Rituximab

from Wikipedia, the free encyclopedia
Rituximab
Rituximab
Fab fragment from rituximab with a peptide epitope

Existing structural data : 2OSL

Mass / length primary structure 143.9  kDa
Identifier
External IDs
Drug information
ATC code L01 XC02
DrugBank DB00073
Drug class Cytostatic , monoclonal antibody

Rituximab is a biotechnologically produced antibody that is used as a drug in cancer immunotherapy , primarily in the treatment of malignant lymphomas (lymph gland cancer). The effectiveness in other diseases, such as autoimmune diseases, is also tested in studies.

Rituximab was one of the first active ingredients in a new generation of drugs in cancer immunotherapy and is therefore considered a pioneer in targeted cancer therapy . The variable part of the antibody is directed against the cell surface molecule CD20 , which can be detected, for example, in some non-Hodgkin lymphomas .

Development and marketing

Rituximab was originally developed at the Dana-Farber Cancer Institute by Lee Nadler, who also first described the CD20 antigen . Rituximab was the first antibody to be approved for the treatment of cancer ( FDA 1997, EC 1998).

Since July 2006, the monoclonal antibody has also been approved in Europe in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis . Rituximab is the first biomarker- based therapy in rheumatoid arthritis. So far, rheumatoid factor and antibodies against citrullinated proteins (ACPA) have been the most relevant biomarkers . In April 2011, the US FDA approved rituximab in combination with glucocorticoids for the treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). The extended approval for the EU was applied for at the European Medicines Agency EMA in April 2012 . In February 2017, the European Commission approved the rituximab biosimilar Truxima .

application areas

Rituximab is a chimeric anti- CD20 monoclonal antibody. In addition to the treatment of cancer, rituximab is also indicated for autoimmune diseases ( rheumatoid arthritis , pemphigus vulgaris (urinary bladder), granulomatosis with polyangiitis and microscopic polyangiitis ). The effectiveness in idiopathic thrombocytopenic purpura (ITP) or lupus nephritis is being studied. In off-label use, the drug is prescribed for the treatment of multiple sclerosis.

oncology

Today, rituximab is part of the standard therapy in the treatment of both high and low-grade non-Hodgkin's lymphomas, usually in combination with conventional chemotherapy ( e.g. CHOP or R-CHOP or in combination with bendamustine ). The use of rituximab only makes sense, however, if the cancer cells are characterized by the surface molecule CD20; therefore, the tumor tissue must be tested appropriately before treatment with rituximab.

Rituximab is the main drug in the treatment of transplant-associated lymphomas (PTLD), which are often CD20 positive.

Rheumatoid arthritis

In rheumatoid arthritis, rituximab is currently used after failure of basic drugs and the initial TNF-α inhibitor . About 30% of patients with rheumatoid arthritis will not respond to a TNF-α inhibitor. If the response and / or intolerance of a TNF-α inhibitor is insufficient, a switch to another TNF-α inhibitor or to biologicals with a different mechanism of action such as z. B. Rituximab recommended.

With two infusions within 14 days, rituximab can significantly improve symptoms over a period of up to over a year. Further treatments can maintain or increase the success of the therapy. A treatment interval of six months is recommended. This will reduce the flare-up of disease activity and improve the response to treatment.

Mechanism of action

Rituximab induces selective cell depletion (removal of endogenous substances) of CD20-positive B-cell subpopulations. For this reason, one also speaks of B-cell therapy with rituximab. B-cell depletion is caused by the following three mechanisms:

  • Apoptosis
  • complement-dependent B-cell lysis (CDC = complement-dependent cytotoxicity)
  • Antibody-dependent cell-mediated cytotoxicity via macrophages, granulocytes and natural killer cells (ADCC = antibody-dependent cell-mediated cytotoxicity)

unwanted effects

oncology

During treatment with rituximab, up to 50% of patients experience sometimes severe side effects with fever , chills , difficulty breathing and skin rashes . The symptoms are probably caused by the massive breakdown of the cancer cells, which releases a large number of cytokines . This syndrome is therefore also known as the “ cytokine release syndrome”. These problems occur primarily in patients with a high tumor burden (a lot of tumor mass) during the first treatment; the side effects usually improve in the further course of treatment.

