Treatments > Rituxan

Last update: 01/15/2019

TOPICS
Basics |  About CD20 | Resources | Who is Rituxan for? |
Why give Rituxan with chemo if resistant to Rituxan monotherapy?
How is it made? | Scheduling Rituxan | What should I expect? |
How does Rituxan work? | Common Side Effects -  Other |  PML | Maintenance
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 | Maintenance

Rituxan® (Rituximab/anti-cd20/MabThera) is an antibody that may induce killing of b-cells - malignant and normal - directly, by causing the self-killing  of the cells, or indirectly,  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. 

About antibodies: 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.

Overview on the Clinical Use of Rituxan  -
there are some uses that are agreed upon, other uses require more data or longer follow-up

Prompted by a caregiver's comment:
"I was looking at Rituxan, and the reports I read disturbed me a little ... the warning blurbs."

It's challenging to get balanced information about the agents used to treat lymphoma ... and when we get pieces of information it's easy to be frightened by the warnings we read.

The warnings for Rituxan and other lymphoma drugs deserve our concern ... but must be weighed against the risk of the disease when left untreated or treated differently.   

For Rituxan, a small fraction of patients will have serious infusion-related reactions, but the majority of these reactions (which can sometimes be life-threatening) can be managed by slowing down the infusion rate or discontinuation. It seems -- based on the results of large studies (not testimonials) -- that the known risks of Rituxan appear to be offset and outweighed in most cases by the potential benefits.

Below we provide fairly readable (for lay audiences) scientific review articles on Rituxan. The articles summarize some landmark trials using Rituxan (rituximab) in combination with chemotherapy for both indolent and aggressive b-cell lymphomas.   

Landmark trials are those that provide sufficient evidence to change clinical practice.  Such trials must be of adequate size (and use random assignments of the participants to the competing protocols) to reliably compare the outcomes.   

Today, Rituxan is almost always combined with chemotherapy in b-cell lymphomas -- clearly showing improved response rates and duration of response compared to chemotherapy alone.

Noting that improvements in response rates and response duration - if of sufficient magnitude - can support the claim of providing clinical benefit: defined as providing a survival advantage compared to the disease if treated differently.

Further, "... recent data from the Surveillance Epidemiology and End Results database and retrospective analysis of clinical trials in indolent NHL suggest an improved overall survival (OS) with the use of rituximab"  Source: ncbi.nlm.nih.gov  

Noting that OS is the most reliable measurement of clinical benefit because it accounts for all factors - both measured and unknown. 

Rituxan can be used as single agent, in combination with chemotherapy, or as a single agent following chemotherapy (maintenance). Please note that not every use of Rituxan has clearly shown a survival advantage for every type of b-cell lymphoma in every clinical setting (first use, relapsed etc). 

Of the many uses of Rituxan briefly touched on here, only Rituxan with chemo is widely accepted as proven to provide clinical benefit compared to chemo alone ... based on adequately sized and well-designed studies with sufficient follow up. 

... For example, maintenance Rituxan after Rituxan-based chemo for follicular lymphoma delays the time to relapse in most patients, but we don't yet know if it will also provide a survival advantage in that setting - if, for example, late-emerging side effects or resistance to Rituxan from long term use, might will offset the earlier gains. 

As always, the outline above cannot replace a conversation with your doctor who will take into account your unique clinical circumstances. 

See also Summary of factors that can influence choice of therapy

(Lay commentary, by Karl Schwartz)

Select Review Article:

	ASH Education: Unique Toxicities and Resistance Mechanisms Associated with Monoclonal Antibody Therapy http://bit.ly/1ldsuU7
	Rituximab In Indolent Lymphomas, Sousou, and Friedberg ncbi.nlm.nih.gov
	Impact of Rituximab (Rituxan) on the Treatment of B-Cell NHL Dotan, Aggarwal, Smith ncbi.nlm.nih.gov
	Rituximab in the treatment of NHL, Beate Hauptrock and Georg Hess ncbi.nlm.nih.gov
	Risk of infection in patients with lymphoma receiving rituximab: systematic review and meta-analysis Molloy et al. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094236/
	See alsoAsheducationbook.org - Articles on Rituxan

Prescribing Details

	Rituxan: Full prescribing information  Rituxan.com
	Rituxan:  ChemIDplus.gov  Type "Rituxan" then click Search to find comprehensive information on this agent.
	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

Detailed 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

Who is Rituxan for? 

