Rituximab

Genetically engineered tumor therapeutic directed against a CD surface antigen. Rituximab is a monoclonal, chimeric mouse-human antibody that binds to the human transmembrane antigen CD20 in B cells. Since hematopoietic stem cells do not express CD20 antigen, they are not attacked by the antibody.

Binding of the Fc moiety of the CD20 antibody to the CD20 surface marker on B cells activates the complement cascade and causes cytolysis of these cells. In addition, the antibody with the Fc moiety binds to macrophages, NK cells, and other effector cells, which subsequently induce a cell-mediated cytotoxic response with apoptosis of CD20-positive cells.

Notice. Physiological B cells are also affected by cytolysis (regeneration of the population approx. 6 months after the last application).

Rituximab is approved in Germany for the treatment of patients with stage III-IV follicular lymphoma that is resistant to chemotherapy or who have a second or recurrent relapse after chemotherapy, and for the treatment of CD20-positive large B-cell diffuse non-Hodgkin's lymphoma in combination with CHOP chemotherapy. Since 2018, rituximab has also been approved for therapy in pemphigus disease and, with an 89% remission rate after 2 years of therapy, has been a significant breakthrough in PV therapy since the introduction of systemic corticosteroids in the 1950s.

Rituximab is also approved for the treatment of severe active rheumatoid arthritis in adults in combination with methotrexate. Approval is limited to patients who have responded inadequately to or have been intolerant of other disease-modifying antirheumatic drugs, including one or more therapies with tumor necrosis factor inhibitors.

Experimental and Casuistic Contributions:

• Therapeutic successes ( off-label use!) are described according to studies for the treatment of thrombocytopenic purpura u. systemic lupus erythematosus.
• Casuistic articles on efficacy (off-label use) have been published on marginal zone lymphoma and epidermolysis bullosa acquisita, among others.Experimental: In a smaller study, the CD20 antibody rituximab was used in patients with advanced malignant melanoma with very good success. The results should be verified in a larger multicenter study.
• Experimental: Sustained success has been reported with rituximab use in IgG4-associated nephropathy and pemphigus vulgaris (Chen DM et al 2020; Frampton JE 2020).

Monotherapy: 375 mg/m2 KO i.v. 4 times weekly. The infusion rate should be cautiously adjusted to 50 ml/hr for 30 minutes on initial administration and may be subsequently increased to 100 ml/hr, 200 ml/hr and 300 ml/hr. Concomitant medication: Uricostatic drugs, e.g. 150 mg allopurinol p.o. 1 time/day to control the uric acid increase in tumour decay during the entire therapy period. Analgesics (e.g. Indometacin) and antihistamines as well as volume administration (1000 ml NaCl 0.9% i.v.) approx. 30-60 minutes before infusion start, 4 hours and 8 hours after application to avoid side effects.

Whether intravenous is superior to intralesional application is still under discussion.

Combination with CHOP regimen: 375 mg/m2 KO i.v. on day 1 of each chemotherapy cycle after application of the corticosteroid component of the chemotherapy cycle. Concomitant medication as above.

Up to 50 % of patients experience side effects, some of which are severe, with fever, chills, breathing difficulties and skin rashes. The symptoms are presumably triggered by a large number of cytokines that are released during therapy due to cell decay (cytokine release syndromes, see also under biologics). The clinical symptoms correspond to a Jarisch-Herxheimer reaction. Acute infusion-dependent reactions occur more frequently in oncological indications than in rheumatological indications (Jung JW et al. 2014).

Some UAWs (5-10% of cases?) are reminiscent of IgE-mediated allergic reaction (positive skin test reactions (Sachs B et al. 2018).

Other serious adverse reactions include the occurrence of progressive multifocal leukoencephalopathy (PML) in isolated cases.

