The pivotal phase III, randomized ALFA-0701 study (NCT00927498) compared the safety and efficacy of induction therapy [DA] with daunorubicin (60 mg/m2 for 3 days) and cytarabine (200 mg/m2 for 7 days) plus fractionated doses of gemtuzumab ozogamicin (3 mg/m2 on days 1, 4, 7) versus DA alone in patients aged 50–70 years with treatment-naive acute myeloid leukemia (AML). Patients in complete remission (CR) were administered two consolidations courses of intermediate doses of cytarabine with or without one dose of gemtuzumab ozogamicin (3 mg/m2 on day 1, maximum dose: 5mg), according to initial randomization.
Two-hundred and eighty patients with untreated de novo AML were randomized 1:1 to receive DA plus gemtuzumab ozogamicin (GO arm, n = 140) or DA alone (control arm, n = 140). The primary endpoint of the study was event-free survival (EFS). Initial results at data cutoff of 1st August 2011, published in Lancet by Castaigne S. et al. in 2012, showed that the estimated 2-year EFS was significantly longer in patients in the GO arm compared to the control arm (40.8 vs 17.1 months respectively, HR = 0.58, P = 0.0003). Although, the CR rates were similar in patients between the GO and control arm as was the treatment-mortality rates.1
The final safety and efficacy data with a longer follow-up (data cutoff: 30th April, 2013) of the phase III randomized ALFA-0701 study was reported by Juliette Lambert from Centre Hospitalier de Versailles, Le Chesnay, France, and colleagues, in an article published in Haematologica on 3rd August, 2018.2 Of the 280 patients randomized in this study, data was reported for 271 patients (GO arm, n = 135; control arm, n = 136).
- Data presented are representative of GO vs control arms, respectively
- Median overall survival: 27.5 months (95% CI, 21.4–45.6) vs 21.8 months (95% CI, 15.5–27.4), HR = 0.81 (95% CI, 0.60–1.09), P = 0.16
- Total number of death before April 30, 2013: 80 (59.3%) vs 88 (64.7%)
- Blinded independent review of median EFS: 13.6 months (95% CI, 9.0–19.2) vs 8.5 months (95% CI, 7.5−12.0), HR = 0.66 (95% CI, 0.49−0.89), P = 0.006
- Thirty-two (23.7%) patients in the GO arm and 53 (39.0%) in the control arm proceeded to hematopoietic stem cell transplant in first CR or after induction failure or relapse
- Two-hundred and eight (77.6%) patients experienced grade ≥ 3 infections in the GO (77.9%) and control (77.4%) arm
- The rate of hemorrhage was significantly higher among patients in the GO (90.1%) than control (78.1%) arm, P = 0.008
- Veno-occlusive disease occurred in six (4.6%) and two (1.5%) in the GO and control arm, respectively, P = 0.165
- Forty-one (31.3%) and 10 (7.3%) patients discontinued treatment in the GO and control arm respectively due to treatment-emergent adverse events (AEs)
- The most common reasons for discontinuation in the GO and control arm were thrombocytopenia (15.3% vs 0%) patients and hepatobiliary disorders (6.1% vs 0.7%)
- Median time to recovery of platelets was longer for patients in the GO arm than in the control arm for each treatment course
The authors concluded that the final results of the ALFA-0701 study demonstrate that fractionated doses of gemtuzumab ozogamicin added to standard chemotherapy significantly prolongs EFS in patients with previously untreated de novo AML and has an “acceptable safety profile”. This phase III study formed the basis of approval for gemtuzumab ozogamicin in Europe and the United States.