Download Immune Thrombocytopenic Purpura (ITP)

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ADDITIONAL RESOURCES:
Patients requiring evaluation or further management of ITP may be referred to the IHTC by calling
1-317-871-0000.
Multiple web resources exist for patients with ITP:
1. Patient Information and Support Groups
• Platelet Disorder Support Association PDSA: www.pdsa.org
• The ITP Support Association: www.itpsupport.org.uk/
• Children's Cancer and Blood Foundation: www.childrenscbf.org/medical/whatsitcalled.html
2. Vaccine safety
• www.cdc.gov/vaccinesafety/vsd/vsd_studies.htm#thrombocytopenia
3. Medication Support Programs
• WinRho: www.baxterbiotherapeutics.com/us/us_patient_itp_programs.html
• Nplate: www.amgen.com/pdfs/misc/Fact_Sheet_NplateNexus.pdf
• Pomacta: www.promactacares.com/index.html
To request a copy of Part I - Immune Thrombocytopenia Purpura (ITP):
A New Look at an Old Disorder, contact the IHTC at 877-256-8837.
8402 Harcourt Road, Suite 500
Indianapolis, IN 46260
© Copyright Indiana Hemophilia &
Thrombosis Center, Inc. 2010
Fall 2010
Immune Thrombocytopenic Purpura (ITP):
A New Look at an Old Disorder - Part II - Treatment
TREATMENTS: WHEN, WHY AND WHAT THE PEDIATRIC VERSUS ADULT PERSPECTIVE
How is a patient with ITP treated?
Once the diagnosis of ITP has been confirmed the most
important question to address is whether an indication is
present that would warrant treatment. Common treatment
modalities utilized in both pediatric and adult ITP include
close clinical monitoring with pharmacologic intervention,
use of steroids, intravenous immune globulin and anti-D.
Treatment decisions are individualized for each patient. In
general, patients with platelet counts above 20,000-30,000
cells/mm3 may only require close monitoring in the absence
of a planned surgical procedure, acute illnesses or another
symptom of concern including bleeding. Treatment decisions
should be grounded on a good working relationship between
the physician and patient should be cognizant of the rationale for observation only, and that they promptly report
symptoms that might warrant further evaluation and/or
a change in strategy.
Corticosteroids
If therapy is indicated, patients may be initially treated
with some form of corticosteroid with the most commonly
utilized formulations including prednisone, methylprednisolone, and dexamethasone. Pediatric patients are
commonly treated with an initial dose of prednisone of
1-2 mg/kg for a duration of 1-2 weeks; some physicians
utilize a weaning schedule while others do not based upon
response to and length of therapy. The majority of patients
experience some initial response to therapy, with only 30%
or less representing durable responses maintained greater
than 5 years after a single steroid treatment. Pulsed high
dose dexamethasone administered over 4 days in monthly
cycles up to 6 months has been shown to induce remissions
even in the chronic form of this disorder; the durability of
these responses is not well established.
Intravenous immune globulin
Intravenous immunoglobulin (IVIG) is derived from the
plasma of many blood donors. When administered intravenously in greater than replacement doses, a reduction in
reticuloendothelial system clearance of antibody coated
platelets ensues resulting in increased platelet counts. In
addition, other pathophysiologic mechanisms have been
purported to contribute to this therapy's efficacy including
increased clearance of pathogenic platelet antibodies
through the presence of anti-idiotypic antibodies. IVIG has
been shown to be effective in the treatment of acute and
chronic ITP. A variety of dosing regimens have been reported
including lower dose regimens of ~200-500 mg/kg/day for
5 days or higher dose regimens of ~1 gram/kg/day for 1-2
days. Reported side effects include those associated with
mild serum sickness including urticarial rash, but may also
include a severe headache associated with aseptic meningitis.
Sucrose formulations should be avoided in patients with
renal dysfunction. Few patients experience durable responses to IVIG administered as a sole therapy; however, this has
been reported most commonly in the pediatric population
in acute disease in patients less than 8-10 years of age.
Anti-D
Another immune based therapeutic utilized as first line
agent for treatment of ITP is Anti-D immunoglobulin.
