Page 2202 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 131 Diseases of Platelet Number 1949

Disadvantages of splenectomy include a lack of validated development of cross-reactive antibodies against endogenous TPO,
predictors of response, surgical risk with 30-day mortality, and which led to severe and sustained thrombocytopenia in some healthy
complication rates of 0.2% and 9.6% for laparoscopic splenectomy, volunteers. These findings prompted the development of second-
respectively, and 1.0% and 12.9% for open splenectomy, respectively, generation TPO receptor agonists that have no homology to endog-
and an increased risk of postsplenectomy infection, and vascular enous TPO. Two such drugs are now approved for the treatment of
thrombosis. patients with chronic ITP, romiplostim (Nplate, Amgen) and eltrom-
bopag (Promacta/Revolade, GlaxoSmithKline). These agents increase
the platelet count in most ITP patients including those with refrac-
Rituximab tory disease. The effect on platelet count is generally sustained as long
as the TPO receptor agonists are administered; when they are stopped,
Rituximab has been widely used in patients with various autoimmune platelet counts tend to fall rapidly to baseline levels.
diseases, including ITP. Rituximab is an anti-CD20 monoclonal Romiplostim (administered as a once-weekly subcutaneous injec-
+
antibody that targets and destroys CD20 B lymphocytes, some of tion) is a synthetic peptibody consisting of four peptides linked to an
which are likely involved in autoantibody production. Data correlat- IgG Fc fragment. The molecule binds the c-Mpl receptor at the same
ing cellular profiles with clinical outcomes suggest that the efficacy location as endogenous TPO and stimulates megakaryocyte prolifera-
of rituximab reflects improvement in T-cell function and reversion of tion and platelet production through intracellular JAK/STAT and
T-cell abnormalities; processes downstream to its direct effect on mitogen-activated protein kinase signaling. In a phase III trial, a
B-cell depletion. The effects of rituximab on platelets and autoanti- durable platelet count response (defined as the achievement of a
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bodies require further investigations. platelet count of 50 × 10 /L or higher for 6 or more of the last 8
In a systematic review of 19 observational studies that enrolled weeks of treatment) was achieved in 41 of 83 patients (49.4%)
313 ITP patients of whom 46.2% were not splenectomized, rates of receiving romiplostim compared with 1 of 42 (2.4%) patients receiv-
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complete response (platelet count >150 × 10 /L) and overall response ing a placebo. In a subsequent randomized trial that compared
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(platelet count >50 × 10 /L) with rituximab after a median follow romiplostim plus standard of care with standard of care alone,
up of 9.5 months were 43.6% (95% CI, 29.5–57.7) and 62.5% (95% romiplostim was associated with more platelet count responses, fewer
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CI, 52.6–72.5), respectively. The typical rituximab regimen was treatment failures, fewer splenectomies, less bleeding, and better
2
2
375 mg/m administered by intravenous infusion once weekly for 4 quality of life. Weekly doses of romiplostim ranged between 1 and
consecutive weeks. The median time to response was 5.5 weeks, and 10 µg/kg; however, most patients achieved a suitable response with
responses lasted a median of 10.5 months. Other observational a dose of 3 µg/kg. Weekly doses were titrated up or down to maintain
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studies have reported lower rates of durable remission, ranging from the platelet count in the appropriate range (30–100 × 10 /L).
24% at 12 months to 35% at 57 months. A metaanalysis of five Eltrombopag (administered as an oral daily tablet, 50–75 mg
randomized trials demonstrated that complete platelet count response daily) is a small molecule, nonpeptide TPO receptor agonist. Eltrom-
was more frequent with rituximab plus standard of care than with bopag also activates the c-Mpl receptor, but unlike romiplostim,
standard of care alone (relative risk 1.4, 95% CI, 1.1–1.8); however, eltrombopag binds to the transmembrane domain of the receptor and
there was limited evidence for sustained platelet count responses does not compete with circulating TPO for binding. In a phase III
beyond 6–12 months. 13 trial, eltrombopag was associated with an eightfold increase in platelet
In a prospective observational study that included 60 nonsplenec- count response compared with placebo throughout the 6-month
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tomized adult patients with ITP who had a median of two prior treatment period. The time to response was 1–2 weeks (similar to
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therapies, 24 (40%) achieved a platelet count above 50 × 10 /L and romiplostim) and there was minimal need for dose titration. Durable
at least twice their baseline value at 1 year, and 20 (33%) maintained responses were achieved in 57 of 95 patients (60%) receiving main-
their platelet count response at 2 years with rituximab treatment. In tenance eltrombopag and in only 4 of 39 patients (10%) receiving
a follow-up study of 72 adults and 66 children with chronic ITP who placebo.
achieved an initial response to rituximab, 21% to 26% maintained a In a recent systematic review that summarized the data from
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treatment-free response for at least 5 years. Low-dose rituximab randomized trials comparing TPO receptor agonists with standard of
(100 mg per week for 4 weeks) has been shown to be effective in ITP, care in ITP patients, the authors concluded that although romiplos-
but the frequency of durable responses is uncertain. tim and eltrombopag increased the platelet count response, neither
Minor infusion-related side effects of rituximab occur in approxi- agent significantly lowered the rate of severe, life-threatening, or fatal
mately 30% of patients with ITP and include hypotension, rash, sore bleeding. These findings highlight the need for studies that evaluate
throat, fever, and rigors. Severe or fatal infusion reactions are rare in patient focused outcomes.
patients treated for autoimmune diseases. Serum sickness, which is TPO receptor agonists are generally well tolerated but have been
characterized by arthropathy, fever, and low serum complement associated with headache, fatigue, and insomnia. The development
levels, may be more common in children than in adults and often of BM reticulin in patients with ITP was an early concern; however,
necessitates treatment interruption. Progressive multifocal leukoen- this problem was rarely encountered in prospective studies and the
cephalopathy (PML) is a rapidly fatal neurologic syndrome caused changes improved with discontinuation of the medication. TPO
by reactivation of latent JC virus in the brain. Rare reports have receptor agonists have also been associated with thromboembolic
linked PML with rituximab treatment. events (independent of platelet count), although the strength of this
Rituximab also interferes with the response to polysaccharide association remains uncertain. One study of eltrombopag in patients
vaccines. This is of potential concern in patients who may subse- with advanced liver disease was ended early because of an increase in
quently undergo splenectomy and supports the practice of adminis- portal vein thrombosis. Eltrombopag has been associated with serum
tering immunizations before initiating rituximab therapy. liver function test abnormalities in approximately 10% of patients.
The 2011 ASH treatment guidelines gave rituximab a weak (grade Treatment-related serious adverse events were infrequent even after
2C) recommendation for patients who have failed corticosteroids, prolonged exposure to romiplostim (n = 292) or eltrombopag (n =
IVIg, or splenectomy. 299). Thromboembolic events occurred in 6.5% of patients on
romiplostim and 4% of patients on eltrombopag.
Thrombopoietin Receptor Agonists Long-Term Follow-Up
The best treatment for patients with ITP who fail to respond to
Drugs aimed at increasing platelet production by stimulating the first-line therapy remains controversial and depends on the severity
c-Mpl receptor have been investigated for the treatment of thrombo- of symptoms, side effect profile, and patient preference. Splenectomy
cytopenia. Initial studies with pegylated recombinant human mega- has been used for many years and is the treatment option most likely
karyocyte growth and development factor were halted because of the to be associated with durable remissions. Rituximab may achieve a