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Treatment  > Bexxar vs. Zevalin: Comparing Properties

Last update: 08/16/2013
 

Comparing Properties of Bexxar & Zevalin

Patients often ask us:  Which of these agents is better?

Because Zevalin and Bexxar have not been compared head-to-head in a controlled study, it is not known which is better. 

Perhaps it will be useful to review the properties of these agents, and ask the experts if your specific clinical circumstance makes one or the other a more reasonable choice. Because these agents are relatively new, community oncologists may not have had the time to explore the differences fully.

Articles that discuss differences: 
radiologytodaybloodjournal.org | cecity pdf 
 
NEW Comparing Zevalin and Bexxar in clinical practice http://bit.ly/8U6IBD

Features

Bexxar
(tositumomab)

Zevalin
(Ibritumomab tiuxetan)

antibody

mouse 
anti-CD20+ antibody

mouse 
anti-CD20 + antibody [E]

basis for FDA approval - indications

"for the treatment of patients with CD20 positive, follicular, non-Hodgkin's lymphoma, with and without transformation, whose disease is refractory to Rituximab and who have relapsed following chemotherapy."  Bexxar.com 

"for the treatment of relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). 

 In September 2009, Zevalin received additional indication for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.   

cost
per patient

These comparisons are very rough estimates from different 
sources at different times. Probably, the costs are about the same.

"..., persuading the government to pay full price for a new lymphoma drug that costs $26,000 a patient."   seattletimes.nwsource.com

".. and one regimen of Zevalin can cost as much as $30,000."  cincinnati.bizjournals.com 

dosing
determination

dosimetry [A] - imaging of gamma is used to determine uptake and clearance of the drug for patient-specific dosing   Medscape (free login) 

based on calculation to deliver 75 cGy of TBI 8

body weight and 
baseline platelet count  

fixed dose 0.4 mCi/kg up
to a maximum of 32 mCi 8

dosing / migration - absorbed radiation in normal tissue

To Thyroid: " [C]

To Liver: "Liver to whole body ratio was > 8:1. Please note that the liver dose was estimated to be 900cGy)." [3]

Energy (MeV)

Lower: 0.6

Higher: 2.3

HAMA
(human anti-mouse antibodies) results in flu-like symptoms
Rate of HAMA is higher (~10%) Rate of HAMA is lower (~1%)
path length 
of radiation

Shorter: 
0.8 mm (average) 
2.4 mm (maximum) [5]

Longer:
5 mm (average) [4]

pre-dosing with naked antibody

yes

yes

radioisotope - radiation

Iodine131
emitting gamma & beta radiation 

gamma rays emitted by Bexxar present a potential radiation hazard that may require hospitalization for isolation. 

Ytrium90
emitting beta radiation

radioisotope clearance

Faster

Slower

radioisotope excretion

 131I cleared in urine within 48 hours 8

5-10% of 90Y-chelate cleared in urine, some through bowel 8

radioisotope half-life

Longer: 8 days [1]

Shorter: (2.7 days) [2]

risk of MDS/AML

see report (11)

see report (10) 

scans

Scans to determine residence time and rate of clearance 8

Scans to verify expected biodistribution 8

targets

CD20 receptor on mature b-cells

CD20 receptor on mature b-cells


References and Related Resources

1) Radioimmunotherapy Agents: What They Are and How They Work www.bloodline.net

2)  Biodistribution and dosimetry results from a phase III prospectively randomized controlled trial of Zevalin radioimmunotherapy for low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma. Crit Rev Oncol Hematol. 2001 Jul-Aug;39(1-2):181-94.PMID: 11418315  PubMed

3) FDA Review of Biologics License Application for IDEC Pharmaceutical ZEVALIN™ Kit - BLA# 125019  fda.gov - backgrounder.pdf 

4) Zevalin Resource Guide  zevalin.com 

5) 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 © 2004 AlphaMed Press   theoncologist.alphamedpress.org  

