CLINICAL TRIAL, PHASE III
JOURNAL ARTICLE
RANDOMIZED CONTROLLED TRIAL
Add like
Add dislike
Add to saved papers

Hepatic adverse event profile of inotuzumab ozogamicin in adult patients with relapsed or refractory acute lymphoblastic leukaemia: results from the open-label, randomised, phase 3 INO-VATE study.

Lancet Haematology 2017 August
BACKGROUND: The INO-VATE study demonstrated efficacy and safety of inotuzumab ozogamicin versus standard care in adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Here, we report the frequency of, and potential risk factors for, hepatotoxicity in patients in this trial and after treatment and subsequent haemopoietic stem-cell transplantation (HSCT).

METHODS: In this open-label, phase 3, multicentre, international study, adults with relapsed or refractory, CD22-positive, Philadelphia chromosome (Ph)-positive or Ph-negative B-cell acute lymphoblastic leukaemia who were due to receive first or second salvage treatment were randomly assigned (1:1) via an interactive voice response system to receive inotuzumab ozogamicin (starting dose 1·8 mg/m2 per cycle [0·8 mg/m2 on day 1; 0·5 mg/m2 on days 8 and 15 of a 21-28 day cycle for ≤6 cycles]) or standard care (either fludarabine plus cytarabine plus granulocyte colony-stimulating factor, mitoxantrone plus cytarabine, or high-dose cytarabine). Stratification factors at randomisation were duration of first remission (<12 months vs ≥12 months), salvage treatment phase (first vs second), and age (<55 years vs ≥55 years). We present data up to March 8, 2016. At this cutoff date, all patients had been discontinued from treatment but 54 patients were continuing in long-term follow-up. Long-term follow-up has now been completed, with the final patient's last visit on Jan 4, 2017. This prespecified safety analysis describes investigator-assessed treatment-emergent hepatotoxicity, including sinusoidal obstruction syndrome (also known as veno-occlusive disease) in patients during study treatment or thereafter (without follow-up HSCT) and after study treatment and subsequent HSCT, for all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT01564784.

FINDINGS: Between Aug 27, 2012, and and the data cutoff of March 8, 2016, 326 patients were randomly assigned to receive inotuzumab ozogamicin (n=164) or standard care (n=162). 164 patients in the inotuzumab ozogamicin group and 143 in the standard care group received at least one dose of study treatment and were included in the safety population. At data cutoff, median duration of treatment (induction) was 8·9 weeks (IQR 4·1-13·1) in the inotuzumab ozogamicin group and 0·9 weeks (0·9-1·1) in the standard care group. Treatment-emergent hepatotoxicities (of all grades) were more frequent in the inotuzumab ozogamicin group (83 [51%] of 164 patients) than in the standard care group (49 [34%] of 143 patients). The frequency of sinusoidal obstruction syndrome-comprising events occurring during treatment (or follow-up without HSCT) and after treatment and subsequent HSCT-was higher in the inotuzumab ozogamicin group (22 [13%]; 18 [82%] of which were grade 3 or worse) than in the standard care group (one [<1%]). During study therapy or follow-up without HSCT, five (3%) patients in the inotuzumab ozogamicin group developed sinusoidal obstruction syndrome compared with no patients in the standard care group. Of the 77 patients who received inotuzumab ozogamicin and proceeded to HSCT, 17 (22%) had sinusoidal obstruction syndrome; five events after follow-up HSCT were fatal. Of 32 patients who received standard care and proceeded to HSCT, one (3%) had (non-fatal) sinusoidal obstruction syndrome that was ongoing at the time of death due to septic shock. In multivariate analysis, conditioning with two alkylating agents (p=0·015 vs one alkylating agent) and last available pre-HSCT bilirubin concentration of greater than or equal to the upper limit of normal (ULN; p=0·009 vs <ULN) were associated with increased risk of sinusoidal obstruction syndrome in patients who received inotuzumab ozogamicin. The estimated hazard ratio for overall survival in patients with follow-up HSCT (inotuzumab ozogamicin vs standard care) was 1·227 (97·5% CI 0·656-2·292; one-sided stratified log-rank p=0·77); at 24 months, the estimated probability of survival was 38·9% (95% CI 27·6-50·0) in the inotuzumab ozogamicin group versus 28·7% (11·2-49·1) in the standard care group.

INTERPRETATION: Treatment with inotuzumab ozogamicin is associated with increased hepatotoxicity, especially after follow-up HSCT, compared with standard care.

FUNDING: Pfizer.

Full text links

We have located links that may give you full text access.
Can't access the paper?
Try logging in through your university/institutional subscription. For a smoother one-click institutional access experience, please use our mobile app.

For the best experience, use the Read mobile app

Mobile app image

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app

All material on this website is protected by copyright, Copyright © 1994-2024 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

By using this service, you agree to our terms of use and privacy policy.

Your Privacy Choices Toggle icon

You can now claim free CME credits for this literature searchClaim now

Get seemless 1-tap access through your institution/university

For the best experience, use the Read mobile app