Bexxar – ¹³¹I-tositumomab

1. Non-Hodgkin’s lymphoma (NHL) is a B-lymphocyte cancer
1. The most commonly occurring hematological cancer in the US that ranks sixth in leading cancer death
2. Approximately 98,982 people died of NHL between 1990 to 1994. In 2004, the estimate is around 21,000
3. For more information on cancer mortality rates in US go to the following link: http://cancercontrolplanet.cancer.gov/atlas/timeall.jsp?ac=1
4. Histological there are three grades of NHL (low, medium, and high). This ranking is related to: the progression of the disease, relapse after chemotherapy, and the patient's life expectancy
2. Application of therapeutic antibodies (monoclonal)
   1. Known as immunotherapy where a specific monoclonal antibody is developed to treat disease. Why does Bexxar work?
      1. It recognizes a specific protein found on a tumor cell
      2. Without a radioactive tracer it, the moab can binds to the tumor cell causing apoptosis(cell death)
      3. The moab specifically targets the CD20 antigen that is located on the surface of malignant and normal lymphocytes
   2. Radioimmunotherapy application and use of beta radiation
      1. Allows for specific targeting of tumor cells yet significantly reduces the radiation burden to the patient
      2. ¹³¹I -beta particles travel approximately 0.8 mm, which is about 70 to 80 times the diameter of a lymphocyte. Therefore, after the radio-moab attaches to the tumor surface beta-particles destroy the tumor. This is sometimes referred to as "crossfire effect"
      3. Because of specific targeting of the tumor cells health tissue receives a lot less radiation, which overall reduces the radiation burden to the patient





4. The above charge shows the development of B-lymphocytes and several points are pertinent to our understanding of why this therapy works so well
   1. The moab is stable, tumor-specific, and attaches to the surface of the Antigen (these are all ideal properties)
   2. Note the development of the B cell and when the CD20 expression occurs on the surface of the B-lymphocyte
   3. The undifferentiated stem cell does not have the CD20 expression, hence the radiation burden to those cells that procedure lymphocytes are not "effected"
   4. The B-cell type lymphoma has the CD20 expression that allows for radioimmunotherapy
5. The therapeutic dose




1. Maximum total body dose is between 65 - 75 cGy
2. At issue is that the biological T_1/2 varies between patients
3. Hence, it is important to determine how quickly a patient eliminate the radio-moab
4. The faster the body eliminate the moab the higher the dose must be
5. Consider the variation of ¹³¹I given to patients that has hyperthyroidism (size of the gland and uptake is taken into account). With Bexxar the same principle applied
6. How is the therapeutic dose determined?
   1. 5mCi of ¹³¹I-tositumomab is given to the patient
   2. ¹³¹I standard must be kept for the procedure
   3. On the 2^nd, 3^rd, or 4^th day a whole-body scan is acquired and can be collected within a 2-minute time frame (we're not concerned about resolution, just want to look at count distribution)
   4. A second whole body scan is completed on the 6^th or 7^th day
   5. All data must be acquired with a computer
   6. Patient counts, standard counts, and background counts are determined from both whole body scans
   7. Standard is used as QC, to take into account possible variations in the gamma camera's ability to pickup counts over the different times the whole body scan is acquired (consider the use of a standard in thyroid uptake - its the same principle)
   8. Patient background counts are used to determine dose residence time
   9. Key - determine when the activity drops to 37% from the initial administration
3. Why is 450 mg of non-radioactive tositumomab injected prior to the radioactive dose?



