Page 2031 - Williams Hematology ( PDFDrive )

2006 Part XII: Hemostasis and Thrombosis Chapter 117: Thrombocytopenia 2007

platelet donors was halted because of its stimulation of autoantibodies their plasma concentrations. Eltrombopag is metabolized in the liver,
that cleared endogenous TPO. Because of this untoward effect, the use and causes liver function abnormalities in approximately 13 percent of
of recombinant TPO was abandoned, and a search for molecules that patients administered the drug. Reduced initial doses are recommended
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might bind to and stimulate the TPO receptor ensued. Since then, the in patients with liver disease. Eltrombopag increases platelet counts
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TPO receptor agonists romiplostim and eltrombopag have been clini- (50 × 10 /L) in 80 percent of splenectomized and 88 percent of nonsple-
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cally shown to stimulate platelet production. 224,225 nectomized chronic ITP patients. A newer study evaluated repeated
short-term doses of eltrombopag (50 mg daily for up to 6 weeks fol-
Romiplostim This drug is a peptibody that carries four copies of a lowed by up to 4 weeks off therapy over three cycles) and suggested that
14-amino-acid TPO-receptor–binding peptide fused to an immuno- eltrombopag can be used as on-demand therapy and repeated courses
globulin scaffold, and binds to the TPO-binding site of the TPO recep- would be effective and safe. 230
tor with high affinity. The TPO receptor agonist induces megakaryocyte
proliferation and differentiation by activating Janus-type tyrosine Newer Thrombopoietin Receptor Agonists Other congeners are cur-
kinase (JAK)–signal transducer and activator of transcription (STAT) rently being evaluated. An oral, nonpeptide TPO-receptor agonist,
and mitogen-activated protein (MAP) kinase pathways. The inser- avatrombopag, binds to the transmembrane domain of TPO receptor,
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tion of dimeric peptide into the IgG heavy chain increases the half-life and increases platelet counts. Lack of significant food interaction is an
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of the molecule. Romiplostim has no homology with endogenous important feature of this new drug. Its use is pending FDA approval.
TPO, thus the risk of the development of antibodies against TPO is Common side effects of TPO receptor agonists include mild head-
very low. Romiplostim and TPO may also increase platelet responses to ache, arthralgia, nasopharyngitis, fatigue, diarrhea, and nausea. These
agonists. Weekly subcutaneous injection of romiplostim at doses of 1 side effects are generally mild and usually of insufficient severity to
to 3 mcg/kg produced a dose-dependent increase in the platelet count, cause the discontinuation of the drugs. Abnormalities of liver function
starting from day 5, with peak platelet levels reached by days 12 to 15, tests (elevated alanine aminotransferase [ALT], aspartate aminotrans-
and platelet counts returning to baseline by day 28. 131,135,224 Therapy for ferase [AST], and bilirubin levels) occur in approximately 2 percent
ITP is usually initiated at a dose of 1 mcg/kg per week, and the dose of ITP patients receiving eltrombopag therapy but not with romiplos-
is then increased by 1 mcg/kg to a maximum of 10 mcg/kg until the tim. Autoantibodies against romiplostim may develop but rarely have
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patient reaches target platelet counts (>50 × 10 /L). Higher starting neutralizing activity.
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doses up to the maximum dose can be used in emergency situations. If TPO-receptor agonists can induce extreme thrombocytosis, some-
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the platelet count does not increase to safe levels after 4 weeks of romi- times exceeding 1000 × 10 /L. Careful dose titration is very important,
plostim treatment at the maximum dose, the drug should be discon- because cessation of the TPO-receptor agonists cause rebound throm-
tinued. Because platelet responses are highly variable, patients should bocytopenia in approximately 10 percent of ITP patients. Rates of
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be evaluated periodically, and the dose adjusted based on the platelet thromboembolic events were reported as 6.5 percent and 4 percent with
counts. Although discontinuation of romiplostim is recommended extended romiplostim and eltrombopag treatment, respectively. 225,230
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when the platelet count exceeds 400 × 10 /L, it should be kept in mind The authors of these studies concluded that thromboembolic events are
that platelet counts can drop to extremely low levels. Close monitoring not associated with the dose of TPO receptor agonists or platelet counts,
of the platelet counts is therefore crucial. Romiplostim can be used in and at least one acquired and inherited thrombotic risk factor was pres-
patients with hepatic or renal insufficiency, but is not recommended ent in most of the patients who experienced thrombosis while they
in pregnant patients because it can cross the placenta. Two parallel were taking TPO-receptor agonists. 226,230 Nevertheless, the frequency of
placebo-controlled trials examined response rates to romiplostim in thrombosis in these studies was slightly higher than observed in other
both splenectomized and nonsplenectomized patients treated for 24 ITP studies. Secondary myelofibrosis (increased marrow reticulin) is
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weeks. Durable platelet responses and overall platelet responses were sometimes associated with therapy with TPO receptor agonists, and is
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achieved by 38 percent and 79 percent of splenectomized patients, and usually reversible. Concerns have also been expressed that these drugs
by 61 percent and 88 percent of nonsplenectomized patients who were might accelerate the progression of hematologic and solid malignancies.
given the drug. A newer study evaluating long-term (up to 5 years) Under normal circumstances, expression of the TPO receptor (mpl) is
results of romiplostim therapy showed that a platelet count of greater highly restricted to hematological tissues including marrow, spleen,
than 50 × 10 /L was achieved at least once by 95 percent of treated ITP placenta, brain and fetal liver cells. TPO receptor expression has been
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patients. 226 demonstrated on the leukemic cells of patients with acute myelogenous
leukemia (AML) and MDS, but not in lymphoid malignancies, mye-
Eltrombopag This agent is a small (442 Da) nonpeptide molecule that loproliferative neoplasms, or other nonhematologic malignancies.
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binds to the transmembrane domain of the TPO receptor and triggers Although romiplostim therapy was discontinued in a study of its use
megakaryocyte growth and differentiation, increasing platelet produc- in patients with low-/intermediate-risk MDS and thrombocytopenia
tion. Eltrombopag has some distinctive features compared to recombi- because of increased blast and AML rates (interim hazard ratio: 2.51),
nant human thrombopoietin (rhTPO) and romiplostim: Eltrombopag long-term analysis of the study showed similar survival and AML rates
does not compete with TPO binding, and while it induces the phospho- in the romiplostim and control groups. The question of whether use
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rylation of STAT proteins, it does not affect the AKT pathway. Eltrom- of TPO-receptor agonists increases the risk of leukemia warrants fur-
bopag has no effect on platelet activation in response to agonists. In ther study.
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healthy volunteers, daily doses given for 10 days elevated platelet counts
beginning at 8 days and peaking at 16 days. Eltrombopag is used orally Azathioprine This purine analogue is converted to 6-mercaptopurine
at daily doses of 25 to 75 mg, and should be given 2 hours before or following gastrointestinal absorption and works by suppressing the
after meals because food can affect its absorption. Ethnic differences immune response. At least 4 months of azathioprine therapy at doses
in eltrombopag pharmacokinetics have been described. Lower initial ranging from 50 to 250 mg/day are necessary to evaluate therapeutic
doses and slower titration is preferred in East Asian patients. Diva- efficacy. One study reported that azathioprine produced a sustained
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lent cations such as calcium interfere with absorption of the drug, so normalization of the platelet counts in up to 45 percent of patients with
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it should not be taken with dairy products or antacids. Eltrombopag refractory ITP. Azathioprine can be used in pregnancy if necessary
can also interfere with the uptake and metabolism of statins, increasing (see “Thrombocytopenia During Pregnancy” below). As with other

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