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J. Lambert et al.
2-sided P=0.0002
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.
Non-hematologic laboratory test results revealed that liver chemistry abnormalities were generally similar between treatment arms, except that GO treatment was associated with more frequent elevations of aspartate aminotransferase than the control treatment (all grades: 89.2% and 73.9%; grade 3 / 4 : 14% and 9.0%, respective- ly) and more frequent elevations of alkaline phosphatase (all grades: 79.7% and 68.9%; grades 3 / 4: 13.3% and 5.3%, respectively) (Online Supplementary Table S7).
Discussion
A previously published analysis of the ALFA-0701 study was based on a cut-off date of August 1, 2011.6 In this report, we present the final analysis of OS based on a cut- off date of April 30, 2013, and the results of a blinded, independent analysis of the primary end point, EFS.
The final results demonstrate a trend toward longer OS for patients in the GO arm than in the control arm, although this difference did not reach statistical signifi- cance. Nevertheless, the longer OS trend in the GO arm observed in ALFA-0701 is consistent with a significant improvement in OS demonstrated in an individual patient data meta-analysis (IPD-MA).8 This IPD-MA consisted of 5 randomized studies comprising more than 3300 patients and included the ALFA-0701 study, in which GO was used in intensive induction chemotherapy in adult patients with newly diagnosed AML. In this IPD-MA, the primary end point of OS showed a significant improvement at five years for patients who received GO [Odds Ratio (OR): 0.90; 95%CI: 0.82-0.98; log-rank 2-sided P=0.01], corre- sponding to a 10% reduction in risk of death in the GO arm.8 The OS benefit was the most apparent in patients with favorable (OR: 0.47; 95%CI: 0.31-0.73) and interme- diate (OR: 0.84; 95%CI: 0.75-0.95) cytogenetic risk dis- ease.8 However, as mentioned in the most recent version of the ELN guidelines,2 OS may not be the best indicator of the efficacy of a new drug because of confounding
effects of allogeneic transplant or rescue therapies given after relapse or failure to reach CR. However, EFS, which includes failure to reach CR, relapse, or death due to any cause, including drug toxicity, may better reflect the effi- cacy of a single treatment. In the ALFA-0701 study, we reported that the majority of patients did receive post- study treatment, including allogeneic transplant and res- cue therapy after induction failure or relapse. Of note, this includes 30 patients from the control arm who finally received GO as rescue therapy. Furthermore, in the ALFA- 0701 study, the sample size was calculated to show a dif- ference in EFS; thus, the relatively low number of patients in the study was probably not appropriate to show an OS benefit.
At the time of the final EFS analysis of ALFA-0701, the addition of GO to D+A approximately doubled the medi- an EFS compared with chemotherapy alone, with a medi- an EFS of 17.3 months for patients randomized to the GO arm and 9.5 months for patients in the chemotherapy- alone arm. Multiple sensitivity analyses demonstrated the robustness of the EFS results, and in this report, we estab- lished the reproducibility of the EFS end point in this trial via a blinded, independent review. A significant prolonga- tion of EFS is considered by hematologists to contribute to the clinical benefit received by patients, as this translates into a durable first remission, increasing the probability of a patient being cured. The subgroup analyses of the effect of GO on EFS in ALFA-0701 generally supports the poten- tial benefit with GO for patients with AML independently of the degree of CD33 positivity, although few enrolled patients (13.7%) had low CD33 expression (<30% of blasts positive). The effect of GO on EFS in ALFA-0701 is consistent with the positive effect of GO on RFS, as well as with the previously reported significant effect of GO on minimal residual disease assessed by NPM1 status.9 This enhancement of the quality of the response and the pro- longation of the response are the 2 factors that sustained the prolongation of EFS with GO.
In ALFA-0701, there was no difference in early mortal-
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haematologica | 2019; 104(1)