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   The role of TPO receptor
agonists in the treatment of ITP


               Angela C. Hirbe
      Hematology/Oncology Grand Rounds
                  9-23-2011
•••••••••••••••••
Outline
 Case presentation
 Background
  • Platelet production
  • Pathophysiology of ITP
  • First-line treatment of ITP
 Review data regarding TPO receptor agonists
  in the treatment of ITP
 Return to our case
 2011 ASH Guidelines for treatment of ITP
•••••••••••••••••
Case
 58yo male with Hep C cirrhosis and HCC s/p
  chemoembolization and orthotopic liver
  transplant in May 2010. Liver bx in May 2011
  with mild recurrent Hep C. Patient noted to
  have bruising on his arms and abdomen for
  several days PTA. He was seen by his PCP
  and had bloodwork that showed a plt count of
  4K and as such was admitted on 6/28.
 Meds: cellcept, tacro, paxil, calcium, Vit D
 Smear: notable only for decreased number of
  plts
  •••••••••••••••••
  Regulation of Platelet Production
 TPO is produced in
  the liver
 Inflammation and
  thrombocytopenia
  enhance TPO
  production
 Platelets have high
  affinity TPO receptors
  and remove TPO
  from the circulation

          The molecular mechansims that control hematopoesis. JCI. 2005.
    •••••••••••••••••
    Regulation of Platelet Production
 Free plasma
  thrombopoeitin binds
  to megakaryocytes
  stimulating
  megakaryocytopoesis

                           Thrombocytosis. NEJM. 2004
•••••••••••••••••
TPO receptor




     The molecular mechansims that control hematopoesis. JCI. 2005.
•••••••••••••••••
ITP
 Thrombocytopenia with an otherwise normal
  CBC and WBC diff, including with a normal
  peripheral blood smear
 No clinically apparent associated conditions
  or medications that may cause
  thrombocytopenia are present
  •   Primary
  •   Secondary
  •   Acute
  •   Chronic
   •••••••••••••••••
   Pathophyisiolgy of ITP

• Platelets coated
  with IgG
  autoantibodies
  undergo
  accelearted
  clearance in the
  spleen or liver




                     Immune Thrombocytopenic Purpura. NEJM. 2002.
     •••••••••••••••••
     Treatment of ITP
   Corticosteroids
   Rituximab
   Splenectomy
   TPO receptor
    agonists




                      Immune Thrombocytopenic Purpura. NEJM. 2002.
     •••••••••••••••••
     Treatment of ITP
  Eltrombopag
   (Promacta)
     • Small molecule synthetic
       non-peptide
     • Binds the
       transmembrane domain
     • Oral
     • Action in 7-28d
  Romiplostim (Nplate)
     • Fc portion of IgG1
       coupled to 2 14aa
       peptides of TPO
     • Mimics binding of TPO
     • Subcutaneous
     • Action in 5-14d

