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://www.cdc.gov/cancer/index.htm (select the type of cancer and then statistics)
4. Histologically 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 there are specific monoclonal antibodies that treat this type of cancer. Why does Bexxar work?
      1. It recognizes a specific protein found on a tumor cell
      2. Without a radioactive tracer this MoAb can binds to a specific tumor cell resulting in apoptosis(cell death)
      3. This MoAb targets the CD20 antigen located on the surface of malignant and normal lymphocytes
   2. Radioimmunotherapy application's use with beta radiation
      1. By targeting just the tumor cells it significantly reduces the radiation burden to the patient
      2. Once the MaAb is attached to the tumor ¹³¹I -beta particles travel approximately 0.8 mm in every direction, (~ 70 to 80 times the diameter of a lymphocyte). This results in a "crossfire effect" to the the surround tumor cells
      3. Because of specific targeting, healthly cells/tissue receive less radiation. End result reduces radiation burden to the patient





4. The above diagram shows the development of B-lymphocytes over time and helps us understand how/why this type of therapy works
   1. Under ideal situations, the MoAb is stable, tumor-specific, and attaches to the surface of the Antigen
   2. The key to attacking tumor cells is its CD20 expression
   3. Under normal developement of lymphocytes the undifferentiated stem cell does not have the CD20 expression, hence the radiation burden to those cells are not "effected." In addition, the final point on B-cell development (plasma cell) no longer has the CD 20 expression. HOwever, the Pre-B to Acitve B cell does have the CD20 expression
   4. Those cells that have the CD20 (normal and tumor) will undergo radioimmunotherapy when this agent is injected
5. The therapeutic dose



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1. Maximum total body dose should be  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 in order to receive the same therapeutic dose
5. Consider the variation of ¹³¹I given to patients that has hyperthyroidism (size of the gland and uptake is taken into account). With Bexxar a similar principle is applied
6. How is the therapeutic dose determined?
   1. Initially, 5mCi of ¹³¹I-tositumomab is given to the patient
   2. ¹³¹I standard is pulled off to the side and used to help calculate the patient's dose
   3. On the 2^nd, 3^rd, or 4^th day a whole-body scan is acquired and is usually collected within a 2-minute a time frame. The concern is not resolution, but count distribution
   4. To higher resolutions scans are completed on day 1 and 6 or 7
   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 that 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 determines the dose given to the patient
   
   10. Above is an example on how this would be done. Note - Standard dose to calculate % efficiency is first applied, the 5 mCi dose is converted to dpm, multiplied by the efficiency and then multiplied by 37%.
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 then spleen
3. If the same process was used in a therapeutic administration of tositumomab, too much of the radiotracer would radiate the wrong cells and tissues
4. Therefore, pre-treatment will
   1. Reduces a immune cytotoxic response via cold moab binds to the non tumor B-cells, hence blocking uptake of the radioactive moab
   2. Questions - So if it blocks the healthily B-cells does it not also block the cancer cells that have the CD 20 expression?
4. Clinical trails
1. Multi center single-arm study
2. Forty patients were initially studied
1. Overall, 68% of the patients responded to the treatment
2. 33% after the patients studied had no disease at 26 months post dose
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 pre dosing 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 images
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 biodistribuiton of moab at various time points and targeting of axillary, para aortic, 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)

Your are required to read reference number 3.