1. Notice the difference between the pre-treatment (tositumomab) image and non pre-treated
2. The non-treated image shows that a significant portion of the radiotracer has gone to spleen
3. If the same process was used in the therapeutic dose of tositumomab, too much of the radiotracer would radiate the wrong cells and tissue
4. Two aspects occur with pre-treatment
   1. Reduces a immune cytotoxic response
   2. Cold moab binds to the non tumor B-cells, hence blocking uptake of the radioactive moab
4. Clinical trails
1. Multicenter single-arm study
2. Forty patients were initially studied
1. Overall response 68%
2. Complete response 33% after 26 months
5. Gamma camera specifications
1. Collimator for 364 keV gamma with less than 7% septal penetration
2. Single or dual detectors with whole body imaging capacity
3. Use 20 - 25% window
4. Use minimum whole body matrix if more than one is available
5. Scan speed 10-30 cm/minute, however for predosing see above
6. Patient preparation
   1. Prior to any radioactive dose potassium iodine must be administered
   2. Dosing
      1. OD - One day prior
      2. OD - Continue for fourteen days
7. Patient dosing
1. Dosing is specifically calculated for each patient and is determined by the initial 5mCi dose, see above.   Once the dosimetry is determined the following platelet counts defines the actual dose. 
   1. Platelets/mm 3 is >150k patient’s whole body dosimetry should be 75 cGy
   2. Platelets/mm 3 is between 150k-100k patient patient’s whole body dosimetry should be 65 cGy
   3. Platelets/mm 3 is <100k should not undergo treatment
2. Calculation of this dose will be discussed in clinic
8. Diagram and process of administering Bexxar – diagnostic and therapeutic timeline

1. Patient is initially premedicated with acetaminophen and disphenhydramine
1. Used to prevent a reaction of tositumomab
2. Given 30 minutes prior to the the tositumomab dose
3. Infuse over 20 minutes
2. 450 mg tositumomab is infused over a 60 minute time frame
3. 5 mCi of ¹³¹I-tositumomab is administered over 20-minutes
4. Document residual dose in syringe
5. Optional - 1-hour post dose whole body images should be take ANT and POST
6. Scan speed should be set between 10-30 cm/minute
7. At day 2, 3, or 4 take another whole body image
8. At day 6 or 7 take the last whole body image

8. Therapeutic dose can now be calculated
9. Administration of the therapeutic dose
1. Is the same as above
1. Acetaminophen and disphenhydramine
2. 450 tositumomab
3. ¹³¹I-tositumomab
10. Other comments
1. Eight percent of 873 patients dosed with Bexxar became hypothyroid within 18 months post therapy
2. Adverse reaction including anaphylaxis have been reported (based on 230 patients)
1. Therapeutic administration of Bexxar has resulted in significant cytopenia (71%)
2. Hypothyroidism (8%)
3. Infusion toxicity included fever, chills, seating, hypotension, dyspnea, bronchospasm, and nausea within 48 hours post dose.  
4. A percent of patients (7%) had to have their infusion rate reduced and two patients had to have the procedure discontinued
5. Thirty-eight percent had GI issues:   nausea, vomiting, abdominal pain, and diarrhea
6. Secondary malignancies were reported in 8%
11. Images

Normal distribution is noted in the above images.   At day 0 activity is mainly in the vascular pool.   Day 3 the activity is significantly reduced from the vascular pool with activity noted in the liver and lungs.   At day 6 activity is further reduced with progressively less activity seen in the blood pool, liver, and spleen

Is similar to the pervious image, however, activity is noted in the thyroid and stomach.   These variations are considered normal.

Scan shows expected acceptable biodistribution of moab at various time points and targeting of axillary, paraaortic, bilateral iliac, and femoral lymphadenopathy

2. Radioimmunotherapy of B-Cell Non-Hodgkin’s Lymphoma: From Clinical Trials to Clinical Practice by Malik E. Juweid, MD Journal of Nuclear Medicine Vol. 43 No. 11 1507-1529.

3. Techniques for Using Bexxar for the Treatment of Non-Hodgkin’s Lymphoma. David W. Seldin, MD . Journal of Nuclear Medicine Technology Volume 30, Number 3, 2002 109-114
© 2002 by (This article is very similar to the first reference)

Please read this article - reference number 3.