In February 2002, Zevalin was the first radioimmunotherapy to receive FDA approval.   Zevalin is indicated for the treatment of relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkin's lymphoma (NHL). This indication includes patients with Rituxan (rituximab)-refractory follicular NHL.  Zevalin has been approved as part of a therapeutic regimen involving Rituxan.

On June 30, 2003 Corixa and GlaxoSmithKline announced FDA approval of BEXXAR (Tositumomab and Iodine I 131 Tositumomab) for the treatment of patients with CD20 positive, follicular NHL, with and without transformation, whose disease is refractory to Rituximab and has relapsed following chemotherapy.(see site for Zevalin) for Bexxar Corixa site and comparisons.)

Zevalin consists of a monoclonal antibody linked to the radioactive isotope yttrium-90. After infusion into a patient, the monoclonal antibody targets the CD20 antigen, which is found on the surface of mature B cells and B-cell tumors. In this manner, cytotoxic radiation is delivered directly to malignant cells.x

Zevalin received both a full approval and an accelerated approval based on results from two major US efficacy studies.

The study that supported the full approval of Zevalin included 54 subjects. The subjects were diagnosed with relapsed follicular lymphoma, and they no longer adequately responded to Rituxan treatment. An overall response rate of 74% was achieved with Zevalin treatment, with 15% of subjects experiencing a complete response.

Accelerated approval of Zevalin was supported by a randomized, controlled phase III trial. The trial included 143 subjects with relapsed or refractory, low grade or follicular NHL or transformed B-cell NHL. An overall response rate of 80% was obtained in subjects receiving the Zevalin therapeutic regimen (73 subjects), compared to 56% for the subjects receiving Rituxan alone (70 subjects). Thirty percent of Zevalin-treated subjects experienced a complete response, compared to a 16% complete response rate for Rituxan-treated subjects.       Some studies are noted below

131I-Tositumomab Therapy as Initial Treatment for Follicular Lymphoma
Mark S. Kaminski, M.D.,    NEJM 2005;352_441

Background Advanced-stage follicular B-cell lymphoma is considered incurable. Anti-CD20 radioimmunotherapy is effective in patients who have had a relapse after chemotherapy or who have refractory follicular lymphoma, but it has not been tested in previously untreated patients.

Methods Seventy-six patients with stage III or IV follicular lymphoma received as initial therapy a single course of treatment with 131I-tositumomab therapy (registered as Tositumomab and Iodine I 131 Tositumomab [the Bexxar therapeutic regimen]). This consisted of a dosimetric dose of tositumomab and 131I-labeled tositumomab followed one week later by a therapeutic dose, delivering 75 cGy of radiation to the total body.

Results Ninety-five percent of the patients had any response, and 75 percent had a complete response. The use of polymerase chain reaction (PCR) to detect rearrangement of the BCL2 gene showed molecular responses in 80 percent of assessable patients who had a clinical complete response. After a median follow-up of 5.1 years, the actuarial 5-year progression-free survival for all patients was 59 percent, with a median progression-free survival of 6.1 years. The annualized rate of relapse progressively decreased over time: 25 percent, 13 percent, and 12 percent during the first, second, and third years, respectively, and 4.4 percent per year after three years. Of 57 patients who had a complete response, 40 remained in remission for 4.3 to 7.7 years. Hematologic toxicity was moderate, with no patient requiring transfusions or hematopoietic growth factors. No cases of myelodysplastic syndrome have been observed.

Conclusions A single one-week course of 131I-tositumomab therapy as initial treatment can induce prolonged clinical and molecular remissions in patients with advanced follicular lymphoma.

Monoclonal antibody therapy for lymphoma.

Dillman RO.  Cancer Pract 2001 Mar-Apr;9(2):71-80

Robert O. Dillman, MD, FACP, Medical Director, Hoag Cancer Center, Director, Laboratory and Clinical Research, Hoag Cancer Center, Newport Beach, California.

The history of clinical applications of monoclonal antibodies has been intertwined with that of lymphomas. The first report of a complete remission in 1981 described a patient with follicular lymphoma who was treated with a murine anti-idiotype antibody. Later that decade there appeared additional encouraging reports of radiolabeled monoclonal antibodies, immunotoxins, and other antibodies with antitumor effects against lymphoma and chronic lymphocytic leukemia. Monoclonal antibodies as a treatment of malignancy became reality in late 1997 when the US Food and Drug Administration approved the anti-CD20 chimeric monoclonal antibody rituximab for the treatment of B-cell lymphoma. Since that time an anti-CD25 monoclonal antibody (dacliximab) and an anti-CD25 immunotoxin fusion product (denileukin diftitox) have become clinically available. Several radio- labeled antibodies, including the murine anti-CD20 products 131I-tositumomab and 90Y-ibritumomab tiuxetan, are in advanced stages of clinical testing as are other unlabeled monoclonal antibodies with antilymphoma activity. Other antilymphoma immunotoxins that react with CD25, CD19, and CD22 also have shown promise.