Progressive multifocal leukoencephalopathy (PML) has occurred in individual patients during treatment with rituximab . PML is a serious opportunistic viral infection of the brain that is caused by the JC virus in patients with immunodeficiency and is often fatal. The majority of known PML cases after treatment with rituximab occurred in patients with lymph node cancer. The patients who developed PML after therapy with rituximab were usually also treated with other immunosuppressive cytostatics. Therefore, the causal relationship with rituximab cannot be classified as certain in individual cases. Many of these patients had other risk factors as well . Additional cases of PML have been reported in patients with autoimmune diseases.

Rheumatoid arthritis

Long-term safety data show that rituximab is well tolerated over a period of 10 years. Patients taking rituximab do not have an increased risk of infection. The most common side effects occur predominantly with the first administration in the form of mild to moderate infusion reactions within the first 24 hours after the start of the infusion.

The “ cytokine release syndrome” is also thought to be responsible for the occurrence of deaths that occurred in rare cases during the treatment of rheumatoid arthritis. Patients are given a combination of protective drugs ( antihistamines , cortisone , NSAIDs ) for prevention , so that the therapy is generally well tolerated.

General

Serious side effects reported very rarely (less than 0.01% of those treated) include skin reactions such as toxic epidermal necrolysis and Stevens-Johnson syndrome . Since cases of hepatitis B reactivation, including severe fatal courses, have been reported, screening for hepatitis B virus prior to initiating treatment is recommended .

Contraindications

Like all other drugs, rituximab must not be used if you are hypersensitive to the active ingredient. Above all, known hypersensitivity to mouse proteins must also be taken into account.

Acute and severe infections must be healed, or at least controlled, before rituximab is used. In the case of chronic infections and severely impaired immune defense , a precise evaluation of the benefit and risk must be carried out. This also applies in particular to hepatitis B patients with active hepatitis B disease; they must not be treated with rituximab

Rituximab must not be used in severe heart failure that can not be controlled with medication or other severe heart disease that cannot be controlled.

Due to insufficient data, it is recommended that rituximab be avoided during pregnancy and breastfeeding. However, studies show that there is likely to be no harm to the fetus after all .

Studies

Study data from oncology

The largest study to date for patients with aggressive non-Hodgkin's lymphoma (RICOVER-60) achieved the best results compared to other combination treatments. According to the study, 78% of patients with aggressive NHL after the combination therapy CHOP-14 (6 ×) plus rituximab (8 ×) are alive after 3 years. Because of this superiority, the study was terminated early.

Rheumatoid arthritis study data

The approval for rituximab is based on the results of the REFLEX study. In the study, it was possible to improve the physical functioning of patients taking rituximab. The progression of joint destruction was also inhibited.

Certain biomarkers in the blood such as rheumatoid factor or ACPAs can indicate the disease and the severity of its course. Various studies have found that rheumatoid factor or ACPA-seropositive patients usually respond particularly well to rituximab.

Seropositive patients in whom previous therapy with a TNF-α inhibitor proves to be inadequate and / or who are intolerant usually respond better to treatment with rituximab than to therapy with another TNF-α inhibitor.

Study data on chronic fatigue syndrome

A study with 30 participants showed good results in the treatment of chronic fatigue syndrome in 67% of the sufferers, but in some individuals had unexpectedly severe side effects that made their condition significantly worse. A subsequent, more detailed study could not determine any effect of rituximab on chronic fatigue syndrome.

Further studies on rituximab

The approval application for granulomatosis with polyangiitis and microscopic polyangiitis is based on the positive results of the US study RAVE.

Trade names

Roche / Genentech : MabThera ( EU ), Rituxan ( USA )

Biosimilars

Rixathon (EU), Truxima (EU, USA)

See also

literature

  • McLaughlin, P. et al. (1998): Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. In: J. Clin. Oncol. Vol. 16, pp. 2825-2833. PMID 9704735
  • Singh JA, Christensen R, Wells GA, et al. : Biologics for rheumatoid arthritis: an overview of Cochrane reviews . In: Cochrane Database Syst Rev . No. 4, 2009, p. CD007848. doi : 10.1002 / 14651858.CD007848.pub2 . PMID 19821440 .

