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?
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 all CD20-expressing B lymphocytes, both malignant and nonmalignant (cancerous and normal).
CD20 is a receptor (or antigen, marker, protein) ... with a
specific shape, that's found on mature B lymphocytes, but not on stem cells, plasma cells,
or other tissues ...
... importantly, the cd20 receptor is not found on precursor B cells
- immature b-cells which can later mature to replenish the supply of
normal mature b-cells.
In the initial Rituxan trials, circulating mature B lymphocytes were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. Also, in some patients there were sustained and statistically significant reductions in both
serum IgM and IgG (antibody) levels observed from 5-11 months following Rituxan
administration.
"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
How Rituxan may induce lysis (killing) of lymphoma cells:
apoptosis is
a natural mechanism by which cells "commit suicide" when
they have outlived their purpose, become defective, or have
aged. Apoptosis prevents cells from accumulating
and forming tumors. Understanding
of the control of apoptosis in normal and malignant cells will help to
improve the diagnosis and treatment of malignancies.
The goal of many treatments, including chemo and and antibody-based
therapy is to induce malignant
cells to undergo apoptosis. Picture
it
antibody-dependent cell-mediated cytotoxicity (ADCC) - An
immune response triggered by the presence of antibody (Abs)
coating the target cell (such
as Rituxan).
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. - (adapted from
the Merck Manual)
complement-dependent cytotoxicity (CDC): A mechanism of killing
cells 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.
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.
~ KarlS

Recommended Resources:
Prescribing Details
 | Rituxan: Questions and Answers for Medical Professionals Rituxan.com
PDF
|
 | Rituxan: Full prescribing information Rituxan.com
|
 |
|
 | 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
|
 | Rituxan - A scientific and technical discussion emea.europa.eu
pdf
Provides detailed information on pharmacokinetics; tables on time
to response, toxicity etc.
|

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 - 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 PDF
| PDF-Help 07_03
|
 | Monoclonal
Antibody Therapy for Non-Hodgkin's Lymphoma
Sledge
Jr, MD, and Plante
(Medscape)
|
 | Riuximab anti-CD20 antibody therapy of B cell non-Hodgkin's lymphomas - David C. Maloney Haematologica 1999.
PDF | PDF-Help
|
 | Rituxan in Perspective - includes abstract,
timeline, and more Rituxan.com
|
 |
Rituxan checklist for the
patient PAL-
print
version
(what to expect, how to prepare)
|

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

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
|
Type |
Dose |
Infusions |
Courses |
Interval |
Study |
|
Standard
(single agent)
|
375
mg/m2
|
4
|
1
|
4x
weekly
|
JCO |
|
|
Approved
by FDA at this schedule for relapsed NHL. The rationale based mostly
on empiric
and logistic considerations. 1
|
|
Extended (single
agent)
|
375 mg/m2 |
8
|
1
|
4 x weekly |
AO |
|
|
Rationale: "The
pharmacokinetic (PK) analysis in the first pivotal study of
rituximab indicated that patients maintaining a higher
and more prolonged blood level of rituximab had an
increased chance of responding" 1 |
|
Scheduled
Retreatment (single agent)
|
375 mg/m2 |
4
|
4
|
4
x weekly,
at 6 mo. course intervals |
JCO |
|
|
Patients
restaged at week 6 for response; those with objective response or
stable disease received maintenance rituximab courses (identical
dose and schedule) at 6-month intervals
|
|
Scheduled
retreatment
vs. Retreat on Progression (single
agent)
|
375 mg/m2 |
4
plus
|
variable
|
4 x weekly
on progression
VS.
Scheduled: 1 X
at 12 week intervals |
NCT00075946 |
|
|
Comparing
scheduled vs rituximab retreatment for patients who respond (PR/CR) to
standard dose of Rituxan.
|
|
Maintenance
(after chemo)
|
375 mg/m2 |
1
|
variable
|
1
x
at 8 week intervals for 1 to 2 years |
MAXIMA |
|
|
MAXIMA
study objective is to evaluate the safety and efficacy of MabThera
(Rituxan) maintenance therapy following a MabThera-containing
induction regimen in first line or relapsed patients with follicular
non-Hodgkin's lymphoma. |
|
Maintenance
(after chemo)
|
375 mg/m2 |
1
|
~12
|
1 x
at 8 week intervals for 2 years. |
PRIMA |
|
|
First period: Induction of response with 8 x rituximab, 375 mg/m2/dose
combined with 8 cycles of CVP or 6 cycles of CHOP in 21-day cycles or 6
cycles of FCM in 28-day cycles. Second period: rituximab 375 mg/m2 every 8 weeks for 24 months (12
injections) or control with no treatment |
|
Consolidation
post-ASCT
|
375 mg/m2 |
4
|
1
|
4 x weekly,
8 weeks after engraftment |
AO |
|
|
"One
single course of rituximab after ASCT is safe, may help to eliminate
MRD and may translate into improved EFS in both FL and MCL
patients." See AO
|
-
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

