Therapeutic Challenges

Some challenges have been encountered with radioim-munoconjugates as well. Tumor bulk, location, and burden vary greatly among patients and can significantly affect the distribution of the drug. Complex and meticulous dosimetry studies using trace-labeled radioimmunoconjugates must be conducted with each patient prior to initiating therapy. This determines where the highest concentration of radiation will be delivered; ideally, tumor sites receive the largest dose, while healthy organ and tissue sites are exposed to smaller doses.5 If dosimetry studies show unfavorable distribution of radiation, patients do not receive adequate therapy. Other issues hindering the success of these compounds include large tumor burden, which prevents access of the radionuclide to the site; shedding of the antigen and circulating tumor cells, both of which deplete drug from the circulation; and nonspecific binding of the compound by normal host tissues, subsequently enhancing the toxicity.5 Some adverse effects encountered with these agents are similar to those experienced with other MoAbs, such as fever, chills, rash, nausea, and other infusion reactions as well as potential development of HAMA. Of particular concern is the myelosuppression, especially thrombo-cytopenia, seen with these compounds.45 46 While considerable patient variability exists, peripheral blood counts typically nadir at 3-4 weeks and stay low for up to 16 weeks after treatment. Bone marrow involvement, prior radiation, and chemotherapy exposure can enhance this effect.43

APPROVED COMPOUNDS 90Y-Ibritumomab tiuxetan (Zevalin)

90Y-Ibritumomab tiuxetan is a radioimmunoconjugate comprising a murine-derived MoAb, targeting cell surface protein CD20, bound to the radionuclide 90Y. The cell surface protein CD20 is expressed on >95% normal B lymphocytes and B-cell lymphomas, yet not stem cells. Additionally, CD20 is not internalized upon antibody binding; thus, the antibody-CD20 complex remains on the surface of the cell, available to bind and stimulate antibody-dependent and complement-mediated cytotoxicity.47 The bridge between the Fc portion of the MoAb and the 90Y isotopes is achieved through the linking compound tiuxetan. Isotopes are electrostatically chelated to tiuxetan, which is then attached to exposed amino acids in the antibody by very stable thiourea covalent bonds. Upon selective binding of the compound to CD20 receptors, 90Y emits p-radiation that is discharged over 1-5 mm, damaging the DNA of B lymphocytes and immediately surrounding cells.43 In addition, it is thought that some contributory activity of the drug is derived from CMC and effector cell mechanisms induced by the MoAb component. Because the half-life of this compound is relatively short (64 h) and 90Y does not emit y-rays, ibritu-momab tiuxetan is considered the safer of the approved radioimmunoconjugates.2843

Administration and pharmacokinetics Treatment with ibritumomab tiuxetan can be divided into two phases 1-week apart: a "cold" phase and a "hot" phase. The cold phase consists of delivery of an imaging agent, 111In, which lacks therapeutic p-emissions but does emit y-radiation for imaging. This serves to map the distribution and uptake of the drug. In addition, ritux-imab is administered with the goal of clearing circulating CD20+ B lymphocytes from the circulation. This dose of rituximab is repeated in 1-2 weeks, again clearing the bloodstream of circulating CD20+ lymphocytes in order to better facilitate uptake of radiolabeled drug into the tumor mass.43 Administering therapeutic radiolabeled drug without first priming the system with cold anti-CD20 antibody merely results in uptake of drug by circulating B lymphocytes and the reticuloendothelial system.28 By initially binding up circulating B lymphocytes, as well as tumor cells on the periphery of the mass, drug penetration of the tumor is enhanced. Additionally, the unlabeled anti-CD20 antibody also stimulates immune effector cells and leads to more effective tumor kill.43

Adverse effects The major adverse effect associated with ibritumomab tiuxetan is myelosuppression, consisting mainly of neutropenia and thrombocytopenia.45 46 Because of this, several parameters must be met before patients can be treated with this agent. Qualifications for therapy include <25% lymphoma involvement of bone marrow, platelet count >100,000 cells/mm3, and no history of hypocellular marrow or failed stem cell collection.28 The average time to neutrophil nadir is 62 days, while platelets typically nadir around day 53. Cells recover after approximately 22-35 days.43 Additional adverse effects include those seen with other anti-CD20 agents, such as fever, hypotension, chills, skin rash, and rarely nausea and vomiting.45

131I Tositumomab (Bexxar)

131I tositumomab is a radioimmunoconjugate comprising a murine anti-CD20 MoAb covalently linked through tyrosine amino acids in the immunoglobulin protein to iodine-131. Tositumomab does not require a linker due to direct covalent bonding between the MoAb and the radionuclide. 131I is more readily available than 90Y and is relatively inexpensive. However, 131I emits both p- and 7-irradiation, necessitating special radiation precautions for patients receiving this compound. Dehalogenation (cleaving of the radionuclide from the compound) can occur as well; this results in potential uptake of free iodine by the thyroid and stomach. Oral thyroid blockade is recommended beginning 24 h before therapy and continuing for 14 days in order to prevent iodine uptake and subsequent hypothyroidism.47 The rate of dehalogenation varies significantly among patients, resulting in fluctuating rates of urinary clearance. Thus, dosimetry calculations incorporating total-body distribution and tissue uptake must be completed for each patient. Doing this enables maximal tumor targeting while minimizing toxic effects to normal tissues.43 Because 131I emits 7-radiation as well, it can be used as the tracer agent for the cold phase of treatment. Thus, the imaging agent is the same 131I tositumomab, used at a lower dose. Unlabeled tositumomab is also used as the cold antibody to deplete the CD20T B-lymphocyte "sinks," resulting in a higher dose of drug delivered to the tumor.47

Pharmacokinetics The half-life of 131I tositumomab is approximately 8 days, but varies somewhat among individuals because of fluctuating clearance rates of the compound.1 The major dose-limiting toxicity of 131I tositumomab is myelosuppression, similar to that seen with 90Y ibritumomab. Therefore, patients must have <25% lymphoma involvement of bone marrow, platelet count >100,000 cells/mm3, and no history of hypocellular marrow or failed stem-cell collection in order to receive drug.28 Other acute toxicities include infusion-related effects such as nausea, vomiting, skin rash, hypotension, fever, and chills.45 It is thought that these effects are related to the clearance of CD20T cells.

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