title: Evaluation of gemtuzumab ozogamycin associated sinusoidal obstructive syndrome: Findings from an academic pharmacovigilance program review and a pharmaceutical sponsored registry.
abstract: BACKGROUND
  In 2000, the Food and Drug Administration (FDA) approved gemtuzumab ozogamycin for monotherapy for older patients with relapsed AML. A 0.9% rate of hepatic sinusoidal obstructive syndrome (SOS) was noted in licensing trials. In 2001, FDA received reports of 14 GO-associated SOS cases from MD Anderson Cancer Center. A State of South Carolina/National Cancer Institute funded pharmacovigilance program and a manufacturer sponsored registry independently evaluated this concern.
  
  
  METHODS
  The manufacturer's registry and the academic program focused on risk factors and incidence of GO-associated SOS in routine clinical practice and clinical trial settings, respectively. Comparisons were made of findings and dissemination efforts from the two studies.
  
  
  RESULTS
  Retrospective analysis of clinical trials by the academic initiative identified 99 cases of SOS among 221 GO-treated stem cell patients and 649 patients who did not undergo HSCTs. SOS rates were 3% when GO was administered at doses ≤6 mg/m(2) as monotherapy or with non-hepatotoxic agents; 28% when administered with 6-thioguanine, a hepatotoxic agent; 15% when administered as monotherapy at doses at a dose of 9 mg/m(2), and between 15% and 40% if a stem cell transplant (SCT) was performed within 3 months of GO administration. Death from SOS occurred in 33% of the cases. The manufacturer's registry prospectively evaluated 482 GO-treated patients who received a mean dose of 7.8 mg/m(2). Overall, 41% received concomitant chemotherapy, 18% had undergone prior SCT, 9.1% developed SOS, and death from SOS occurred in 60% of the SOS cases. Findings from each initiative were disseminated at national conferences and in peer-reviewed manuscripts beginning in 2003.
  
  
  CONCLUSIONS
  Retrospective review of clinical trials, case series, and FDA reports and prospective registries can provide important information on safety signals initially identified in licensing trials.
authors.affiliation: Southern Network on Adverse Reactions (SONAR), South Carolina Center of Economic Excellence for Medication Safety, College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States. Electronic address: jametta.magwood@palmettohealth.org.
authors.forename: Jametta S
authors.initials: JS
authors.lastname: Magwood-Golston
authors.affiliation: Southern Network on Adverse Reactions (SONAR), South Carolina Center of Economic Excellence for Medication Safety, College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kessler
authors.affiliation: Southern Network on Adverse Reactions (SONAR), South Carolina Center of Economic Excellence for Medication Safety, College of Pharmacy, University of South Carolina, Columbia, SC 29208, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bennett
mesh_terms: D000046:Academic Medical Centers; D016907:Adverse Drug Reaction Reporting Systems; D000617:Aminoglycosides / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002986:Clinical Trials as Topic; D003131:Combined Modality Therapy / Q000009:adverse effects; D016208:Databases, Factual; D005500:Follow-Up Studies; D000079982:Gemtuzumab; D006504:Hepatic Veno-Occlusive Disease / Q000139:chemically induced / Q000453:epidemiology*; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute / Q000150:complications* / Q000628:therapy; D060735:Pharmacovigilance; D011379:Prognosis; D015397:Program Evaluation; D011446:Prospective Studies; D012042:Registries; D014481:United States / Q000453:epidemiology; D014486:United States Food and Drug Administration
chemical_list: D000617:Aminoglycosides; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000079982:Gemtuzumab
keywords: Acute myeloid leukemia; Adverse drug reactions; Hematopoietic stem-cell transplant; Veno-occlusive disease