Title: 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

Kantarjian, HM et al.


What You Need to Know:

According to analysis of the INO-VATE trial, treatment with inotuzumab ozogamicin is associated with an increased risk of hepatotoxicity, especially after subsequent hematopoietic stem-cell transplantation (HSCT), compared to standard-of-care treatment in patients with relapsed or refractory B-cell acute lymphoblastic leukemia.

Trial Design:

  • Analysis of the phase 3 INO-VATE study assessed “the frequency of, and potential risk factors for, hepatotoxicity in patients in this trial and after treatment and subsequent haemopoietic stem-cell transplantation (HSCT)”
  • Included adult patients 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”
  • 326 patients were randomized (1:1) to receive inotuzumab ozogamicin (1.8 mg/m2 per cycle starting dose; n=164) or standard of care (n=162)
  • Standard of care: fludarabine + cytarabine + granulocyte colony-stimulating factor, mitoxantrone + cytarabine, or high-dose cytarabine
  • At the end of the study, 54 patients continued treatment during a long-term follow-up phase
  • Analysis described “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”

Key Outcomes:

  • Safety population included 164 inotuzumab ozogamicin patients and 143 standard-of-care patients
  • Median duration of treatment (induction): 8.9 weeks for inotuzumab ozogamicin patients (IQR: 4.1, 13.1) vs 0.9 weeks for standard-of-care patients (IQR: 0.9, 1.1)
  • Treatment-emergent hepatotoxicities (any grade): experienced by 51% of inotuzumab ozogamicin patients (83/164) vs 34% of standard-of-care patients (49/143)
  • Frequency of sinusoidal obstruction syndrome (“comprising events occurring during treatment [or follow-up without HSCT] and after treatment and subsequent HSCT”): 13% for inotuzumab ozogamicin patients (22/164) vs <1% for standard-of-care patients (1/143)
  • 82% of sinusoidal obstruction syndrome events in inotuzumab ozogamicin patients were considered grade 3 or higher
  • Sinusoidal obstruction syndrome developed in 3% of inotuzumab ozogamicin patients (5/164) during treatment or follow-up without HSCT compared to zero standard-of-care patients
  • 22% of inotuzumab ozogamicin patients with subsequent HSCT (17/77) had sinusoidal obstruction syndrome (5 events were fatal) vs 3% of standard-of-care patients with subsequent HSCT (1/32) (event was non-fatal)
  • “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
  • Estimated overall survival for patients who received HSCT (inotuzumab ozogamicin vs standard of care): HR: 1.227 (97.5% CI: 0.656, 2.292; P=0.77)
  • Estimated probability of survival at 24 months: 38.9% for inotuzumab ozogamicin patients (95% CI: 27.6, 50.0) vs 28.7% for standard of care patients (95% CI: 11.2, 49.1)