Who
is Bexxar For | How it works | How
long does it take to work | Repeat Use?
Find centers that administer Bexxar | Toxicity
| Delayed effects on blood counts
Contraindications (excluding conditions)
| Bulky disease and
RIT?
Precautions
and safety information following treatment
Information & Resources | Background
| Related Abstracts
Bexxar™ is a monoclonal antibody that has a
radioactive substance called iodine 131 attached to it. The monoclonal
antibody in Bexxar seeks and binds to a protein receptor (named CD20) on the
surface of both normal and malignant B cells. Once
bound to the target cells, Bexxar delivers radiations, which enhances the
killing effect of the antibody.
Normal
b-cells will recover in 6 to 9 months because the parent b-cells do not
have the CD20 receptor.
Technical
name: Tositumomab, Iodine I 131
http://www.fda.gov
pdf
Who is
Bexxar for? "BEXXAR is indicated for the
treatment of patients with CD20 positive relapsed or refractory low
grade, follicular, or transformed non-Hodgkin's lymphoma,
including patients whose disease is
refractory to Rituximab and who have relapsed following
chemotherapy." Bexxar.com
Bulky disease might work
against obtaining a complete response with Bexxar as with other
therapies. For a discussion on how pretreatment with other agents
might optimize Bexxar, see Bulky disease and
RIT?
Note: Prior radiotherapy and extranodal
disease does not seem to preclude use. "The BEXXAR therapeutic regimen should not be administered to patients with >25% lymphoma marrow involvement and/or impaired bone marrow 14 reserve (See WARNINGS and ADVERSE
REACTIONS and Contraindications
below)."
Possible
mechanisms of tumor killing
When radio-labeled antibody binds to tumor cells it can cause tumor
killing by:
(1) Self- killing (apoptosis) - programmed cell death triggered by the
antibody
(2) Complement-dependent cytotoxicity (CDC) - where antibody fixes complement
that kills the tumor cells
(3) Antibody-dependent cellular cytotoxicity (ADCC) - where effector cells
(immune cells) kill the tumor cells
(4) Ionizing radiation from the radioisotope damages the tumor cells, leading
to cell death
(5) Vaccine-like effect - leading to adaptive immunity against cells
that survive initial treatment.
TECHNICAL
Clinical
Pharmacology
"Utilizing the gamma emissions, relatively
simple dosimetry can be performed and used to calculate the clearance
rate of the radionuclide in an individual patient, thus determining
the patient-specific therapeutic dose.
The half-life of I-131 (approximately 8 days) is also well suited for
RIT [21], because it is similar to the half-life of
murine antibodies in humans. Therefore, when I-131-labeled tositumomab
is bound to CD20, a stable cell-surface molecule, the tumor receives
high doses of radiation over several days.
Another advantage of I-131 is the relatively short average path length
of the beta emissions (approximately 1 mm), which minimizes collateral
damage to healthy tissue surrounding the tumor. As the
I-131-conjugated antibody is metabolized, the free I-131 metabolites
are released into the bloodstream and are rapidly excreted in the
urine [22–24]. Free I-131 in
the blood may also be taken up by the thyroid; however, accumulation
in the thyroid can be effectively blocked by administering a
supersaturated potassium iodine (SSKI) solution to patients before and
during treatment, thus limiting potential damage. Nevertheless,
thyroid dysfunction has been observed in approximately 5% of patients
treated with Bexxar." Source:
Bexxar®: Novel Radioimmunotherapy for the
Treatment of Low-Grade and Transformed Low-Grade Non-Hodgkin’s
Lymphoma Julie M. Vose theoncologist
Imaging and
Dosimetry
... The ultimate goal in drug therapy is to provide the most
effective dose to optimize benefit and minimize toxicity. The
tositumomab and 131I-tositumomab therapeutic regimen seeks to approach
this goal by evaluating individual patient drug distribution and
elimination over time.
These aspects of drug behavior are
termed pharmacokinetics. With conventional pharmaceutical agents, the
best that clinicians can do in this regard is to measure the time
course for the drug (or metabolites) in the blood.