Antibody therapy of lymphoma.

Illidge TM, Bayne MC.   Expert Opin Pharmacother 2001 Jun;2(6):953-61

Wessex Cancer Centre, Southampton, UK.

The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (90Y)-ibritumomab and Iodine-131(131I)-tositumomab) have captured much attention in the treatment of lymphoma. The chimeric monoclonal anti-CD20 antibody, rituximab has truly heralded a new era for the treatment of lymphoma and human malignancies. The full potential of antibody-based therapy to improve the outcome in patients with B-cell non-Hodgkin's lymphoma has yet to be defined, but recent data suggests that the combination of chemotherapy plus rituximab may significantly improve outcome for patients with aggressive lymphoma over chemotherapy alone. Highly promising data are also emerging for the use of rituximab in combination with chemotherapy in other types of lymphoma. New advances in antibody therapy, driven by new technologies and defining novel antigen targets, offer the promise of more effective tumour specific therapies. Combinations of antibodies, either conjugated with radioisotopes or unlabelled, used with chemotherapy are likely to provide definitive advances in the treatment of lymphoma in the immediate future.

Radioimmunotherapy for patients with relapsed B-cell non-Hodgkin lymphoma.

Witzig TE.  Cancer Chemother Pharmacol 2001 Aug;48 Suppl 1:S91-5

Division of Internal Medicine and Hematology, Mayo Clinic, Rochester 55905, USA. witzig@mayo.edu

Clinical trials of an yttrium-90 (90Y)-conjugated monoclonal antibody to CD20 in patients with relapsed B cell non-Hodgkin lymphoma (NHL) are reviewed. Ibritumomab is the murine parent anti-CD20 antibody engineered to make the human chimeric antibody rituximab. Tiuxetan is an MX-DTPA linker chelator attached to ibritumomab to form ibritumomab tiuxetan (Zevalin). Ibritumomab tiuxetan can react with indium-111 (111In) or 90Y to form 111In-ibritumomab tiuxetan, which is used for dosimetry, or 90Y-ibritumomab tiuxetan, which is used for therapy of B cell NHL. In this report, the results of five separate clinical trials of ibritumomab tiuxetan are reviewed. Two phase I trials of 90Y-ibritumomab tiuxetan were performed, one using cold ibritumomab prior to 90Y-ibritumomab tiuxetan, and one using rituximab prior to 90Y-ibritumomab tiuxetan. The optimal schedule was found to be rituximab on days I and 8, and 90Y-ibritumomab tiuxetan 0.4 mCi/kg i.v. on day 8; no stem cells or prophylactic growth factors were used. A dose of 0.3 mCi/kg was recommended for patients with a baseline platelet count of 100,000-149,000x10(6)/l. The only significant toxicity was reversible myelosuppression. With this schedule, the overall response rate (ORR) was 67% of all patients and 82% of those with low-grade NHL. The phase I/II trials were followed by a phase III trial that randomized 143 eligible patients to either rituximab or 90Y-ibritumomab tiuxetan radioimmunoconjugate to demonstrate that the combination of the 90Y radioisotope to the murine anti-CD20 antibody provided additional efficacy over the unconjugated ("cold") rituximab alone. A planned interim analysis of the first 90 patients demonstrated an ORR of 80% with 90Y-ibritumomab tiuxetan vs 44% for rituximab (P < 0.05). To provide additional evidence of the benefit of 90Y radioimmunotherapy over rituximab immunotherapy, patients who were nonresponsive or refractory to rituximab were enrolled in an additional trial and treated with 90Y-ibritumomab tiuxetan 0.4 mCi/kg. An ORR of 46% was achieved in these rituximab-refractory patients. These results provide further evidence of the added value of 90Y. Therefore 90Y-ibritumomab tiuxetan radioimmunotherapy is a useful new treatment modality for patients with B cell NHL. Future trials are needed to define the optimal time in the disease course when this modality should be used.

Outpatient radioimmunotherapy with Bexxar. Closed, clean air reservoir minimizes personnel radiation exposure.

