Treatments > Rituxan

Last update: 08/23/2010

TOPICS
Basics | Resources | Who is Rituxan for? | How is it made? | Scheduling Rituxan
What should I expect? | How does Rituxan work? | Side Effects |  About cd20
How long does it take to respond? | What is the expected response rate? How long does it take normal b-cells to recover?  
Also see: Categorized Abstracts | Therapeutic antibodies for Lymphoma

Asheducationbook.org - Articles on Rituxan

Antibodies are the proteins made by the body's immune system cells. These proteins recognize and attack specific foreign invaders, such as infectious germs. The body makes millions of antibodies, each of which has a specific shape to recognize and bind to a foreign molecule. Many years ago, scientists discovered how to make large quantities of identical antibodies - hence ''monoclonal'' - in mice. 

Rituxan® (Rituximab/anti-cd20/MabThera) is an antibody that may induce killing of b-cells - malignant and normal - by inducing self killing, or by flagging the cells for attack by the immune system:

     
          Click images to enlarge

Rituxan is the first monoclonal antibody found to be effective and safe for the treatment of cancer in the United States.

The standard recommended dose of Rituxan is 375 mg/m² given as an IV infusion weekly for 4 doses. The "/m2" means per meter squared ... that is, the actual dose is calculated by the size of the patient. 

When your body detects something that does not belong, such as bacteria, one way it eliminates the threat is to produce antibodies that bind to the protein shapes that are specific to the pathogen.  

--

Rituxan is a man-made antibody that binds to a molecule that exists only on mature b-cell lymphocytes, both malignant and nonmalignant (cancerous and normal). It binds to this unique molecule like a key fits a lock; its shape complementary to a portion of the cd20 receptor.

Rituxan is given as systemic therapy, meaning it's infused into the blood and then circulates throughout the body until it sticks to its target.

Recommended Resources:

Rituxan:  ChemIDplus.gov 
Links to comprehensive information on this agent.

Prescribing Details

	Rituxan dailymed.nlm.nih.gov (fixed)
	Rituxan: Full prescribing information  Rituxan.com
	Rituxan overview  www.omsusa.org | Medlineplus
	Rituxan: Dosage and Administration Guide Rituxan.com
	From the bench to the bedside: ways to improve rituximab efficacy (technical)  bloodjournal.org PDF  Guillaume Cartron1, 2, 6, Hervé Watier1, 3, 6, Josée Golay4, Philippe Solal-Celigny5, 6 Running Title: Rituximab - Mechanisms of Action

Access to Drug

	Contact the company (now Biogen IDEC)  idecpharm.com
	Off-Label Uses of Monoclonal Antibodies for Treatment of  B-Cell Lymphoid or Myeloid Malignancies  PDF
	Rituxan in Canada? cancercare.on.ca
	Rituxan - Help for patients who are underinsured or uninsured  NeedyMeds     Also call Genentech: 800-530-3083

Background on Use

	Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy Jonathan W. Friedberg  asheducationbook.org "Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, direct apoptotic signaling, and possible vaccinal effects."
	Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example,  Michele Ghielmini  asheducationbook.org A thorough examination of how dosing, and scheduling of Rituxan might be done in future or in clinical trials.
	Rituximab therapy for follicular lymphoma: a comprehensive review of it's efficacy as  primary treatment, treatment for relapsed disease, re-treatment and maintenance  - Yossi Cohen, Philippe Solal-Céligny, Aaron Polliack  haematologica.org  | 07_03
	Monoclonal Antibody Therapy for Non-Hodgkin's Lymphoma  Sledge Jr, MD, and Plante (Medscape)
	Rituximab anti-CD20 antibody therapy of B cell non-Hodgkin's lymphomas - David C. Maloney Haematologica 1999. PDF
	Rituxan in Perspective -  includes abstract,  timeline, and more  Rituxan.com
	Rituxan checklist for the patient  PAL- print version  (what to expect, how to prepare)

	The treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell, non-Hodgkin's lymphoma.
	The first-line treatment of diffuse large B-cell, CD20-positive, non-Hodgkin's lymphoma in combination with CHOP or other anthracycline-based chemotherapy regimens.
	The first-line treatment of follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma in combination with CVP chemotherapy.
	The treatment of low-grade, CD20-positive, B-cell non-Hodgkin's lymphoma in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy.

