Rituximab (Rituxan, Mabthera) in the Treatment Of B-Cell Non-Hodgkin’s Lymphoma

A. Kaviyarasi

Clinical Pharmacist, Kauvery Hospital, Hosur

Correspondence: clinicalpharma.hosur@kauveryhospital.com

Abstract

Rituximab is a monoclonal, anti-CD20, chimeric humanized antibody. The FDA initially approved it as an anti-neoplastic drug to treat B-cell cancers. Low-grade or follicular non-Hodgkin lymphoma’ that has relapsed or is resistant to chemotherapy is one condition for which it is approved (NHL). Direct effects of Rituximab include complement-mediated cytotoxicity and antibody-dependent cytotoxicity. Indirect effects of Rituximab include structural modifications, apoptosis, and the sensitivity of cancer cells to chemotherapy

This article focuses on mechanism of action and clinical application, effects of Rituximab during the past 20 years on the treatment, prognosis, and long-term results of patients with indolent and aggressive lymphomas.

Key words: Non- Hodgkin’s, Rituximab, CD20, mAb, Biosimilar

Background

Lymphoma is a lymphatic system cancer that develops when healthy B-cells, T-cells, and NK-cells interact and develop excessively, sometimes resulting in a tumour. Non-Hodgkin’s lymphoma (NHL) is the most common adult hematopoietic malignancy in people over 55.

Hematologic B-cell malignancies are a broad, varied group of lymphoproliferative disorders that can include aggressive NHLs as well as NHLs that grow slowly and are indolent, like follicular lymphoma.

White blood cells called lymphocytes develop abnormally and they may develop into different kinds of growths (tumours) throughout the body in Non-Hodgkin lymphoma. After squamous cell carcinoma, NHL is the second most frequent tumour in the head and neck area. This category includes a large number of different subtypes. The two most prevalent sub kinds are diffuse large B-cell lymphoma and follicular lymphoma

Rituximab is the first chimeric (murine-human) monoclonal antibody (mAb) against the CD20 antigen developed by genetic engineering. It was approved for the treatment of follicular Non Hodgkin’s Lymphoma by the Food and Drug Administration on November 26, 1997 (and by the European Union on June 2, 1998). In 2014 the European Commission further approve Rituxan® (rituximab) for the treatment of diffuse B cell lymphoma and also for follicular lymphoma. [1]

Rituximab was the first mAb used in cancer and is still the most commonly used antibody currently. When administered alone, Rituxan for NHL treats some types of the cancer non-Hodgkin lymphoma (NHL), which affects B cells and is CD20-positive. The type of malignancy must be follicular lymphoma or low grade (slow spreading) for this therapy (FL). In addition, the cancer should have relapsed or be refractory.

Relapsed means that the cancer returned after preliminary treatment. Moreover, the term “refractory” means a cancer that has not responded to other therapies. Rituxan is a medication in the class of drugs known as monoclonal antibodies and contains the active component rituximab. The safety and efficacy of biosimilars are thought to be identical to those of the parent drug.Rituxan is a biologic mediaction,which is also called a biologic. Drugs manufactured from live cells are called biologics.

Rituxan is a brand-name medication.

It has two bio-similar versions:

  1. Rituximab-pvvr (Ruxience)
  2. Rituximab-abbs (Truxima)

Rituximab (Rituxan, Genentech/Biogen Idec), whose use in the United States was approved by the FDA in 1997. [1]

The most prevalent type of non-lymphoma Hodgkin’s (NHL), which accounts for 30-35% of cases, is diffuse large B-cell lymphoma (DLBCL). Rituximab’s adverse effects, including as infusion responses, lower immunoglobulin tiers, and an increased risk of infections, are mostly attributable to the immune system’s activation caused by its use of b cells, as well as to Rituximab’s immunogenicity and immunosuppressive properties.[7]

History-Of-Monoclonal

Pathophysiology Of Non-Hodgkin’s Lymphoma

Several stages of B cell development can result in lymphomas.

  • The primary lymphoid tissue, the bone marrow, is where B cell development begins.
  • Secondary lymphoid tissue, including the spleen and lymph nodes, is where B cells mature after encountering antigen.

At the germinal centre of lymphoid tissue, B cells interact with antigen through T cells, go through affinity maturation, and then go through affinity maturation to create immunoglobulin with a high affinity.