Anti-D is a concentrated formulation of antibodies against
the red blood cell antigen "D" also commonly known as part
of the Rh complex. Anti-D is effective only in patients with
an Rh positive blood type and with an intact spleen. The
pathophysiologic mechanism of action of Anti-D is thought
to be similar to that of IVIG with decreased reticuloendothelial system clearance of antibody coated platelets; this may
occur through occupation of the majority of Fc receptors
with numerous antibody-coated erythrocytes. Anti-D is
commonly administered as an intravenous infusion for the
treatment of ITP. Reported side effects are similar to those
observed with IVIG including allergic reactions. Although
a decrease in hemoglobin is expected with the use of
Anti-D, exaggerated intravascular red cell hemolysis may
occur resulting in acute anemia, multi-system organ failure,
difficulty breathing, and even death. In December 2009,
the FDA revised the package insert to highlight these
warnings while also suggesting additional tests and patient
monitoring to identify and treat those patients at highest
risk. Patients should immediately report back pain, shaking
chills, fever, discolored urine, decreased urine output, sud-
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den weight gain, fluid retention, edema and/or shortness of
breath to their physician.
Rituximab
Chronic and/or refractory ITP has been treated with other
immune modulating agents including Rituximab, an antiCD20 antibody that decreases B-lymphocytes. Modulation
and reduction in B-lymphocytes interferes with the B-CellT-cell interaction pivotal to continued antibody formation
and resultant platelet destruction observed in ITP. Rituximab
has been demonstrated in certain studies to be efficacious
as an initial treatment in selected patients, most commonly
adult patients with strong markers of refractory disease.
More than 50% of patients in early studies showed a
response to Rituximab with the majority of responses
maintained over one year.
As it is generally used as an alternative therapy after failure
of other agents it is still unknown whether use as a first
line agent would increase the number of observed durable
responses. Rituximab is generally well tolerated despite
infusion reactions that often abate with a slower infusion
rate and usually do not recur with subsequent re-exposure.
Rituximab causes mild lymphopenia; there is no evidence to
support the need for antibacterial prophylaxis. A more concerning yet less common adverse event associated with the
use of this agent has been the development of progressive
multifocal leukoencephaly in previously treated patients.
Splenectomy
Splenectomy is one of the oldest and most common
treatments for ITP. Splenectomy is typically reserved for
patients who have failed other medical therapies, often
including Rituximab. The majority of patients experience
durable responses (~66%). Splenectomy is now commonly
performed laparoscopically, and as such the overall acute
morbidity is fairly low. Patients in whom elective splenectomy is considered should receive required supplemental
vaccinations at least 2 weeks prior to the procedure
including consideration of pneumococcal, meningococcal,
and Hemophilus influenza B vaccinations. For patients
who have been recently or chronically treated with corticosteroids, the use of stress doses should be administered for
coverage during and after the procedure. Currently, splenectomy is postponed for longer periods of time with increased
or repeated utilization of currently available agents including
IVIG, anti-D, or Rituximab; splenectomy is less commonly
utilized in the pediatric populations as compared to adults.
Patients may relapse post splenectomy; relapses most
commonly occur in the first two years post-procedure.
If patients relapse or are refractory to splenectomy, the
presence of an accessory spleen should be considered.
Second-line therapies
Other medications have been demonstrated to have variable efficacy in the treatment of ITP. These agents include
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danazol, cyclophosphamide, vincristine, azathioprine, and
dapsone; the overall use of these agents is decreased compared to previously discussed agents and as such their clinical
efficacy has been less systematically evaluated. The use of
second-line agents should be pursued after consultation with
a hematologist familiar with their use and the treatment of
acute and chronic ITP.
Table 5. Individual agents for treatment of ITP with time to first and peak response with reported dose range.
Newly approved agents
A newer class of agents for treatment of ITP is medications
that are second-generation thrombopoietic growth factors.
Thrombopoietin (TPO) glycoprotein hormone produced
mainly by the liver and the kidney that regulates the production of platelets by the bone marrow. The first-generation
recombinant forms of human TPO were discontinued after
healthy volunteers developed antibodies against TPO and
subsequent thrombocytopenia.