Thrombopoetin-Receptor Agonists for Primary Immune Thrombocytopenia. NEJM. 2011.
       •••••••••••••••••
       Eltrombopag for the treatment
       Chronic ITP-Phase II
 Multicenter randomized
  double-blind placebo
  controlled trial
 Once daily treatment for 6
  weeks
 Inclusion: 6 mo hx of ITP,
  plt<30K, at least one prior tx
  for ITP
 Exclusion: secondary ITP,
  Hgb<10, CHF, arrythmias,
  thrombosis within 1yr of
  enrollment, MI within 3 mos
  of enrollment, pregnacy
 Primary endpoint: plt>50K
 Secondary endpoint: safety,
  tolerability, signs of bleeding
                                    Bussel et al. NEJM. 2007. 357:2237-47
     •••••••••••••••••
     Analyses of Platelet counts
 By Day 8 44% of
  patients on
  50mg and 62%
  of patients on
  75mg had
  plt>50K
 Plt counts return
  to baseline when
  the drug is
  stopped
•••••••••••••••••
Incidence of bleeding before and
after Treatment
   •••••••••••••••••
   Adverse Events
•Similar number of
adverse events in all
groups.
•One death in 50mg
eltrombopag group
(h/o NSCLC with
COPD, 25d after
enrollment he was
hospitalized with
PNA/sepsis/hepatitis/
AKI, thromboemboli in
liver and kidney on
autopsy
               ••••••••••
  • • • • • • •eltrombopag on plt count and
Effect of
bleeding during treatment of chronic ITP
 Double blind randomized
  placebo-controlled trial
 Treated for up to 6 weeks
 Inclusion:18yrs or older, ITP
  for 6 mos, plts<30K, tried at
  least one other treatment
 Exclusion: Secondary ITP,
  CHF, arrythmia, thrombosis
  in the previous year, MI in
  the prior 3 mos, pregnant
 Primary endpoint: number of
  responders (plt>50K by
  week 6)
 Secondary endpoints: plt
  count, bleeding, symptoms,
  safety
                                  Bussel et al. Lancet. 2009. 373:641-648
  •••••••••••••••••
Median plt count
   •••••••••••••••••
Percent of responders
•••••••••••••••••
Adverse effects
 Similar numbers of
  adverse events
 No deaths
 Nausea/vomiting
  were the only 2
  adverse events
  recorded in 5% or
  more of the
  eltrombopag group
  not noted in the
  placebo group
     •••••••••••••••••
  Eltrombopag for managment Chronic ITP:
  RAISE: a 6 month phase III study
 Multicenter randomized double blind
  placebo-controlled phase III study of
  once daily oral treatment.
 Inclusion: 18yrs or older, primary ITP
  of >6mos duration, plt<30K
 Exclusion:participation in a previous
  eltrombpag study, secondary ITP,
  malignancy, chemo/radiation,
  arrythmia, arterial or venous
  thrombosis (or 2 thrombosis risk
 Response=plts 50-400K
 Primary endpoint:odds of response to
  eltrombopag
 Secondary:median plt counts, mean
  cumulative weeks of response,
  bleeding sx, reduction in other
  therapies, and use of rescue tx      Cheng et al. Lancet. 2011. 377:393-402
•••••••••••••••••
Dosing Algorithm
 Dose increases to a max of 75mg were allowed after
  day 22 for plt count lower than 50K.
 Dose decreases to 25mg for plt>200K
 Treatments held for plt>400K
 After 6 weeks, patients with plt counts > 100K for 2 or
  more weeks could decrease or d/c other therapies.
 Rescue tx was allowed, but patients were then
  considered non-responders.
 Assessed weekly and then post tx at week 1, 3, 4,
  month 3, month 6
   •••••••••••••••••
Odds of
responding were
8x greater in the
eltrombopag
group compared
to placebo
   •••••••••••••••••
   Adverse reactions
 Increases in ALT
  and bilirubin
 3 thromboembilic
  events: PE in a
  smoker with a
  lupus
  anticoagulant,
  DVT in a smoker
  on OCP and PE
  in new rectal ca
  patient s/p
  surgery with no
  prophylactic
  anticoagulation
       •••••••••••••••••
       Efficacy of romiplostim in patients with

