management of chronic lymphocytic leukemia (CLL) a malignant disorder of the lymphoid lineage (primarily B cells) has changed considerably Solcitinib (GSK2586184) in recent years. with or without rituximab in 761 previously untreated patients with CLL and demonstrated significant improvements in complete response median progression-free survival Solcitinib (GSK2586184) (PFS) and overall survival (OS) in those who received rituximab (Hallek et al. 2010 This study thus established chemoimmunotherapy as the standard of care in young symptomatic patients with CLL. A second anti-CD20 monoclonal antibody ofatumumab (Arzerra) was granted accelerated approval by the FDA in 2009 2009 for patients with fludarabine-refractory/alemtuzumab-refractory CLL and subsequently in 2014 for previously untreated patients with CLL unable to tolerate fludarabine-based chemotherapy (Wierda et al. 2010 GlaxoSmithKline 2014 This updated indication was based on a randomized trial comparing ofatumumab plus chlorambucil vs. chlorambucil alone in 447 treatment-naive patients with CLL (Hillmen et al. 2013 Overall response and PFS were significantly longer in the ofatumumab-chlorambucil group. In November 2013 the third anti-CD20 monoclonal antibody obinutuzumab (Gazyva) was approved by the FDA in combination with chlorambucil for patients with previously untreated CLL. The growing number of targeted immunotherapies in CLL including obinutuzumab may Solcitinib (GSK2586184) represent a paradigm shift in the management of this disease. DRUG CLASS AND MOLECULAR TARGET CD20 is a transmembrane calcium channel involved in B-cell activation proliferation and differentiation (Cheson & Leonard 2008 Type I anti-CD20 monoclonal antibodies rituximab and ofatumumab lead to complement-dependent cytotoxicity (CDC) stimulation of signaling leading to apoptosis and antibody-dependent cell-mediated cytotoxicity (ADCC) through the recruitment of immune mediator cells (Herter et al. 2013 Obinutuzumab is a type II fully humanized anti-CD20 monoclonal antibody that binds in a unique conformation to the protein epitope on the CD20 channel which partially overlaps with the section recognized by rituximab (Bologna et al. 2011 Due to its glycoengineered design obinutuzumab has an increased affinity for natural killer cells macrophages and dendritic cells which allows for greater ADCC than rituximab (Golay et al. 2013 M?ssner et al. 2010 Although obinutuzumab does not stabilize CD20 in lipid rafts and therefore has less CDC it has more effective direct B-cell apoptosis than rituximab via activation of polymorphonuclear neutrophils which results in phagocytosis and cell death (Golay et al. 2013 M?ssner et al. 2010 The broadened mechanism of action of obinutuzumab in contrast to the mechanisms of rituximab and ofatumumab is theorized to provide greater efficacy (Bologna et al. 2011 Golay et al. 2013 STUDY RESULTS The FDA approval of obinutuzumab was based on a randomized open-label phase III study conducted in 781 adult patients with previously untreated CD20-positive CLL with a Cumulative Illness Rating Scale (CIRS) score of > 6 indicating a higher number of baseline comorbidities (Goede Rabbit polyclonal to NOTCH1. et al. 2014 Patients were randomized to receive one of three treatments: chlorambucil monotherapy obinutuzumab with chlorambucil or rituximab with chlorambucil. Patients in the obinutuzumab/chlorambucil arm demonstrated significant PFS benefit compared with both chlorambucil alone and rituximab-chlorambucil (26.7 months vs. 11.1 months and 15.2 months respectively; < 0.001 for both comparisons). Obinutuzumab/chlorambucil had a significant OS benefit over chlorambucil monotherapy (death rates 9% vs. 20% respectively; = .002); however there was no significant OS benefit with obinutuzumab/chlorambucil vs. rituximab/chlorambucil (death rates 8% vs. 12% respectively; = .08). A PFS benefit with obinutuzumab/chlorambucil was demonstrated regardless of age gender lymphocyte count or CIRS score but was not demonstrated in patients with the poor prognostic cytogenetic marker del(17p). DOSING AND ADMINISTRATION Prior to administration of obinutuzumab patients should be evaluated for tumor lysis syndrome risk and hepatitis B reactivation. All patients should be tested for hepatitis B surface Solcitinib (GSK2586184) antigen (HBsAg) and hepatitis B core antibody (anti-HBc). If either serology is positive consultation with an experienced physician in the management of hepatitis B is warranted to evaluate for appropriate prophylaxis and monitoring prior to initiating therapy.