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

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

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
|
|

Side Effects
|
TYPES:
Infusion Reactions,
Infectious Events,
Hematologic Events,
Pulmonary (lung) Events,
Immunogenicity (antibodies to mouse)
Source: Rtuxan.com
|
COMMON:
Aching joints
Chills
Cough
Fever
Headache
Hives
Itching
Nausea
Shakes
Sneezing
Swelling
Throat irritation or tightness
Upper respiratory tract infection
|
"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
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).
|
TYPE
|
All
Grades (%)
|
Grade
3 and 4 (%)
|
|
Any Adverse Events
|
99%
|
57%
|
|
Body as a Whole
|
86%
|
10%
|
|
Fever
|
53%
|
1%
|
|
Chills
|
33%
|
3%
|
|
Infection
*
|
31%
|
4%
|
|
Asthenia
|
26%
|
1%
|
|
Headache
|
19%
|
1%
|
|
Abdominal Pain
|
14%
|
1%
|
|
Pain
|
12%
|
1%
|
|
Back Pain
|
10%
|
1%
|
|
Throat Irritation
|
9%
|
0
|
|
Flushing
|
5%
|
0
|
|
Cardiovascular
|
25%
|
3%
|
|
Hypotension (low blood pressure)
|
10%
|
1%
|
|
Hypertension (high blood
pressure)
|
6%
|
1%
|
|
Digestive
|
37%
|
2%
|
|
Nausea
|
23%
|
1%
|
|
Diarrhea
|
10%
|
1%
|
|
Vomiting
|
10%
|
1%
|
|
Hemic and Lymphatic System
|
67%
|
48%
|
|
Lymphopenia
(decrease in number
of lymphocytes in the blood)
|
48%
|
40%
|
|
Leukopenia
(decrease in number of circulating
white blood cells (leukocytes)
in the blood
|
14%
|
4%
|
|
Neutropenia
|
14%
|
6%
|
|
Thrombocytopenia
(low platelets)
|
12%
|
2%
|
|
Anemia
|
8%
|
3%
|
|
Metabolic and Nutritional Disorders
|
38%
|
3%
|
|
Angioedema
(swelling is beneath the skin)
|
11%
|
1%
|
|
Hyperglycemia (high
blood sugar)
|
9%
|
1%
|
|
Peripheral Edema (swelling
of tissues)
|
8%
|
0
|
|
LDH Increase (blood test marker)
|
7%
|
0
|
|
Musculoskeletal System
|
26%
|
3%
|
|
Myalgia (muscle
pain)
|
10%
|
1%
|
Arthralgia (pain
in the joints)
|
10%
|
1%
|
|
Nervous System
|
32%
|
1%
|
|
Dizziness
|
10%
|
1%
|
|
Anxiety
|
5%
|
1%
|
|
Respiratory System
|
38%
|
4%
|
|
Increased Cough
|
13%
|
1%
|
|
Rhinitis (irritation
and
inflammation of the nose)
|
12%
|
1%
|
|
Bronchospasm (difficulty
in breathing
caused by a sudden constriction
of the muscles)
|
8%
|
1%
|
|
Dyspnea (shortness
of breath)
|
7%
|
1%
|
|
Sinusitis
(sinus openings become
blocked and mucus accumulates)
|
6%
|
0%
|
|
Skin and Appendages
|
44%
|
2%
|
|
Night Sweats
|
15%
|
1%
|
|
Rash
|
15%
|
1%
|
|
Pruritus (itching)
|
14%
|
1%
|
|
Urticaria
(hives
– a type of allergic reaction)
|
8%
|
1%
|
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 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). A small minority 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.
 | Box warning for possible severe side effects IDEC
Fatal infusion reactions | Tumor Lysis Syndrome | Severe
Mucocutaneous reactions
|
 | Rituxan and late onset neutropenia following Auto stem cell
transplants haematologica.org
|
 | 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 | |