Harwood SJ, Gibbons LK, Goldner PJ, Webster WB, Carroll RG.   Cancer 2002 Feb 15;94(4 Suppl):1358-62

Department of Nuclear Medicine, Veterans Affairs Medical Center (VAMC) Bay Pines, Bay Pines, Florida 33744, USA. Steven_J@Bay-Pines.va.gov

BACKGROUND: Radioimmunotherapy (RIT) with Bexxar (tositumomab and iodine-131 tositumomab; Coulter Pharmaceutical, South San Francisco, CA) has been shown to be effective in the treatment of low-grade and transformed low-grade non-Hodgkin lymphoma (NHL). METHODS: Patient-specific dosimetry with 5 mCi of iodine-131 tositumomab preceded by 450 mg of tositumomab was utilized to calculate the radionuclide dose needed to deliver 75 cGy whole-body radiation (65 cGy for platelet counts of 100,000-149,000/mm(3)). To safely infuse the approximately 95 mCi (range, 52-211mCi) of iodine-131 needed for this treatment, a shielded, closed system was developed to minimize radiation exposure for personnel administering the treatment infusions and to eliminate possible release of aerosolized iodine-131. RESULTS: Twenty-five patients who could be evaluated were infused with a single course of iodine-131 tositumomab therapy and achieved a 76% total response rate at 3 months (32% complete response [CR], 44% partial response [PR]); 59% total response at 6 months (40% CR, 18% PR); and 38% total response at 12 months (31% CR, 6% PR). Administration of RIT using our unique, totally closed system significantly reduced personnel exposure and potential for radioactive spills. The sum of all individuals who administered and monitored the infusions was < 120 mRem whole body exposure over 22 months, well within the ALARA (as low as reasonably achievable) Level I guideline limits. No radioiodide was detectable in the thyroid of any staff member. CONCLUSIONS: In NHL patients who had experienced failure with conventional therapy, RIT with iodine-131 tositumomab therapy was safe and effective. Response rates obtained were equivalent to those obtained at the university medical centers where the Phase I-III clinical trials were performed.

Zevalin: 90yttrium labeled anti-CD20 (ibritumomab tiuxetan), a new treatment for non-Hodgkin's lymphoma.

Krasner C, Joyce RM.  Curr Pharm Biotechnol 2001 Dec;2(4):341-9

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA 02115, USA.

Zevalin (ibritumomab tiuxetan, IDEC-Y2B8) is a murine IgG1 kappa monoclonal antibody conjugated to tiuxetan (MXDTPA) that chelates Yttrium or Indium and is directed against the CD 20 molecules of B lymphocytes. Phase I studies have determined the optimal dose of pretreatment rituximab to be 250 mg/m2 seven days prior and immediately prior to the administration of Zevalin. Phase I/II data have determined the dose of 0.4 mCi/kg to be the maximum tolerated dose (MTD) for patients with platelet counts > 150,000 and < 25% bone marrow involvement with NHL. The dose of 0.3 mCi/kg is the MTD in patients with platelet counts between 100,000-149,000. Toxicity is primarily hematologic, transient, and reversible. Dosimetry has been completed using 111In-2B8. Results to date demonstrate that, at the above doses, no patients exceeded the protocol-prescribed organ maximum dose of 2,000 cGy or red marrow maximum dose of 300 cGy. Therefore, future use will not require pretreatment dosimetry. Zevalin contains a pure beta-emitting isotope; no protective patient or staff isolation procedures are required. A randomized Phase III trial has been completed, comparing Zevalin with a standard dose of rituximab (375 mg/m2 q week for four weeks) in patients with relapsed indolent or follicular transformed NHL. The overall response rate (ORR) was 80% in the Zevalin arm compared to 56% (p = 0.002) in the rituximab arm. The CR was 30% vs. 16% (p=0.04). A nonrandomized trial in patients refractory to rituximab demonstrated an ORR of 74% and a CR rate of 15%. A Phase II study of a reduced dose of Zevalin in patients with mild thrombocytopenia demonstrated an ORR of 67% and a 33% CR rate. Zevalin is safe and effective in patients with relapsed or refractory NHL, even in patients refractory to prior rituximab therapy.

A practical methodology for patient release after tositumomab and (131)i-tositumomab therapy.

Siegel JA, Kroll S, Regan D, Kaminski MS, Wahl RL. J Nucl Med 2002 Mar;43(3):354-63

Nuclear Physics Enterprises, Cherry Hill, New Jersey. Corixa Corporation, South San Francisco, California. University of Michigan Medical Center, Ann Arbor, Michigan. Johns Hopkins Medical Institutes, Baltimore, Maryland.