See Indications below

Rituxan in Canada?  cancercare.on.ca

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Scheduling Rituxan (under construction)

Dose: "Many studies have been performed to optimize its dose and schedule, and more are ongoing. The dose of 375 mg/m² has become standard, mainly because it shows activity and has little associated toxicity." 1

Interval between treatments and courses: "The half-life of rituximab is about 1 week; median duration of persistence in the blood at active levels is of about 3 months: .... A prospective PK-based study by Gordan et al addressed the optimal interval between administrations. ....  the great majority of patients could maintain active levels of drug with an infusion interval of 3 months, and all of the patients could be kept with blood levels in this range if they were treated every 2 months. We can therefore assume that an infusion of rituximab every 2–3 months should be sufficient to maintain tumors constantly exposed to active concentrations of the drug. This is actually the schedule that was chosen by many cooperative study groups for their maintenance strategy." ¹

The goal of maintenance therapy is to "prolong the duration of chemotherapy-obtained remissions. "Data on long-term administration of rituximab are scarce and we need to await the results of prospective randomized trials of maintenance versus no maintenance before we can recommend this treatment as standard." ¹ 

1. Optimal Schedule of Antibodies: Rituximab in Lymphoma as an Example, 
   Michele Ghielmini  asheducationbook.org

   A thorough examination of how dosing, and scheduling of Rituxan might be done in future
   or in clinical trials.

About CD20 -- the target of Rituxan

. Click to enlarge | Source rheuma-online.de

CD20 is GOOD TARGET for b-cell lymphomas (notes from 2007 presentation by Dr. Maloney)

- Not tumor specific, but b cell restricted
- Not custom made - off the shelf
- Has minimal hematologic or other toxicity other than infusion-related symptoms
- High expression level in most histologies (subtypes), except low level on most CLL
- Present on all tumor cells
- Infrequently lost in progression

But CD20 target is not an IDEAL

- Causes b-cell depletion (but does not effect immature b-cells)
- Does not have critical biologic function for survival of malignant cells
- CD20 negative b cell NHL's do occur, but rarely
- Selective pressure could lead to escape mutations
- Has only modest direct effects

"Anti-CD20 therapy has had a truly dramatic impact on treatment and outcome of patients with follicular lymphoma. Unfortunately, the majority of responses to single-agent rituximab are incomplete, and all patients with follicular lymphoma will experience disease progression at some point following rituximab therapy.

Rituximab has multiple mechanisms of inducing in vivo cytotoxicity, including antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDCC), direct apoptotic signaling, and possible vaccinal effects. Rituxan also increases the sensitivity of lymphoma cells to several chemotherapy agents.

The cellular microenvironment within follicular lymphoma has a profound impact on which mechanism is dominant, and confers resistance in many situations. Both tumor-associated and host-associated factors also contribute to rituximab resistance." 

 - Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy, Jonathan W. Friedberg See asheducationbook.org

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How is it made? 

Rituxan is genetically engineered from portions of mouse and human antibodies and is produced through recombinant DNA technology.

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What should I expect, and how should I prepare for my first 
treatment with Rituxan?

Preparations

	Review and print out the Dosage and Administration Guide for details  Rituxan.com  This will help familiarize yourself with the details of the procedure and allow you to ask informed questions.
	Do not be shy about asking questions of your doctor about your specific risk factors in advance of the treatment. (... " pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events, and those with high numbers of circulating malignant cells (25,000/mm³) with or without evidence of high tumor burden."  Rituxan.com
	You should plan to stay the day for the first infusion -- which should be given very slowly to minimize infusion-related risks. If you tolerate the first infusion well, you may be done in as little as three hours after that.
	Prepare a thank-you-in-advance gift, such as baked goods, for the nursing staff.  They work very hard and appreciate being appreciated.
	Arrange to have a friend or relative accompany you, if at all possible.  The therapy can make you drowsy and impact your ability to drive.
	Bring your favorite reading material, or a portable audiotape/CD player with headphones to help pass the time.
	Bring some favorite snacks, bottled water, and a pillow as well. Many centers will have snacks and drink available.
	Be positive! Most patients have little problem at all. It's common to experience fatigue for the remainder of the day, and the next day as well.

