Clinical trialPhase 3Leukaemia

Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia

N Engl J Med · 2016326 randomised patients (the first 218 patients, 109 in each group, in the primary intention-to-treat analysis of complete remission)

Kantarjian HM, DeAngelo DJ, Stelljes M, Martinelli G, Liedtke M, Stock W, et al. N Engl J Med. 2016. 375:740-753

Study type: Clinical trial
Study name: INO-VATE ALL
Phase: Phase 3
Design: Randomised phase 3 trial comparing inotuzumab ozogamicin with standard intensive chemotherapy
Sample size: 326 randomised patients (the first 218 patients, 109 in each group, in the primary intention-to-treat analysis of complete remission)
Source: N Engl J Med · 2016
Trial registration: NCT01564784

In plain words

In this study, adults whose acute lymphoblastic leukaemia had come back or had not responded to earlier treatment received either the drug inotuzumab ozogamicin or standard chemotherapy. In the inotuzumab group, more patients reached complete remission, and they lived longer without the disease getting worse. The most important side effect of this drug was a type of liver damage called veno-occlusive disease of the liver, so decisions about this treatment should be made with a specialist.

Key results

80.7% vs 29.4%

Complete remission rate (first 218 patients)

95% CI 72.1–87.7 vs 21.0–38.8; P<0.001

78.4% vs 28.1%

Result below the minimal residual disease threshold (0.01% bone marrow blasts) in patients with complete remission

P<0.001

4.6 months vs 3.1 months

Duration of remission (median)

Hazard ratio 0.55 (95% CI 0.31–0.96); P=0.03

5.0 months vs 1.8 months

Progression-free survival (median, all 326 patients)

Hazard ratio 0.45 (97.5% CI 0.34–0.61); P<0.001

7.7 months vs 6.7 months

Overall survival (median, all 326 patients)

Hazard ratio 0.77 (97.5% CI 0.58–1.03); P=0.04

15 patients (11%) vs 1 patient (1%)

Veno-occlusive liver disease (VOD) of any grade

Safety population; inotuzumab group vs standard therapy

Dose and schedule cards

Inotuzumab ozogamicin (INO-VATE)

Relapsed or refractory CD22-positive B-ALL (adults and children aged 1 year and older)On the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

Relapsed or refractory CD22-positive B-ALL (adults and children aged 1 year and older)

Drug	Dose	Route	Schedule
Cycle 1 (all patients)
Inotuzumab ozogamicin	0.8 mg/m² (Day 1), 0.5 mg/m² (Days 8 and 15)	IV	Days 1, 8 and 15
Subsequent cycles, in CR or CRi
Inotuzumab ozogamicin	0.5 mg/m²	IV	Days 1, 8 and 15
Subsequent cycles, without CR or CRi
Inotuzumab ozogamicin	0.8 / 0.5 / 0.5 mg/m²	IV	Days 1, 8 and 15

Cycle length: Cycle 1: 21 days (up to 28 days in CR/CRi or to allow recovery from toxicity); subsequent cycles: 28 days
Duration: If proceeding to transplantation: 2 cycles (a third cycle if MRD-negative CR/CRi has not been reached after 2 cycles); without transplantation: up to 6 cycles; no CR/CRi within 3 cycles: discontinue

Premedication before each infusion: a corticosteroid, an antipyretic and an antihistamine. Boxed warning: hepatotoxicity, including hepatic veno-occlusive disease (VOD in 11% of INO-VATE patients), and increased non-relapse mortality after transplantation; monitor liver tests.

On the page “Leukaemia” · Regimens and dosing in relapsed or refractory B-ALL

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

1Inotuzumab ozogamicin group

Inotuzumab ozogamicin starting dose 1.8 mg/m² IV per cycle: 0.8 mg/m² on day 1 and 0.5 mg/m² on days 8 and 15; cycle 1: 21 days, later cycles: 28 days; maximum 6 cycles. After CR or CRi, the day 1 dose was reduced to 0.5 mg/m². According to the FDA label: premedication (corticosteroid, antipyretic and antihistamine) before each infusion and, in transplant candidates, preferably 2 cycles (boxed warning for VOD and non-relapse mortality after transplant).

2Standard therapy group

Investigator's choice: FLAG (cytarabine 2.0 g/m² per day, days 1 to 6, fludarabine 30 mg/m² per day, days 2 to 6, G-CSF 5 µg/kg per day; 28-day cycle, up to 4 cycles); cytarabine + mitoxantrone (cytarabine 200 mg/m² per day, days 1 to 7, mitoxantrone 12 mg/m² per day, days 1 to 3; ‎15-‎ to 20-day cycle, up to 4 cycles); or high-dose cytarabine (3 g/m² every 12 hours, up to 12 doses; 1.5 g/m² for patients aged 55 years and older).

Source of the regimen details: Full text of the paper in PMC (PMC5594743), Treatments section; FDA label for inotuzumab (DailyMed) for premedication and warnings

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

Adults with relapsed or refractory acute lymphoblastic leukaemia.

Endpoints

Primary endpoints: complete remission (including complete remission with incomplete haematological recovery) and overall survival.

The abstract also reports progression-free survival, depth of remission based on minimal residual disease (threshold 0.01% bone marrow blasts) and duration of remission.

Safety and side effects

In the safety population, the most common grade 3 or higher non-haematological adverse events with inotuzumab ozogamicin were hepatic. Veno-occlusive liver disease of any grade occurred in 15 patients (11%) in the inotuzumab group and 1 patient (1%) in the standard therapy group and was an important adverse effect of this drug.

Clinical significance and place in guidelines

This trial showed that in adults with relapsed or refractory acute lymphoblastic leukaemia, inotuzumab ozogamicin gives a higher complete remission rate and better progression-free survival than standard chemotherapy, but carries a risk of veno-occlusive liver disease. The abstract gives no information on drug approvals or formal guideline recommendations; its current place in clinical guidelines should be checked separately.

Limitations

The primary complete remission analysis was based on the first 218 patients only. In the overall survival analysis, the 97.5% confidence interval for the hazard ratio (0.58–1.03) includes 1, so the overall survival benefit should be interpreted with caution. Veno-occlusive liver disease was more frequent in the inotuzumab group. Dose details and other limitations should be checked in the full text.

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.