Obinutuzumab (Gazyva), manufactured by Genentech, is a novel anti-CD20 monoclonal antibody FDA approved, in combination with chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).1
Approved November 1, 2013, Gazyva is the first drug with breakthrough therapy designation to receive FDA approval. This designation, requested by a pharmaceutical company, is designed to expedite the development and review process of drugs that are intended to treat serious conditions when preliminary clinical evidence demonstrates that the drug clearly shows substantial improvement over current therapies on clinically significant end points.2
As a monoclonal antibody, obinutuzumab targets the CD20 antigen expressed on the surface of both mature and immature B-lymphocytes and, upon binding, mediates the lysis of these cells through 3 mechanisms: engaging immune effector cells to result in antibody-dependent cellular cytotoxicity and phagocytosis, directly activating apoptosis signaling pathways, and/or activating the complement protein cascade. Obinutuzumab has a volume of distribution of approximately 3.8 L, a total body clearance of 0.09 L/day, and an elimination half-life of approximately 28.4 days.1,3
Treatment with obinutuzumab is completed in 6 cycles, and premedication before each infusion during the 28-day cycle is strongly recommended to reduce the risk of potentially severe, life-threatening infusion reactions. Obinutuzumab is administered only as an intravenous (IV) infusion via a dedicated line. On day 1 of cycle 1, a dose of 100 mg should be administered at 25 mg/h over 4 hours, and the infusion rate should not be increased. On day 2 of cycle 1, 900 mg should be administered at 50 mg/h, and the infusion rate may be increased in increments of 50 mg/h every 30 minutes to a maximum rate of 400 mg/h. This is followed by 1000 mg weekly for 2 doses on days 8 and 15 of cycle 1. Following completion of cycle 1, 1000 mg of obinutuzumab should be administered every 28 days with each dose designated as day 1 of 5 subsequent cycles. The 1000-mg doses should be infused at a rate of 100 mg/h and may be increased by 100 mg/h increments every 30 minutes to a maximum of 400 mg/h. Thus, for 1 course of treatment lasting approximately 6 months, a total of 9 doses of obinutuzumab would be administered to a patient.1
For patients with high tumor burden and/or high circulating absolute lymphocyte counts (>25 × 109/L), premedication with an antihyperuricemic, such as allopurinol, starting 12 to 24 hours prior to start of therapy is advised. Adequate hydration should also be ensured to prevent tumor lysis syndrome in these patients. All patients on days 1 and 2 of cycle 1 should receive an IV glucocorticoid, such as 20 mg dexamethasone or 80 mg methylprednisolone, at least 1 hour prior to obinutuzumab, as well as 650 to 1000 mg acetaminophen and an antihistamine (eg, diphenhydramine 50 mg) at least 30 minutes before infusion as premedication therapy. The acetaminophen should be repeated for all patients on days 8 and 15 of cycle 1, as well as on the first day of subsequent cycles. The antihistamine may also be repeated on these days only for patients with an infusion-related reaction (IRR) of Grade 1 or higher from the previous infusion, and the IV glucocorticoid should only be repeated on those same days for patients with a Grade 3 IRR or with a lymphocyte count >25 × 109/L prior to the next treatment.1
Approval for Gazyva was based on a randomized, open-label multicenter phase III trial of 356 participants with previously untreated CLL comparing obinutuzumab in combination with chlorambucil to chorambucil alone. Obinutuzumab was given according to the dosing protocol established above, and chlorambucil was given orally at 0.5 mg/kg on day 1 and 15 of all 6 treatment cycles. In the study, 95% of participants were Caucasian, 60% were male, and 76% had multiple coexisting medical conditions. The median age was 73 years, and the median estimated CrCL was 61 mL/min. At the conclusion of the study, 81% of patients treated with obinutuzumab and chlorambucil in combination received all 6 cycles of therapy compared with 67% of patients receiving chlorambucil alone. The median progression-free survival was 23.0 months in the arm receiving obinutuzumab and chlorambucil in combination and 11.1 months in the chlorambucil alone arm, deemed a significant difference (log-rank P
The most common adverse reactions seen during treatment with obinutuzumab are infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, and musculoskeletal disorders. Black box warnings associated with use of obinutuzumab include risk of hepatitis B virus reactivation that may result in fulminant hepatitis, liver failure, or death, as well as risk of progressive multifocal leukoencephalopathy, which may also be fatal. Because hypotension may occur during obinutuzumab infusions, providers should consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion, as well as for the first hour after administration. It is highly recommended that patients with neutropenia receive antimicrobial prophylaxis throughout the treatment period. Obinutuzumab should not be administered to patients with an active infection, and patients with a history of chronic or recurring infections may also be at an increased risk of infection with obinutuzumab. Patients should not be immunized with live virus vaccines during treatment. Platelet counts should be monitored in patients who develop grade 3 or 4 thrombocytopenia while being treated with obinutuzumab; transfusion of blood products may be necessary.1
Availability and Cost
Gazyva is available as 1000 mg/40 mL (25 mg/mL) single-use vials containing preservative-free solution. The vials should be protected from light and refrigerated, as they are stable at 2°C to 8°C (36°F to 46°F). Cost of Gazyva is $41,300 for one 6-month course of treatment.4
Additional information can be found at www.gazyva.com.
Ashley L. Pappas, PharmD, BCPS, is a drug information specialist at University of North Carolina (UNC) Hospitals and an adjunct assistant professor at the UNC Eshelman School of Pharmacy.
Sandra Hanna, PharmD candidate, is a second-year pharmacy student at the UNC Eshelman School of Pharmacy and an intern at the UNC Hospital Drug Information Center in Chapel Hill, North Carolina.
Gazyva [package insert]. South San Francisco, CA: Genentech, Inc; November 2013.
FDA approves Gazyva for chronic lymphocytic leukemia [press release]. November 1, 2013. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm.
Gazyva. Drug Facts & Comparisons [online database]. Wolters Kluwer Health, Inc; November 2013.
Leuty R. Genentech scores FDA approval for new leukemia drug. San Francisco Business Times. November 1, 2013. www.bizjournals.com/sanfrancisco/blog/biotech/2013/11/genentech-cll-leukemia-gadcyla-rituxan.html?page=all.