Page 124 - 2019_01-Haematologica-web

J. Lambert et al.
Introduction
Acute myeloid leukemia (AML) is a heterogeneous dis- ease, with classification based on morphological, cytoge- netic, molecular, and immunophenotypic characteristics,1 which, along with patients' characteristics, such as age and Eastern Cooperative Oncology Group Performance Status (ECOG PS), influence treatment recommendations and out- comes.2 Gemtuzumab ozogamicin (GO) is an antibody- drug conjugate composed of the CD33-directed monoclon- al antibody that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin.3 Efficacy with single-agent GO (9 mg/m2 for each of 2 doses administered 14 days apart) was initially established in patients with CD33-posi- tive AML in first recurrence based on clinically meaningful response rates observed in 3 phase II studies in patients with AML in first relapse. However, liver toxicity and a long duration of cytopenia were observed.4 Additional in vitro study results, showing that CD33-expressing leukemic cells rapidly re-express CD33 molecules on their cell surface after treatment with an anti-CD33 antibody,5 led the Acute Leukemia French Association (ALFA) to investigate the use of a fractionated dosing regimen of GO that might enhance the internalization process while improving safety com- pared with higher unfractionated dosing.6
The randomized, phase III ALFA-0701 study compared the efficacy and safety of the standard 3+7 daunorubicin (DNR; days 1-3) and cytarabine (AraC; days 1-7) induction regimen (D+A), with or without fractionated dosing of GO (3 mg/m2 on days 1, 4, and 7), in patients aged 50-70 years with treatment-naive AML.6 Patients in remission following induction therapy received 2 courses of consolidation ther- apy consisting of D+A with or without GO (3 mg/m2/day on day 1) according to their initial randomization. The ini- tial results as of the cut-off date of August 1, 2011, reported for the ALFA-0701 trial by Castaigne et al. in 2012 showed that the study met its primary end point, with a significant improvement in investigator-assessed event-free survival (EFS) without an increase in the risk of death from toxicities when GO was added to the standard chemotherapy.6 Following publication of the initial results, the Centre Hospitalier de Versailles, in collaboration with Pfizer, per- formed a retrospective collection of additional data to pro- vide a more complete assessment of the safety profile of GO, and to conduct a retrospective, independent, blinded review of EFS. This report presents the final overall survival (OS) results from the ALFA-0701 study based on a longer follow-up date (cut-off date, April 30, 2013), the results of the independent review of EFS, as well as additional safety results focused on adverse events (AEs) of special interest considered the most important for understanding the safety profile of GO.
Methods
Details of this randomized, open-label, multicenter, phase III ALFA-0701 study have been previously described.6
Patients and treatment
A total of 280 patients were randomized 1:1 to receive conven- tional 3+7 D+A induction chemotherapy, with DNR 60 mg/m2/d on days 1 to 3 and AraC 200 mg/m2/d on days 1 to 7 without (con- trol arm) or with GO (GO arm) 3 mg/m2/d on days 1, 4, and 7; the total dose of GO per infusion was not to exceed one 5 mg vial.
A second induction course, with DNR and AraC, was given if leukemic blasts persisted at day 15 bone marrow aspirate (BMA). Patients with a complete remission (CR) or CR with incomplete platelet recovery (CRp) after induction treatment received 2 cours- es of consolidation, including DNR and AraC with or without GO 3 mg/m2/d on day 1 according to their randomization, provided the platelet count was ≥50x109/L on the planned day 1 of the con- solidation course.
Patients who experienced CR could be considered for allogeneic transplant according to ECOG PS, age, if a donor had or had not been found, and cytogenetic and molecular risk categories. An interval of two months between the last dose of GO and trans- plantation was recommended.
The study was approved by the Saint-Germain en Laye ethics committee in France and the institutional review board of the French Regulatory Agency. All procedures were conducted in com- pliance with the Declaration of Helsinki. Written informed consent was provided by all patients (EuduraCT n.: 2007-002933-36).
Efficacy analyses
This report presents: 1) final results of the secondary end point of OS, defined as the time from date of randomization to date of death from any cause at the cut-off date of April 30, 2013; 2) results of a blinded and independent review of the EFS end point, defined as the time from randomization to relapse, death from any cause, or failure to achieve CR or CRp, performed by hematology experts to study the reproducibility of this clinically important end point in AML trials; 3) results of the secondary end point relapse-free sur- vival for patients experiencing a response; and 4) hematologic response by investigator assessment. The independent review committee analysis was based on the retrospective collection of all data used for efficacy measurements, including reports of BMA, complete blood count, extramedullary disease, or molecular or cytogenetic relapse available at the site from screening until death, or up to 28 days after either induction failure or relapse as deter- mined by the investigator (whichever happened first).
Safety analyses
Safety data presented in this report were collected retrospective- ly and consist of events of special interest considered the most important for understanding the safety profile of GO and serious AEs (SAEs). This includes all grades of hemorrhage, all grades of veno-occlusive disease (VOD), severe (grade ≥3) infections, any adverse event (AE) that led to early permanent discontinuation of either GO or chemotherapy, and laboratory data. Serious AE reporting contains all SAEs reported to the Pfizer safety database throughout the study and was not restricted to causality or prede- fined categories.
Statistical analyses
Sample size calculations have been reported previously.6 The modified intent-to-treat (mITT) population was the primary pop- ulation for evaluating efficacy end points and included all patients who were randomized, unless consent was withdrawn before treatment initiation. Analyses were made according to the initial randomization arm, regardless of whether patients received the study drug to which they were randomized.
Results
Patients
Of the 280 patients randomized in this study, data from 9 patients were excluded from the analyses because no signed copy of the informed consent was available in the
114
haematologica | 2019; 104(1)