Monitoring your reactions

	Talk to the nurse and your doctor about treatment risks and what they will do to monitor you. Indicate that you are in no hurry to complete the infusion and that you will appreciate being monitored closely, especially the first time.
	Ask the nurse or doctor about sensations that are to be expected and what to report immediately. Also refer to the Dosage and Administration Guide for details.
	Just before treatment, you will also receive Tylenol in pill form.
	You will receive Benadryl to help you tolerate the infusion better. This will make you drowsy. The same IV used to administer the Benadryl will be used to administer the Rituxan. The Benadryl may cause a temporary burning sensation.
	The rate of administering the Rituxan is very slow at the start; it may be increased when it's determined you are tolerating it well.
	Your vitals (temperature and blood pressure)  will be taken and monitored throughout the treatment session, as often as every 30 minutes.  Use this time to report unusual sensations.
	Notify the nurse when you have any unusual sensations.

The above Rituxan checklist - Print version 

Rituxan circulates in the lymphatic system and tissue. It binds specifically to the CD20 antigen, a molecule present on the surface of the normal and malignant pre-B and mature B cells. This binding can be imagined as a lock fitting a key. More than 90 percent of B-cell NHL express CD20. Once bound to B-cells, Rituxan induces lysis (destruction of the cell) through several possible mechanisms: 

Apoptosis: The Rituxan antibody induces cells to which it is bound to initiate programmed cell death. The activation of this program by the cell results in the death of the cell (a kind of suicide).

Antibody-dependent Cell-mediated Cytotoxicity (ADCC) - An immune response triggered by  the presence of antibody coating the target cell. Upon binding its antigen, the Antibody's Fc region is exposed and will bind its receptor on the NK cell (or other effector cells) to form a bridge. Once the bridge is formed, a poorly understood lytic (killing) signal is delivered to the target cell by the effector cell, resulting in its demise.

Click image to enlarge.

	Complement-dependent cytotoxicity (CDC): A mechanism in which antibody bound to the target cell surface fixes complement, which results in assembly of the membrane attack complex that punches holes in the target cell membrane resulting in subsequent cell lysis.  Dr David J. Flavell
	Inhibition of proliferation: The Rituxan antibody sends signals to the cell that stops the cell from dividing further.
	Vaccinal effect - when a therapy leads to recognition of tumor antigens (abnormal proteins) as foreign leading to an attack of the remaining tumors by effector cells in the immune system.
	Synergistic effects with chemotherapy: The Rituxan antibody sends signals to the cell that sensitizes it to killing mechanisms of chemotherapy agents. Shifts it towards apoptosis, perhaps.     Rituximab [Rituxan] Inhibits the Constitutive Nuclear Factor-{kappa}B Signaling Pathway in Non-Hodgkin's Lymphoma B-Cell Lines: Role in Sensitization to Chemotherapeutic Drug-induced Apoptosis. Cancer Res. 2005 Jan 1;65(1):264-276  PMID: 15665303

Types | Common | Incidence of | Serious infusion-related |
Other Risks:  Rare, Viral, Immune deficiency

"Incidence of Side Effects (Adverse Events) in > 5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N=356)^a,b

NEW See also eHealthMe.com reports

NOTE: AE rates in this one study (non-random sample; probably younger patients) 
may not predict the incidence of AEs in the general population (of patients who use Rituxan to treat disease). 

Adapted from: Full Prescribing Information gene.com 

* Infection when Rituxan is used as monotherapy:

"There were sustained reductions in serum levels of both IgM and IgG observed from 5 through 11 months following single agent RITUXAN administration, which  were statistically significant. It is important to note that  only 14% of patients had reductions in serum IgM and/ or IgG to values below the normal range.1 Despite  profound B-cell depletion, the incidence of infection  did not appear to be increased. During treatment in the  large multicenter trial of single-agent RITUXAN,  68 infectious events occurred. Of these, 7 were  Grade 3 and none were Grade 4.5"  http://www.rituxan.com/lymphoma/HCP/Files/PDFs/HCP_Q&A_Guide.pdf 

 

Because of its specificity of action (it targets specific cells), Rituxan is generally less toxic than chemotherapies. However, it's not uncommon for patients to experience transient side effects -- mainly mild to moderate flu-like symptoms (fever, chills, rigors). 