The two procedures known as somatic hyper-mutation (SHM) and immunoglobulin class switching, it supports rapid B-cell proliferation for immunoglobulin affinity maturation and production of antibody variety.

Both of these procedures involve a lot of double-stranded DNA breakage and rapid cell turnover, which is dangerous. The basic cause of lymphoma genesis is probably Somatically acquired genetic abnormalities (mostly translocation) of these pathways.[3]

Mechanism of Action

Rituximab is a monoclonal immunoglobulin G1 antibody that is chimeric between human and Murine that targets the B-cell differentiation marker CD20. A cell-surface marker called CD20 is only present on Pre-B and mature B lymphocytes; it is not present on any other types of cells or in free circulation. Rituximab binding site is CD20 on B-cells. Rituximab binds to the B lymphocytes’ cell surface CD20, which causes the lymphocyte to be destroyed by one of three possible mechanisms: complement-dependent cytotoxicity, apoptosis promotion, or antibody-dependent cytotoxicity. The predominant mechanism in vivo is most likely complement-mediated cytotoxicity [5,6].

Mechanisms-through-which-Rituximab

Antibody dependent phagocytosis, through both Fc and complement receptors.

These effects occur simultaneously and may complement one another, leading to a synergistic effects.

Dosing

Mechanisms through which Rituximab acts.

Dosing

Adult Dosing

  1. Non-Hodgkin’s lymphoma, Diffuse, large B-cell, CD20-positive, in combination for first-line treatment
  2. 375 mg/m(2) IV infusion on day 1 of each anthracycline-containing chemotherapy cycle, for up to 8 cycles
  3. Non-Hodgkin’s lymphoma, Follicular, CD20-positive, B-cell, in combination with first-line chemotherapy & as single-agent maintenance Induction,
  4. 375 mg/m(2) IV given on day 1 of each cycle of chemotherapy, for up to 8 cycles
  5. Non-Hodgkin’s lymphoma, Low-grade, CD20-positive, B-cell, stable or responsive to prior CVP
  6. 375 mg/m(2) IV infusion once weekly for 4 doses every 6 months for MAX of 16 doses
  7. Non-Hodgkin’s lymphoma, Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell
  8. 375 mg/m(2) IV infusion once weekly for 4 or 8 doses; may retreat once weekly for 4 doses with progressive disease.

Paediatric Dosing

Non-Hodgkin’s lymphoma, Diffuse, large B-cell, CD20-positive, in combination for first-line treatment (6 months or older) Induction (courses 1 and 2)

Rituximab 375 mg/m(2) IV infusion on day -2 (first and third Rituximab infusion) and on day 1 (second and fourth Rituximab infusion); during the first induction course.

INDICATION

The FDA has approved Rituximab for a variety of B-cell non-Hodgkin lymphomas and rheumatoid arthritis. Off-label uses include treating conditions like chronic lymphocyte leukaemia, systemic lupus erythematosus, multiple sclerosis, autoimmune hemolytic anaemia, post-transplant lymph proliferative disorder, graft versus host disease, pemphigus vulgaris, chronic immune-mediated thrombocytopenia, and Evans Syndrome. [4]

Drug – Drug Interaction

Chemotherapeutic agents + Live vaccine

The risk of infection from live vaccines may rise if chemotherapy agents and live vaccines are used concurrently.

Rituximab+ COVID -19 vaccine

The immunological response to the COVID-19 vaccine may be lowered if RITUXIMAB and COVID-19 VACCINES are used concurrently.

Cisplatin + Rituximab

The risk of developing renal failure may be raised when CISPLATIN and RITUXIMAB are used concurrently.

Drug – Pregnancy Interaction

Fetal abnormalities or risks when used during pregnancy. Prescribe an alternative, if possible. Advise women of childbearing potential of possible fetal risk.

Drug – Lactation Interaction

Infant risk when Rituximab is used during breast-feeding. Weigh the potential benefits of treatment against potential risks before prescribing Rituximab during breast-feeding. [4]

Side Effects

Transfusion Reaction

Anaphylactic reactions to transfusions that are so severe they cause a fever, hypotension, bronchospasm, urticaria, and angiodema.

Progressive Multi focal leukoencephalopathy

The JC virus causes a significant central nervous system infection that normally develops within 12 months of the initial injection. Spinal tap and MR imaging are required for diagnosis.

