International Journal of Hematology

, Volume 76, Issue 5, pp 401–410 | Cite as

Development of Radioimmunotherapy for the Treatment of Non-Hodgkin’s Lymphoma

  • P. Multani
Progress in hematology


The goal of radioimmunotherapy (RIT) is to target radiation to tumor tissue with radiolabeled monoclonal antibodies while limiting toxicity to normal cells. Radionuclide emission properties and the chemical stability of radioimmunoconjugates are important factors that contribute to the effectiveness of RIT.A 1994 review of early clinical trials with RIT in treating non-Hodgkin’s lymphoma (NHL) reported a 40% response rate with nonmyeloablative doses of yttrium 90 (90Y) or iodine 131 (131I) antibodies. Of the radiolabeled antibodies currently in pivotal trials or approved by the US Food and Drug Administration, those targeted to the CD20 antigen have produced the highest response rates. Response rates for ibritu-momab tiuxetan, the recently approved RIT for NHL, ranged from 74% in rituximab-refractory patients to 80% in the pivotal trial. The iodine-labeled anti-B1 antibody has been evaluated in previously treated and previously untreated patients with NHL. In the pivotal trial, previously treated patients achieved a response rate of 65%, whereas previously untreated patients had a 97% response rate. Radiolabeled anti-HLA DR has been evaluated in NHL patients and has demonstrated a 53% response rate. Murine antibody LL2, which recognizes the CD22 antigen, has been radiolabeled with90Y and131I, with response rates ranging from 15% to 33%. The development of radioimmunotherapy has led to meaningful advances in the treatment of B-cell NHL. Int J Hematol. 2002;76:401-410.