       chronic ITP III studies lasting 6
    2 parallel multicenter phase
    mos (splenectomy and non-splenectomy)
   Eligibility criteria: plt<30K, 18yrs or older, no
    active malignancy, normal Cr, bili no more than
    1.5x the upper limit of normal, patients older
    than 60yo had to have a BM bx c/w ITP.
    Patients could receive concurrent therapy with
    other agents at a constant dose and schedule.
   Randomly assigned 2:1 to receive weekly
    romiplostim or placebo for 24 weeks
   Patients completed the study at 36 weeks or if
    plt count fell below 50K
   Primary: durable plt response (weekly plt
    responses during 6 or more of the last 8 weeks
    of tx.)
   Secondary: frequency of overall plt response
    (durable +transient responses), proportion of
    people needing rescue drugs, frequency of           Kuter et al. Lancet. 2008.
    durable plt response with a stable dose of drug.    371:395-403
•••••••••••••••••
Dosing Algorithm
 The starting dose was 1ug/kg
 During the first 12 weeks, there could be dose
  reductions in concurrent ITP therapies if plt>100K.
 Increases in concurrent therapy or the use of rescue
  drugs at any point in the study led to exclusion from
  the analysis of the primary endpoint.
 To achieve a target plt count>50K, the following dosing
  algorithms were used:
    • Increase by 2ug/kg every week if plts less than 10K or 2ug/kg every
      2 weeks if plt =11-50K
    • Once plts reached 50K, increase by 1ug/kg per week if there was a
      fall to 10K or less, increase by 1ug/kg every 2 weeks, if plts falling
      between 11-50K, reduce by 1ug/kg after 2 consecutive weeks of
      plts=200-400K, hold dose if >400K and subsequent doses would be
      decreased by 1ug/kg and given after plt count less than 200K
    • Max dose=15ug/kg
    •••••••••••••••••
Median plt count each week and incidence of
durable response
•Target plt count reached by 25% in
both romiplostim groups after 1 week
•Target plt count reached by 50% in
both romiplostim groups after 2-3
weeks
•Between weeks 18-24 when the
durable plt count was assessed, the
median weekly plt count for
romiplostim/splenectomy: 56-85
romiplostim non-splenectomy: 63-95
placebo/splenectomy: 13-21
placebo/non-splenectomy: 29-38
•••••••••••••••••
Secondary outcomes
   •••••••••••••••••
   Adverse Events
 2 deaths in the placebo
  group: cerebral
  hemmorrhage and PE
 1 splenectomized non-
  responding patient in
  the romiplostim group
  had increased BM
  reticulin, but returned to
  baseline
 CVA in a patient on
  romiplostim with CHF,
  DM, HTN
 Popliteal artery
  thrombosis in a patient
  on romiplostim with
  PVD and afib.
   • • • • • • • • • • or • • • •
 Romiplostim • • •Standard of Care in Patients
 with Immune Thrombocytopenia
 Open label 52 week study randomly assigning adults with
  ITP to standard of care vs weekly romiplostim
 Inclusion: plt<50K, one or more treatments, BM bx if >60yo
 Exclusion: splenectomy, active malignancy, previous
  exposure to TPO agonist, pregnancy
 Primary endpoints: incidence of treatment failure and
  splenectomy
 Secondary Endpoint: rate of platelet response, safety, quality
  of life
 Target plt count: 50-200K
 Start dose: 3ug/kg (max dose 10ug/kg)
 Weekly visits for 8 weeks, then monthly or as needed to
  adjust dose
 Plts <20K for 4 consecutive weeks on max dose led to
  discontinuation                 Kuter et al. NEJM. 2010. 363: 1889-99
•••••••••••••••••
Incidence of Treatment failure and
of Splenectomy
•••••••••••••••••
Platelet Count
 •••••••••••••••••
 Adverse Events
•Headache and fatigue were the most common complaints
in both groups
•One death in the rompiplostim group 2/2 PNA
•Two deaths in the standard-of-care group 2/2 hepatic
failure and cardiopulmonary arrest
•••••••••••••••••
Summary
 Significant increases in plt count with minimal
  side effects (headache, nausea, vomiting,
  fatigue, diarrhea, arthralgias)
 FDA approved for patients with chronic ITP with
  insufficient response to to glucocorticoids, IVIg
  or splenectomy
 $4000 per month for eltrombopag and $5000
  per month for romiplostim
•••••••••••••••••
Long-Term Implications: Efficacy
and Side Effects
 Unknown long-term efficacy and side effects
  • Ongoing open-label single-arm extension study with
    142 patients with plt<5 who had completed another
    romiplostim study were put back on romiplostim for
    up to 156 weeks: 87% achieved a plt count >50K
    during the study (mean 69wks), 9% with serious
    adverse events (1MI, portal vein thrombosis, DVT, 5
    BM reticulin formation, anemia, abd pain, 2
    plt>1000K, blindness)
           Bussell et al. Blood. 2009. 113:2161-71

 Studies exclude secondary ITP
        •••••••••••••••••
        Long-term implications: reticulin
 Reticulin formation is associated
  with myelofibrosis
 Animal models overexpressing
  TPO result in a phenotype
  similar to myelofibrosis
 Animals injected with 10x the
  recommended dose of
  romiplostim have reversible
  changes in the bone marrow.
 Retrospective data:
    •   271 patients,
    •   11 BM bx,
    •   10/11 with reticulin fiber
    •   formation=4-91%
 Prospective study with 10
  patients,
    • 6 with adequate pre and post-tx
      BM bx,
    • only one pt with reticulin
                                      Kuter et al. Blood. 2009. 114:3748-56
      formation
•••••••••••••••••
Back to our patient…
 Treated with IVIG x2 doses and 2 doses of promacta
  and plts increased from 4K to 32K by d/c.
 Started on promacta on 7/1 and sent out on promacta
  25mg daily
 Promacta dose increased to 50mg daily 8/1
 Readmitted to BJH on 8/13 with plt=3K and a
  subdural hematoma despite promacta
 Treated with IVIg and steroids, but plts did not
  respond
 BM bx with normocellular marrow with multilineage
  hematopoesis and mild megakaryocytic hyperplasia
 Treated with rituximab with no response
 Splenectomy on 9/2 plts=5 on 9/1 and 177 on
  discharge on 9/5
  •••••••••••••••••
ASH Guidelines for Treatment of ITP




               Neunert et al. Blood. 2011.117:4190-4204
•••••••••••••••••
References
   Cines et al. NEJM. 2002. 346:995-1008
   Kaushansky K. JCI. 2005. 115:3339-47
   Imbach et al. NEJM. 2011.365:734-41
   Bussel et al. NEJM. 2007. 357:2237-47
   Bussel et al. Lancet. 2009. 373:641-648
   Cheng et al. Lancet. 2011. 377:393-402
   Kuter et al. Lancet. 2008. 371:395-403
   Kuter et al. NEJM. 2010. 363: 1889-99
   Bussell et al. Blood. 2009. 113:2161-71
   Kuter et al. Blood. 2009. 114:3748-56
   Neunert et al. Blood. 2011.117:4190-4204
•••••••••••••••••
Treatment of ITP

				
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