Rituxan^® (Rituximab) is indicated for ( www.rituxan.com/lymphoma/HCP/index.jsp ) Jan 2007  

	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

Why give Rituxan with chemo if resistant to Rituxan monotherapy?

This is a commonly asked question and we believe the answer is yes, that adding Rituxan to the chemo is generally recommended even if you haven't responded well to prior Rituxan monotherapy.

While Rituxan alone might not be enough to tilt the balance of survival forces (die vs. don't die signals) within a cell to favor apoptosis*, it could well be sufficient to sensitize the lymphoma cells to the effects of chemotherapy.

* Apoptosis protects the body by getting rid of defective cells.  It is a kind of suicide program that is carried out by the cell when defects are detected within the cell. (Peeling skin cells in reaction to sun burn is a common example).   

… Lymphoma cells are thought to have defects in the apoptosis program.  Both Rituxan and chemo are thought to be active against lymphoma cells by activating the self-destruct program -- chemo by damaging the dividing cells further; Rituxan by altering the pro-survival signals within the cells in a way that favors self-destruction.

Rituxan has other immune-mediated mechanisms of action, which may be strong or weak depending on normal variations in characteristics of the immune system.  These mechanisms may not be as important when Rituxan is combined with chemotherapy (which depresses immunity).

Most times a lack of responsiveness to Rituxan is not because the CD20 target no longer exists … loss of cd20 expression on lymphoma cells happens rarely. For example, responses to radioimmunotherapy (which depends on the cd20 target) are often very good in those who have Rituxan-resistant lymphoma.

In other words Rituxan and chemo are thought to be synergistic when combined. 

Footnote:  We should note that this notion of synergy hasn’t been tested in a controlled way in patients with lymphoma refractory to Rituxan monotherapy – to our knowledge. We suppose the decision to add Rituxan to chemo could depend also on how you define Rituxan-refractory, so conceptually it's also possible that leaving it out would not matter in many cases. Thus this seems to be an appropriate population to evaluate chemotherapy followed by vaccines - perhaps compared to Rituxan-based chemo. 

Karl Schwartz (lay perspective)

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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 target:

- 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 

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How does Rituxan work?  

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

Mechanisms of Action and Resistance

	Semin Hematol - Weiner: Rituximab: mechanism of action snip on challenges for discovery: "the conditions we have available in the research laboratory vary significantly from the real-world clinical environment. Studies of rituximab mechanisms of action often utilize rapidly dividing tumor lines that have been selected based on their ability to grow rapidly in vitro, and sometimes their relative sensitivity to therapy. Effector cells, when present, are usually not syngeneic and often come from normal donors, not patients with malignancy. In vivo, lymphocyte behavior changes within seconds of cells being exposed to hypoxic conditions (6). It takes minutes to hours to harvest, wash and otherwise manipulate peripheral blood cells for in vitro analysis."
	AACR - Czuczman: Acquirement of Rituximab Resistance in Lymphoma Cell Lines Is Associated with Both Global CD20 Gene and Protein Down-Regulation Regulated at the Pretranscriptional and Posttranscriptional Levels snip: "It is postulated that the majority of patients retreated with rituximab will eventually relapse with variable degrees of resistant disease (16). There is an urgent need to conduct translational studies that will explore the mechanisms of resistance to mAbs in non–Hodgkin's lymphoma (NHL), and to develop therapeutic strategies to limit and/or overcome resistance pathways."
	Blood - Hilchey: Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a “vaccinal effect” of rituximab "Given that the Id-specific responses shown in this study were not very robust, to elicit such clinically relevant responses, rituximab treatment will need to be coupled with strategies designed to overcome the FL-induced inhibition of the immune response."

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Potential Side Effects

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

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). 

See also Grades of Toxicity

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 

 

Adverse infusion reactions and risks

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.

Clinical applications of drug desensitization in the Asia-Pacific region http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3206230/

"Principles in drug desensitization

Several cardinal principles in drug desensitization [4, 5, 27] for drug allergy/hypersensitivity are as follows:

• There is no alternative drug available for the treatment of the underlying condition (e.g. allopurinol in chronic tophaceous gout, penicillin in pregnant women with syphilis, platinum salts in recurrent ovarian cancer).

