Drug for Relapsed, Refractory ALL Increased Hepatotoxicity

Treatment of adult relapsed or refractory acute lymphoblastic leukemia (ALL) with inotuzumab ozogamicin was associated with increased hepatotoxicity, especially after follow-up hematopoietic stem cell transplantation (HSCT), compared with standard of care, according to the results of the INO-VATE trial published in Lancet Haematology.

“Although associated with significant risks, including severe hepatotoxicity, HSCT is a treatment option that offers the possibility of cure in the relapsed or refractory ALL setting,” wrote Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center, and colleagues. “Compared with patients assigned to standard care, significantly more patients in the inotuzumab ozogamicin group achieved complete remission or complete remission with incomplete hematologic recovery, and more than twice as many proceeded to HSCT.”

The INO-VATE trial was an open-label, phase III, international study of adults with relapsed or refractory CD22-positive, Philadelphia chromosome–positive, or Philadelphia chromosome–negative B-cell ALL who were going to receive first or second salvage treatment. Patients were randomly assigned to inotuzumab ozogamicin or standard care.

Previous results showed that inotuzumab ozogamicin was safe and effective compared with standard care in this patient population. During the study, the researchers noted an increase in hepatic adverse events in patients assigned to inotuzumab ozogamicin. Therefore, they conducted a comprehensive analysis of the hepatic adverse event profile of inotuzumab ozogamicin.

Treatment-emergent hepatotoxicities occurred in 51% of patients assigned inotuzumab ozogamicin compared with 34% of patients assigned standard care. Patients assigned to inotuzumab ozogamicin experienced a greater frequency of sinusoidal obstruction syndrome-either during or after treatment and subsequent transplant-compared with standard care (13% vs < 1%).

The researchers noted that “because investigators were aware of study treatment assignment and the similarities in the antibody–drug complex design of inotuzumab ozogamicin and gemtuzumab ozogamicin and its safety profile, they might have been more watchful for sinusoidal obstruction syndrome in the inotuzumab ozogamicin group.”

Of the patients assigned inotuzumab ozogamicin that proceeded to transplant, 22% had sinusoidal obstruction, and five events after transplant resulted in death. In comparison, of the patients assigned standard care that proceeded to transplant, 3% had non-fatal sinusoidal obstruction syndrome.

A multivariable analysis showed that conditioning with two alkylating agents compared with one agent, and last available pre-transplant bilirubin concentration at or above the upper limit of normal were associated with increased risk for sinusoidal obstruction syndrome in patients that received inotuzumab ozogamicin.

“Our current data show an apparent, but non-significant, long-term survival advantage for patients who received inotuzumab ozogamicin and proceeded to HSCT compared with patients who received standard care and proceeded to HSCT, despite the higher frequency of sinusoidal obstruction syndrome in the inotuzumab ozogamicin group,” the researchers wrote. “Additional studies are needed to confirm long-term survival after inotuzumab ozogamicin treatment and subsequent HSCT, because this study was not powered to detect differences in overall survival.”