Forewarned Is Forearmed- Comparison of Southern Network on Adverse Reactions (SONAR) Versus an FDA-Mandated Prospective Observational Registry Assessment of Gemtuzumab Ozogamycin-Associated Sinusoidal Obstructive Syndrome

Abstract

Gemtuzumab ozogamycin (GO) received initial approval in 2000 from the Food and Drug Administration (FDA) for patients age 60 and older suffering with relapsed acute myeloid leukemia. After 10 years of administering GO-containing combination chemotherapy regimens, the drug was voluntarily removed from the commercial market in 2010 amid reports of unexpected development of sinusoidal obstructive syndrome (SOS); which has the potential to be fatal. Four months after the initial approval for marketing in 2000, SONAR initiated an investigation of GO-associated SOS. SONAR reported an incidence rate of 38% among allogeneic stem-cell transplants and 16% among autologous stem-cell transplant (SCT) patients. Ultimately, there was an overall incidence rate of 3% when single-agent GO was administered as directed by the FDA. In 2007, as a result of the examination of the reports from clinical trials and observational studies; data mining of interim reports from the manufacturer’s Prospective Observational Registry and the FDA’s Adverse Event Reporting System was undertaken. In 2013, the pharmaceutical manufacturer reported results from its FDA-mandated prospective observational study. Major differences between the SONAR report and the mnaufacturer’s report include: timing of publication (2007 versus 2013); inclusion of information on allogeneic stem cell versus autologous stem cell transplantation prior to GO administration (in our reports only) and identification of risk factors associated with higher rates of SOS (SCT within 3 months of GO administration, off-label administration of high doses of GO, and concomitant administration of 6-TG in our analysis versus no identified risk factors in the manufacturer’s analysis). The incidence of SOS was 9.1% among 482 patients at 54 centers in the manufacturer’s registry.Table 1:Comparison of gemtuzumab ozogamycin (GO) safety reports analyses between SONAR and manufacturerSONARPharmaceutical Investigation# of pts who received GO1071482# of pts with SOS9944DATA METHODS# of centers involved50 centers (US and UK)54 centers (US only)Interim analysisNot doneYes (2002 and 2005)Concomitant chemo given67%41%# of pts with concomitant HCT26%0%% with prior alloSCT2.6%Not reported% with prior autoSCT3.9%Not reported% with prior HSCT6.5%18.3%% with subsequent alloSCT1.2%0%% with subsequent autoSCT2.0%0%Publication Date*20072013* Gemtuzumab ozogamycin voluntarily removed from market in 2010 by the pharmaceutical manufacturer DisclosuresNo relevant conflicts of interest to declare.