Key words

Radioimmunotherapy Non-Hodgkin’s lymphoma Ibritumomab tiuxetan Anti-B1 antibody 


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  1. 1.
    Eary JF, Badger CC, Press O, et al. Treatment of B-cell lymphoma with I-131 labeled murine monoclonal antibodies.J Nucl Med. 1988;29:757–758.Google Scholar
  2. 2.
    Press OW, Farr AG, Borroz KI, Anderson SK, Martin PJ. Endocytosis and degradation of monoclonal antibodies targeting human B-cell malignancies.Cancer Res. 1989;49:4906–4912.PubMedGoogle Scholar
  3. 3.
    Kaminski MS, Zasadny KR, Francis IR, et al. Radioimmunotherapy of B-cell lymphoma with iodine-131 anti-B1 (anti-CD20) antibody.N Engl J Med. 1993;329:459–465.CrossRefPubMedGoogle Scholar
  4. 4.
    Kaminski MS, Zasadny KR, Milik AW, et al. Updated results of a phase I trial of131-I-anti-B1 (anti-CD20) radioimmunotherapy (RIT) for refractory B-cell lymphoma [abstract].Blood. 1993;82: 332a.Google Scholar
  5. 5.
    Wahl RL, Zasadny KR, Milik AW, et al. 131 I anti-B1 radioim-munotherapy of non-Hodgkin’s lymphoma without marrow transplantation: expanded phase I study results.J Nucl Med. 1994;35: 101P.Google Scholar
  6. 6.
    Press O, Eary J, Martin P, et al. A phase II trial of iodine-131-labelled anti-CD20 (B1) antibody therapy with bone marrow transplantation for relapsed non-Hodgkin’s lymphomas [abstract].Blood. 1995;14:388. Abstract 1212.Google Scholar
  7. 7.
    Press OW, Shan D, Howell-Clark J, et al. Comparative metabolism and retention of iodine-125, yttrium-90, and indium-111 radioim-munoconjugates by cancer cells.Cancer Res. 1996;56:2123–2129.PubMedGoogle Scholar
  8. 8.
    Scheinberg DA, Strand M. Kinetic and catabolic considerations of monoclonal antibody targeting in erythroleukemic mice.Cancer Res. 1983;43:265–272.PubMedGoogle Scholar
  9. 9.
    Anderson WT, Strand M. Radiolabeled antibody: iodine versus radiometal chelates.NCI Monogr. 1987;(3):149–151.Google Scholar
  10. 10.
    Ward J. Radiology brings biotechnology into the picture to combat cancer. ADVANCE for Radiologic Science Professionals. 1998; 104-106.Google Scholar
  11. 11.
    Gates VL, Carey JE, Siegel JA, Kaminski MS, Wahl RL. Nonmye-loablative iodine-131 anti-B1 radioimmunotherapy as outpatient therapy.J Nucl Med. 1998;39:1230–1236.PubMedGoogle Scholar
  12. 12.
    Chinn PC, Leonard JE, Rosenberg J,Hanna N, Anderson DR. Preclinical evaluation of 90Y-labeled anti-CD20 monoclonal antibody for treatment of non-Hodgkin’s lymphoma.Int J Oncol. 1999;15: 1017–1025.PubMedGoogle Scholar
  13. 13.
    Prestwich WV, Nunes J, Kwok CS. Beta dose point kernels for radionuclides of potential use in radioimmunotherapy.J Nucl Med. 1989;30:1036–1046.PubMedGoogle Scholar
  14. 14.
    Carrasquillo JA, White JD, Paik CH, et al. Similarities and differences in111In- and90Y-labeled 1B4M-DTPA antiTac monoclonal antibody distribution.J Nucl Med. 1999;40:268–276.PubMedGoogle Scholar
  15. 15.
    Murray JL, Rosenblum MG, Sobol RE, et al. Radioimmunoimaging in malignant melanoma with111In-labeled monoclonal antibody 96.5.Cancer Res. 1985;45:2376–2381.PubMedGoogle Scholar
  16. 16.
    Dillman RO, Beauregard J, Ryan KP, et al. Radioimmunodetection of cancer with the use of indium-111-labeled monoclonal antibodies.NCI Monogr. 1987;(3):33–36.Google Scholar
  17. 17.
    Lamki LM, Babaian R, Murray JL, et al. The effect of increasing “cold” antibody dose on prostatic cancer metastases detection and on body distribution of PAY-276 monoclonal antibody.J Nucl Med. 1986;27:1021.Google Scholar
  18. 18.
    Rosenblum MG, Murray JL, Haynie TP, et al. Pharmacokinetics of111In-labeled anti-p97 monoclonal antibody in patients with metastatic malignant melanoma.Cancer Res. 1985;45:2382–2386.PubMedGoogle Scholar
  19. 19.
    Press OW, Appelbaum FR, Eary JF, Bernstein ID. Radiolabeled antibody therapy of lymphomas.Biol Ther Cancer Updates. 1994;4: 2–13.Google Scholar
  20. 20.
    Maloney DG, Levy R, Miller RA. Monoclonal anti-idiotype therapy of B cell lymphoma.Biol Ther Cancer Updates. 1992;2:1–10.Google Scholar
  21. 21.
    Miller RA, Maloney DG, Warnke R, Levy R. Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody.N Engl J Med. 1982;306:517–522.CrossRefPubMedGoogle Scholar
  22. 22.
