Obinutuzumab for chronic lymphocytic leukemia: promise of the first treatment approved with breakthrough therapy designation

Abstract

Obinutuzumab (also known as GA101, afutuzumab, Gazyva) is a humanized, glycoengineered type II monoclonal antibody targeted against CD20. The US Food and Drug Administration has approved obinutuzumab for use with chlorambucil in patients with previously untreated chronic lymphocytic leukemia. The drug is the first treatment to receive approval under the agency's breakthrough therapy designation, a program intended to facilitate and expedite the review and development of therapies for serious and life-threatening conditions. In preclinical studies, obinutuzumab has showed superior efficacy, as compared with rituximab, by inducing direct cell death and increased antibody-dependent cellular cytotoxicity activity with less complement-dependent cytotoxicity. Regulatory approval of obinutuzumab is based on a phase III (CLL11) study that demonstrated improved outcomes with a combination of obinutuzumab with chlorambucil in previously untreated patients with chronic lymphocytic leukemia and comorbidities. Obinutuzumab plus chlorambucil induced deeper and longer remissions than rituximab plus chlorambucil combination as evidenced by prolongation of progression-free survival and higher complete response and molecular response rates. Marketing applications for obinutuzumab have also been submitted to other regulatory authorities including the European Medicines Agency.

Affecting NF-κB cell signaling pathway in chronic lymphocytic leukemia by dendrimers-based nanoparticles

“…Currently the treatment of patients with CLL is undergoing fundamental changes (Burger et al, 2017). One promising approach to achieve more durable responses might be the development of glycodendrimers coated with sugar layer which presents unique and functional characteristics (Kakkar and Balakrishnan, 2015;Eichhorst et al, 2016).…”

Hepatitis B Reactivation with Novel Agents in Non-Hodgkin’s Lymphoma and Prevention Strategies

“…However, no published data exist to support this report. 39 , 40 A search from the FDA Adverse Event Reporting System database did not yield any data to support this report ( http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm111085.htm#O ; http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm373263.htm ). A Japanese Phase I study of obinutuzumab in refractory B-cell NHL excluded patients with seropositive HBV status, 41 thereby precluding the usefulness of identifying adverse events through clinical trials.…”

Clinical role of obinutuzumab in the treatment of naive patients with chronic lymphocytic leukemia

“…The elimination of obinutuzumab is likely target-mediated drug disposition. 46 , 47 The relationship between pharmacokinetics and clinical response and/or tumor burden could not be concluded based on Phase I/II trials due to small population numbers. However, the Phase II study reported disappointing response rates in patients with higher tumor burden, suggesting that dosing schedules may be very important for obinutuzumab’s efficacy.…”

“… 48 Insufficient data exist on the effect of severe renal or hepatic impairment; however, no modifications are expected since monoclonal antibodies are metabolized via ubiquitous proteolytic enzymes. 46 , 47 Further pharmacokinetic data are anticipated with the currently ongoing GAGE study, which is comparing the efficacy and safety of obinutuzumab dosed intravenously at 1,000 mg vs 2,000 mg. Preliminary results at week 32 describe overall response rates (ORRs) of 48.8% and 66.7% ( P =0.0779) among patients receiving 1,000 mg (n=41) and 2,000 mg intravenous infusions (n=39), respectively.…”

“… 14 Though no unusual infections were reported in the CLL11 study, a recent case of an invasive fungal infection was reported using obinutuzumab monotherapy in a heavily pretreated refractory CLL patient, 62 and cases of progressive multifocal leukoencephalopathy and hepatitis B reactivation have also been reported similar to other novel anti-CD20 mAbs after more patients have been exposed. 47 The lack of detection of unusual or invasive infections in the CLL11 study relates to the patient population as multiply pretreated patients and refractory CLL patients have significantly higher risks of invasive infections than previously untreated patients. To date, no unusual AEs have been reported with obinutuzumab, and there were no differences between the obinutuzumab and rituximab chemoimmunotherapy arms in terms of the development of ≥1 malignant, benign, or unspecified neoplasm 6 months postinitiation of therapy.…”