Continuing Education Activity

This activity centers on rituximab, an anti-CD20 monoclonal antibody pivotal in treating various lymphoproliferative and autoimmune disorders. The program provides an in-depth exploration of rituximab's indications, mechanisms of action, and crucial aspects of its therapeutic application. From lymphomas to autoimmune conditions, the activity elucidates the clinical efficacy of rituximab, shedding light on the intricate mechanisms that underlie its targeting of CD20-positive cells, thereby modulating immune responses and delivering therapeutic effects. Emphasis is placed on essential pharmacological considerations and monitoring parameters vital to ensuring patient safety.

This activity systematically addresses the validated indications and potential off-label applications of rituximab across diverse medical contexts, equipping healthcare team members with a comprehensive understanding of its adverse effects and contraindications. This knowledge is vital for informed decision-making in treatment planning. The activity aims to enhance healthcare professionals' ability to manage rituximab therapy effectively by outlining monitoring strategies. This optimization of therapeutic outcomes and vigilance for potential complications contribute to fostering competent and safer patient care.

Objectives:

• Identify the appropriate indications and patient profiles suitable for rituximab therapy in the setting of lymphoproliferative and autoimmune disorders.

• Screen patients thoroughly for contraindications, previous allergic reactions, and underlying health conditions prior to initiating rituximab therapy.

• Assess the clinical response and monitor for potential adverse reactions during and after rituximab therapy, adjusting treatment plans as necessary.

• Develop effective communication with patients, caregivers, and the healthcare team, discussing the benefits, risks, and expectations related to rituximab treatment.

Indications

Rituximab is an anti-CD20 monoclonal antibody that was first approved by the FDA in 1997. Currently, the drug has received FDA approval for use in several conditions.

FDA-Approved Indications

• CD20-positive B-cell non-Hodgkin’s lymphoma (NHL)
  • Approved for use as a single agent in relapsed/refractory, low-grade, or follicular B cell NHL
  • Single-agent maintenance therapy for patients with previously untreated follicular B cell NHL who are achieving a complete or some degree of response to combination chemotherapy with rituximab
  • As a single agent in low-grade non-progressive/stable B cell NHL after Cyclophosphamide, Vincristine, and Prednisolone (CVP) chemotherapy.
  • In combination with anthracycline-based chemotherapy in previously untreated diffuse large B cell NHL

• Chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL): Approved for use in combination with fludarabine and cyclophosphamide to treat newly diagnosed or previously treated CLL.

• Rheumatoid arthritis (RA): Rituximab is considered a biologic disease-modifying antirheumatic drug (DMARD) for the treatment of RA. Rituximab is approved for use with methotrexate in adult patients who have an inadequate response to anti-TNF therapy.

• Microscopic olyangiitis (MP) and granulomatosis with polyangiitis (GPA): Approved for use in combination with glucocorticoids.

• Pemphigus ulgaris (PV): Approved in 2018 for glucocorticoid use for adult patients with moderate to severe disease.[1]

In addition, rituximab has orphan designations for immune thrombocytopenic purpura (ITP) and Rasmussen encephalitis.

Off-Label Uses

Myasthenia gravis

The FDA has recently approved 2 biosimilars of rituximab for adult patients. Biosimilars are drugs that have no clinically significant difference from the reference drug. These have a similar structure, safety profile, and function. Developing biosimilars aims to make medicines more accessible by lowering the cost.[2] Rituximab-abbs is approved for use in NHL alone or as part of a combination chemotherapy regimen and CLL in combination with fludarabine and cyclophosphamide. Rituximab-pvvr has approval for use in non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA).

There are numerous off-label uses of rituximab. According to a retrospective cross-sectional study performed in the US, the use of rituximab for off-label indications increased from 1.2% in 2009 to 55.6% in 2017.[1] Off-label uses include refractory autoimmune hemolytic anemia, refractory myasthenia gravis, multiple sclerosis, chronic steroid-refractory GVHD, Hodgkin lymphoma, systemic lupus erythematosus, thrombotic thrombocytopenic purpura, Waldenstrom macroglobulinemia, and membranous nephropathy.