However, some patients may experience significant side effects. Most commonly, these adverse events occur during the first infusion.  Severe and fatal reactions are uncommon but have occurred. See box warning below. 

	About Infusion-related reactions:  The mechanism most commonly involves the release of protein signals called cytokines.  See for illustration http://www.rituxan.com/lymphoma/content/Cytokine.pdf
	About HAMA PAL
	Some patients taking Rituxan may experience bowel obstruction aol.mediresource.com  "Patients taking Rituxan who experience abdominal pain, especially early in treatment, should contact their physician immediately," Health Canada advised. The average time for patients on the medication to develop bowel perforation was six days from the beginning of therapy."
	Box warning for possible severe side effects  IDEC Fatal infusion reactions | Tumor Lysis Syndrome | Severe Mucocutaneous reactions
	Serum sickness (uncommon) : "shivering fever (38.5°C) and polyarthralgias presented.  The next day fever was higher (39.3°C) and associated with diffuse urticaria (hives)." rheumatology.oxfordjournals.org
	Tumor lysis syndrome (uncommon) : "Rituximab-induced ATLS has been reported in  2 patients with chronic lymphocytic leukemia and in 2 patients with non-Hodgkin's lymphoma." Acute tumor lysis syndrome induced by rituximab in diffuse large B-cell lymphoma

Management and Preparedness for [Rituxan] Infusion and Hypersensitivity Reactions 
theoncologis t.alphamedpress. org  

Results. Severe hypersensitivity reactions are rare, with an incidence of 5%, provided patients receive proper premedication, close monitoring, and prompt intervention when symptoms occur. 

Reactions to taxanes and monoclonal antibodies produce similar symptoms, but are generally immediate, occurring during the first few minutes of the first or second infusion. However, 10%–30% of reactions to monoclonal antibodies are delayed, and may occur in later infusions, indicating the importance of close observation of the patient following administration.  

Mild-to-moderate reactions can be managed by temporary infusion interruption, reduction of the infusion rate, and symptom management. Rechallenge should be considered after complete resolution of all symptoms. 

Severe reactions may require treatment discontinuation.

Conclusion. Hypersensitivity or infusion reactions to platinum compounds are acquired; reactions to taxanes and monoclonal antibodies are immediate and typically occur during the first few minutes of the first infusion. The different time of onset should be considered when developing strategies for preventing and managing hypersensitivity reactions. The decision to rechallenge or discontinue treatment after a reaction occurs depends on the severity of the reaction and other clinical factors.

Factors that may influence risks of adverse reactions

"Patients requiring close monitoring during first and all subsequent infusions include those with pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events and those with high numbers of circulating malignant cells (> 25,000/mm3) with or without evidence of high tumor burden.  IDEC

"Major risk factors include high numbers of circulating malignant lymphoma cells, pulmonary infiltrates or lymphoma involvement, and prior cardiovascular disease. This report updates the safety experience of Rituximab therapy with data from clinical trials and postmarketing safety experience, and examines how this information can be used to optimize therapy." See Optimizing the use of rituximab for treatment of B-cell non-Hodgkin's lymphoma: a benefit-risk update.  Kunkel

Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001 Dec;115(4):807-11  PMID: 11843813

Other Risks:  Rare/Less common, Viral, Immune deficiency

Rare / Uncommon: 

	Monoclonal antibody-associated progressive multifocal leucoencephalopathy (PML) in patients treated with rituximab, natalizumab, and efalizumab:  a Review from the Research on Adverse Drug Events and Reports (RADAR) Project  thelancet.com
	Progressive multifocal leukoencephalopathy [PML] after Rituxan therapy in  HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project  bloodjournal.hematologylibrary.org
	"Hypoglycemia is a very rare toxicity of rituximab. The exact mechanism of rituximab  induced hypoglycemia is not clear."  Case report: wjso.com

