Incidence of Sinusoidal Obstruction Syndrome Following Mylotarg (Gemtuzumab Ozogamicin, GO): a Prospective Observational Study in Routine Clinical Practice.

Objectives: GO is a conjugate of calicheamicin and a monoclonal antibody that targets CD33⁺ myeloblasts in acute myeloid leukemia (AML). After GO administration, ascites, weight gain, elevated aminotransferase enzymes, and jaundice (Sinusoidal Obstruction Syndrome, SOS, formerly known as VOD) have been reported. After approval by the FDA for relapsed AML in 2000 and its introduction into routine clinical practice, the incidence of SOS after GO infusion has been the subject of debate. The objectives of this study were to

1. estimate the incidence rate of SOS after GO infusion in routine clinical practice,

2. identify risk factors associated with the development of SOS,

3. describe the incidence rates of serious adverse events (SAEs) and nonserious adverse events of special interest (ESIs).

Methods: This study was a prospective observational study that enrolled consenting patients who were to receive GO for AML, with assessments at baseline, weekly x6 after the 1st dose of GO or 4 weeks after the last dose (whichever was later), and at 6 months. There were no exclusion criteria. Two hepatologists (GBM, LDD) reviewed cases with liver abnormalities and classified patients as either SOS, liver disease unlikely to be SOS, or no SOS. A diagnosis of SOS was based on 2 of the following 3 criteria:

1. elevated bilirubin (>34 mmol/L or 2 mg/dL),

2. increase in liver size or right upper quadrant liver pain,

3. weight gain (>2.5% after GO infusion), along with exclusion of other liver diseases with this presentation.

The study was conducted according to the Declaration of Helsinki and its amendments.

Results: 512 patients were enrolled at 54 U.S. centers and 482 were analyzed. The study population consisted predominantly of men (59%); the mean age was 61.5 years; 73% had an ECOG performance status of 0 or 1 at baseline. 18% had received prior hematopoietic cell transplant (HCT), 4% had prior graft versus host disease (GVHD), 11% prior irradiation, 40% reported alcohol intake, and 19% were smokers. Most patients had received prior chemotherapy (87%). AML in first relapse was the indication for GO in 44%. Most patients received chemotherapy concomitantly with GO, most common were cytarabine (16%) and hydroxycarbamide (14%). The mean number of GO infusions per patient was 1.5 and the mean dose of GO per infusion was 7.8 mg/m². The incidence of SOS was 8.9% (43/482; 95% confidence interval [CI]: 6.5% to 11.8%), with 19 cases classified as severe, 15 moderate, and 9 mild. Of 43 patients with SOS, 33 died within 6 months; of these, 20 died of AML progression. By multivariate analysis, only prior HCT was significantly related to development of moderate/severe SOS (odds ratio 2.2, CI 1.01–4.99). There was no evidence to suggest that age, blast count, body weight, GO dosing, prior chemotherapy, concomitant chemotherapy, or use of acetaminophen were related to development of SOS. 68% of patients died within 6 months. Progression of AML was the primary cause of death (73% of deaths); 7% were due to cardiovascular causes, 7% were due to infection, 6% were due to multiorgan failure, and 7% were due to other causes. SAEs occurred in 85% of patients; most (81%) due to other reasons, including AML, febrile neutropenia, pyrexia, and sepsis. Of the special interest categories, most SAEs were due to hepatic events (10%). 73% of patients experienced ESIs (both serious and nonserious); most ESIs were infusion-related events (46%) and 44% were hepatic events.

Conclusions: GO can be safely administered in routine clinical practice with an overall 8.9% risk of SOS and with most cases moderate to severe. The only risk factor identified was prior HCT. Development of SOS following GO cannot be predicted in the majority of cases. Most ESIs were infusion-related events and most SAEs of the special interest categories were due to hepatic events.