• The drugs for the treatment of the underlying condition are superior to the alternatives (e.g. isoniazid for tuberculosis).

• The initial reaction should not be potentially life-threatening reaction. Drug induced hypersensitivity syndrome (DiHS), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) are absolute contraindications to desensitization. However, anaphylaxis is not a contraindication.

• The benefits of desensitization outweigh the risks of recurrence of drug hypersensitivity/allergy.

• Starting doses are at 1:1,000,000 to 1:100 of the target therapeutic dose depending on the severity of the initial reaction, or based on end-point intradermal skin testing to a non-irritative concentration of the drug.

• Dose escalations are doubled at 15-30 min intervals for immediate reactions, or at intervals of up to 24 h for non-immediate reactions.

• Close monitoring and resuscitative equipment with staff trained in resuscitation should be available for rapid desensitization.

• Pre-medications with systemic corticosteroids or anti-histamines should be avoided.

• Concomitant medical conditions should be stable (e.g. asthma, cardiac insufficiency).

• The patient is still deemed allergic to the drug to which he/she has been successfully desensitized.

• The patient must adhere to the drug daily in order for tolerance to be maintained, unless breakthrough reactions occur where dose escalations may need to be interrupted/slowed down.

• In desensitization for non-immediate reactions, periodic monitoring of complete blood count and liver enzymes should be considered prior to interval dose escalations.

J Allergy Clin Immunol. 2008 Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. http://www.ncbi.nlm.nih.gov/pubmed/18502492 Ninety-eight patients who had HSRs in response to treatment with ... or rituximab received rapid desensitization to these agents. A standardized 12-step protocol was used, with treatment given intravenously or intraperitoneally. Initial desensitizations occurred in the medical intensive care unit, whereas most subsequent infusions took place in an outpatient setting. Safety and efficacy of the protocol were assessed by review of treatment records.

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

Overview:

Semin Hematol 47:187–198, 2010 Rituximab-Associated Infections Juan C. Gea-Banacloche  pdf

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 Symptoms | Association with Rituxan The incidence of PML in NHL is unknown; the 57 cases were reported over a long period of time from 12 centers and other sources ... thus the incidence is *very* low.
	"Hypoglycemia is a very rare toxicity of rituximab. The exact mechanism of rituximab  induced hypoglycemia is not clear."  Case report: wjso.com

PML - Progressive multifocal leukoencephalopathy (rare)

Topic search: http://www.ncbi.nlm.nih.gov/

Inclusion of Rituximab in Treatment Protocols for Non-Hodgkin's Lymphomas and Risk for Progressive Multifocal Leukoencephalopathy http://1.usa.gov/1SC4oxv The statistical analysis performed in the present study suggested (does not prove) a higher risk for PML in NHL patients exposed to rituximab. The higher occurrence of PML can be calculated as being in the range of 0.1–4.3 for every 1,000 patient-years for NHL patients exposed to rituximab, as compared with unexposed patients. This risk is likely low enough to not overcome the benefits in terms of mortality exerted by rituximab in most NHL patients. Comment: .1 to 4.3 is a very wide confidence interval ... indicating low confidence in the finding due to the retrospective method of study, the study size, and other confounders.  Even at the highest estimate of possible risk, the benefits of Rituxan appear to far exceed this and other risks.