Prednisone
Newer second-generation formulations have been developed
without significant resemblance to human TPO but with
the ability to stimulate the TPO receptor. These new agents,
Romiplostim (AMG 531 or Nplate®) and Eltrombopag
(Promacta®) are FDA-approved for chronic ITP. In general,
these agents are fairly well tolerated; care must taken with
their use due to an increased incidence of bone marrow
reticulin deposition. To date, this appears to be reversible and
there does not appear to be a clinical correlation between reticulin deposition to other bone marrow failure syndromes,
including myelofibrosis. Overall, these medications have
a proven efficacy in maintaining clinically "safe" platelet
counts; however the response is lost when the agent is
discontinued. The current adverse event profile appears
tolerable, yet patients do require close continued observation.
Platelet transfusions
Patients who experience emergent, life-threatening bleeding, such as central nervous system or gastrointestinal
with altered vital signs or significant anemia, may be treated
with a platelet transfusion in addition to use of other agents.
Transfused platelets would be expected to have an altered
half-life due to the presence of anti-platelet antibodies;
however, when administered acutely in larger doses, from
a single donor, or as a continuous infusion, they may achieve
hemostasis either in association with or in the absence of
an improvement in the platelet count.
Supportive agents
Other hemostatic agents may be utilized in specific patients
or types of bleeding events. These agents are not well studied in this specific disorder but do have well documented use
in other bleeding diatheses such as hemophilia. Examples
of these adjunctive therapies include antifibrinolytic agents
such as tranexamic acid and aminocaproic acid that are useful for mucosal bleeding. There are also reports of the use of
recombinant factor VIIa, Novoseven®, in thrombocytopenic
states.
Recommended
Dose Range
Recommended Duration
1-4 mg/kg po daily; Max per
day: 1 mg/per kg body weight
For 1-4 weeks
4 - 14
7 - 28
40 mg po/IV daily
For 4 days every 2-4 weeks
2 - 14
4 - 28
IVIG
0.4 or 1 g/kg per dose IV
0.4 g/kg for 5 days or 1 mg/kg for 1-2 days
1-3
3-7
Anti-D
50-75 µg/kg per dose IV
1-4 doses; administered 3-4 weeks apart
1-3
3-7
375 mg/m2 per dose IV
Weekly X 4 doses
7 - 56
14 - 180
1 - 56
7 - 56
Agent
Time To Initial Time To Peak
Response: Days Response: Days
First-Line therapy
Dexamethasone
Second-Line therapy
Rituximab
Splenectomy
Not applicable
Vincristine
Dosed per m2;
max dose 2 mg IV
Weekly X 4-6 doses
7 - 14
7 - 42
Vinblastine
0.1 mg/kg per dose IV
Weekly X 6 doses
7 - 14
7 - 42
400-800 mg po daily
in divided doses
Up to 6 months as tolerated & with response
14 - 90
28 - 180
Azathioprine
2 mg/kg po daily
Up to 6 months as tolerated & shows
response
30 - 90
30 - 180
Cyclosporin A
5 mg/kg x6 days
then 2.5-3 mg/kg
Titrate dose to blood level 100-200 ng/ml
21-28
30-180
1-2 mg/kg po
For 16 weeks minimum
7-112
30 - 180
1000 mg twice daily
For 4 weeks minimum
28-42
30-180
Dapsone
75-100 mg daily
Long-term as tolerated & shows response
21
14-21
AMG531
3-10 µg/kg weekly
subcutaneously
Long-term as tolerated & shows response
5 - 14
14 - 60
Eltrombopag
50-75 mg po daily
Long-term as tolerated & shows response
7 - 28
14 - 90
Danazol
Cyclophosphamide
Mycophenolate mofetil
Adapted from: Provan D et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood 2009; 115: pages 172-33 and Rodeghiero F et al. Standardization of terminology, definitions and outcome criteria in
immune thrombocytopenic purpura of adults and children: report from an international working group. Blood 2009; 113: page 2389.5