Background
Two simultaneous Phase 3 double-blind placebo-controlled RCTs (Kuter DJ et al, Lancet 2008). Cohort 1 (splenectomized): 42 patients. Cohort 2 (non-splenectomized): 41 patients. All adults with chronic ITP (≥6 months), platelet count ≤30×10⁹/L, and ≥1 prior ITP therapy. Romiplostim (AMG-531; Nplate) is a peptibody — a thrombopoietin receptor (c-Mpl) agonist peptide fused to an IgG1 Fc fragment — that stimulates megakaryocyte proliferation and platelet production. Subcutaneous weekly dosing. Randomized 2:1 to romiplostim or placebo in each cohort.
Interventions and follow up
Arm A: Romiplostim 1 mcg/kg SC weekly, titrated weekly to 10 mcg/kg maximum to maintain platelet count 50–200×10⁹/L
Arm B: Placebo SC weekly, with same dose-adjustment simulatio
Primary endpoint: Durable platelet response (≥50×10⁹/L for ≥6 of the last 8 weeks on study without rescue therapy)
mFollow up: 24 week
Arm B: Placebo SC weekly, with same dose-adjustment simulatio
Primary endpoint: Durable platelet response (≥50×10⁹/L for ≥6 of the last 8 weeks on study without rescue therapy)
mFollow up: 24 week
Results
Durable platelet response (non-splenectomized): 61% (romiplostim) vs 5% (placebo), P<.0001
Durable platelet response (splenectomized): 38% vs 0%, P=.0013
Overall platelet response (non-splenectomized): 88% vs 14%
Rescue medication use: 23% vs 56% (non-splenectomized)
Durable platelet response (splenectomized): 38% vs 0%, P=.0013
Overall platelet response (non-splenectomized): 88% vs 14%
Rescue medication use: 23% vs 56% (non-splenectomized)
Adverse events
Main adverse events: Headache most common (35% vs 32%). Fatigue, arthralgia, dizziness comparable between arms. Bone marrow fibrosis: reticulin increase reported in 14% on long-term extension, typically grade 1. Thrombotic events: 1 (romiplostim) vs 1 (placebo) during study. No grade ≥3 ALT elevation. Neutralizing antibodies: rare and without clinically meaningful consequence. Discontinuation due to AEs: 3% vs 0%.
Conclusions
Romiplostim substantially increased durable platelet response rates compared to placebo in both splenectomized and non-splenectomized chronic ITP patients, establishing SC weekly romiplostim as an effective TPO-RA for ITP.
Key Limitations
Key Limitations: Combined trial interpretation: each cohort was small (n=41–42). Splenectomized patients had lower response rate (38%), reflecting more refractory biology. Bone marrow reticulin fibrosis (14% on long-term extension) requires periodic bone marrow monitoring in some guidelines. Rebound thrombocytopenia on discontinuation is a clinical concern. Long-term use: durable remission after discontinuation occurs in ~10–20% of patients over time. Weekly SC injection is a burden vs daily oral eltrombopag.
Clinical Context
FDA approved August 2008 (Nplate) — the first TPO-RA approved for chronic ITP, co-approved with eltrombopag in close succession. Nplate is given weekly SC with dose titration; Promacta is daily oral with liver monitoring. Both are second-line ITP standards. Novel agents (fostamatinib [SYK inhibitor], avatrombopag [oral TPO-RA]) have expanded the arsenal for refractory ITP. ASH 2019 ITP guidelines recommend TPO-RAs as preferred second-line therapy over splenectomy in most patients.
References