In combination with hyaluronidase (rituximab-hyaluronidase human), rituximab was approved by the FDA in 2017. This formulation is available for use in the subcutaneous form, giving the advantage of a faster administration over 5 to 7 minutes instead of prolonged infusion times with IV formulations. This combination is approved for use in chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B-cell lymphoma. One limitation of use is that it can only be given after receiving a full dose of a rituximab product by IV infusion.[3]

Mechanism of Action

Rituximab is an anti-CD20 chimeric antibody with human IgG1 immunoglobulin constant regions and variable regions from an anti-CD20 murine antibody. CD20 is a surface transmembrane protein marker expressed on B cells during differentiation from the pre-B cell until the plasma cell stage. CD20 is believed to function as a calcium channel and play a role in the maturation and activation of B cells.[4][5]

Once rituximab is bound to CD20-positive cells, cell death is induced by various mechanisms, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated-cytotoxicity (CDC), antibody-dependent phagocytosis (ADP), and direct effects of binding of rituximab to CD20.[4] The mechanism of action of rituximab in autoimmune disease is thought to be due to a disruption in B cells' function in the immune system or a decrease in plasma cell production, as CD20-positive B cells are intermediates in the process of maturation.[6]

The combination of rituximab and hyaluronidase (rituximab-hyaluronidase human) is used in the subcutaneous form. Hyaluronidase causes a reversible increase in permeability of subcutaneous tissue by causing depolymerization of hyaluronan, which leads to an increase in the absorption rate of rituximab.

Pharmacokinetics

Absorption: Rituximab follows a linear pharmacokinetic model.[7] Intravenously administered rituximab has close to 100% bioavailability.

Distribution: Per the packaging insert available at the FDA, rituximab has a volume of distribution of 3.1 L.

Metabolism: Rituximab is metabolized by various proteases throughout the body and the hepatic CYP450 system of enzymes.

Elimination: The endogenous elimination of rituximab occurs following its formation of antidrug-monoclonal antibody immune complexes and is mediated by the reticuloendothelial system, most likely via the action of fragment crystallizable-gamma (Fcγ)-mediated endocytosis.[7] The drug's half-life is 18 to 32 days.

Administration

Dosage Forms

Rituximab and its biosimilars are approved for use by intravenous infusion. They should not be administered as an IV bolus or push. Patients should be given acetaminophen and antihistamines before each infusion. Rituximab should be diluted in an infusion bag of 0.9% sodium chloride, 5% dextrose in water, or USP. No other drugs should be mixed with it, and patients should be closely monitored for infusion reactions.[8]

Rituximab-hyaluronidase human is approved for subcutaneous use. The drug should be administered in the subcutaneous abdominal tissue over 5 to 7 minutes. Patients should be observed for 15 minutes after administration.[3]

Adult Dosing 

The following are adult dosing regimens for approved indications. Clinicians should refer to institutional protocols and the packaging insert for indications, premedications, and dosing.

Relapsed or refractory CD20-positive B-cell NHL: 

• Monotherapy: 375 mg/m²/dose IV weekly for 4 or 8 weeks.
• Ibritumomab tiuxetan combination therapy: 250 mg/m²/dose IV x 1 on the first day, then on days 7, 8, or 9 of the regimen.

Previously untreated CD20-positive B-cell NHL:

• Follicular type - combination chemotherapy: 375 mg/m²/dose IV x 1 on day 1 of each cycle for up to 8 cycles.
• Follicular type - ibritumomab tiuxetan combination therapy: 250 mg/m²/dose IV x 1 on the first day, then on days 7, 8, or 9 of the regimen.
• Diffuse large B-cell type - combination chemotherapy: 375 mg/m²/dose IV x 1 on day 1 of each cycle for up to 8 cycles.

Non-progressing CD20-positive B-cell NHL: 

• 375 mg/m²/dose IV x 1 on days 1, 8, 15, 22, or a 6-month cycle.

CD-20-positive CLL/SLL:

• Start 375 mg/m²/dose IV x 1 on the day before cycle 1; then 500 mg/m²/dose IV x 1 on day 1 of cycle 2 of a 28-day cycle, for 6 cycles.

Moderate to severe rheumatoid arthritis:

• 1000 mg IV every 2 weeks for 2 doses.

