ASH 2018 | Phase III study of gemtuzumab ozogamicin in NPM1-mutated acute myeloid leukemia

The prospective randomized AMLSG 09-09 phase III study (NCT00893399) is assessing the efficacy of gemtuzumab ozogamicin (GO) in combination with intensive induction and consolidation therapy with all-trans-retinoic-acid (ATRA) in patients with NPM1-mutated acute myeloid leukemia (AML). The early and late primary endpoints were event-free survival (EFS) at 6 months and overall survival (OS) tested at 4 years, respectively. The secondary endpoint was response to induction therapy. The data from this study were presented at the 60^th American Society Hematology Annual Meeting and Exposition by Richard Schlenk from the National Center of Tumor Diseases, Heidelberg, Germany. The speaker reported data from the early primary and secondary endpoints.

In this phase III study, 588 evaluable patients with AML were randomized to receive induction therapy consisting of two cycles of A-ICE (idarubicin 12 mg/m² intravenously [IV] day 1,3,5 [in induction II and for patients >60 years reduced to d 1, 3]; cytarabine 100 mg/m² continuous IV, day 1–7; etoposide 100 mg/m² IV, day 1–3 [in induction II and for patients > 60 years reduced to d 1, 3]; ATRA 45 mg/m²/day on days 6–8 and 15 mg/m² days 9–21, with or without GO [3 mg/m² IV day 1]). Consolidation therapy consisted of 3 cycles of high-dose cytarabine (HiDAC; 3 g/m² [reduced to 1 g/m² in patients > 60 years] bid, days 1–3; pegfilgrastim 6 mg subcutaneously, day 10; ATRA 15 mg/m²/day, days 4–21; with or without GO 3 mg/m² on day 1 [first consolidation only]). Two hundred and ninety-two patients (median age = 58.6; range: 18–82) were randomized to the GO arm and 296 patients (median age = 58.7; range: 20–80) were in the standard arm.

Key findings:

• Most common adverse events in the GO and standard arms, respectively, include blood/bone marrow (83% vs. 85%), gastrointestinal (85% vs. 81%), infection (79% vs. 73%), and constitutional symptoms (85% vs. 81%)
• Data below is representative of response to induction therapy in the GO and standard arm, respectively
  • Death rates: 10.3% vs. 5.7%, P = 0.06
    • Death rates in patients > 70 years: 20.4 vs. 4.0
    • Death rates in patients aged 60–70 years: 10.8 vs. 11.1
  • Refractory disease: 4.1 vs. 5.4, P = 0.56
  • Complete remission (CR) and CR with incomplete count recovery (CRi): 85.5% vs8%, P = 0.28
  • 2-year EFS:  44% (95% CI, 38–52%) vs. 53% (95% CI, 48–60%), P = 0.21
  • 5-year cumulative incidence of death (CID): 7.6% vs. 8.2%, P = 0.80
• Cumulative incidence of relapse was significantly reduced in the GO-arm compared to the standard-arm, P = 0.005

In summary, the addition of GO to intensive induction therapy with ICE plus ATRA in patients with NPM1-mutated AML was associated with a higher death rate, particularly in patients aged over 70 years. Moreover, the early primary endpoint to improve EFS based on significance in this phase III study was not reached. In patients achieving a CR/CRi after induction therapy, significantly less relapses occurred in the GO-arm compared to the standard-arm with no difference in the CID.

The speaker, Richard Schlenk, concluded by stating that the findings of this phase III study indicate that “GO associated with a higher rate of induction death when combined with ICE, while at the same time it was effective at preventing relapse.”