Some reports exist on the triggering of various autoimmune diseases such as psoriasis, autoimmune lymphoproliferative syndrome, systemic lupus erythematosus and immune complex vasculitis (see below leukocytoclastic vasculitis)

Kaposi's sarcoma: There are isolated reports of the occurrence of iatrogenic Kaposi's sarcoma during therapy with rituximab.

Hypersensitivity to mouse proteins. Immune deficiency diseases e.g. with CD20 immunodeficiencies(see below CVID5 with mutation in the CD20 gene).

MabThera®

Reminder. Women of childbearing age should use effective contraceptive measures during and 12 months after treatment with MabThera!

Caution! In individual cases, therapy with rituximab has led to progressive multifocal leukoencephalopathy (PML) with a fatal outcome. This is shown in a Health Professional Letter from the manufacturers, which was published on the pages of the US regulatory authority FDA. In addition, there is a warning in this regard in the manufacturers' product information.

Test concentrations for suspected allergic reactions (recommended test concentrations cited from Sachs B et al. 2018)

• Prick: 10mg/ml
• i.c.: 0.1;1.0; 10mg/ml

1. Ahmed AR et al (2007) Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin. N Engl J Med 355: 1772-1779
2. Avivi I et al (2003) Clinical use of rituximab in haematological malignancies. Br J Cancer 89: 1389-1394
3. Bengtson KL et al (2003) Successful use of anti-CD20 (rituximab) in severe, life-threatening childhood immune thrombocytopenic purpura. J Pediatr 143: 670-673
4. Billon E et al (2018) Reversible rituximab-induced rectal Kaposi's sarcoma misdiagnosed as ulcerative colitis in a patient with HIV-negative follicular lymphoma. Clin Sarcoma Res 8:11.
5. Binstadt BA et al (2003) Rituximab therapy for multisystem autoimmune diseases in pediatric patients. J Pediatr 143: 598-604
6. Forstpointner R et al. (2003) Increased response rate with rituximab in relapsed and refractory follicular and mantle cell lymphomas -- results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Dtsch Med Wochenschr 127: 2253-2258
7. Fra GP et al (2003) Remission of refractory lupus nephritis with a protocol including rituximab. Lupus 12: 783-787
8. Gellrich S et al (2001) Anti-CD20 antibodies in primary cutaneous B-cell lymphoma. Initial results in dermatologic patients. Dermatologist 52: 205-210
9. Jung JW et al. (2014) The incidence and risk factors of infusion-related reactions to rituximab for
10. treating B cell malignancies in a single tertiary hospital. Oncology 86:127-134.
11. Kerl K et al. (2006) Intralesional and intravenous treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20 antibody rituximab: report and follow-up of eight cases. Br J Dermatol 155: 1197-1200
12. Narang M et al (2003) Refractory autoimmune thrombocytopenic purpura: responses to treatment with a recombinant antibody to lymphocyte membrane antigen CD20 (rituximab). Am J Hematol 74: 263-267
13. Omine T et al (2020) Iatrogenic Kaposi's sarcoma in a myelofibrosis patient treated with ruxolitinib. J Dermatol 47:e131-e132.
14. Sachs B et al (2018) Acute hypersensitivity reactions to monoclonal antibodies for targeted therapy. Dermatol 69: 268-277
15. Saigal K et al (2003) Hypocomplementemic urticarial vasculitis with angioedema, a rare presentation of systemic lupus erythematosus: rapid response to rituximab. J Am Acad Dermatol 49: S283-285
16. Saito K et al (2003) Successful treatment with anti-CD20 monoclonal antibody (rituximab) of life-threatening refractory systemic lupus erythematosus with renal and central nervous system involvement. Lupus 12: 798-800
17. Smith MR (2003) Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 22: 7359-7368
18. Soda R et al (2001) Systemic therapy of primary cutaneous B-cell-lymphoma, marginal zone type, with rituximab, a chimeric anti-CD20 monoclonal antibody. Acta Derm Venereol 81: 2007-2008
19. Weide R et al (2003) Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy. Lupus 12: 779-782