A methodology was developed determining patient releasability after radioimmunotherapy with tositumomab and (131)I-tositumomab for the treatment of non-Hodgkin's lymphoma. METHODS: Dosimetry data were obtained and analyzed after 157 administrations of (131)I-tositumomab to 139 patients with relapsed or refractory non-Hodgkin's lymphoma. Tositumomab and (131)I-tositumomab therapy included dosimetric (low activity) and therapeutic (high activity) administrations. For each patient, the total-body residence time was calculated after the dosimetric administration from total-body counts obtained over 6 or 7 d and was then used to determine the appropriate therapeutic activity to deliver a specific total-body radiation dose. Patient dose rates at 1 m were measured immediately after the therapeutic infusion. Patient-specific calculations based on the measured total-body residence time and dose rate for (131)I-tositumomab were derived to determine the patient's maximum releasable dose rate at 1 m, estimated radiation dose to maximally exposed individuals, and the amount of time necessary to avoid close contact with others. RESULTS: The mean administered activity (plus minusSD), determined by dosimetry studies for each patient before therapy, was 3,108 plus minus 1,073 MBq (84 plus minus 29 mCi) (range, 1,221 plus minus 5,957 MBq [33--161 mCi]). Immediately after treatment, the mean measured dose rate (plus minusSD) at 1 m was 0.109 plus minus 0.032 mSv/h (10.9 plus minus 3.2 mrem/h; range, 0.04--0.24 mSv/h [4--24 mrem/h]). The measured dose rates were 60% (range, 37%--90%; P < 0.0001) of the theoretic dose rates from a point source in air predicted using the dose equivalent rate per unit activity of (131)I (5.95 x 10(-5) mSv/MBq h [0.22 mrem/mCi h] at 1 m). The mean estimated radiation dose to the maximally exposed individual was 3.06 mSv (306 mrem) (range, 1.95--4.96 mSv [195--496 mrem]). On the basis of current regulatory patient-release criteria, all (131)I-tositumomab--treated patients were determined to be releasable by comparing the dose rate at 1 m with a predetermined maximum releasable dose rate. Detailed instructions were provided to limit family members' exposure. CONCLUSION: A methodology has been developed for the release of patients administered radioactive materials based on the new Nuclear Regulatory Commission regulations. This approach uses a patient-specific dose calculation based on the measured total-body residence time and dose rate. This analysis shows the feasibility of outpatient radioimmunotherapy with tositumomab and (131)I-tositumomab.

Administration guidelines for radioimmunotherapy of non-Hodgkin's lymphoma with (90)Y-labeled anti-CD20 monoclonal antibody.

Wagner HN Jr, Wiseman GA, J Nucl Med 2002 Feb;43(2):267-72

School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, USA. hwagner@jhsph.edu

90Y-ibritumomab tiuxetan is a novel radioimmunotherapeutic agent recently approved for the treatment of relapsed or refractory low-grade, follicular, or CD20+ transformed non-Hodgkin's lymphoma (NHL). (90)Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates (111)In for imaging and (90)Y for therapy. Both health care workers and patients receiving this therapy need to become familiar with how it differs from conventional chemotherapy and what, if any, safety precautions are necessary. Because (90)Y is a pure beta-emitter, the requisite safety precautions are not overly burdensome for health care workers or for patients and their families. (90)Y-ibritumomab tiuxetan is dosed on the basis of the patient's body weight and baseline platelet count; dosimetry is not required for determining the therapeutic dose in patients meeting eligibility criteria similar to those used in clinical trials, such as <25% lymphomatous involvement of the bone marrow. (111)In- and (90)Y-ibritumomab tiuxetan are labeled at commercial radiopharmacies and delivered for on-site dose preparation and administration. Plastic and acrylic materials are appropriate for shielding during dose preparation and administration; primary lead shielding should be avoided because of the potential exposure risk from bremsstrahlung. Because there are no penetrating gamma-emissions associated with the therapy, (90)Y-ibritumomab tiuxetan is routinely administered on an outpatient basis. Furthermore, the risk of radiation exposure to patients' family members has been shown to be in the range of background radiation, even without restrictions on contact. There is therefore no need to determine activity limits or dose rate limits before patients who have been treated with (90)Y radioimmunotherapy are released, as is necessary with patients who have been treated with radiopharmaceuticals that contain (131)I. Standard universal precautions for handling body fluids are recommended for health care workers and patients and their family members after (90)Y-ibritumomab tiuxetan administration. In summary, (90)Y-ibritumomab tiuxetan introduces (90)Y into clinical practice and expands the role nuclear medicine plays in the care of patients with cancer. Understanding the unique properties of this novel radioimmunoconjugate will facilitate its safe and effective use.