage of Responders (Plt count of 50 400 x 109/L)
Secondary endpoint Median platelet count Bleeding symptoms Reduction of baseline treatment for ITP Use of rescue treatment
Results Primary endpoint Odds of response 79 (eltrombopag) vs. 28 (placebo) Odds ratio 8.2 99 CI 3.59 18.73 p lt0.0001 Safety endpoint ALT 3x ULN 7 (eltrombopag) vs. 3 (placebo) Serious Bleeding Event 1 (eltrombopag) vs. 7 (placebo) p 0.03
Cheng G et al. Lancet. Jan 29 2011377(9763)393-4
02.
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Eltrombopag for management of chronic immune
thrombocytopenia (RAISE) 6 month, randomized,
phase III study
Results
Cheng G et al. Lancet. Jan 29 2011377(9763)393-4
02.
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Eltrombopag for management of chronic immune
thrombocytopenia (RAISE) 6 month, randomized,
phase III study
Results
Cheng G et al. Lancet. Jan 29 2011377(9763)393-4
02.
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Conclusion

• ITP is an disorder of exclusion
• Multiple therapies available
• may be needed to induce remission
• Goal of treatment prevention of complications

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Comparison of TPO Receptor AgonistsRomiplostim
Vs. Eltrombopag
Romiplostim Eltrombopag
Formulation Reconstitutable powder Tablet
Administration Subcutaneous Injection Orally
Storage Refrigerated Room temperature
Metabolism None known Substrates CYP1A2, CYP2C8 (minor) Inhibits CYP1A2, CYP2C8 (mod), various UGT enzymes
Price (AWP) One vial of 250 mcg 1,062.50 One vial of 500 mcg 2,125.00 25 mg (30 tabs) 1,980.00 50 mg (30 tabs) 3,960.00
Adverse Effects Headache Injection site reaction Myelodysplastic syndromes Paresthesia Myalgia Hepatotoxicity
REMS None None
AWP Average Wholesale Price Murray L, ed. 2009
Red Book. Montvale, NJ Thomson PDR 2009.
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Case

• Subjective 60 yo female who notice sudden
  appearance of multiple petechiae on her
  extremities and mild epistaxis. She had no other
  symptoms.
• PMH Hep C related liver cirrhosis (status post
  liver transplant in 2010) and
• Meds Cyclosporine A, mycophenolate and a low
  dose prednisone.
• Objective Platelet count 20 x 109/L
• Bone marrow biopsy was suggestive with
  ITP, showing an activated
  megakaryocytopoiesis and normal reticulin
• distribution.

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Case

• Assessment According to the AHS guidelines, pt
  received standard therapy (prednisone 1
  mg/kg/day) obtaining only a transient response.
• Plan Her physician would like treat the patient
  with one of the new TPO receptor agonists and he
  turns to you to recommend one of the two agents
  available on formulary, Romiplostim or
  Eltrombopag. Based on the data presented, which
  of the two agents do you recommend?

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References

1. Stasi R. Immune thrombocytopenia
   pathophysiologic and clinical update. Semin
   Thromb Hemost. 201238(5)454-62.
2. Cuker A., Cines DB. Immune Thrombocytopenia.
   Hematology. 201033377-383.
3. Lakshmanan S, Cuker A. Contemporary Management of
   Primary Immune Thrombocytopenia (ITP) in Adults.
   J Thromb Haemost. 2012.
4. George JN. Sequence of treatments for adults with
   primary immune thrombocytopenia. Am J Hematol.
   201287 Suppl 1S12-5.
5. Chong BH. Primary immune thrombocytopenia
   understanding pathogenesis is the key to better
   treatments. J Thromb Haemost. 20097(2)319-21.
6. Cines DB, Blanchette VS. Immune Thrombocytopenic
   Purpura. N Engl J Med. 2002346995-1008
7. Beutler E, Lichtman, MA, Coller BS et al.
   Williams Hematology, 5th ed. McGraw-Hill, New
   York, 1995.
8. Nplate package insert. Thousand Oaks, CA
   Amgen, Inc. 2011.
9. Rituxan package insert. San Francisco, CA
   Genentech, Inc. 2012.
10. Promacta package insert. Research Triangle
    Park, NC GlaxoSmithKline 2011.
11. Kuter DJ, Rummel M, Boccia R. et. al. Romiplostim
    or standard of care in patients with immune
    thrombocytopenia. N Eng J Med. 20103631889-99.
12. Cheng G, Saleh MN, Marcher C, et al. Eltrombopag
    for management of chronic immune thrombocytopenia
    (RAISE) a 6-month, randomised, phase 3 study.
    Lancet. Jan 29 2011377(9763)393-402.

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Questions?