Web links

Individual evidence

  1. ↑ https://www.gelbe-liste.de/nachrichten/truxima-zulassung-erstes-rituximab-biosimilar .
  2. ↑ Braendstrup, P. et al. (2005): Rituximab chimeric anti-CD20 monoclonal antibody treatment for adult refractory idiopathic thrombocytopenic purpura. In: Am. J. Hematol. Vol. 78, pp. 275-280. PMID 15795920
  3. ↑ Camous L. et al .: Complete remission of lupus nephritis with rituximab and steroids for induction and rituximab alone for maintenance therapy. In: Am J Kidney Dis . 2008; 52: 346-52 PMID 18572292
  4. ↑ https://arznei-news.de/rituximab/
  5. ↑ https://www.kompetenznetz-multiplesklerose.de (Ed.): KKNMS_Qualit% C3% A4tshandbuch-MS-NMOSD_2018_webfrei.pdf .
  6. ^ Georgi A. et al .: Treatment options after non-response to TNF blockers in rheumatoid arthritis . In: J Miner Metabolism 2010; 17: 15-20.
  7. ↑ Smolen JS et al .: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs . In: Ann Rheum Dis 2010; 69: 964-975.
  8. ↑ Emery P et al .: Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis . In: Rheumatology 2011; doi : 10.1093 / rheumatology / ker253 .
  9. ↑ a b Technical information MabThera® 100 mg / 500 mg, as of June 2013
  10. ↑ US Food and Drug Administration. Information for Healthcare Professionals. Rituximab (marketed as Rituxan) information. Accessed September 17, 2008.
  11. ↑ Drug Commission of the German Medical Association: Progressive multifocal leukoencephalopathy according to rituximab (from the UAW database) . Retrieved November 7, 2008.
  12. ^ Van Vollenhoven RF et al .: Long-term safety of Rituximab: 10-year follow-up in the rheumatoid arthritis global clinical trial program. In: Ann Rheum Dis 2012; 71 (Suppl 3): 195
  13. ↑ Roche Red Hand Letter on August 5th, 2011 (PDF; 2.1 MB) Retrieved on August 8th, 2011 .
  14. ↑ Roche's Red Hand Letter in April 2013 (PDF; 2.1 MB) Retrieved on April 17, 2013 .
  15. ↑ a b Roche: Specialist information MabThera iv , as of March 2019.
  16. ^ RE Fischer-Betz, M. .. Schneider: Biologika in pregnancy and lactation. In: Journal of Rheumatology. 69, 2010, pp. 780-787, doi : 10.1007 / s00393-010-0640-2 .
  17. ^ Congress report , 2 European Congress on Hematologic Malignancies, February 25, 2006, Barcelona: Indolent and aggressive lymphomas . In: ONKOLOGIE, 2/2006, Haug-Verlag, pp. 28–30, here online ; last accessed on May 15, 2014
  18. ↑ Cohen SB et al .: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. In Arth Rheum 2006; 54: 2793-2806
  19. ↑ Keystone E et al .: Sustained inhibition of structural damage in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitors prior to rituximab treatment: 5-year data from the REFLEX study. In: Ann Rheum Dis 2012; 71 (Suppl 3): 374
  20. ↑ Tony H et al .: Impact of rheumatoid factor and anti-CCP antibodies on EULAR response to long-term treatment with Rituximab in patients with rheumatoid arthritis after failing one TNFI (FIRST and ReFIRST). In: Ann Rheum Dis 2012; 71 (Suppl 3): 500
  21. ↑ Emery P et al .: Relative effectiveness of Rituximab versus an alternative TNF inhibitor in patients with rheumatoid arthritis and an inadequate response to a single previous TNF inhibitor: results from SWITCH-RA, a global, comparative-effectiveness, observational study. EULAR 2012, abstract 2203
  22. ↑ Øystein Fluge, Ove Bruland u. a .: Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. In: PLoS ONE . 6, 2011, p. E26358, doi : 10.1371 / journal.pone.0026358 .
  23. ↑ Øystein Fluge, Ingrid G. Rekeland, Katarina Lien, Hanne Thürmer, Petter C. Borchgrevink: B-Lymphocyte Depletion in Patients With Myalgic Encephalomyelitis / Chronic Fatigue Syndrome . In: Annals of Internal Medicine . April 2, 2019, doi : 10.7326 / M18-1451 ( annals.org [accessed April 16, 2019]).
  24. ↑ Stone et al .: Rituximab versus Cyclophosphamide for ANCA-associated vasculitis. In: N Engl J Med 2010; 363: 221-232