Clinical trialPhase 3Blood cancers (leukaemia, lymphoma and myeloma)Leukaemia

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 · 2012280 patients (140 in each group; 139 patients analysed in each group)

Castaigne S, Pautas C, Terré C, Raffoux E, Bordessoule D, Bastie JN, et al. Lancet. 2012. 379:1508-1516

Study type: Clinical trial
Study name: ALFA-0701
Phase: Phase 3
Design: Randomised (1:1, computer-generated sequence with blocks of four), open-label, multicentre trial at 26 haematology centres in France; intention-to-treat analysis
Sample size: 280 patients (140 in each group; 139 patients analysed in each group)
Source: Lancet · 2012
Trial registration: NCT00927498

In plain words

Gemtuzumab ozogamicin is a medicine made of an antibody joined to a drug, which targets leukaemia cells carrying the CD33 marker. In this study of 280 patients aged 50 to 70 with newly diagnosed acute myeloid leukaemia, adding small, divided doses of this drug to the usual chemotherapy raised the proportion of patients who were alive two years after starting treatment without relapse or treatment failure from about 17% to about 41%, and raised two-year survival from about 42% to about 53%. A long-lasting drop in platelets was more common in this group. This drug can harm the liver (including blockage of the small veins of the liver), so your doctor will monitor your liver and blood counts during treatment.

Key results

40.8% vs 17.1%

2-year event-free survival

HR 0.58 (95% CI 0.43–0.78); p=0.0003

53.2% vs 41.9%

2-year overall survival

HR 0.69 (95% CI 0.49–0.98); p=0.0368

50.3% vs 22.7%

2-year relapse-free survival

HR 0.52 (95% CI 0.36–0.75); p=0.0003

81% vs 75%

Complete response (with or without incomplete platelet recovery) after induction

113 vs 104 patients; odds ratio 1.46 (95% CI 0.20–2.59); p=0.25

16% vs 3%

Haematological toxicity, especially persistent thrombocytopenia

22 vs 4 patients; p<0.0001; no increase in the risk of death from toxicity

Dose and schedule cards

7+3 + gemtuzumab ozogamicin (ALFA-0701)

Newly diagnosed CD33-positive AML; greatest benefit in favourable and intermediate cytogenetics (patients aged 50 to 70 in ALFA-0701)On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

Newly diagnosed CD33-positive AML; greatest benefit in favourable and intermediate cytogenetics (patients aged 50 to 70 in ALFA-0701)

Drug	Dose	Route	Schedule
Induction
Daunorubicin	60 mg/m²	IV	Days 1 to 3
Cytarabine	200 mg/m² a day	IV	Days 1 to 7
Gemtuzumab ozogamicin	3 mg/m² (maximum one 4.5 mg vial)	IV	Days 1, 4 and 7
Consolidation (2 cycles)
Daunorubicin	60 mg/m²	IV	Cycle 1 day 1; cycle 2 days 1 and 2
Cytarabine	1 g/m² every 12 hours	IV	Days 1 to 4
Gemtuzumab ozogamicin	3 mg/m² (maximum one vial)	IV	Day 1

Cycle length: One induction cycle and 2 consolidation cycles
Duration: Gemtuzumab is not given in a second induction

Premedication in adults: paracetamol 650 mg and diphenhydramine 50 mg one hour before the infusion, and methylprednisolone 1 mg/kg within 30 minutes before it. Stop permanently for VOD; if platelets do not reach 100×10⁹/L within 14 days of the planned start of consolidation, do not give gemtuzumab in consolidation; in ALFA-0701 an interval of at least 2 months from the last dose to transplant was recommended. Persistent thrombocytopenia was more common in the gemtuzumab group (16% vs 3%), without an increase in toxic deaths.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Induction and consolidation in patients fit for intensive treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Standard chemotherapy + gemtuzumab ozogamicin

Induction: daunorubicin 60 mg/m² on days 1 to 3 and cytarabine 200 mg/m² on days 1 to 7, with gemtuzumab ozogamicin 3 mg/m² (up to one vial) IV on days 1, 4 and 7.

Second induction (only for non-responders, without gemtuzumab ozogamicin): daunorubicin 35 mg/m² per day on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1 to 3.

Consolidation (2 cycles for responders): daunorubicin (cycle 1: 60 mg/m² on day 1; cycle 2: 60 mg/m² on days 1 and 2) and cytarabine 1 g/m² every 12 hours on days 1 to 4, with gemtuzumab ozogamicin 3 mg/m² (up to one vial) on day 1 of each cycle; 5 doses of gemtuzumab ozogamicin in total.

According to the FDA label (Mylotarg): premedication in adults: acetaminophen 650 mg and diphenhydramine 50 mg one hour before infusion and methylprednisolone 1 mg/kg within 30 minutes before infusion. If the white cell count is 30×10⁹/L or more, cytoreduction is recommended. Boxed warning: hepatotoxicity, including hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS).

2Standard chemotherapy (control group)

The same chemotherapy without gemtuzumab ozogamicin: induction with daunorubicin 60 mg/m² on days 1 to 3 and cytarabine 200 mg/m² on days 1 to 7; second induction for non-responders (daunorubicin 35 mg/m² per day on days 1 and 2 and cytarabine 1 g/m² every 12 hours on days 1 to 3); and 2 consolidation cycles for responders (daunorubicin 60 mg/m² on day 1 of cycle 1 and on days 1 and 2 of cycle 2, with cytarabine 1 g/m² every 12 hours on days 1 to 4).

Source of the regimen details: Abstract of the paper (Lancet 2012; dose and schedule of gemtuzumab ozogamicin) and the FDA label for gemtuzumab ozogamicin (Mylotarg; section 14.1, which describes the ALFA-0701 trial: backbone chemotherapy doses, second induction and consolidation; also premedication and the boxed warning)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 50 to 70 years with previously untreated de novo acute myeloid leukaemia (AML). Other inclusion criteria are not stated in the abstract.

Endpoints

Primary endpoint: event-free survival (EFS).

Secondary endpoints: relapse-free survival (RFS), overall survival (OS) and safety; analysis by intention to treat.

Safety and side effects

Haematological toxicity, especially persistent thrombocytopenia, was more common in the gemtuzumab ozogamicin group (22 patients [16%] versus 4 patients [3%]; p<0.0001), without an increase in the risk of death from toxicity. According to the FDA label, the drug carries a boxed warning for hepatotoxicity, including hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS), and adults receive premedication (acetaminophen, diphenhydramine and methylprednisolone) before infusion.

Clinical significance and place in guidelines

ALFA-0701 showed that adding low-dose, fractionated gemtuzumab ozogamicin (3 mg/m² on days 1, 4 and 7 of induction and day 1 of each consolidation cycle) to standard first-line chemotherapy improves event-free survival without increasing death from toxicity. The FDA label (Mylotarg) describes this trial in section 14.1. In the label analysis (modified intention-to-treat population, mITT, 271 patients), median event-free survival was 17.3 months versus 9.5 months (HR 0.56; 95% CI 0.42–0.76), but no statistically significant difference in overall survival was seen in the label analysis.

Limitations

The trial was open-label and included only patients aged 50 to 70 with de novo AML in France; the sample size was relatively small (280 patients). The complete response rate after induction did not differ significantly (p=0.25). The overall survival benefit was significant in the paper's analysis (p=0.0368), but in the separate FDA label analysis (mITT population) no statistically significant difference in overall survival was seen. Persistent thrombocytopenia was more frequent with gemtuzumab ozogamicin.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.