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Thrombopoietin receptor agonists in ITP
patients included in the pivotal studies and “real-life” reports generally give reassuring data. Many of the initial theoretical concerns, such as uncontrolled stem cell prolif- erations and myelofibrosis with TPO-RA, have not mate- rialized. However, there are emerging reports of adverse events, such as an increased incidence of thrombosis, which remains unexplained.
In the EXTEND study, evaluating long-term safety and efficacy of eltrombopag in 302 adults ITP patients treated with eltrombopag for a mean duration of >2 years, impor- tant adverse events were rare and did not increase with treatment duration over one year.24 Fourteen percent of patients on eltrombopag stopped treatment because of adverse events. Although plasma levels and exposure have been shown to be much higher in Asian populations,44 tol- erability of eltrombopag in the Chinese population appears similar to that observed in Caucasian populations. The good tolerance of eltrombopag observed in pivotal studies has been confirmed in the Spanish eltrombopag registry including 220 ITP adults.45
In a pooled analysis from 13 completed studies of romi-
plostim including 1111 patients, exposure-adjusted rates of adverse events were lower in the romiplostim group than in the placebo/SoC group.46 These data were con- firmed in another registry study.36
Bone marrow reticulin deposition and TE events are associated with the TPO-RA drug class. However, the safety profiles of TPO-RA do not fully overlap and specific adverse events, i.e. cataract and transaminitis, are more frequently seen with eltrombopag. Others, such as devel- opment of neutralizing antibodies, are mainly observed with romiplostim, as is pain after administration. This absence of overlapping toxicity encourages switching when a TPO-RA is stopped because of an adverse event that is not due to class effect.
Bone marrow fibrosis
Early concerns were raised regarding the possible induction of bone marrow fibrosis because of sustained stimulation of megakaryopoiesis by TPO-RA, as seen in animal studies.47 Table 3 summarizes results of the pub- lished trials showing that, in most patients, grade of fibro-
Table 3. Summary of studies determining the grade of bone marrow fibrosis in patients treated with thrombopoietin receptor agonists.
Author
Ghanima48
Brynes51
Brynes49
Janssens50
Study design N Agent Staging
Retrospective, single center. BM biopsies 66 R, E ECS were performed at different intervals.
Prospective, open-label multicenter study 117 E ECS of patients who were included in the EXTEND trial
and received eltrombopag were followed up
with annual BM biopsies
Prospective, open-label multicenter. 162 E ECS Biopsy specimens were collected at baseline
(before treatment) and after 1 and 2 years
of treatment
Prospective, open-label multicenter. 131 R Bauer-
Bone marrow biopsies were scheduled after 1, 2, or 3 years of romiplostim or earlier if patients discontinued
or failed to achieve/maintain a response to romiplostim.
Results
After a median treatment duration of 29 months (range: 16-47), 22% of the BM biopsies were graded as MF-0, 59% as MF-1 and 18% as MF-2.
The proportion of MF-0 decreased from 67% in the pre-treatment biopsies to 22% first on-treatment biopsies, which were largely MF-1.
Two or more biopsies were available in 32 patients; comparing the first to the last on-treatment bone marrows, the grade of fibrosis increased in 11 cases, remained the same in 15 and decreased in 6.
209 on-treatment biopsies collected from 115 patients were re-evaluated. Median duration of treatment was 45 months (range: 2-73m).
98% of patients had findings of MF-0 or MF-1 in any given year over the 5-year study period. Five biopsies from 3 patients (2%) were reported as MF-2 or MF-3 at 25 months; collagen was present in these 5 specimens.
Of 18 patients with 3 biopsies, 8 patients remained at MF-0 over the treatment period and 5 had an increase of one grade. The remaining 5 patients showed a decrease of one grade when compared with the grade from the first on-treatment biopsies.
Median time on treatment was 104 weeks
(range: 2.4-113). At 1 year (n=127), 69% had a grade
of MF-0, 28% had MF-1, 2% had MF-2, and 2% had MF-3. Compared with baseline, 79 out of 93 patients (85%) had MF-0 at 2 years, 9 (10%) had a 1-grade increase, 2 (2%) had a 1-grade decrease, 1 (1%) remained MF-1, and none had 2- or 3-grade increases. Five out of 127 patients (4%) at 1 year and 1 out of 93 (1%) at 2 years had collagen deposition.
The median (Q1, Q3) duration of treatment was in cohort meister 1, 147 (17-156) weeks; cohort 2, 155 (66, 156) weeks;
and cohort 3, 155 (66-156) weeks.
9 of 131 (6.9 %) included in the 3 cohorts
had increases of ≥2 grades (cohort 1: 0/34; cohort 2: 2/39; cohort 3: 7/58), including 2 with collagen.
R: romiplostim; E: eltrombopag; ECS: European Consensus Staging; BM: bone marrow; MF: marrow fibrosis.
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