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B-cell Depletion (anti-CD20)

Rituximab (Rituxan, MabThera) is the most commonly used preparation in this category.  It is a monoclonal antibody approved by the FDA in November 1997 for use in the treatment of mild cases of B-cell non-Hodgkin Lymphoma (NHL), a type of cancer, and in 2006 for rheumatoid arthritis.1 Other anti-CD20 treatments, including Veltuzumab, a pill version, are in clinical trials.9

Rituximab reduces the number of B cells in your body. B cells are a type of white blood cell that, when activated, multiply and produce antibodies. Antibody production is triggered by antigens. An antigen and antibody fit together like a key in a lock. When an antigen lock (in this case CD20) and antibody key (anti-CD20 in rituximab) are joined in a B cell, the body eliminates the complex since the B cell's work is assumed to be done.

Since rituximab reduces the number of B cells that contain CD20, it reduces the total number of cells that produce antibodies. This may include the antibodies that attach to platelets. There is also evidence that rituximab alters T cells, another type of white blood cell, and that this may be the reason rituximab raises the platelet count of some patients with ITP.5

The short-term response rate for rituximab is about 60%. About 25% of patients achieve a longer-term (5 year) rise in platelet count.6,10 To enhance the response, rituximab is sometimes used in combination with dexamethasone (similar to prednisone) in newly diagnosed patients.11  It can also be repeated with some success in those people who initially responded.12

Rituximab can be given before or after a splenectomy. However, systemic infection is a concern,8 especially when it is used in combination with other therapies that suppress the immune system. Because rituximab removes the cells involved in immune memory, vaccines are not always effective.13

IMPORTANT: Rituximab can activate hepatitis B or C. It is important to check for antibodies to these diseases before getting the treatment.

Note: The B cells that are eliminated are not specific B cells that target cancer or ITP. Rituxan reduces the general population of all B cells that include CD20. It could take up to nine months for someone to replace those B cells and have their immune system and antibody production (including the helpful antibodies) back in working order.

Dosage

The usual dose for patients with ITP is 375 mg/m2 once weekly for four weeks, the same regimen used for NHL patients. In some small trials, lower doses have been shown to be as effective as the higher dose in raising platelet counts.3,4

Rituxan is to be given only as an IV infusion, not an IV push or bolus. Patients with pre-existing cardiac and pulmonary conditions or who experienced cardiopulmonary adverse events in the past need to be closely monitored 2

The manufacturer recommends premedication with acetaminophen (ex.Tylenol) and an antihistamine (ex. Benadryl) before each infusion.2

Side Effects

About 77% of patients have infusion reactions such as fever, chills, weakness, nausea and headaches with the first dose. These reactions often decrease with subsequent doses.2 Rituximab can prompt serious, sometimes fatal, infusion reactions. These usually occur from 30 to 120 minutes after administering the first dose.2 An allergy-type reaction called serum sickness can occur from 7 to 21 days after a treatment. In a review of published studies about 3% of ITP patients treated with rituximab had become extremely ill or died.6

"Physicians who are thinking about treating a patient with Rituxan for any condition should tell their patients about the chance of PML [progressive multifocal leukoencephalitis] because there is no effective treatment for the disease."7,14

Rituximab can also reduce IgG (antibody) levels on very rare occasions. The reduced IgG levels may appear months after the infusions and be long-lasting. The authors of a study recommend an IgG level test before beginning rituximab and periodically after the treatment.17

Predicting Success

There have been few studies that give us clues about predicting the success of rituximab. In one study children who responded to steroids had a better response to rituximab.15 In another study, people with the FCGR3A V/V genetic type were more likely to respond to rituximab. Those who had very high levels of CD8 (proteins that work with T-cells) didn't respond despite a drop in anti-platelet antibodies.16

References

1. Food and Drug Administration: Questions and Answers on Rituximab  http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm109107.htm
2. Rituxan package insert http://www.gene.com/gene/products/information/pdf/rituxan-prescribing.pdf (package insert)
3.
Zaja F et al. “Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura.” Haematologica. 2008 Jun;93(6):930-3.http://www.ncbi.nlm.nih.gov/pubmed/18403395
4.
Provan D et al. “Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults.” Haematologica. 2007 Dec;92(12):1695-8.http://www.ncbi.nlm.nih.gov/pubmed/18055995
5.
Stasi R et al. “Response to B-cell depleting therapy with rituximab reverts the abnormalities of T-cell subsets in patients with idiopathic thrombocytopenic purpura.” Blood. 2007 Oct 15;110(8):2924-30. http://www.ncbi.nlm.nih.gov/pubmed/17548576
6.
Arnold DM et al. “Systematic review: efficacy and safety of rituximab for adults with idiopathic thrombocytopenic purpura.” Ann Intern Med. 2007 Jan 2;146(1):25-33.http://www.ncbi.nlm.nih.gov/pubmed/17200219
7.
"Serious Infection in Lupus Patients Treated with Rituxan." FDA Patient Safety News: Show #61, March 2007 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/psn/printer.cfm?id=501
8.
Gürcan HM et al. “A review of the current use of rituximab in autoimmune diseases.” Int Immunopharmacol. 2009 Jan;9(1):10-25.http://www.ncbi.nlm.nih.gov/pubmed/190007869.
9. Milani C et al. “Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura. “ Curr Opin Mol Ther. 2009 Apr;11(2):200-7. http://www.ncbi.nlm.nih.gov/pubmed/19330725
10. Patel VL et al. “Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia.” Blood. 2012 Jun 21;119(25):5989-95. http://www.ncbi.nlm.nih.gov/pubmed/22566601
11. Gudbrandsdottir S, "Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia." Blood. 2013 Jan 4.http://www.ncbi.nlm.nih.gov/pubmed/23293082
12. Hasan A et al. “Repeated courses of rituximab in chronic ITP: Three different regimens. “ Am J Hematol. 2009 Oct;84(10):661-5.http://www.ncbi.nlm.nih.gov/pubmed/19731307
13. Yri OE et al. “Rituximab blocks protective serologic response to influenza A (H1N1) 2009 vaccination in lymphoma patients during or within 6 months after treatment.” Blood. 2011 Dec 22;118(26):6769-71.http://www.ncbi.nlm.nih.gov/pubmed/22058114
14. Carson, K et al, “Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.” Blood. 2009 May 14;113 (20):4834-40 http://www.ncbi.nlm.nih.gov/pubmed/19264918
15. Grace RF et al. “Response to steroids predicts response to rituximab in pediatric chronic immune thrombocytopenia.” Pediatr Blood Cancer. 2011 Jun 14.http://www.ncbi.nlm.nih.gov/pubmed/21674758
16. Cooper, N. et al. (2012), "Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia." Br J Haematol. 2012 Aug;158(4):539-47.
http://www.ncbi.nlm.nih.gov/pubmed/22775462
17. Levy R et al. “Profound symptomatic hypogammaglobulinemia: A rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.” Autoimmun Rev. 2014 Aug 27. http://www.ncbi.nlm.nih.gov/pubmed/25183241