With radiolabeled agents, however, a much more accurate estimate of
patient-specific pharmacokinetics is possible. Because 131I is both a  -emitter
and a ß-emitter, it is possible to obtain whole-body -counts
from imaging of the patient after a relatively small (dosimetric) dose
(184 MBq [5 mCi]) of 131I-tositumomab to estimate the total-body
residence time (TBRT). This determination allows consideration of the
factors shown to be influential in the pharmacokinetics of the
tositumomab and 131I-tositumomab therapeutic regimen, such as extent
of disease, bone marrow involvement, spleen size, and renal function (5).
In addition to enabling an estimation of TBRT, imaging also provides
an opportunity for the nuclear medicine physician to evaluate
biodistribution with the same isotope, unlike other regimens that use
a -emitting surrogate to
predict biodistribution.
However, unlike most nuclear medicine imaging procedures, this process
is intended to evaluate gross biodistribution only, not provide
detailed diagnostic information. The expected biodistribution after a
dosimetric dose of 131I-tositumomab is illustrated by whole-body scans
of a patient with the typical pattern for NHL (Fig. 3),
whereas biodistribution may be different in patients with solid tumors
or other cancer types, such as a retroperitoneal tumor with thyroid
uptake (Fig. 4) or cutaneous lymphoma (Fig.
5), respectively. In addition to visual inspection of the images,
biodistribution also may be assessed by evaluating the TBRT (day 6 or
7). For the tositumomab and 131I-tositumomab therapeutic regimen, the
expected biodistribution is defined as a TBRT of between 50 and 150 h. snmjournals
Essential Role of Nuclear Medicine Technology in
Tositumomab and 131I-Tositumomab Therapeutic Regimen for
Non-Hodgkin's Lymphoma, William C. Cole1, Jennifer Barrickman, CNMT2
and Glen Bloodworth, CNMT2
How long does
it take for Bexxar to work? When given as initial
treatment: "Responses were observed in
72 of the 76 patients, most of
whom reported regression of palpable tumor within two weeks. Complete
responses were observed in 57 of 76 patients (Table 1), with a median
time to an evaluated complete response of 202 days (range, 55 to 693).
The five-year rate of progression-free survival for all patients was
estimated at 59 percent (95 percent confidence interval, 49 to 71)
(Fig. 2). The median progression-free survival was 6.1 years (95
percent confidence interval, 3.0 years to [upper confidence
level not reached]), with a median follow up of 5.1 years. The 5-year
progression-free survival for patients with a complete response was 77
percent (95 percent confidence interval, 67 to 89); 40 of the 57
patients (70 percent) who had a complete response (53 percent of the
entire study population) remained in complete remission for 4.3
to 7.7 years after treatment." ~ NEJM,
February 3, 2005 Vol. 352 no. 5 -131 I-Tositumomab Therapy as Initial
Treatment for Follicular Lymphoma
What
about repeated use of Bexxar? "There are very
limited data on repeated dosing with radioimmunoconjugates. Can it be
done? In Kaminski's recent paper in Blood, seven of the 53 patients
got a second dose in order to get a better response, but it didn't
work. Only one patient went from stable disease to partial response.
None of the other patients improved the quality of their response.
However, there were 16 patients who progressed after getting the
antibody and were re-treated. They had nine responses of the 16,
including five complete remissions, with a median progression-free
survival of 11 and a half months. So, yes, they can be
re-administered." ~ Dr Bruce Cheson - bloodline.net
Where
to receive treatment with Bexxar
BEXXAR Treatment Center
Locations
Use the search
feature to find a treatment center near you.
Treatment Centers continue to be added. For the most up-to-date list
of Treatment Centers,
contact the BEXXAR Service Center at 1-877-4BEXXAR
(1-877-423-9927).
What about tolerability and safety?
See table provided by the sponsor:
www.bexxar.com
What about toxicity to the bone
marrow?
