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Published on 1 November 2004

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Radioimmunoconjugate therapy for B-cell NHL

teaser

Darlene Fink-Bennett
MD
Co-Chief
Department of Nuclear Medicine
William Beaumont Hospital
Royal Oak, MI
USA
E:dfink@beaumont.edu

Radioimmunoconjugate (RIC) therapy is a new option for the treatment of relapsed or refractory cluster designation 20 (CD20) antigen-positive B-cell non-Hodgkin’s lymphoma (NHL). Two FDA-approved RIC therapeutic agents are now available for the treatment of this condition:(90)Y-ibritumomab tiuxetan (Zevalin) and (131)I- tositumomab (Bexxar). (90)Y-ibritumomab tiuxetan and (131)I-tositumomab are RICs, as they are composed of an isotope ((90)Y or (131)I), an immunoglobulin (murine IgG1k anti-CD monoclonal antibody ibritumomab or murine IgG2a anti-B1 monoclonal antibody tositumomab) and a conjugate/chelator (tiuxetan or covalent bond). It is the chelator/covalent bond that links/conjugates the isotope to the monoclonal antibody to create the RIC therapeutic agent.

RIC therapy
(90)Y-ibritumomab tiuxetan (Zevalin) is an FDA-approved RIC therapeutic agent for the treatment of refractory or relapsed low-grade, follicular or transformed CD20-positive B-cell NHL. (131)I-tositumomab (Bexxar) is FDA approved for the treatment of patients with CD20-positive follicular NHL, with or without transformation, whose disease is refractory to rituximab (Rituxin) and has relapsed following chemotherapy. Rituximab is the nonradioactive (cold/naked) anti-CD20 monoclonal antibody used routinely for the early treatment of patients with CD20-positive B-cell NHL.(1–3)

RIC therapeutic agents are effective as cell lysis/death occurs not only from recruitment of immune effector functions postbinding of CD20 antibodies with CD20 antigens located on the surface of B-cell lymphoma cells, but also from the absorbed radiation dose and crossfire created by the 2.3MeV (90)Y or 0.6MeV (131)I beta-emissions, whose path length is approximately 5mm and 0.8mm, respectively. It is this crossfire that enables RIC therapeutic agents to penetrate deep into bulky B-cell NHL tumours.(4–7)

The therapeutic efficacy of Zevalin and Bexxar in patients with refractory or relapsed B-cell NHL has been evaluated in single and multicentre trials. Enrolled patients had extensive disease (high tumour load), including bone marrow and spleen involvement, elevated lactate dehydrogenase (LDH) levels, poor prognostic indicators and bulky disease (tumour masses of up to 10cm in size). All had failed at least 2–4 prior treatment regimens and had a generally poor prognosis. Despite this, the overall response rate (ORR) and complete response rate (CRR) post-RIC therapy ranged from 57–83% and 15–34%, respectively. The mean duration of response (DR) and mean time to progression (TP) ranged from 6.5 to 16 months and 6.8 to 12 months, respectively. Some patients who had a CR are still in remission 3.5 years post-RIC therapy.(8–13) These response rates (RRs) are noteworthy, as they are similar to those achieved with first- and second-line combination chemotherapy. In previously untreated patients with NHL, combination chemotherapy regimens usually result in ORRs of approximately 70–95%.(14–16)

A study was also performed that compared RIC treatment (Zevalin) with cold/naked monoclonal antibody therapy (rituximab). The RIC ORR and CR rates with RIC therapy were 80% and 30%, respectively, and 56% and 16% with monoclonal antibody therapy. Patients enrolled in this study also had a large tumour burden and had failed at least two prior treatment regimens.(8,9) The superior RIC therapeutic responses should not be surprising, as tumour death resulted not just from the binding of the CD20 antibodies to the CD20 antigens on the lymphoma cells, but also from the absorbed tumour dose delivered to them and nearby cells (crossfire) by the (90)Y linked to ibritumomab.(9)

New treatment options are needed for CD20
B-cell NHL as the majority of indolent and follicular forms of it are currently incurable. The median survival of patients with low-grade NHL is only 6.2 years, with intermediate rate as little as 2.5 years. The incidence of this disease is increasing. B-cell NHL lymphoma is the most frequently diagnosed malignancy of the immune system and the sixth most common newly diagnosed cancer in the USA. Approximately 55,000 patients are diagnosed with it each year. Over 200,000 people are currently undergoing treatment for it, the majority of which will eventually fail therapy. Without additional therapeutic options, they will succumb to their disease.(17–20)