6) Arming antibodies, prospects and challenges  chem.indiana.edu  PDF 

7) Briefing Document on Bexxar submitted to FDA www.fda.gov

8) Radioimmunotherapy in the treatment of low grade b-cell lymphoma www.cecity.com/nocr/ash2003/section3.pdf 
   Robert O. Dillman, M.D., Medical Director, Hoag Cancer Center, Newport Beach, California 

Radiation dosimetry results and safety correlations from 90Y-ibritumomab tiuxetan radioimmunotherapy for relapsed or refractory non-Hodgkin's lymphoma: combined data from 4 clinical trials. J Nucl Med. 2003 Mar;44(3):465-74. PMID: 12621016 

Relapsed or refractory NHL in patients with adequate bone marrow reserve and <25% bone marrow involvement by NHL can be treated safely with (90)Y-ibritumomab tiuxetan RIT on the basis of a fixed, weight-adjusted dosing schedule. Dosimetry and pharmacokinetic results do not correlate with toxicity.

9) Alexandra M. Levine, MD   Robert S. Mocharnuk, MD 
Rituximab, Tositumomab (Bexxar), Ibritumomab (Zevalin): And the Winner Is...  Medscape.com (free login req.)

10) Zevalin: Risk of MDS/AML update  www.fda.gov | Zevalin_PI.pdf 

"Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML) were reported in 5.2% (11/211) of patients enrolled in clinical studies and 1.5% (8/535) of patients included in the expanded-access trial, with median follow-up of 6.5 and 4.4 years, respectively. Among the 19 reported cases, the median time to the diagnosis of MDS or AML was 1.9 years following treatment with the Zevalin therapeutic regimen; however, the cumulative incidence continues to increase."

11)  Specific Regimen [Bexxar] Influences Risk of Myelodysplasia After Lymphoma Treatment  BloodJournal

A total of 1071 patients were enrolled in 7 studies: 995 with relapsed/refractory low-grade NHL, ± transformation (median, 3 prior regimens [range, 1-13 regimens]) and 76 patients with previously untreated low-grade follicular NHL.

Median follow-up was 6 years from diagnosis and 2 years from radioimmunotherapy (RIT) for previously treated patients, and 4.6 years from radioimmunotherapy for previously untreated patients. tMDS/tAML was reported in 35 (3.5%) of 995 patients (annualized incidence, 1.6%/y [95% confidence interval, 1.0%-2.0%/y]), and 52% of the tMDS/tAML diagnoses of tMDS/tAML were confirmed in a blinded review (annualized incidence of 1.1%/y [95% confidence interval, 0.7%-1.6%/y]). 

Of the 25 cases, 10 patients (40%) were diagnosed with tMDS/tAML prior to receiving radioimmunotherapy; 2 (8%) had no pathologic or clinical evidence to support such a diagnosis; and 13 (52%) were confirmed to have developed tMDS/tAML following RIT. This incidence is consistent with that expected on the basis of patients' prior chemotherapy for NHL. 

With a median follow-up approaching 5 years, no case of tMDS/tAML has been reported in any of the 76 patients receiving iodine I131 tositumomab as their initial therapy (P = .011 compared with previously treated patients).


Questions for Experts

Clearance: Does the faster (Bexxar) or slower (Zevalin) clearance of these agents - and other properties of the radioisotopes - tell us anything about relative risks and potential efficacy of these two agents? 

Comparing Sequential chemo-RIT with autologous SCT?  We believe a study comparing the following protocols would answer an important clinical question, and would also be of interest to patients with high risk lymphoma referred to a transplantation center:  Sequential HD chemo (with harvesting), sequenced with RIT versus Autologous SCT  

HAMA (human anti-mouse antibodies): What is the clinical significance of developing HAMA?