Relationship of degree of bone marrow involvement with hematologic
toxicity in patients with non-Hodgkin's lymphoma treated with
tositumomab and iodine I 131 tositumomab. ASCO
2003
Lack of treatment-related MDS/AML in patients with follicular lymphoma
after frontline therapy with tositumomab and iodine I 131 tositumomab
ASCO
2003
The iodine I-131 tositumomab therapeutic regimen: Summary of safety in 995 patients with relapsed/refractory low grade (LG) and transformed LG non-Hodgkin's lymphoma (NHL)
jco.org
 | Specific Regimen Influences Risk
of Myelodysplasia After Lymphoma Treatment BloodJournal
Aug 2005: "... none of the 76
patients with previously untreated, advanced-stage follicular
large granular non-Hodgkin lymphoma (LG-NHL) who received [bexxar]
as initial therapy
developed t-MDS or t-AML over the 4.6 years of
median follow-up.
"While longer follow-up is needed,"
the authors conclude, "these results suggest that
radioimmunotherapy will, with acceptable toxicity, take its place
among the more effective
therapies for LG-NHL."
|
Hematological
(blood cell) Toxicity in Patients receiving Bexxar as Initial
Treatment:
| Variable |
Absolute
Neutrophil Count |
Hemoglobin |
Platelet Count |
Median (average)
nadir (lowest) value |
1300 per mm3 |
12.2 g/dl |
83,000 per mm3 |
| Median time to
nadir |
47 days |
44 days |
29 days |
| Toxicity (%) * |
|
|
|
| Grade 3 or 4 |
34 of 76 pts |
0 |
17 of 76 pts |
| Grade 4 |
5 of 76 pts |
0 |
0 |
Median
duration
of toxicity** |
|
|
|
| Grade 3 or 4 |
22 days |
NA |
22 days |
| Grade 4 |
5 days |
NA |
NA |
|
Median time to return to
baseline grade |
60 days |
56 days |
43 days |
* Common Toxicity Criteria of the National Cancer Institute define a grade 3
absolute Neutrophil count as 500 to less than 1000 per cubic millimeter and a
grade 4 count as less than 500 per cubic millimeter, a grade 3 hemoglobin level
as 6.5 to less than 8.0 g per deciliter and a grade 4 level as less than 6.5 g per
deciliter, and a grade 3 platelet count as 10,000 to less than 50,000 per cubic
millimeter and a grade 4 count as less than 10,000 per cubic millimeter.
** The duration of grade 3 or 4 toxicity was defined as the number of days from
the last count before grade 3 or 4 toxicity to the first day of the documented
return to grade 2 toxicity.
Adapted from 131 I-Tositumomab
Therapy (Bexxar) as Initial Treatment for Follicular Lymphoma ~
Kaminiski et al, NEJM, Feb 3 2005.
Aug 2005: "...none
of the 76 patients with previously untreated, advanced-stage
follicular large granular non-Hodgkin lymphoma (LG-NHL) who received
tositumomab and I131 tositumomab as initial therapy developed t-MDS
or t-AML over the 4.6 years of median follow-up.
"While longer follow-up is needed,"
the authors conclude, "these results suggest that
radioimmunotherapy will, with acceptable toxicity, take its place
among the more effective therapies for LG-NHL." - Medscape
Specific Regimen Influences Risk of Myelodysplasia After Lymphoma Treatment
-
HAMA
About one-third of patients with relapsed B-cell malignancies
develop human
anti-mouse antibody (HAMA) following mouse antibody treatment
|
Survival benefit associated with human
anti-mouse antibody (HAMA) in patients with
B-cell malignancies. Cancer Immunol Immunother. 2006
Dec;55(12):1451-8.
Epub 2006 Feb 22. PMID:
16496145
Patients with B-cell malignancies that developed high HAMA
titers had longer survival
that was not explained by risk factors or histologic grade, suggesting
the importance of the
immune system.
|
"Although
approximately 10% of patients treated with tositumomab and iodine I
131 tositumomab (bexxar)
developed human-anti-mouse antibodies, treatment with
tositumomab does not preclude the
administration of subsequent chimeric (mouse-human) antibody
therapies."