    White CA, Halpern SE, Parker BA, et al. Radioimmunotherapy of relapsed B-cell lymphoma with yttrium 90 anti-idiotype monoclonal antibodies.Blood. 1996;87:3640–3649.PubMedGoogle Scholar
  23. 23.
    Maloney DG, Smith B, Appelbaum FR. The anti-tumor effect of monoclonal anti-CD20 antibody (MAb) therapy includes direct anti-proliferative activity and induction of apoptosis in CD20 positive non-Hodgkin’s lymphoma (NHL) cell lines [abstract].Blood. 1996;88(suppl 1):637a. Abstract 2535.Google Scholar
  24. 24.
    Witzig TE, Flinn IW, Gordon LI, et al.Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma.J Clin Oncol. 2002;20: 3262–3269.CrossRefPubMedGoogle Scholar
  25. 25.
    IDEC Pharmaceuticals Corporation. 106-01-01: a phase I/II clinical trial of yttrium-[90]-labeled IDEC-2B8 given every six to eight weeks to patients with B-cell lymphoma. BB-IND 4850 and 4851. San Diego, CA: IDEC Pharmaceuticals Corporation; January 31, 1996.Google Scholar
  26. 26.
    Witzig TE,White CA,Wiseman GA, et al. Phase I/II trial of IDEC- Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20+ B-cell non-Hodgkin’s lymphoma.J Clin Oncol. 1999;17: 3793–3803.CrossRefPubMedGoogle Scholar
  27. 27.
    Witzig TE. The use of ibritumomab tiuxetan radioimmunotherapy for patients with relapsed B-cell non-Hodgkin’s lymphoma.Semin Oncol. 2000;27:74–78.PubMedGoogle Scholar
  28. 28.
    Witzig TE, Gordon LI, Cabanillas F, et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioim- munotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma.J Clin Oncol. 2002;20:2453–2463.CrossRefPubMedGoogle Scholar
  29. 29.
    Wiseman GA, Gordon L, Multani PS, et al. Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin’s lymphoma and mild thrombocytopenia: a phase II multicenter trial.Blood. 2002;99:4336–4342.CrossRefPubMedGoogle Scholar
  30. 30.
    IDEC Pharmaceuticals Corporation. 106-05: a phase II, open-label, multicenter trial to evaluate the safety and efficacy of IDEC-Y2B8 radioimmunotherapy of relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s lymphoma in patients with mild throm-bocytopenia. San Diego, CA: IDEC Pharmaceuticals Corporation; June 20, 2000.Google Scholar
  31. 31.
    IDEC Pharmaceuticals Corporation. 106-06: a phase III, openlabel, nonrandomized controlled, multicenter trial to evaluate the safety and efficacy of IDEC-Y2B8 radioimmunotherapy in patients with B-cell non-Hodgkin’s lymphoma who are refractory to prior rituximab therapy. San Diego, CA: IDEC Pharmaceuticals Corporation; 2000.Google Scholar
  32. 32.
    Kantarjian HM, Keating MJ. Therapy-related leukemia and myelodysplastic syndrome.Semin Oncol. 1987;14:435–443.PubMedGoogle Scholar
  33. 33.
    Pedersen-Bjergaard J, Ersboll J, Mygind Sorensen H, et al. Risk of acute nonlymphocytic leukemia and preleukemia in patients treated with cyclophosphamide for non-Hodgkin’s lymphomas.Ann Intern Med. 1985;103:195–200.CrossRefPubMedGoogle Scholar
  34. 34.
    Stabin MG. MIRDOSE: personal computer software for internal dose assessment in nuclear medicine.J Nucl Med. 1996;37: 538–546.PubMedGoogle Scholar
  35. 35.
    Wiseman GA, Leigh BR, Gordon LI, et al. Zevalin(tm) radioim-munotherapy (RIT) for B-cell non-Hodgkin’s lymphoma (NHL): biodistribution and dosimetry results [abstract].Proc Am Soc Clin Oncol. 2000;19:10a. Abstract 29.Google Scholar
  36. 36.
    Press OW, Eary JF, Appelbaum FR, et al. Phase II trial of131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas.Lancet. 1995;346: 336–340.CrossRefPubMedGoogle Scholar
  37. 37.
    Press OW. Radiolabeled antibody therapy of B-cell lymphomas.Semin Oncol. 1999;26:58–65.PubMedGoogle Scholar
  38. 38.
    Liu SY, Eary JF, Petersdorf HS, et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue.J Clin Oncol. 1998;16: 3270–3278.CrossRefPubMedGoogle Scholar
  39. 39.
    Kaminski MS, Zasadny KR, Francis IR, et al. Iodine-131-anti-B1 radioimmunotherapy for B-cell lymphoma.J Clin Oncol. 1996;14: 1974–1981.CrossRefPubMedGoogle Scholar
  40. 40.
    Wahl RL, Zasadny KR, MacFarlane D, et al. Iodine-131 anti-B1 antibody for B-cell lymphoma: an update on the Michigan phase I experience.J Nucl Med. 1998;39(suppl):21s-27s.PubMedGoogle Scholar
  41. 41.