Granulomatosis with polyangiitis (GPA):

• Induction: 375 mg/m²/dose IV weekly for 4 weeks.
• Subsequent: 500 mg/m²/dose IV every 2 weeks for 2 doses, then 500 mg/m²/dose IV every 6 months.

Microscopic polyangiitis (MPA)

• Induction: 375 mg/m²/dose IV weekly for 4 weeks; use with glucocorticoids.
• Subsequent: 500 mg/m²/dose IV every 2 weeks for 2 doses, then 500 mg/m²/dose IV every 6 months; start 16 to 24 weeks after the induction dose.

Moderate to severe pemphigous vulgaris:

• Start with 1000 mg IV every 2 weeks for 2 doses, then 500 mg IV every 6 months.

Special Patient Populations

Hepatic impairment: Hepatic dosing for rituximab is undefined.

Renal impairment: Renal impairment requires no dose adjustments.

Pregnancy considerations: Rituximab has no known risk of teratogenicity, although there is a risk of transient B-cell depletion based on limited human data. Females of reproductive potential should obtain a pregnancy test before initiation of treatment and avoid pregnancy by using effective contraception during treatment and for 12 months following the end of treatment.

Breastfeeding considerations: Women should avoid breastfeeding during treatment and for 6 months following cessation.

Pediatric patients:

• Approved pediatric indications include CD20-positive B-cell NHL, GPA, and MPA.
• Rituximab is used off-label in pediatric patients for relapsed or refractory B-cell precursor ALL, moderate to severe pemphigus vulgaris, refractory autoimmune hemolytic anemia, chronic immune thrombocytopenia (ITP), post-transplant lymphoproliferative disorder (11 months and older), and refractory systemic lupus erythematosus (8 years and older). Consult package inserts or institutional guidelines for dosing and premedication regimens.

Older patients: Rituximab is a viable treatment in older patients, albeit with diligent monitoring and vigilance.[9]

Adverse Effects

Infusion reactions: These are the drug's most common and most serious adverse effects. In randomized controlled trials, allergic or anaphylactic reactions were seen in 80% to 90% of patients receiving rituximab.[10] These are usually seen within 30 to 120 minutes after the first infusion and range from mild to life-threatening. Infusion reactions can include fever, chills, skin rash, urticaria, angioedema, hypotension, ARDS, ventricular fibrillation, shock, anaphylaxis, and death.

Infections: Serious bacterial, viral, and fungal infections can occur. New or reactivated viral infections can include JC virus, herpes simplex, CMV, varicella-zoster, West Nile Virus, and hepatitis B and C. Due to the risk of reactivation, live vaccines are contraindicated during treatment with rituximab. They should be given at least 4 weeks before starting rituximab.

Reactivation of hepatitis B with fulminant hepatitis, hepatic failure, and death can occur. Before starting rituximab, all patients should be screened with hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). Patients should also be monitored for hepatitis B reactivation during and after treatment.[11][12]

Reactivation of Hepatitis B and the development of PML (progressive multifocal leukoencephalopathy) due to the JC virus are indications to discontinue rituximab.

PCP is an opportunistic fungal infection whose prophylaxis is recommended in patients receiving a fludarabine/cyclophosphamide/rituximab combination to treat CLL. This combination should be started during treatment and continued for a year following completion, and it is also recommended in patients with GPA and MPA during treatment and for at least 6 months after stopping rituximab.[13]

Hematologic adverse effects: Lymphopenia is the most commonly seen hematologic adverse effect. Others include leukopenia, neutropenia, thrombocytopenia, and anemia.

Dermatologic/mucocutaneous reactions:

These include pruritis, alopecia, skin rash, and life-threatening reactions like toxic epidermal necrolysis, paraneoplastic pemphigus, and Stevens-Johnson syndrome.

Renal adverse effects: Tumor lysis syndrome can present with hypocalcemia, hyperphosphatemia, hyperkalemia, hyperuricemia, and acute renal failure within 24 hours of the first infusion. Aggressive hydration and uric acid-lowering therapy should be given to high-risk patients. Renal toxicity has been seen in trials where rituximab was administered with cisplatin.

