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W. Ghanima et al.
RA is thought to be due to increased platelet production, both TPO-RA have also been described to have immunomodulatory effects, with increased regulatory T- and B-cell effects in patients on TPO-RA.13 This effect has been suggested to be mediated by TGF-B, a major cytokine involved in T-regulatory (Treg) cell development, and found in abundance in MK and platelets.14,15 Alternatively, TPO-RA may also affect antigen processing and presentation by MK.16 Whether these potential immunomodulatory effects result in the treatment-free durable responses reported with both TPO-RA has not yet been understood.
Efficacy of romiplostim and eltrombopag
Platelet response
The response rate of these agents depends on the defi- nition of “response.” If a consistent “durable” platelet count response is required, then the response rate may be 40-60%. This type of response, with platelet counts con- sistently higher than 50x109/L without bleeding and/or need for rescue therapy, is a realistic goal for patients with ITP. If, however, a “response” is a single platelet count over 50x109/L during a finite period of time, then the response rate is closer to 60-90%.17-23
Table 2 summarizes the effect of the two agents in ran- domized controlled trials (RCT) performed in adult ITP patients. The rate for a durable response in the pivotal tri- als for romiplostim was around 60% in non-splenec- tomized patients but lower in previously splenectomized patients. Splenectomized patients treated with eltrom- bopag in the Randomized Placebo-Controlled Idiopathic Thrombocytopenic Purpura (RAISE) and Eltrombopag Extended Dosing (EXTEND) studies also had lower response rates than non-splenectomized patients. While splenectomized patients and those with platelet counts <15x109/L respond less well to both romiplostim18 and eltrombopag,24,25 there is still good evidence of the effect of these agents in these patients.
A recent meta-analysis, which included 1126 patients from 13 RCT performed in eight adult and five pediatric ITP populations, showed that TPO-RA significantly increased platelet response by 3-fold and durable response rates by almost 8-fold as compared to placebo or Standard of Care (SoC).26 In adult studies, a 3-fold increase in response [Risk Ratio (RR): 3.1, 95% Confidence Interval (CI): 2.0-5.0] and 7.5-fold increase in durable response (RR: 7.4, 95%CI: 3.2-17.1) was seen.26 Therefore, while this is a very effective approach to treatment of ITP, not all patients will have a clinically meaningful response to TPO-RA, whereas some have to discontinue TPO-RA because of the lack of response.20,24,27 In the EXTEND study, of the 302 patients enrolled, 55% withdrew from the study due to adverse events (14%), patient decision (13%), lack of efficacy (11%), or other reasons,20,24,27 whereas, in the long-term romiplostim study, 31% of the 292 enrolled patients discontinued because of patient deci- sion (27%), adverse events (12%), alternative therapy (12%), or for other reasons.20,24,27
Reduction in bleeding and concomitant medications
The meta-analysis showed that TPO-RA significantly reduced incidences of any or severe bleeding events (RR: 0.8, 95%CI: 0.7-0.9; RR: 0.5, 95%CI: 0.3-0.99, respective- ly).26 Especially with eltrombopag, there were substantial reductions in any or severe bleeding events in treated patients compared with controls (RR: 0.7, 95%CI: 0.5-0.9; and RR: 0.3, 95%CI: 0.1-1.0, respectively). In parallel with reduced bleeding episodes, pooled results of eight studies indicated a significant reduction in the need for rescue medications in the TPO-RA groups compared with con- trol groups (RR: 0.5, 95%CI: 0.4-0.6).26 Treatment studies with both agents have also demonstrated an ability to reduce or stop concomitant medications (RR: 1.8, 95%CI: 1.1-3.0).
Health-related quality of life and thrombopoietin treatment
Health-related quality of life (HRQoL) was studied in many of the RCT and extension studies conducted with
Table 1. Characteristics and down-stream effect of eltrombopag, romiplostim and endogenous thrombopoietin.
Structure and discovery
Binding site
Effect on endogenous thrombopoietin
Demonstrated down-stream effect on various signal pathways*
Effect on MK
Off-target effect
Eltrombopag
Small molecule discovered by screening libraries of small molecules that stimulate the TPO receptor down-stream pathways
Binds the transmembrane and juxtamembrane domains of the TPO receptor
No displacement of TPO, may be additive
JAK2/STAT5 PI3K/Akt ERK
Earlier MK (including CD41-) and late MK
Iron and Ca chelation
Romiplostim
Peptibody developed by screening peptide libraries for sequences that can
stimulate the TPO receptor
Binds to the extracytoplasmic domain of the TPO receptor in same manner
as TPO
Can displace TPO from its receptor
JAK2/STAT5 PI3K/Akt ERK
STAT3
Mature MK (CD41+ CD61+)
Thrombopoietin
Acts at TPO binding site
JAK2/STAT5 PI3K/Akt ERK
STAT3 MAPK, STAT1
All stages
TPO: thrombopoietin; MK: megakaryocytes; Ca: calcium. *Not all pathways have been fully explored.
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haematologica | 2019; 104(6)