Patient selection is critical to the success and safe administration of RIC therapeutic agents. Before a patient receives an RIC therapeutic agent, adequate bone marrow reserve must be established. RIC therapeutic agents cause myelosuppression. Grade 3 and 4 haematological nadirs occur at approximately 6–9 weeks (Zevalin) and 4–7 weeks (Bexxar) post-therapy. They occur as CD20-positive antigens are not only located on approximately 90% of NHL B-cell tumours, but also on normal peripheral lymphocytes and on pre-B-cells within the bone marrow. Thus, when the (90)Y or (131)I anti-CD20 antibody binds with the CD20 antigen located on these cells, lysis/destruction occurs. If CD20 B-cell NHL tumour cells are present within the bone marrow, they too will by lysed/destroyed along with nearby normal or NHL cells from the beta-emission crossfire. Thus, patients who have >25% tumour involvement of their bone marrow are not candidates for RIC therapy. If treated, myeloablation, as opposed to transient myelosuppression, may occur. To avoid this, a bone marrow biopsy should be performed within six weeks of anticipated treatment.(2,3,21)

Other conditions indicative of a lack of adequate bone marrow reserve and contraindications to RIC therapy include a platelet count of <100,000/mm(3), an absolute neutrophil count of <1,500/mm(3), the presence of a hypocellular bone marrow (<-15% cellularity, marked reduction in bone marrow precursors), a history of autologous bone marrow transplant (ABMT) or peripheral blood stem cell transplantation (PBSCT), a history of failed stem cell collection, and a history of prior external beam radiation to >25% of the active marrow. Adequate renal function must also be assured. Patients with a known hypersensitivity to murine proteins should also not undergo RIC therapy.(2,3,21)

To administer an RIC therapeutic agent efficiently and safely, a master plan/process needs to be created to coordinate the multidisciplinary personnel that are a part of it – the haematologist/oncologist, nuclear medicine physician or radiation oncologist, chemotherapy nurse, nuclear pharmacist/technologist and radiation safety officer. The evaluation and management assessment are performed by the nuclear medicine physician or radiation oncologist to assure appropriate patient selection. At that time, a rapport is established with the patient, and he/she is familiarised with the Zevalin or Bexxar therapeutic regimen. A schedule must be set up with haematology/ oncology or the infusion centre for the administration of the RIC therapy. The drug must be ordered and arrangements made for the performance of (111)In Zevalin and (131)I Bexxar biodistribution images and Bexxar dosimetric determinations. A post-therapy radiation safety plan then needs to be established.(21)

The Zevalin regimen
The Zevalin therapeutic regimen consists of the following: on day 1, the patient is given 250mg/m(2) of cold/naked anti-CD20 monoclonal antibody (rituximab). Following this, the patient receives 5mCi of (111)In-Zevalin intravenously (IV) over 10 minutes. Arrangements are then made for the patient to have a total-body (111)In-Zevalin scan at 2–24 hours and at 48–72 hours after its administration. Images can also be obtained at 90–120 hours if deemed indicated. The cold/naked antibody is given before the RIC therapy to bind CD20-positive antigens on normal peripheral lymphocytes, those within the liver and spleen, and on B-cells within the bone marrow, thereby enhancing tumour uptake of the RIC. (111)In-Zevalin images are performed to assure that the CD20 monoclonal antibody is distributed appropriately. Once demonstrated, arrangements are made for treatment. Again, the patient is pretreated with 250mg/m(2) (of cold/naked monoclonal antibody) rituximab to enhance RIC tumour uptake. Once complete, the therapeutic dose of (90)Y-Zevalin is administered IV again over 10 minutes. Following this, the patient can be released.(2)

To minimise the risk of radiation exposure to others, the patient is instructed for the first seven days post-treatment to wash their hands thoroughly after using the toilet, avoid transfer of bodily fluids (saliva, blood, urine or stool), clean up any spilled urine and dispose of any material contaminated with body fluids so that others will not inadvertently handle them. The patient is also asked to use condoms for sexual relationships. No other precautions are required as, once (90)Y-Zevalin is administered, little (approximately 7.3% ± 3% is excreted in the urine in one week) leaves the body. (90)Y is a pure beta-emitter with a short path length (5mm), and thus the energy emitted from it is contained within the body.(21–23)