A clinical and scientific overview of tositumomab and iodine I 131
tositumomab.
Semin Oncol. 2003 Apr;30(2 Suppl 4):22-30. Review. PMID: 12728404
Contraindications for use
|
Bone marrow biopsy
results:
 |
Hypocellular bone
marrow (<15% cellularity) |
|
Marked reduction
of bone marrow precursors |
|
|
Impaired bone marrow
reserves as indicted by:
|
prior
myeloablative therapies with ABM or PBSC transplantation |
|
Platelet count
< 100,000 cells/mm3 |
|
ANC (Neutrophil Count (Absolute))
< 1,500 cells/mm3 |
|
History of failed
stem cell collection |
|
|
Known type I
hypersensitivity or anaphylactic reactions to murine (mouse)
proteins
or to any component of the therapeutic regimen |
|
Positive pregnancy
test - test required for women of child-bearing age. |
|
Serum Creatinine >
1.5 X the upper limit of normal |
Adapted from: interactive.snm.org
| Re-Treatment With I-131 Tositumomab
in Patients With Non-Hodgkin's Lymphoma
Who Had Previously Responded to I-131 Tositumomab ASCO
|
Does spleen involvement
preclude use of radioimmunotherapy?
Residual splenomegaly in a patient who has otherwise successfully
responded in other sites following chemotherapy for lymphoma is
another reason for performing a splenectomy. In these cases, the
procedure may be performed for both diagnostic and therapeutic
reasons; it can determine if the splenomegaly is due to persistent
lymphoma, and should this be true, it can potentially eliminate the
focus of residual disease. A less common indication for splenectomy
that may be seen more frequently in the future is to allow patients
to become eligible for enrollment onto novel treatment protocols. An
example of this is in patients with lymphoma refractory to
conventional chemotherapy who were treated with radioimmunotherapy
using a radiolabelled anti-CD20 antibody.
In some of these patients, splenomegaly was found to complicate
treatment, as the large organ served as an “antigen sink”,
effectively decreasing the dose of radionuclide available to treat
other sites of disease. Thus, pretreatment splenectomy
may be indicated to eliminate this complicating factor.
Precautions and safety information following treatment
The following measures should be taken by the patient for
up to 2 weeks (generally) after receiving bexxar. The
specifications can vary. Carefully read the written
instructions provided by your doctors.
Following the
therapeutic dose:
|
Avoid contact with infants, young children, and
pregnant women. |
|
Sleep in a separate bed
separated by a distance of at least 6 feet (2 to 3 meters). |
|
Maintain an appropriate
distance of 6 feet (2 meters) from others. |
|
Travel alone in a private
automobile if possible, otherwise maintain as great a distance as possible
between patient and driver. |
|
Toilet should be used instead of urinal.
Sit on toilet to prevent splashing, and flush several times after use. |
|
Separate laundry and eating utensils
and wash items separately. |
Ask your Nuclear Medicine physician for more specific information.
Information & Resources:
|
|
| Reimbursement information - link broken
|
|
Complete Prescribing Information for BEXXAR®
(Tositumomab and Iodine I 131 Tositumomab) - us.gsk.com
pdf
|
Background articles
|
|
| Bexxar®: Novel
Radioimmunotherapy for the Treatment of Low-Grade and Transformed
Low-Grade Non-Hodgkin’s Lymphoma ~ The Oncologist, Vol. 9, No.
