Inotuzumab ozogamicin therapy significantly increased the risk of sinusoidal obstruction syndrome (veno-occlusive disease) among adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL), especially when they also received follow-up hematopoietic stem cell transplantation, according to a safety analysis from the INO-VATE trial.

After a median of 9 weeks of treatment, 13% of 164 patients who received inotuzumab ozogamicin (Besponsa, Wyeth/Pfizer) developed sinusoidal obstruction syndrome, compared with less than 1% of 143 patients who received standard care, reported Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his associates (Lancet Haematol. 2017 Jul 4. doi: 10.1016/ S2352-3026[17]30103-5 ).

Follow-up treatment with HSCT increased the risk of sinusoidal obstruction syndrome in both the intervention (22%) and standard-care (3%) groups. Among patients who did not undergo HSCT, rates of this adverse event were 3% and 0%, respectively. Five patients died from sinusoidal obstruction syndrome, all of whom received both inotuzumab ozogamicin and HSCT. The findings earned the newly approved regimen a boxed warning for severe hepatotoxicity.

The open-label, phase 3, multicenter INO-VATE study included 326 adults with CD22-positive, Philadelphia chromosome–negative or Philadelphia chromosome–positive relapsed or refractory B-cell precursor ALL. The safety analysis included 305 patients. Rates of treatment-emergent hepatotoxicities, of all grades, were 51% with inotuzumab ozogamicin and 34% with standard care. Most adverse hepatic events were grade 1-2 liver-related laboratory abnormalities, but 8% of inotuzumab ozogamicin recipients developed grade 3 or higher sinusoidal obstruction syndrome, versus less than 1% of the control group.

“After follow-up HSCT, the frequency of sinusoidal obstruction syndrome was 50% or higher in the following subgroups: patients aged 65 years or older, patients with last available pre-HSCT serum bilirubin concentration more than or equal to the upper limit of normal, and patients who received conditioning regimens with two alkylating agents,” Dr. Kantarjian and his fellow investigators wrote. Conditioning regimens that included thiotepa markedly increased the risk of sinusoidal obstruction syndrome. Additional risk factors included HSCT before study enrollment, history of liver disease, and a final pre-HSCT platelet count of less than 100 × 109 platelets per L.

Rates of sinusoidal obstruction syndrome were 42% with four to six cycles of inotuzumab ozogamicin, 23% with three cycles, 19% with two cycles, and 8% with one cycle, said the investigators. In multivariate analysis, conditioning with two alkylating agents (P = .02 compared with one alkylating agent) and pre-HSCT bilirubin of at least the upper limit of normal (P = .01) significantly increased the risk of sinusoidal obstruction syndrome during or after treatment with inotuzumab ozogamicin.

Notably, inotuzumab ozogamicin did not significantly increase the chances of survival compared with standard care among patients who also received follow-up HSCT (hazard ratio, 1.3; 97.5% confidence interval, 0.66 to 2.3; P = 0.77). Among HSCT recipients, the chances of surviving to 24 months were 39% (95% CI, 28%-50%) with inotuzumab ozogamicin and 29% (11%-49%) with standard care. Nonetheless, HSCT “offers possibility of cure in the relapsed or recurrent [ALL] setting,” the researchers wrote. Clinicians should be especially wary of sinusoidal obstruction syndrome if patients are 65 years or older, received HSCT before inotuzumab ozogamicin treatment, or have a baseline history of liver disease, they said. Strategies to minimize risk include shortening the duration of inotuzumab ozogamicin treatment and avoiding conditioning regimens that contain two alkylating agents.

Pfizer funded and collaborated in the trial. Dr. Kantarjian disclosed ties to Pfizer and numerous other pharmaceutical companies.