In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms of action, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On June 22, 2017, the combination of rituximab (Rituxan) and hyaluronidase human (Rituxan Hycela; RHH) was approved for treatment of adults with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL).1,2 The product is a combination of the CD20-directed cytolytic antibody rituximab and recombinant human hyaluronidase, an endoglycosidase that increases the dispersion and absorption of coadministered drugs when given subcutaneously. The combination product reduces the administration time to 5 to 7 minutes vs the several hours required for intravenous (IV) infusion of rituximab and permits flat dosing.
The product is indicated for the following previously approved indications for rituximab: relapsed or refractory FL as a single agent; previously untreated FL in combination with first-line chemotherapy and in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy; nonprogressing FL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy; previously untreated DLBCL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens; and previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC).
Supporting Efficacy Data
Approval is based on randomized trials demonstrating: (1) noninferior rituximab trough concentrations (C-trough) for RHH at 1,400 mg/23,400 U vs intravenous (IV) rituximab at 375 mg/m2 (SABRINA trial); (2) noninferior rituximab C-trough levels for RHH at 1,600 mg/26,800 U vs IV rituximab at 500 mg/m2 (SAWYER trial); and (3) comparable efficacy and safety of the two products.
The combination of rituximab and hyaluronidase human has boxed warnings for severe mucocutaneous reactions, hepatitis B virus reactivation, and progressive multifocal leukoencephalopathy.
In the SABRINA trial in previously untreated FL, 410 patients were randomized to receive 8 cycles of IV rituximab at 375 mg/m2 (n = 205) or 1 cycle of IV rituximab followed by 7 cycles of RHH at 1,400 mg/23,400 U both every 3 weeks (n = 205) in combination with a total of 6 to 8 cycles of CHOP or 8 cycles of CVP. Patients who received CHOP and achieved stable disease or better at interim assessment after four cycles could receive either four more cycles of R-CHOP or two cycles of R-CHOP followed by two cycles of rituximab or RHH depending on the randomization arm; patients with at least a partial response after combination treatment with chemotherapy continued with single-agent maintenance with rituximab or RHH every 8 weeks for 24 months. At the end of combination treatment, the overall response rate was 84% in the RHH group vs 85% in the rituximab group, with a complete response in 32% vs 32%. At the end of maintenance treatment, the overall response rate was 78% vs 78%, with a complete response in 51% vs 56%.
In the MabEASE trial in previously untreated patients with DLBCL, 576 patients were randomized 2:1 to receive 1 cycle of IV rituximab followed by 7 cycles of RHH at 1,400 mg/23,400 U (n = 381) or IV rituximab at 375 mg/m2 for 8 cycles (n = 195), both in combination with up to 6 to 8 cycles of CHOP chemotherapy every 14 or 21 days. Complete response rates were 47% vs 42%.
In the SAWYER trial in previously untreated patients with CLL, 176 patients were randomized to receive IV rituximab in cycle 1 followed by 5 cycles of RHH at 1,600 mg/26,800 U (n = 85) or IV rituximab at 375 mg/m2 in cycle 1 followed by up to 5 cycles of IV rituximab at 500 mg/m2 (n = 89), both in combination with FL. Overall response rates were 85% vs 81%, with a complete response in 26% vs 33%.
How It Works
RHH is a combination of rituximab and hyaluronidase human. Rituximab is a monoclonal antibody targeting CD20 antigen expressed on the surface of pre-B and mature-B lymphocytes; upon binding to CD20, rituximab mediates B-cell lysis. Hyaluronan is a polysaccharide found in the extracellular matrix of subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has a half-life of approximately 0.5 days. Hyaluronidase human increases the permeability of subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidasenhuman in RHH acts locally. The effects of hyaluronidase human are reversible, with permeability of the subcutaneous tissue being restored within 24 to 48 hours.
How It Is Used
RHH should be administered only by a health-care professional with appropriate medical support to manage severe reactions, which can be fatal. All patients must first receive at least one full dose of a rituximab product by IV infusion without experiencing severe adverse reactions before starting treatment with RHH. Patients unable to receive one full IV dose should continue subsequent cycles with IV rituximab until a full IV dose is successfully administered. Dose reductions are not recommended. When RHH is given in combination with chemotherapy, chemotherapy dosing should be modified to manage adverse reactions.
The recommended doses of RHH are 1,400 mg/23,400 U in FL and DLBCL and 1,600 mg/26,800 U in CLL. Administration schedules for relapsed or refractory FL, retreatment of relapsed/refractory FL, previously untreated FL, nonprogressing FL after first-line CVP, DLBCL, and CLL are detailed in product labeling.
Patients should be premedicated with acetaminophen and an antihistamine before each dose; premedication with a glucocorticoid should also be considered. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes virus infections should be given to patients with CLL during treatment and for up to 12 months after treatment.
In the three trials supporting approval of RHH, the most common adverse events of any grade (> 20%) in RHH recipients included infections (eg, upper respiratory tract in 15%, pneumonia in 11%, nasopharyngitis in 10%), neutropenia (32%), nausea (31%), constipation (25%), and cough (23%) in FL; infections, neutropenia (31%), alopecia (24%), anemia (23%), and nausea (22%) in DLBCL; and infections, neutropenia (65%), nausea (38%), pyrexia (32%), injection-site erythema (26%), thrombocytopenia (24%), and vomiting (21%) in CLL.
In the SABRINA trial in FL, 15% of patients had an administration-related reaction during the first administration of RHH (cycle two), with the incidence decreasing from 9% to 4% over subsequent cycles; during maintenance, such reactions occurred in 14% of patients overall. In total, 96% of reactions were grade 1 or 2. In the MabEASE study in DLBCL, administration-related reactions occurred in 28% (97% grade 1 or 2) of the RHH group and 29% (80% grade 1 or 2) of the rituximab group. In the SAWYER study in CLL, administration-related reactions occurred in 44% vs 45% of patients.
RHH has boxed warnings for severe mucocutaneous reactions, including fatalities; hepatitis B virus reactivation, resulting in some cases in fulminant hepatitis, hepatic failure, and death; and progressive multifocal leukoencephalopathy, including fatality. It also carries warnings/precautions for hypersensitivity and other administration reactions (local cutaneous reactions may occur more than 24 hours after administration); tumor-lysis syndrome; infections; cardiac adverse reactions; renal toxicity; bowel obstruction and perforation; immunizations (live virus vaccination prior to or during treatment is not recommended); and embryofetal toxicity. ■
1. U.S. Food and Drug Administration: FDA approves rituximab plus hyaluronidase combination for treatment of FL, DLBCL, and CLL. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm564235.htm. Accessed September 19, 2017.
2. Rituxan Hycela (rituximab and hyaluronidase human) injection, for subcutaneous use, prescribing information, Genentech, Inc., June 2017. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761064s000lbl.pdf. Accessed September 19, 2017.