2, 160–172,
April 2004 theoncologist.alphamedpress.org
|
| Articles on Bexxar drugs.com
|
| Overview of Radioimmunotherapy: Clinical Experience With Tositumomab,
Iodine I-131 Tositumomab
Mark S. Kaminski, MD - Introduction:
Why Radioimmunotherapy? medscape
(free login)
|
| Patient-Specific Dosing: The Critical Role of Dosimetry
Richard L. Wahl, MD - Dosimetry in RIT Medscape (free login)
|
| Tositumomab, Iodine I-131 Tositumomab as Front-Line Therapy in Non-Hodgkin's Lymphoma
John Leonard, MD Radioimmunotherapy for NHL Medscape (free login)
|
| Future Directions With Iodine-131 Tositumomab in Non-Hodgkin's Lymphoma
Oliver W. Press, MD, PhD Tositumomab: What the Future Holds Medscape (free login)
|
| FDA Drug Advisory transcripts on Bexxar PDF
|
| Radioimmunotherapy Agents: What They Are and How
They Work bloodline.net
|
| Subsequent therapy can be administered after
tositumomab and iodine I-131 tositumomab
for non-Hodgkin lymphoma. Cancer. 2005 Dec 16; PMID:
16362977
|
Related Topics
Related Abstracts
|
NEW:
Re-Treatment With I-131 Tositumomab in Patients With
Non-Hodgkin's Lymphoma Who Had Previously Responded to I-131
Tositumomab http://jco.ascopubs.org/cgi/content/full/23/31/7985
In summary, the results of the current study suggest that
re-treatment with I-131 tositumomab may be a potentially valuable
therapeutic choice for patients who responded previously to
therapy with I-131 tositumomab. Re-treatment with I-131
tositumomab appears to be relatively safe and effective and can
result in durable responses in a subset of patients. Given these
encouraging results, further studies of re-treatment with I-131
tositumomab have been designed and will include patients who
prospectively enroll onto new clinical studies of I-131
tositumomab and have a duration of response of at least 6 months.
|
|
Combo Therapy with Tositumomab (Bexxar) & autoSCT Aids
Elderly Lymphoma Patients cancerpage.com
"These data suggest that potentially curative therapies
should not be denied to patients based solely on age," lead
investigator Dr. Ajay K. Gopal of the University of Washington,
Seattle, told Reuters Health. "In addition, targeted
therapies with individualized dosing strategies, as in this study,
may prove useful to both reduce toxicity and improve outcomes in
patients of all ages."
|
|
The impact of FLIPI on outcome of frontline treatment with
single-agent I-131 tositumomab for follicular lymphoma
ASCO
7509 - 2006
|
|
New treatment, CHOP
followed by Bexxar, shows long-term remission in patients with
follicular non-Hodgkin’s lymphoma bexxar
s0016.pdf
“We feel that the five-year results of the trial are
tremendously encouraging and some of the best ever observed in a
SWOG clinical trial for patients with advanced follicular
non-Hodgkin’s lymphoma,” said Dr. Press, who is a member of
the Fred Hutchinson Cancer Research Center, professor of medicine
at the University of Washington and chairman of the scientific
advisory board of the Lymphoma Research Foundation.
|
|
Iodine-131-Rituximab
Radioimmunotherapy [Bexxar] in Patients With Relapsed or
Refractory Indolent Non-Hodgkin's Lymphoma: Australian Multicenter
Phase II Clinical Study.
J Clin Oncol. 2006 Aug 28; PMID:
16940276
The objective overall response rate (ORR) was 76%, with 53% attaining a complete response (CR) or CR unconfirmed
(CRu). Median duration of response for patients achieving CR/CRu was 20 v 7 months for those with a partial response (P = .0121). Median progression-free survival for the entire cohort was 13 months, with 14% remaining relapse free beyond 4 years. Median follow-up was 23 months, with a 4-year actuarial survival rate of 59% +/- 10%. Toxicity was principally hematologic; grade 4 thrombocytopenia occurred in 4% and neutropenia occurred in 16% of patients, with nadirs at 6 to 7 weeks after treatment.