Respiratory adverse effects: These include cough, upper respiratory tract infections, rhinitis, epistaxis, bronchospasm, dyspnea, pulmonary toxicity, and ILD. There have been reports of rare cases of hypersensitivity pneumonitis, status asthmaticus, diffuse alveolar hemorrhage, and bronchiolitis obliterans.[10]

Cardiovascular adverse effects: Tachycardia, supraventricular arrhythmias, non-ischemic cardiomyopathy, peripheral edema, chest pain, hypertension.[14]

Gastrointestinal adverse effects: Diarrhea, nausea, and vomiting can be seen. Symptoms of abdominal pain should be thoroughly investigated, as there have been reports of bowel obstruction and perforation.

Neuropsychiatric adverse effects: Dizziness, headache, anxiety, depression, and insomnia can occur.

Pregnancy considerations: A limited amount crosses the placental barrier during the first trimester, but crossing increases in the second and third trimesters. Administration of rituximab during the third trimester can lead to immunosuppression in the neonate. Levels of rituximab in fetal circulation are similar to maternal levels near term, and live vaccines are contraindicated in the neonate during the first 6 months of birth.[15] Due to a poor understanding of long-term effects, it is recommended to use effective contraception during treatment with rituximab and for a year after the last dose.[16][17]

Constitutional adverse effects: These include asthenia, fever, chills, myalgia, arthralgia, muscle spasms, back pain, night sweats, and fatigue.

Drug-Drug Interactions

The primary drugs contraindicated for concurrent use with rituximab are live vaccines. Cidofovir and talimogene laherparepvec are also absolutely contraindicated for concurrent use.

Contraindications

Absolute and relative contraindications of the drug exist[6][12] and include the following:

• Severe, active infection
• Hypersensitivity to any of the components of the formulation
• Severe heart failure
• Uncontrolled cardiac disease
• Hypersensitivity to murine protein

Monitoring

Rituximab has an excellent safety profile, and overdosage has not been experienced in clinical trials. Patients should be regularly monitored for the development of adverse effects.

Before initiating treatment with rituximab, a CBC, routine chemistries, serum immunoglobulin levels, a chest x-ray, and serologic testing for hepatitis B, C, and HIV should be obtained. If HBsAg or anti-HBc is positive, HBV DNA PCR should be obtained. If HBV DNA is positive, entecavir should be given for prophylaxis. Lamivudine prophylaxis is indicated if HBV DNA is negative.[11]

The following should be regularly monitored during treatment:

• Development of infusion reactions. Acetaminophen and an antihistamine should be administered before starting the infusion to reduce the incidence of infusion reactions
• CBC to look for the development of any cytopenias
• Electrolytes and renal function in patients at high risk of tumor lysis syndrome
• Cardiac monitoring for patients with a history of cardiac disease
• Serum immunoglobulin levels
• Liver function tests and HBV DNA in patients with risk of reactivation of hepatitis B
• Patients should be monitored for signs and symptoms of opportunistic infections. The neurological function should be assessed to look for the onset of any new deficits.

Toxicity

Toxicity data for rituximab is not available. Patients who have had an overdose are at an increased risk of severe adverse effects, including fatal infusion-related/severe mucocutaneous reactions. Symptomatic and supportive measures are recommended. 

Enhancing Healthcare Team Outcomes

Rituximab is a relatively safe and well-tolerated drug, and its off-label use has increased over the years. Patients should be educated regarding the benefits and risks of rituximab therapy.

Rituximab therapy requires the efforts and collaboration of a coordinated interprofessional healthcare team. Hypersensitivity reactions (HSR) are commonly seen with rituximab infusions. These can be reduced through premedication and titrated infusions. Priming the IV line with rituximab can have a positive impact. Reducing the HSR rate can reduce the cost for cancer centers, improve patient safety and satisfaction, and prevent delays in treatment. Nurses have a crucial role as members of the multidisciplinary team involved in the care of these patients. Care should be coordinated between the oncologist, other physicians/advanced practice practitioners, nurses, and pharmacists.[18]

Recent evidence has shown a comparable clinical efficacy of subcutaneous and IV rituximab. SC rituximab allows faster delivery of the drug and reduces dosage errors and drug wastage. Faster delivery time allows more patients to be scheduled. Cancer centers should consider the subcutaneous route for most patients with chronic lymphocytic leukemia, follicular lymphoma, and diffuse large B cell lymphoma. The subcutaneous route could also be an alternative for patients with poor IV access.[19][20]