No clinical benefit of eltrombopag versus placebo in combination with induction chemotherapy in patients with acute myeloid leukemia

The standard of care first-line treatment of adult patients with acute myeloid leukemia (AML) remains induction chemotherapy with cytarabine and an anthracycline, for example, daunorubicin.¹ Thrombocytopenia is often present in patients with AML, and this associated symptom can also be exacerbated by induction chemotherapy.² The oral thrombopoietin receptor agonist, eltrombopag, has been shown to stimulate platelet production via a similar biological mechanism to endogenous thrombopoietin, suggesting a potential treatment for thrombocytopenia.³

This randomized, double-blind, multicenter, phase II study (NCT01890746) aimed to assess the safety and efficacy of eltrombopag in eligible treatment-naïve adult patients with AML (n = 149), during anthracycline-based induction chemotherapy. Standard induction chemotherapy was administered to patients (n = 148), consisting of daunorubicin (90 mg/m² [18–60 years], 60 mg/m² [>60 years], days 1–3) in combination with cytarabine (100 mg/m², days 1–7). Patients were assigned 1:1 to receive either eltrombopag (200 mg, once daily, n = 74) or matching placebo (once daily, n = 74), starting on day four of induction chemotherapy, until one of the following endpoints were met: platelet counts were ≥ 200 x 10⁹/L, remission, or > 42 days from start of induction chemotherapy treatment.

Key findings:

All data is shown as eltrombopag group versus placebo group, where applicable

Safety

• Mean age of patients were matched: 56.7 years vs 56.6 years
• Decreased left ventricular ejection fraction (LVEF) occurred in 7% (n = 5) vs 10% (n = 7)
• Adverse events (AEs) during treatment: 97% (72/74) vs 93% (66/71)
• Adverse events considered to be related to study treatment: 82% (n = 61) vs 73% (n = 52)
• Most common AEs (≥ 20% incidence) considered related to eltrombopag:
  • Nausea: 38% (n = 28) vs 49% (n = 35)
  • Febrile neutropenia: 23% (n = 17) vs 17% (n = 12)
  • Diarrhoea: 22% (n = 16) vs 25% (n = 18)
• Rate of serious AEs: 32% (n = 24) vs 20% (n = 14)
• Rate of grade 3–5 bleeding events: 9% (n = 7) vs 1% (n = 1)
• Overall, deaths occurred in 53% (n = 39) vs 41% (n = 29) patients

Efficacy

• Patients completing the 2-year follow-up: 30% (n = 22) vs 45% (n = 33)
• Median overall survival: 15.4 months vs 25.7 months, HR = 1.54 (95% CI, 0.96–2.47)

This phase II study concluded that the combination of eltrombopag and induction chemotherapy has no clinical benefit over placebo in patients with AML, with the safety analysis highlighting that eltrombopag increased the rate of serious adverse events.