|
|
Bexxar Following Fludarabine Produced Response in 100% of
patients [first line] med.cornell.edu
Sep 2005
|
|
Health Canada approves new targeted radioimmunotherapy ~
Bexxar(TM) Receives Approval to Treat Follicular Non-Hodgkin's
Lymphoma newswire.ca
|
| Radioactive
Anti-CD 20 Antibody (Bexxar®) May Improve Outcome of Autologous
Transplants for Follicular Lymphomas
cancerconsultants.com
|
| Efficacy
and Safety of Tositumomab and Iodine-131 Tositumomab (Bexxar) in
B-Cell Lymphoma, Progressive After Rituximab. J Clin Oncol. 2004
Dec 21; PMID:
15613695
|
| Tositumomab
and Iodine I 131 Tositumomab [Bexxar] for Recurrent Indolent and
Transformed B-Cell Non-Hodgkin's Lymphoma. J Clin Oncol. 2004 Apr
15;22(8):1469-79. PMID:
15084620 | Related
articles
|
| ASH 2003 - [89] The BEXXAR Therapeutic Regimen (Tositumomab and Iodine I 131 Tositumomab) Produced Durable Complete Remissions in Heavily Pretreated Patients with Non-Hodgkins Lymphoma (NHL), Rituximab-Relapsed/Refractory Disease, and Rituximab-Naive Disease.
abstractsview.com
|
|
FDA Drug
Advisory transcripts on Bexxar PDF
|
|
Techniques for using bexxar for treatment tech.snmjournals.org.pdf
Describes pre-dosing; how dosing is calculated (with dosimetic dose); why the need: individual biologic clearance, etc.
For professionals, but readable. Also tells about importance of avoiding infusion leaks.
|
|
High-dose radioimmunotherapy (Bexxar) versus conventional
high-dose therapy and autologous hematopoietic stem cell
transplantation for relapsed follicular non-Hodgkin's lymphoma: a
multivariable cohort analysis. Blood. 2003 May 15 PMID: 12750161
PubMed
|
|
ASCO 2003 - Bexxar analysis of
long-term responses prnewswire
|
|
Bexxar
2
Bexxar has a radioactive substance called iodine 131 attached to it. The monoclonal
antibody in Tositumomab (Bexxar) targets a protein (CD20) found on the surface of mature B
cells and the radioactive iodine delivers radiation directly to these cells. This destroys
the lymphoma B cells. Unfortunately it may also affect some normal cells. (FDA
is considering approval)
|
|
ASH 2002: Durable Responses With Bexxar (Tositumomab) In Transformed Non Hodgkin's Lymphoma
Docguide.com
|
|
ASH: Durable Responses Reported with Single Dose of Tositumomab and Iodine I-131 Tositumomab (Bexxar) in Relapsed, Refractory Low-grade Non-Hodgkin's Lymphoma
Docguide.com
Dec_9_02
|
|
Efficacy & Background: Antibody Therapy for Non-Hodgkin's
Lymphoma - Mark S. Kaminski, M.D. Professor of Internal Medicine
Director, Multidisciplinary Lymphoma Clinic details
|
| Efficacy as Single Agent in Utreated Patients: Iodine-131: Effective Front-Line Follicular
Lymphoma Treatment -- Of the 76 pts with previously untreated
advanced state follicular lymphoma, 74 had either a complete
response (76%) or a partial response (21%). Progression-free
survival was markedly better for the patients who had a complete
response than for those who had a partial response. As estimated
by Kaplan-Meier survival curves based on current data, the median
progression-free survival for all patients who had a response was
projected to be 59% at three years. Survival curves projected a
71% progression-free survival at three years for pts who had a
complete response. ASCO
|
| Efficacy: BEXXAR EFFECTIVE AS FIRST-LINE TREATMENT
FOR NON-HODGKIN'S LYMPHOMA PATIENTS WHEN USED WITH CHEMOTHERAPY detail
|
|
Efficacy: Bexxar (Tositumomab and Iodine
(I)-131-Tositumomab) Plus CHOP Improves Best Result in Newly
Diagnosed Follicular Non-Hodgkin's Lymphoma. details
|
|
Efficacy: Complete response rate was increased 5-fold by
addition of Bexxar, compared to fludarabine alone. details
|
|
Efficacy: Integrated Analyses of 251 Patients Treated with
Bexxar Shows Thirty-Five Percent of Patients Achieved Durable
Complete Responses Lasting a Median of More Than Three Years details
|
|
Commentary: Dr. Bruce Cheson, bloodline
|
| Patient Anecdote: Bruce's Bexxar Experience details
|
|
TOPIC SEARCH: PubMed ~ 
