Diffuse Large B-Cell Lymphoma (DLBCL)

Rituxan®(rituximab), known as MabThera® in the European Union, is a chimeric murine/human monoclonal antibody used to treat cancer.² Rituximab is a component of the standard first-line therapy in DLBCL and used in combination with chemotherapeutic agents such as cyclophosphamide, hydroxydaunorubicin (sold as Lipodox® or Doxil®), Oncovin® (vincristine), and prednisone (R-CHOP).^2,4 Rituxan Hycela® is a formulation of Rituxan, containing both rituximab and hyaluronidase human, that allows subcutaneous (SC) administration instead of through intravenous (IV) infusion. It is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL) in combination with chemotherapeutic regimens such as CHOP or other anthracycline-based chemotherapy therapies.¹

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Rituxan Hycela is manufactured by Genentech and jointly marketed by Biogen and Genentech.¹ The European Medicines Agency approved the SC formulation for use in the European Union 2014, and it was approved by the US Food and Drug Administration (FDA) in June 2017.^2,3

Mechanism of Action 

After binding to the CD20 antigen at the cell surface of pre-B lymphocytes and mature B lymphocytes, rituximab causes cell lysis via such mechanisms as antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and apoptosis induction.^1,2 Additionally, rituximab has a synergistic effect in combination with drugs such as paclitaxel, gemcitabine, cladribine, bendamustine, mitoxantrone, and doxorubicin.² 

The recombinant human hyaluronidase in Rituxan Hycela is an endoglycosidase that increases the dispersion and absorption of drugs administered subcutaneously by increasing tissue permeability.^1,2

Read more about DLBCL therapies

Administration

Rituximab is traditionally administered through IV infusion over 1.5 to 6 hours. The subcutaneous formulation of Rituxan Hycela was developed to simplify this administration, improve patients’ access to treatment, and decrease the use of healthcare resources.^2,4

Rituxan Hycela can be injected subcutaneously into the abdomen within approximately 5 to 7 minutes. It shouldn’t be injected into areas where the skin is bruised, tender, hard, red, or areas where there are moles or scars.¹

Before Rituxan Hycela can be administered, patients must have received a full dose of IV rituximab. The recommended dose is 1400 mg of rituximab and 23,400 U of hyaluronidase human in combination with CHOP. After rituximab has been infused intravenously on day 1 of cycle 1 of CHOP chemotherapy, Rituxan Hycela should be administered on day 1 of cycles 2 through 8 of CHOP therapy (7 cycles).¹ Before Rituxan Hycela is injected, patients should be premedicated with acetaminophen and an antihistamine. Pre-medication with glucocorticoids can also be considered.¹

Read more about DLBCL treatment

Adverse Effects

Common adverse events following the use of Rituxan Hycela include infection, neutropenia, alopecia, nausea, and anemia.¹ Severe adverse events, such as severe mucocutaneous reactions, reactivation of hepatitis B virus, and progressive multifocal leukoencephalopathy, can also occur.¹

Safety and Efficacy in Trials

The approval of Rituxan Hycela was based on the results of several randomized clinical trials. A pharmacokinetic bridging approach was used to determine whether Rituxan Hycela is pharmacokinetically inferior to the IV formulation. Both the phase 3 SABRINA study (NCT01200758) and the phase 1b SparkThera study (NCT00930514), conducted in patients with a diagnosis of follicular lymphoma, demonstrated that it is not.^5-7 Another phase 1b study, SAWYER (NCT01292603), also reported that the safety profiles of the SC and IV formulations are similar, with no pharmacokinetic inferiority of the SC medication shown in patients being treated for chronic lymphocytic leukemia.^8,9 

Get full prescribing information for Rituxan Hycela at MPR

The safety and efficacy of Rituxan Hycela plus a CHOP regimen in patients with previously untreated DLBCL was demonstrated in the phase 3 MabEase clinical trial (NCT01649856). In this multicenter, randomized, open-label trial, 572 patients were randomized to receive rituximab either subcutaneously (378 patients) or via IV infusion (194 patients).^4,10 The primary endpoint of this trial was the investigator-assessed complete response (CR) rate at the end of combination treatment with chemotherapy. Overall, the efficacy of subcutaneous rituximab was proved comparable with that of intravenous rituximab. The CR rates were of 47% for Rituxan Hycela and 42% for IV rituximab.¹ For the additional endpoints of progression-free survival (PFS) and overall survival (OS), the rates were 27% vs 23% and 17% vs 15% with the subcutaneous and IV formulations, respectively.¹ 

The clinical program for the development of Rituxan Hycela has shown that the safety profile of this formulation is similar to that of Rituxan; similar rates of adverse events for the 2 formulations were reported. Exceptions were an increase in administration-related reactions (ARRs) with SC administration, which were mostly mild to moderate and decreased during subsequent treatments (as they did with IV administration), and an increase in local cutaneous reactions with the injection.² The phase 3 MabRella clinical trial (NCT01987505), designed to assess the safety of switching patients with DLBCL or follicular lymphoma from IV to SC rituximab, with special attention to ARRs, demonstrated that the switch entailed no additional safety concerns or decrease in the efficacy of treatment.¹¹

Read more about DLBCL prognosis

References

1. RITUXAN HYCELA® (rituximab and hyaluronidase human) injection, for subcutaneous use. Highlights of prescribing information. Genentech. Revised June 2021.

2. Davies A, Berge C, Boehnke A, et al. Subcutaneous rituximab for the treatment of B-cell hematologic malignancies: a review of the scientific rationale and clinical development. Adv Ther. 2017;34(10):2210-2231. doi:10.1007/s12325-017-0610-z

3. FDA approves rituximab plus hyaluronidase combination for treatment of FL, DLBCL and CLL. News release. US Food and Drug Administration; June 22, 2017.

4. Lugtenburg P, Avivi I, Berenschot H, Ilhan O, et al. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017;102(11):1913-1922. doi:10.3324/haematol.2017.173583

5. Davies A, Merli F, Mihaljevic B, Siritanaratkul N, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol. 2014;15(3):343-352. doi:10.1016/S1470-2045(14)70005-1

6. Davies A, Merli F, Mihaljević B, et al. Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial. Lancet Haematol. 2017;4(6):e272-e282. doi:10.1016/S2352-3026(17)30078-9

7. Salar A, Avivi I, Bittner B, et al. Comparison of subcutaneous versus intravenous administration of rituximab as maintenance treatment for follicular lymphoma: results from a two-stage, phase IB study. J Clin Oncol. 2014;32(17):1782-1791. doi:10.1200/JCO.2013.52.2631

8. Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics and safety of subcutaneous rituximab plus fludarabine and cyclophosphamide for patients with chronic lymphocytic leukaemia. Br J Clin Pharmacol. 2015;80(5):1001-1009. doi:10.1111/bcp.12662

9. Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial. Lancet Haematol. 2016;3(3):e128-e138. doi:10.1016/S2352-3026(16)00004-1

10. A study of subcutaneous versus intravenous MabThera/Rituxan (rituximab) in combination with CHOP chemotherapy in patients with previously untreated CD20-positive diffuse large B-cell lymphoma. ClinicalTrials.gov. August 24, 2012. Updated October 11, 2017. Accessed August 4, 2022.

11. García-Muñoz R, Quero C, Pérez-Persona E, et al. Safety of switching from intravenous to subcutaneous rituximab during first-line treatment of patients with non-Hodgkin lymphoma: the Spanish population of the MabRella study. Br J Haematol. 2020;188(5):661-673. doi:10.1111/bjh.16227

Reviewed by Debjyoti Talukdar, MD, on 8/28/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.