Viral: 

	Late reactivation of resolved hepatitis B virus infection: an increasing complication post rituximab-based regimens treatment? Am J Hematol. 2008 Aug;83(8):673-5. PMID: 18528824
	Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma. 2007 Jul;48(7):1307-12. Review  PMID: 17613758  Close monitoring for viral infection, particularly HBV and CMV, in patients treated with rituximab should be recommended.
	Hepatitis B virus reactivation in a case of non-Hodgkin's lymphoma treated with  chemotherapy and rituximab: necessity of prophylaxis for hepatitis B virus  reactivation in rituximab therapy. Leuk Lymphoma. 2004 Mar;45(3):627-9.  PMID: 15160930 | Related articles NEWS:  "Also new to the NCCN Guidelines is information regarding the potential for viral  reactivation in hepatitis positive patients being treated with rituximab (Rituxan®, Genentech, Inc.).  Dr. Zelenetz explained Hepatitis B can reactivate with immunosuppression. “More than 1 million people in the United States are infected with Hepatitis B, so this is not an  inconsequential issue. We’ve seen reactivation with all types of chemotherapy regimens,  not just rituximab, further stressing the importance of screening for Hepatitis B before treatment begins,” Dr. Zelenetz stated."  nccn.org/  NCCN Guidelines based on Lymphoma Type PDF
	Shingles reactivation? One case reported on nhl-follic support list when  Rituxan was used as initial monotherapy, but not yet on PubMed

Immune deficiency:  

Hypogammaglobulinemia

	Treatment of HIV-associated Hodgkin's lymphoma (HIV-HL): Results of a prospective multicenter trial http://bit.ly/9h1Tc3 (fixed)   We identified 215 pts treated with R for lymphoma between 12/1998 and 4/2009 and also had quantitative serum immunoglobulin levels (sIg) evaluated prior to and after treatment with R. Data on the use of IVIG was collected. ... Rituxan was associated with developing hypogam in 39% of pts with normal baseline sIg. Pts receiving RM (Rituxan maintenance) had a significantly higher risk of developing hypogam and requiring IVIG. The risk of symptomatic hypogam should be considered in the use of R maintenance.
	Rituximab treatment results in impaired secondary humoral immune responsiveness. Blood. 2002 Sep 15;100(6):2257-9. PMID: 12200395 | Related articles
	Rituxan treatment is associated with decreased serum immunoglobulins in a  minority of patients While Ig infusions, may be considered in these situations,  it is not without risks.     See Immune Globulin Intravenous (Human) (IGIV)  FDA.gov

Late Onset Neutropenia:

	Rituxan and late onset neutropenia following Auto stem cell transplants haematologica.org
	Rituxan and Late-onset neutropenia (LON)  ncbi.nlm.nih.gov PubMed Query: http://www.ncbi.nlm.nih.gov

Other:  

	Serum sickness  "Serum sickness is a reaction similar to an allergy. Specifically, it is an immune system reaction to certain medications, injected proteins used to treat immune conditions, or antiserum, the liquid part of blood that contains antibodies that help protect against infectious or poisonous substances."  MedlinePlus.gov
	Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma. Bone Marrow Transplant. 2007 Sep 17; PMID: 17873917  these results suggest that the use of rituximab-based regimens for the treatment of FL does  not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

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How long does it take to respond?  

How long it takes for Rituxan to work can be very different from one person to the next. Rituxan works gradually, so don't' be discouraged if it takes a while to work for you.  When Rituxan was tested, it often took several months after the completion of Rituxan treatment for the tumor to shrink.

Time to  First Tumor Response in Efficacy Studies
Adapted from table in  http://www.emea.europa.eu/humandocs/PDFs/EPAR/Mabthera/025998en6.pdf 

Monotherapy Studies (follicular NHL)	Responders	Average Time (Days)	Median Time (Days)	Min Time (Days)	Max Time (Days)
102-02 -II  102-05	17 of 37 80 of 166	58.2 65.3	50 50	7 21	112 288
Total	97 of 203	64	50	7	288

The expected response rate is just an average (a statistic calculated for a large group) which cannot predict individual outcomes. Some factors that may influence individual outcomes are: treatment history, tumor burden, type of lymphoma, the number of infusions, serum levels that you obtain, other treatments you are receiving with Rituxan, and perhaps variable molecular characteristics of the malignant cells. 

