Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial

Juliette Lambert, Cécile Pautas, Christine Terré, Emmanuel Raffoux, Pascal Turlure, Denis Caillot, Ollivier Legrand, Xavier Thomas, Claude Gardin, Karïn Gogat-Marchant, Stephen D Rubin, Rebecca J Benner, Pierre Bousset, Claude Preudhomme, Sylvie Chevret, Herve Dombret, Sylvie Castaigne, Juliette Lambert, Cécile Pautas, Christine Terré, Emmanuel Raffoux, Pascal Turlure, Denis Caillot, Ollivier Legrand, Xavier Thomas, Claude Gardin, Karïn Gogat-Marchant, Stephen D Rubin, Rebecca J Benner, Pierre Bousset, Claude Preudhomme, Sylvie Chevret, Herve Dombret, Sylvie Castaigne

Abstract

The randomized, phase III ALFA-0701 trial showed that a reduced and fractionated dose of gemtuzumab ozogamicin added to standard front-line chemotherapy significantly improves event-free survival (EFS) in adults with de novo acute myeloid leukemia (AML). Here we report an independent review of EFS, final overall survival (OS), and additional safety results from ALFA-0701. Patients (n=271) aged 50-70 years with de novo AML were randomized to receive conventional front-line induction chemotherapy (3+7daunorubicin+cytarabine) with/without gemtuzumab ozogamicin 3 mg/m2 on days 1, 4, and 7 during induction. Patients in remission following induction therapy received 2 courses of consolidation therapy (daunorubicin+cytarabine) with/without gemtuzumab ozogamicin (3 mg/m2/day on day 1) according to their initial randomization. The primary end point was investigator-assessed EFS. Secondary end points included OS and safety. A blinded independent review confirmed the investigator-assessed EFS results [August 1, 2011; hazard ratio (HR) 0.66; 95% Confidence Interval (CI): 0.49-0.89; 2-sided P=0.006], corresponding to a 34% reduction in risk of events in the gemtuzumab ozogamicin versus control arm. Final OS at April 30, 2013 favored gemtuzumab ozogamicin but was not significant. No differences in early death rate were observed between arms. The main toxicity associated with gemtuzumab ozogamicin was prolonged thrombocytopenia. Veno-occlusive disease (including after transplant) was observed in 6 patients in the gemtuzumab ozogamicin arm and 2 in the control arm. In conclusion, gemtuzumab ozogamicin added to standard intensive chemotherapy has a favorable benefit/risk ratio. These results expand front-line treatment options for adult patients with previously untreated AML. (Trial registered at clinicaltrials.gov; identifier: 00927498).

Copyright© 2019 Ferrata Storti Foundation.

Figures

Figure 1.
Figure 1.
Overall survival. Control: daunorubicin + cytarabine (D+A); GO: gemtuzumab ozogamicin plus D+A; OS: overall survival; HR: hazard ratio; CI: Confidence Interval; n: number.
Figure 2.
Figure 2.
Event-free survival (EFS) (investigator-assessed). Control: daunorubicin + cytarabine (D+A); GO: gemtuzumab ozogamicin plus D+A; EFS: event-free survival; HR: hazard ratio; CI: Confidence Interval; n: number.

References

    1. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391–2405.
    1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424–447.
    1. Ricart AD. Antibody-drug conjugates of calicheamicin derivative: gemtuzumab ozogamicin and inotuzumab ozogamicin. Clin Cancer Res. 2011;17(20):6417–6427.
    1. Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res. 2001;7(6):1490–1496.
    1. Caron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood. 1994;83(7):1760–1768.
    1. Castaigne S, Pautas C, Terre C, et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012; 379(9825):1508–1516.
    1. International System for Human Cytogenetic Nomenclature. Guidelines for cancer cytogenetics. In: Mittelman F, ed. Supplement to an International System for Human Cytogenetic Nomenclature. Basel, Switzerland: Karger; 1991:1–53.
    1. Hills RK, Castaigne S, Appelbaum FR, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia: a meta-analysis of individual patient data from randomised controlled trials. Lancet Oncol. 2014;15(9):986–996.
    1. Lambert J, Lambert J, Nibourel O, et al. MRD assessed by WT1 and NPM1 transcript levels identifies distinct outcomes in AML patients and is influenced by gemtuzumab ozogamicin. Oncotarget. 2014; 5(15):6280–6288.
    1. Burnett A, Cavenagh J, Russell N, et al. Defining the dose of gemtuzumab ozogamicin in combination with induction chemotherapy in acute myeloid leukemia: a comparison of 3 mg/m2 with 6 mg/m2 in the NCRI AML17 Trial. Haematologica. 2016;101(6):724–731.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する