    Vose JM, Saleh M, Lister A, et al. Iodine-131 anti-B1 antibody for non-Hodgkin’s lymphoma (NHL): overall clinical trial experience [abstract].Proc Am Soc Clin Oncol. 1998;17:10a. Abstract 38.Google Scholar
  42. 42.
    Vose JM, Zelenetz AD, Rohatiner A, et al. Iodine I 131 tositumomab for patients with follicular non-Hodgkin’s lymphoma (NHL): overall clinical trial experience by histology [abstract].Blood. 1999;94(suppl 1):89a. Abstract 387.Google Scholar
  43. 43.
    Kaminski MS, Zelenetz AD, Press O, et al. Multicenter phase III study of iodine-131 tositumomab (anti-BI antibody) for chemothe- raphy-refractory low-grade or transformed low-grade non-Hodg- kin’s lymphoma (NHL) [abstract].Blood. 1998;92:316a.Google Scholar
  44. 44.
    Kaminski MS, Gribbin T, Estes J, et al. I-131 anti-B1 antibody for previously untreated follicular lymphoma (FL); clinical and molecular remissions [abstract].Proc Am Soc Clin Oncol. 1998; 17:2a.Google Scholar
  45. 45.
    Kaminski MS, Estes J, Tuck M, et al. Iodine I 131 tositumomab therapy for previously untreated follicular lymphoma (FL) [abstract].Proc Am Soc Clin Oncol. 2000;19:5a.Google Scholar
  46. 46.
    Zelenetz AD.The future of I-131 anti-B1 antibody therapy—is initial treatment an option? Presented at: VII International Conference on Malignant Lymphoma; June 2-5, 1999; Lugano, Switzerland.Google Scholar
  47. 47.
    Kaminski MS, Zelenetz AD, Press OW, et al. Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas.J Clin Oncol. 2001;19:3918–3928.CrossRefPubMedGoogle Scholar
  48. 48.
    Vose JM. Radioimmunotherapy with autologous stem cell transplantation: overview of clinical experience. Presented at: Emerging Role of Radioimmunotherapy for the Management of Non-Hodg- kin’s Lymphoma, VII International Conference on Malignant Lymphoma; June 2, 1999; Lugano, Switzerland.Google Scholar
  49. 49.
    Bennett JM, Zelenetz AD, Press OW, et al. Incidence of myelodys-plastic syndromes (tMDS) and acute myeloid leukemia (tAML) in patients with low-grade non-Hodgkin’s lymphoma (LG-NHL) treated with BexxarTM [abstract].Blood. 2001;98:335a. Abstract 1416.CrossRefGoogle Scholar
  50. 50.
    DeNardo GL, Lamborn KR, DeNardo SJ, et al. Prognostic factors for radioimmunotherapy in patients with B-lymphocytic malignancies.Cancer Res. 1995;55(suppl):5893s-5898s.PubMedGoogle Scholar
  51. 51.
    DeNardo GL, DeNardo SJ, Goldstein DS, et al. Maximum-tolerated dose, toxicity, and efficacy of (131)I-Lym-1 antibody for fractionated radioimmunotherapy of non-Hodgkin’s lymphoma.J Clin Oncol. 1998;16:3246–3256.CrossRefPubMedGoogle Scholar
  52. 52.
    DeNardo GL, DeNardo SJ, Lamborn KR, et al. Low-dose, fractionated radioimmunotherapy for B-cell malignancies using 131- Lym-1 antibody.Cancer Biother Radiopharm. 1998;13:239–254.CrossRefPubMedGoogle Scholar
  53. 53.
    DeNardo GL, O’Donnell RT, Oldham RK, DeNardo SJ.A revolution in the treatment of non-Hodgkin’s lymphoma.Cancer Biother Radiopharm. 1998;13:213–223.CrossRefPubMedGoogle Scholar
  54. 54.
    Juweid ME, Sharkey RM, Markowitz A, et al. Treatment of non-Hodgkin’s lymphoma with radiolabeled murine, chimeric, or humanized LL2, an anti-CD22 monoclonal antibody.Cancer Res. 1995;55(suppl):5899s-5907s.PubMedGoogle Scholar
  55. 55.
    Lindén O,Tennvall J, Cavallin-Ståhl E, et al. Radioimmunotherapy using131I-labeled anti-CD22 monoclonal antibody (LL2) in patients with previously treated B-cell lymphomas.Clin Cancer Res. 1999;5(suppl):3287s-3291s.PubMedGoogle Scholar
  56. 56.
    Juweid ME, Stadtmauer E, Hajjar G, et al. Pharmacokinetics, dosimetry, and initial therapeutic results with131I- and111In-/90Y-labeled humanized LL2 anti-CD22 monoclonal antibody in patients with relapsed, refractory non-Hodgkin’s lymphoma.Clin Cancer Res. 1999;5:3292s-3303s.PubMedGoogle Scholar
  57. 57.
    Sharkey RM, Behr TM, Mattes MJ, et al. Advantage of residualizing radiolabels for an internalizing antibody against the B-cell lymphoma antigen, CD22.Cancer Immunol Immunother. 1997;44: 179–188.CrossRefPubMedGoogle Scholar

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© The Japanese Society of Hematology 2002

Authors and Affiliations

  1. 1.Medical AffairsIDEC Pharmaceuticals CorporationCaliforniaUSA

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