The therapeutic dose of (90)Y-Zevalin administered to the patient is based on the patient’s platelet count and weight. In patients with pretreatment platelet counts >-150,000/ mm(3), (90)Y-Zevalin is administered at a dose of 0.4mCi/kg. In patients with pretreatment platelet counts of 100,000– 149,000/mm(3), the therapeutic dose of (90)Y Zevalin is reduced to 0.3mCi/kg. The maximum therapeutic dose of Zevalin that can be administered to any patient is 32mCi. If the patient’s platelet count is <100,000/mm(3), he/she is not a candidate for RIC.(2,21,24)

Appropriate anti-CD20 antibody distribution is manifested by (111)In-Zevalin being found within the blood pool (great vessels and heart) and spleen and, to a much lesser degree, in the kidneys, bladder and bowel at 2–24 hours after its administration. Forty-eight to 72 hours post-radiotracer administration, blood pool activity diminishes, activity within the liver and spleen persists and minimal, if any, kidney and bowel activity is demonstrated. Tumour uptake may be seen; a lack of it is not a contraindication to treatment. Altered biodistribution is rare. It is manifested by the lack of blood pool activity 2–24 hours after radiotracer administration, lung or kidney uptake greater than that in the liver or intense bowel uptake.(21)

The Bexxar regimen
The Bexxar therapeutic regimen differs from the Zevalin therapeutic regimen and is as follows: the day before the Bexxar therapeutic regimen begins (day –1) the patient is given a saturated solution of potassium iodide (SSKI; two drops orally three times a day) and is asked to continue ingesting it for 14 days post-therapy. The SSKI is given to prevent thyroid uptake of dehalogenated (free) Bexxar. On day 0 of the Bexxar therapeutic regimen, arrangements are made for the patient to receive 450mg of cold/naked tositumomab (anti-B1 antibody) to bind the CD20 antigens located on normal peripheral lymphocytes, those within the liver and spleen, and on pre-B-cell bone marrow stem cells. Thirty to 60 minutes before this, the patient is premedicated with 650mg of acetaminophen orally and 50mg of diphenhydramine, to reduce the flu-like symptoms produced by the binding of anti-CD20 antibodies (tositumomab) with CD20 antigens. The patient then receives a 20-minute infusion of 5mCi of Bexxar to determine its residence time within the body and assure appropriate biodistribution. To do this, total-body sodium (131)I probe counts and whole-body scans are performed one hour preurination and at two, three or four and six or seven days posturination. Arrangements are then made for a dosimetrist or health physicist to analyse the (131)I total body scans/counts to determine the therapeutic dose of Bexxar that can be administered to the patient. Once calculated, the patient returns (days 7–14) for treatment. Before it, the patient again receives 450mg/kg of anti-B1 antibody to enhance/optimise RIC tumour uptake. Pretreatment with acetaminophen and diphenhydramine is again administered to reduce the flu-like symptoms, which occur from the binding of anti-B1 antibodies to B1 antigens. Following this, the therapeutic Bexxar dose is administered to the patient over 20 minutes.(3) The therapeutic dose administered to the patient is also dependent upon his/her platelet count. If the platelet count is between 100,000 and 149,000/mm(3), the dosimetrist is asked to calculate the maximum amount of (131)I-Bexxar that can be administered to the patient to deliver 65cGy of total body radiation. For patients who have platelet counts Ž150,000/mm(3), the dosimetrist is asked to calculate the maximum amount of (131)I-Bexxar that can be administered to the patient to deliver 75cGy of total body radiation.

The postmanagement plan for a patient undergoing (131)I-Bexxar therapy is more restrictive than that for a patient undergoing (90)Y-Zevalin, as (131)I is not a pure beta-emitter. It also emits gamma rays. Thus, if the patient is able to be dosed and released, he/she is asked to adhere to the following guidelines to minimise exposure to others: for four to seven days, wash their hands frequently, drink plenty of liquids, use separate eating utensils, wash laundry separately, avoid pregnancy, avoid sexual contact, sleep in a separate bed, maintain a distance of six feet from children and pregnant women, do not take long trips (four hours or more), limit times spent in public places, use separate bathrooms and sit while urinating.

Acknowledgement
The author would like to acknowledge the assistance of the following people in the preparation of this manuscript:  Eydie Snowgold, Secretary, Nuclear Medicine Department at William Beaumont Hospital

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