What is the expected time to initial response?  

It can vary by lymphoma subtype. In one study in follicular lymphoma the median time to initial onset of response was 50 days. (Rituxan® full Prescribing Information, April 2001)

In a pivotal, multi-center study, Rituxan achieved an overall response rate of 48 percent (80/166. 

Complete Responses (CR): Six percent (10/166) of patients had complete responses. 
Partial Responses (PR): Forty-two percent (70/166) of patients.
Median Duration of Response: Projected to be 10 to 12 months.

Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825-33. PMID: 9704735  PubMed

Of interest is that median duration of responses can be longer than "the medians achieved in the patients' prior course of rituximab." This is not the rule for cancer treatments, and speaks to the potential of Rituxan and treatments with targeted mechanisms to better manage lymphomas.

• Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol. 2000 Sep;18(17):3135-43. PMID: 10963642  PubMed

Reports on factors associated with response to Rituxan

	Absolute lymphocyte count (ALC) predicts therapeutic efficacy of rituximab therapy in follicular lymphomas. Br J Haematol. 2007 Apr 13  PMID: 17433025  This study supports our hypothesis that a higher ALC predicts longer TTP following rituximab therapy.
	Genetic characteristics (FCGR3A genotype) predict response to Rituxan?  Blood 2002 Feb 1 | PubMed
	Rituxan review article  Medscape (free login req.)
	CLL/SLL: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol. 2001 Apr 15;19(8):2153-64. PMID: 11304767 PubMed
	Prognostic factors for non-Hodgkin's lymphoma patients treated with chemotherapy  may not predict outcome in patients treated with rituximab.  Leuk Lymphoma. 2006 Sep;47(9):1830-40  PMID: 17064996
	Serum levels of Rituxan may influence efficacy Berinstein
	Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma.  PubMed abstract
	Rituxan as frontline treatment "With further follow-up and repeat courses of rituximab, the major response rate increased from 47% to 65% and the complete response rate increased from 7% to 27%."  Semin Oncol 2002 Feb;29(1 Suppl 2):25-9 abstract 4-09-02

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How long does it take normal b-cells to recover following Rituxan? 
 
Are there other effects on immune competence?

TOPIC SEARCH  PubMed 

Rituxan kills both normal and malignant b-cells that express CD20.  Precursor cells from which new b-cells are generated do not express CD20 and are not affected. B-cell recovery begins at approximately six months following completion of treatment, and median B-cell levels return to normal by 12 months. 

B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny.Clin Immunol. 2007 Feb;122(2):139-45. Epub 2006 Sep 27  PMID: 17008130  The long-term immunologic effects of B cell depletion with rituximab and the characteristics of the reconstituting B cell pool in lymphoma patients are not well defined, despite the widespread usage of this therapy.  Here we report that during the B cell reconstitution phase a majority of the peripheral blood B cells have an immature transitional phenotype (47.8%+/-25.2% vs. 4.4%+/-2.4% for normal controls, p<0.0001), similar to what has been described during the original ontogeny of the immune system and following bone marrow transplantation.  Moreover, the recovery of the CD27+ memory B cell pool was delayed compared to normal B cell ontogeny, remaining below normal controls at 1 year post-rituximab (4.4%+/-3% vs. 31%+/-7%, p<0.0001).  Expansion of functionally immature B cells and decreased memory B cells may contribute to an immunodeficient state in patients recovering from rituximab mediated B cell depletion, particularly with repeated treatment.

Immunophenotypic changes and clinical outcome in B-cell lymphomas treated with rituximab. Appl Immunohistochem Mol Morphol. 2006 Mar;14(1):18-23  PMID: 16540725  These results show that in many cases of B-NHL persisting after rituximab therapy, CD20 expression decreases or is lost, raising the possibility of deletion or expression modulation of the CD20 gene in neoplastic cells. This study also underscores the importance of using a panel of antibodies to evaluate rituximab-treated B-NHL.