Approved for use in combination with chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).
A CD20 antibody.
A humanized glycoengineered antibody with enhanced antibody-dependent cellular toxicity.
In combination with chlorambucil, was shown to significantly improve progression-free survival vs chlorambucil alone in the Phase III CLL11 trial.
The patient population in CLL11 had a median age of 73 with previously untreated CD20+ CLL and had a range of coexisting medical conditions or reduced renal function as measured by CrCl <70 mL/min.
Phase III GALLIUM trial combined with chemotherapy in the first line setting and reduces the risk of disease progression or death by 34% vs rituximab in patients with follicular lymphoma.
GAZYVA demonstrated an 84% reduction in the risk of CLL progression, relapse, or death when combined with chlorambucil vs chlorambucil alone.
Overall response rate was 75.9% for the GAZYVA-treated arm and 32.1% for the chlorambucil alone arm, with a complete response rate 27.8% and 0.9%, respectively.
Demonstration of an improvement in progression-free survival (PFS) in a randomized, open-label, multicenter trial comparing obinutuzumab in combination with chlorambucil (GClb) to chlorambucil (Clb) alone in patients with previously untreated CD20-positive CLL.
Progression free survival 15.2 months with combination chlorambucil and rituximab versus 26.7 months with combination chlorambucil and obinutuzumab in CLL.
In a randomized study of previously untreated CLL patients randomized to chlorambucil, chlorambucil plus obinutuzumab, or rituximab plus chlorambucil: combining an anti-CD20 antibodies with chemotherapy improved outcomes in patients with a CLL and coexisting conditions-Obinutuzumab was superior to rituximab when each was combined with chlorambucil (German CLL study group).
In the above studies the median progression free survival was 26.7 months with Obinutuzumab plus chlorambucil versus 11.1 months with chlorambucil alone, versus 16.3 months with rituximab plus chlorambucil.
In the above studies treatment with Obinutuzumab plus chlorambucil compared to rituximab plus chloambucil resulted in prolongation of progression free survival and higher rates of complete response 20.7% versus 7%, respectively.
This combination regimen is now indicated as a first-line treatment CLL patients without del(11q) or del(17p), both those agents 70 years or less in those greater than 70 years with del(17p), and with del(11q) if 70 years or older.
Patients randomized to the combination arm received 1000 mg doses of obinutuzumab intravenously on day 1 (later divided into 100 mg on day 1, followed by 900 mg on day 2), day 8 and day 15 of the first cycle.
Chlorambucil, 0.5 mg/kg, was administered on days 1 and 15.
During treatment cycles 2-6, patients received obinutuzumab, 1000 mg intravenously only on day 1 in combination with chlorambucil, 0.5 mg/kg, on days 1 and 15.
Cycles were repeated every 28 days.
The median PFS was 23.0 and 11.1 months in the GClb and Clb arms, respectively.
Most common Grade 3 or 4 adverse reactions reported with ≥5% incidence were infusion related reactions 21%, neutropenia 34%, thrombocytopenia 11%, and leukopenia 5%.
The incidence of infusion reactions was 69% with the first infusion of the drug, but the incidence of reactions with subsequent infusions is 3% with the second 1000 mg and <1% thereafter.
Thirty-eight percent of patients in the GAZYVA-treated arm experienced an infection, but none were fatal.
Hepatitis B Virus (HBV) reactivation can occur in patients receiving CD20-directed cytolytic antibodies, so all patients should be screened for HBV infection before treatment initiation.
Patients should be monitored in HBV positive patients during and after treatment.
Infusions can result in progressive multifocal leukoencephalopathy (PML).
Can cause severe and life-threatening infusion reactions including: hypotension, tachycardia, dyspnea, respiratory symptoms, nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills
Infusion reactions can occur within 24 hours of receiving the drug.
Patients with pre-existing cardiac or pulmonary conditions, may be at greater risk of experiencing more severe reactions.
Tumor lysis syndrome can occur within 12-24 hours after the first infusion.
Patients with high tumor burden and/or high circulating lymphocyte count (>25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis beginning 12-24 hours prior to the infusion.
Serious bacterial, fungal, and new or reactivated viral infections can occur during and following therapy.
Should not be administered to patients with an active infection.
Patients with severe neutropenia should be monitored frequently until resolution, and are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period.
Patients with severe neutropenia should be considered for antiviral and antifungal prophylaxis.
Neutropenia can occur more than 28 days after completion of treatment and last longer than 28 days.
Can cause acute thrombocytopenia occurring within 24 hours after drug infusion.
Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery.
The most common adverse reactions) with obinutuzumab in combination with chlorambucil were infusion-related reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorder.
The most common grade 3-4 adverse reactions were infusion-related reactions, neutropenia, and thrombocytopenia.
Infusion reactions occurred in 69% of patients receiving obinutuzumab; 21% experienced Grade 3 or 4 reactions.
Symptoms included dyspnea, hypotension, nausea, vomiting, chills, flushing, and fever.
Hepatic transaminitis can occur early in treatment.
The recommended dose and schedule for the approved regimen is:
Obinutuzumab:Cycles 2-6: 1000 mg administered intravenously every 28 days
Cycle 1: 100 mg intravenously on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15.
Chlorambucil:
0.5 mg/kg orally on days 1 and 15 of each cycle