Phase Ib/IIa study of dasatinib in adult patients with newly diagnosed core binding factor acute myeloid leukemia 

Although the prognosis of patients with core-binding factor acute myeloid leukemia (CBF-AML) is favorable, there is still a need for an improvement in the long-term survival for patients. KIT is highly expressed in patients with CBF-AML, and is associated with poor outcomes.¹ Dasatinib, a multi-kinase inhibitor, with KIT inhibitory activities, in combination with cytarabine have been shown to significantly prolong the survival of KIT mutated mice compared to dasatinib alone.² Hence the rationale for the study by a group of researchers from the German-Austrian AML study group.

The AMLSG group conducted an open-label phase Ib/IIa  AMLSG 11–08 trial (NCT00850382), which is investigating the safety, feasibility, and efficacy of the addition of dasatinib to intensive induction and consolidation chemotherapy and administered as a single agent for one-year maintenance in first line treatment for adult patients with newly diagnosed CBF-AML. The primary efficacy objective of this study was to assess feasibility of dasatinib given after intensive induction and consolidation therapy and as single-agent maintenance for one year. The results of the study were reported in Leukemia.¹

Eighty-nine patients (median age = 49.5 years, range, 19–75) with newly diagnosed CBF-AML started treatment in this study at 49 AMLSG sites in Germany (n = 44) and Austria (n = 5). Of these 89 patients, t(8,21) and inv(16) were detected in 37 and 52 patients respectively. The primary combined end point of the study was the rate of early (ED) and hypoplastic (HD) deaths, rate of pleural or pericardial effusion (PEF) 3°/4°, rate of liver toxicity (LTOX) 3°/4° not improving to 2° or less within 14 days after discontinuing responsible medication, and the rate of refractory disease (RD).

Key findings:

Safety

• ED/HD rate: 4.5% (4/89)
• PEF 3°/4° rate: 6.7% (6/89)
• LTOX 3°/4° rate: 6.7% (6/89)
• Thirty-three patients discontinued study treatment with dasatinib due to adverse events (AEs); induction (n = 7), consolidation (n = 11) and maintenance (n = 15)
  • Among the 33 that discontinued treatment, AEs were treatment-related to dasatinib in 23 patients

Efficacy

• Overall complete remission (CR)/CR with incomplete peripheral blood recovery (CRi) rate: 94% (84/89)
  • Overall CR/CRi rate in patients with t(8,21): 92%
  • Overall CR/CRi rate in patients with inv(16): 96%
• Median follow-up: 4 years
  • 4-year cumulative incidence of relapse (CIR): 33.1% (95% CI, 22.7–43.4%)
    • 4-year CIR in patients with t(8,21) and inv(16) was 18.1% (95% CI, 4.7–31.5%) and 43.2% (95% CI, 28.9–57.5%), respectively, P = 0.03
  • 4-year cumulative incidence of death in CR (CID): 6.0% (95% CI, 0.9–11.2%)
  • 4-year overall survival (OS): 74.7% (95% CI, 66.1–84.5%)
    • 4-year OS in patients with t(8,21) and inv(16) was 63.9 (95% CI, 50.0–81.8%) and 82.3% (95% CI, 72.4–93.5%), respectively, HR = 0.45 (95% CI, 0.20 – 1.03), P = 0.05

The AMLSG group concluded that the addition of dasatinib to intensive chemotherapy and administration as single-agent maintenance therapy in CBF-AML was “tolerable and feasible”. They further added that the “beneficial safety profile” in the AMLSG 11–08 trial together with the promising indications for response and long-term outcome provided the basis to begin a phase III randomized study (NCT02013648) assessing dasatinib in combination with intensive treatment and for maintenance in adult patients with newly diagnosed CBF-AML.