Skin

Rituximab may result in toxic epidermal necrolysis of skin cells or severe mucocutaneous reactions resembling Stevens Johnson reactions.

Tumor lysis syndrome

Tumor cell death results in tumor lysis syndrome, which is characterised by hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Acute renal failure may make it more difficult.

Infection

Opportunistic infections, such as pneumocystis pneumonia, can affect patients. Moreover, patients are vulnerable to severe viral infections from herpes simplex, varicella, parvovirus B19, or CMV.

Hepatitis

Rituximab has the potential to reactivate the hepatitis-B virus, which exacerbates the hepatitis condition and contributes to liver failure. Prior to starting therapy, screen patients who are at high risk. [4]

Adverse Effects

Renal disorders

Urine output and trends in serum creatinine need to be closely monitored in patients receiving Rituximab. Acute tumor lysis syndrome (ATLS) leading to acute kidney injury after Rituximab mono-therapy, especially in conditions with high tumor burden, like NHL.

Cardiac disorders

Cardiac monitoring is necessary during and after Rituximab infusions in all patients with a history of arrhythmia’s or angina. Myocardial infractions are rare , as were severe hypertension and cardiac tamponade .Rare cases of fatal heart failure after using Rituximab.

Gastrointestinal disorders

New-onset abdominal pain in patients receiving Rituximab should prompt investigation for an acute abdomen. The average onset of symptoms is approximately 6 days (range of 1 to 77 days) after the first dose.

Neurological disorders

The development of new neurological signs in patients receiving Rituximab should be evaluated with neuro imaging and a lumbar puncture if there is no other obvious etiology.

Dermatological disorder

Rituximab infusions with paraneoplastic pemphigus, lichenoid dermatitis, vesiculobullous dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, from immediately after the infusion until 3 months later. Development of these severe reactions should prompt the discontinuation of Rituximab.

Respiratory, thoracic, and mediastinal disorders

Hypoalbuminemia was identified as an independent risk factor for developing adverse pulmonary events. Bronchiolitis obliterans presenting as cough, dyspnea, and pulmonary nodules in patients receiving Rituximab.

Hyper sensitivity pneumonitis presented as dyspnea, hypoxaemia, eosinophilia, and pulmonary infiltrates. Both Bronchiolitis obliterans and hypersensitivity pneumonitis due to Rituximab improved after stopping Rituximab and administering steroids. [4]

Conclusion

Rituximab (Rituxan) is a medication used to treat NHL; when combined to standard therapy, Rituximab is approved for the treatment of indolent lymphomas that have relapsed or become resistant to traditional chemotherapy regimens, both as a single agent and as the first line of treatment. For usage in conjunction with chemotherapy, the medication has FDA approval. Even in elderly patients, the medication has been well-tolerated and safe. For the past 20 years, there has been an improvement in the overall survival of NHL patients. While better supportive care and earlier or more accurate diagnoses may contribute to some of this improvement, the outcomes of numerous trials examined in this article show that Rituximab addition significantly improves outcomes.

Being the first therapeutic monoclonal antibody approved for the treatment of cancer, rituximab provides a treatment for B-cell NHL and brings in a new era of targeted therapies in oncology. We anticipate further Rituximab-targeted treatment combinations in clinical trials in the upcoming years, which may help to significantly enhance outcomes while lowering toxicity.

Reference

  1. Dotan E, et al. Impact of rituximab (Rituxan) on the treatment of B-cell non-Hodgkin’s lymphoma. Pharmacy and Therapeutics. 2010;35(3):148.
  2. Pierpont TM, et al. Past, present, and future of rituximab – the world’s first oncology monoclonal antibody therapy. Front Oncol. 2018; 4;8:163.
  3. Michael Gibson C, et al. Non-Hodgkin lymphoma pathophysiology. 2020.
  4. Dosing And Adverse effect of Rituximab. www.micromedex.com
  5. Selewski DT, et al. Rituximab (rituxan). Am J Neuroradiol. 2010;31(7):1178-80.
  6. Cerny T, et al. Mechanism of action of rituximab. Anti-cancer drugs. 2002;13:S3-10.
  7. Hanif N, et al. Rituximab. 2022 Sep 26. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2022.

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