"Development of HAMA can occur after exposure to tositumomab, especially in patients who have not received prior chemotherapy for their disease. In this group who receive "front-line" tositumomab, HAMA antibodies have been demonstrated in as many as 64%. In a study by Mark S. Kaminski, from the University of Michigan, Ann Arbor, Michigan, and colleagues,[5] 22 patients with HAMA responses to tositumomab were studied, and 6 were found to have high titer (> 500 mg/mL) antibody. Thirteen of these patients subsequently received rituximab. Although response rates were not reported, it is important to note that there was no evidence of increased severity or frequency of infusion reactions. Therefore, it seems that rituximab can be given safely after development of HAMA responses to tositumomab."  http://www.medscape.com

Wavelength & bulk: Do the different wavelengths (longer for Zevalin, shorter for Bexxar) and other properties of the radioisotopes make one or the other a better choice when the patient has small or large tumors? 

Wavelength/Clearance & bone marrow: Does half life (longer for Zevalin, shorter for Bexxar) and other properties of the radioisotopes favor one agent over another when the patient has minimal or significant bone marrow involvement.?

Migration tenancy: Does the migration tendencies (*Zevalin to the marrow and liver/ Bexxar to the thyroid as a few examples) favor one agent over the other in specific circumstances? 

Data on Treating Refractory Disease: Is there data to tell us that one agent is a more effective than the other for patients refractory to prior rituxan and chemotherapy? Which agent has the most data on this? 

High Dose: When is high dose (HD) radioimmunotherapy indicated? Can HD radiotherapy be used outside a clinical trial in cases where it is indicated?  Lay comment: One indication seems to be in preparation for stem cell transplants, especially when conditioning chemotherapy fails to achieve a remission.

Extranodal: Does extranodal, mucosal, or CNS involvement preclude the use of radioimmunotherapy? 


Notes:

[A] Dosing: Bexxar, being both a gamma and beta emitter, allows doctors to monitor the amount of radiation that actually makes it to the targeted sites. This property allows for accurate dosing in a process called dosimetry.

"The purpose of the dosimetric step is to provide a consistent radiation dose by adjusting for the individual patient's rate of clearance of the drug. Clinical studies found that patients with high tumor burden, splenomegaly, or bone marrow involvement have a faster clearance, shorter terminal half-life, and larger volume of distribution. Patient-specific dosing, based on total body clearance, has been found to provide a consistent radiation dose, despite variable pharmacokinetics, by allowing each patient's administered activity to be adjusted for individual patient variables." - Aetna

For detailed information on absorbed dose of Zevalin see - fda.gov - backgrounder.pdf 

[B] Bexxar, being both a gamma and beta emitter, allows doctors to monitor the amount of radiation that actually makes it to the targeted sites. This property allows for very accurate dosing in a process called dosimetry.

Because of the gamma radiation that exits the person's body, patients who receive Bexxar need to take radiation safety precautions to prevent exposure to other people for up to ~8 days after receiving treatment.

[C] Patients receiving Bexxar may have to take SSKI or Lugol solution (iodine) before and after the administration of the hot dose to block the thyroid and prevent damage to it. 

"dehalogenation of the isotope from the antibody can occur and result in thyroid damage by the radioactive iodine."  www.pharmaweek.com

[D] Because of the gamma radiation that exits the person's body, patients who receive Bexxar need to take radiation safety precautions to prevent exposure to other people for up to ~8 days after receiving treatment.

[E] A mouse (murine) anti-CD20+ antibody is used as the carrier of the yttrium-90 radioisotope (Zevllin) because it's eliminated from the body faster than Rituxan. Rituxan is used as pretreatment, however. Presumably to clear peripheral blood of normal b-cells to reduce radiation exposure to normal circulating b-cells.


Clinical Trials

bullet Bexxar clinicaltrials.gov
bullet Zevalin clinicaltrials.gov


Accuracy: We have not yet confirmed the accuracy of all the details in this table.

Main Sources: Lymphoma.org, IDEC, and NCI websites

 
Disclaimer:  The information on Lymphomation.org is not intended to be a substitute for 
professional medical advice or to replace your relationship with a physician.
For all medical concerns,  you should always consult your doctor. 
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