Progressive multifocal leukoencephalopathy (PML) after rituximab therapy in HIV-negative patients:  a report of 57 cases from the Research on Adverse Drug Events and Reports project  http://1.usa.gov/u3Hhbc  [The 57 ] "Cases were identified among rituximab-treated patients by clinicians from 12 cancer centers or academic hospitals (22 cases) or by reviewing FDA reports (11 cases), the manufacturer's database (30 cases), and publications (18 cases; MeSH search terms: leukoencephalopathy, rituximab, immunosuppressed, lymphoma, and leukemia).18-31 The search covered the period from 1997, the date of the first FDA approval granted for rituximab, to December 31, 2008. Duplicate reports were identified based on age, sex, and underlying illness. Inclusion criteria were receipt of rituximab therapy before PML diagnosis or symptoms; PML confirmation based on histologic examination of brain tissue (histology-confirmed) or magnetic resonance imaging showing lesions consistent with a demyelinating process and documentation of cerebrospinal fluid (CSF) JCV DNA by polymerase chain reaction (PCR; laboratory-confirmed); and no evidence of HIV infection.32 copying from the Discussion: "Some study limitations should be noted. Epidemiologic estimates of PML incidence are difficult to derive. In the general population, PML is estimated to occur at 1 case per 200000 persons. Among HIV-infected populations, incidence rates decreased from 3.3 cases per 1000 person-years at risk in 1995 to 1996 to 1.3 cases per 1000 person-years at risk in 2000 to 2006, after the introduction of highly active antiretroviral therapy. Among persons with multiple sclerosis or Crohn disease, the estimated incidence of natalizumab-associated PML is 1 PML case per 1000 natalizumab-treated patients. For PML-associated with rituximab, Kavanaugh and Matteson reported 2 PML cases per 8000 rituximab-treated SLE patients.68 It is not possible to accurately estimate the incidence of rituximab-associated PML among persons with hematologic malignancies because of incomplete reporting of PML cases among rituximab-treated patients and incomplete data on the number of unique patients with lymphoid malignancies who have received rituximab. It should also be noted that the epidemiology of PML in the setting of lymphoid malignancies has changed over time. Before 1990, most PML cases occurred among persons with Hodgkin disease, whereas in recent years, with the development of purine analogs, hematopoietic stem cell transplantation procedures, and rituximab, most PML cases occur among non-HIV-infected persons with NHL or chronic lymphocytic leukemia. Consideration should be given to conducting epidemiologic studies to prospectively evaluate incidence rates and risk factors for PML among cohorts of rituximab-treated patients with NHL, autoimmune  diseases, SLE (lupus), rheumatoid arthritis, and multiple sclerosis. Finally, causation assessment is more difficult when PML occurs among rituximab- versus natalizumab-treated persons because PML occurs in the absence of rituximab therapy among persons with NHL or autoimmune diseases, whereas it has not been reported in the absence of natalizumab therapy among persons with multiple sclerosis or Crohn disease. In conclusion, rituximab administration may increase risks of developing PML, although the absolute risk of developing PML is probably low. As use of rituximab expands to diverse clinical settings, clinicians and patients should be aware of the potential for PML after rituximab therapy.  Awareness and reporting of rituximab-associated PML cases to the FDA are essential to improve our understanding of risk factors, natural course, and alternative therapeutic approaches. Despite widespread public health advisories describing 2 patients with SLE and 1 patient with rheumatoid arthritis who were diagnosed with rituximab-associated PML, we identified 22 previously unreported cases associated with lymphoid malignancies and immunologically mediated cytopenias. Early diagnosis of PML will prompt efforts at immune reconstitution, which may be beneficial in improving survival rates. Finally, early diagnosis before irreversible neurologic damage has occurred will be crucial for evaluation of the efficacy of new antiviral treatments."

Viral - reactivation: 

	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 "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 and associated complications:  

Hypogammaglobulinemia
(low levels of immunoglobulins (antibodies) from sustained b-cell depletion

Topic Search: PubMed

Late Onset Neutropenia:

2011, Expert Review:  Late-onset neutropenia following rituximab therapy: incidence, clinical features and possible mechanisms,  Daniel Tesfa* and Jan Palmblad

Late-onset neutropenia (LON)

 Late-onset neutropenia (LON) is emerging as a common adverse effect to rituximab therapy owing to widespread use of this drug in the treatment of B-cell lymphomas and autoimmune diseases. However, the true incidence and mechanisms are not fully understood.

 LON has been reported in 5–27% of rituximab-treated lymphoma patients. Similar figures apply for autoimmune patients but they appear to have more infections during the neutropenic period.

Recent reports imply that host factors may play an intriguing role for development of LON, for example, polymorphisms in FCGR3.

Pronounced B-lymphocyte depletion and lower serum IgM, as reported in LON patients during the period of neutropenia compared with matched controls, may play a role for understanding the mechanisms and risk stratification for emergence of LON.  expert-reviews.com

	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 Less Common Side effects 

	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

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What is the expected response rate?  

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.

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In the News:

	Association between rituximab use and progressive multifocal leukoencephalopathy (PML) among non-HIV, non-Hodgkin lymphoma Veteran’s Administration patients. | 2014 ASCO Annual Meeting Abstracts http://bit.ly/1t7c3qY
	News medical: MCCIR scientists use video imaging to investigate effectiveness of rituximab in killing cancerous B cells http://bit.ly/14SmVmb