Journal Article

Obinutuzumab and Non-Overt Disseminated Intravascular Coagulation: A Case Study of Signal Detection and Management in Italy

Rocchi, R E, Tuccori, Marco, Bucaneve, Giampaolo, Valdiserra, G, Cappello, Emiliano, Mores, N, Fresa, Alberto, Sottosanti, L, Felicetti, P, Laurenti, L, Marchione, P

2022

Overview

Introduction: Disseminated intravascular coagulation (DIC) is a rare disorder of coagulation with different etiologies, including treatments with drug [1]. On December 2020, during a scheduled periodic assessment meeting, the Agenzia Italiana del Farmaco (AIFA) evaluated four individual case safety reports (ICSRs) reporting obinutuzumab and non-overt DIC [2] as new possible signal. Objective: We reported the process of signal detection for obinutuzumab-associated non-overt DIC. Methods: Periodic assessments of signal detection for drugs are conducted by AIFA in collaboration with the Italian Regional Centers of Pharmacovigilance. Reporting odds ratio (ROR) is calculated for each drug-event pair as measure of disproportionality. A signal is generated when the number of ICSRs is ≥ 3 and the lower limit of the 95% confidence interval of ROR is ≥ 1. Priority is given to unexpected and important medical events. Possible signals are presented and discussed in the light of information reported in medical literature. Eudravigilance is also checked for similar ICSRs. When a signal is considered enough robust, an assessment report is submitted to the rapporteur country for a possible evaluation by the Pharmacovigilance Risk Assessment Committee (PRAC) at the European Medicine Agency. Results: During routine signal evaluation meetings in December 2020, 4 cases of obinutuzumab-associated non-overt DIC meet the criteria for signal definition (ROR 213.6 and IC025 77). At that time, the Italian database of ICSRs, contained about 150.000 ICSRs. The patients (2 men and 2 women, age 67-77) received obinutuzumab for chronic lymphocytic leukemia. Patients received drug for the treatment of age-related diseases. A subclinical DIC was detected within 48 hours from obinutuzumab administration. After the exclusion of alternative causes, the hematologists decided to report all the 4 cases as suspected adverse drug reactions to obinutuzumab. The DIC spontaneously resolved in all cases. Three more ICRSs were reported in Eudravigilance database. Medical literature reported only one case-report on a woman who developed a DIC following obinutuzumab administration was published [3]. Other authors showed that the administration of the drug induced a pro-inflammatory response with the increase of interleukins and tumor necrosis factor [4, 5]. The DIC is a rare adverse reaction also for rituximab, another anti-CD20 and a rare class effect cannot be excluded [3]. The evidence was robust enough to present the signal to the PRAC. Conclusion: The PRAC identified non-overt DIC as an uncommon adverse reaction to obinutuzumab, and recommended to update the summary of product characteristics (SPC) of obinutuzumab.

• Publisher: Springer Nature B.V
• Subject: Age / Age related diseases / CD20 antigen / Chronic lymphocytic leukemia / Coagulation / Disseminated intravascular coagulation / Evaluation / Immunotherapy / Inflammation / Inflammatory response / Interleukins / Leukemia / Monoclonal antibodies / Patients / Pharmacology / Pharmacovigilance / Risk assessment / Rituximab / Robustness / Side effects / Signal detection / Signal processing / Targeted cancer therapy