Treatments > Radioimmunotherapy > Bexxar

Last update: 10/13/2011

TOPICS
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? 
 Basic outline for patients, including precautions and safety information  
Information & Resources | Background | Related Abstracts

TOPIC SEARCH: PubMed ~ Outcome | Review | Web

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 FDA.gov  pdf  

Who is Bexxar for?  "BEXXAR is indicated for the treatment of patients with CD20 antigen-expressing relapsed or refractory, low grade, follicular, or transformed non-Hodgkin's lymphoma, including patients with Rituximab-refractory non-Hodgkin’s lymphoma. Determination of the effectiveness of the BEXXAR therapeutic regimen is based on overall response rates in patients whose disease is refractory to chemotherapy alone or to chemotherapy and Rituximab. The effects of the BEXXAR therapeutic regimen on survival are not known." 

Source: Dailymed.nlm.nih.gov/ May 2008

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)."

How it works - mechanisms of action

Bexxar Mechanism-of-Action (MOA) from Jack Hyndman on Vimeo.

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) Potentially, 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

Repeat treatment with iodine-131-rituximab is safe and effective in patients with relapsed indolent B-cell non-Hodgkin's lymphoma who had previously responded to iodine-131-rituximab

annonc.oxfordjournals.org  

Where to receive treatment with Bexxar

BEXXAR Treatment Center Locations

For the most up-to-date list of Treatment Centers, 
contact the BEXXAR Service Center at 1-877-4BEXXAR (1-877-423-9927).

Centers that Administer Bexxar by State (last update, 2007)
 

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."

Harvesting Stem Cells for Transplant in Non-Hodgkin's Lymphoma Patients  Is Still Possible After Treatment with Bexxar  news.cornell.edu What Dr. Shore found was that, in 13 of 16 patients undergoing a clinical trial of Bexxar at NewYork- Presbyterian Hospital’s Weill Cornell Medical Center, a harvesting of stem cells from the blood  produced enough stem cells for these patients to have a transplant. “The prior use of Bexxar does  not preclude adequate stem cell collection for autologous [self-donated] stem cell transplantation  in non-Hodgkin’s lymphoma,” Dr. Shore said. “This allows the patients who relapse after Bexxar  the option to proceed to transplant, whereas, before, it was uncertain if this could ever be done.”

Hematological (blood cell) Toxicity

 in Patients receiving Bexxar as Initial Treatment:

* 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.

	See also HAMA
	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 

Potential contraindications for use

	Bone marrow biopsy results: Hypocellular bone marrow (<15% cellularity) Marked reduction of bone marrow precursors NOTE:  The bone marrow findings must be within 30 days
	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
	Previous external beam radiation involving >25% of the active bone marrow
	Pregnancy and continuing breast feeding
	Children and adolescents under 18 years of age
	Prior bone marrow or stem cell transplantation (this is being studied)

Adapted from: interactive.snm.org  |  eanm.org  pdf  

 

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?

Splenectomy in Non-Hodgkin's lymphoma  ncbi.nlm.nih.gov/books

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.

Basic outline for patients, including general precautions and safety information

BEXXAR is administered in two steps: (1) the dosimetric and (2) therapeutic steps.

Non-radioactive antibody (similar to Rituxan) is given before both the “dosimetric” infusion and the “therapeutic” infusion to improve distribution of these doses throughout the body - clear the blood of normal b-cells, so the more active radio-labeled dose is focused on tumor cells.

1. dosimetric dose: Following the cold antibody,  "a trace amount of radio-labeled antibody, is given to evaluate the clearance of radiation from the patient’s body with gamma camera scans. This allows for patient-specific dosing of the therapeutic dose.  

2. therapeutic dose:  7-14 days after the dosimetric step, the therapeutic dose is administered, again after administration of cold (unlabeled) antibody.

Following the therapy: 

	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.

"The amount of radiation received by close contacts of patients who followed the instructions is well within the guidelines deemed acceptable by the government agency regulating radiation exposure, namely, the Nuclear
Regulatory Commission (NRC)." See also Facts on Bexxar PDF

Ask your Nuclear Medicine physician for more specific information, which can vary by State.

Information & Resources:

	About Bexxar: cancerbacup.org | bexxar.com | Oliver Press MD, PhD
	Complete Prescribing Information for BEXXAR®  (Tositumomab and Iodine I 131 Tositumomab) us.gsk.com pdf
	Bexxar: Characteristics, Clinical Pharmacology and Rationale for Dosing Regimen http://www.nucmedtutorials.com/dwrit-nhl/bexxar3.html

Background articles

	Facts on Bexxar PDF  (Dr. Oliver Press, LRF)
	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

	Antibodies for NHL
	HAMA and pet mice?

Related Abstracts

	NEW: Re-Treatment With I-131 Tositumomab in Patients With NHL 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
	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