Myeloablative radioimmunotherapy in conditioning prior to haematological stem cell transplantation: closing the gap between benefit and toxicity?

  • Inga Buchmann
  • Ralf G. Meyer
  • Walter Mier
  • Uwe Haberkorn
Review Article

Abstract

High-dose radio-/chemotherapy in the context of autologous and allogeneic haematopoietic stem cell transplantation is a double-edged sword. The requirement for dose intensification is linked to an increase in toxicity to noninvolved organs. Particularly for older patients and patients with comorbidities, efficient but toxicity-reduced schemes are needed. Myeloablative radioimmunotherapy is a targeted, internal radiotherapy that uses radiolabelled monoclonal antibodies (mAb) with affinity to the bone marrow. It involves the administration of high radiation doses (up to 30 Gy) to the bone marrow and spleen but without exposing radiosensitive organs to doses higher than 1–7 Gy. Added to conventional or intensity-reduced conditioning, myeloablative radioimmunotherapy may achieve a pronounced antileukaemic effect with tolerable toxicities. A rational and individual design of the ideal nuclide–antibody combination optimizes therapy. The anti-CD33, anti-CD45 and anti-CD66 mAbs appear to be ideal tracers so far. The β-emitter 90Y is coupled by DTPA and is the best nuclide for myeloablation. Approval trials for DTPA anti-CD66 mAb are underway in Europe, and in the near future these therapies may become applicable in practice. This review gives an overview of current myeloablative conditioning radioimmunotherapy. We discuss the selection of the optimal radioimmunoconjugate and discuss how radioimmunotherapy might be optimized in the future by individualization of therapy protocols. We also highlight the potential advantages of combination therapies.

Keywords

Leukaemia Multiple myeloma Myeloablative conditioning Myeloablative radioimmunotherapy Stem cell transplantation 

References

  1. 1.
    Kröger N. Mini-Midi-Maxi? How to harness the graft-versus myeloma effect and target molecular remission after allogeneic stem cell transplantation. Leukemia 2007;21:1851–58.PubMedCrossRefGoogle Scholar
  2. 2.
    Blaise D, Vey N, Faucher C, Mohty M. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukaemia. Haematologica 2007;92:533–41.PubMedCrossRefGoogle Scholar
  3. 3.
    Mulford DA, Scheinberg DA, Jurcic JG. The promise of targeted [alpha]-particle therapy. J Nucl Med 2005;46(Suppl 1):1995–2045.Google Scholar
  4. 4.
    Jurcic JG. Antibody therapy for residual disease in acute myelogenous leukemia. Crit Rev Oncol Hematol 2001;38:37–45.PubMedCrossRefGoogle Scholar
  5. 5.
    Chaidos A, Kanfer E, Apperley JF. Risk assessment in haemotopoietic stem cell transplantation: disease and disease stage. Best Pract Res Clin Haematol 2007;20:125–54.PubMedCrossRefGoogle Scholar
  6. 6.
    Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008;111:1827–33.PubMedCrossRefGoogle Scholar
  7. 7.
    Wheatley K, Burnett AK, Goldstone AH, et al. A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. United Kingdom Medical Research Council’s Adult and Childhood Leukaemia Working Parties. Br J Haematol 1999;107:69–79.PubMedCrossRefGoogle Scholar
  8. 8.
    Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 2001;98:1752–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Preudhomme C, Sagot C, Boissel N, et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 2002;100:2717–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimen. Blood 1990;76:1867–71.PubMedGoogle Scholar
  11. 11.
    Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292–302.PubMedCrossRefGoogle Scholar
  12. 12.
    Kröger N, Bornhäuser M, Ehninger G, et al. Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol 2003;82:336–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Martino R, Iacobelli S, Brand R, et al.; Myelodysplastic Syndrome subcommittee of the Chronic Leukemia Working Party of the European Blood and Marrow Transplantation Group. Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood 2006;108:836–46.PubMedCrossRefGoogle Scholar
  14. 14.
    Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. N Engl J Med 1996;335:91–7.PubMedCrossRefGoogle Scholar
  15. 15.
    Child JA, Morgan GJ, Davies FE, et al.; Medical Research Council Adult Leukaemia Working Party. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. N Engl J Med 2003;348:1875–83.PubMedCrossRefGoogle Scholar
  16. 16.
    Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US Intergroup Trial S9321. J Clin Oncol 2006;24:929–36.PubMedCrossRefGoogle Scholar
  17. 17.
    Matsui W, Huff CA, Wang O, et al. Characterization of clonogenic multiple myeloma cells. Blood 2004;103:2332–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Santos GW, Tutschka PJ, Brookmeyer R, et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide regimen. N Engl J Med 1983;309:1347–53.PubMedGoogle Scholar
  19. 19.
    Copelan EA. Hematopoietic stem cell transplantation. New Engl J 2006;354:1813–26.CrossRefGoogle Scholar
  20. 20.
    Ferrara JL, Reddy P. Pathophysiology of graft-versus-host disease. Semin Hematol 2006;43:3–10.PubMedCrossRefGoogle Scholar
  21. 21.
    Hill GR, Crawford JM, Cooke KR, et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines. Blood 1997;8:3204–13.Google Scholar
  22. 22.
    Holler E, Kolb HJ, Mittermüller J, et al. Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor α (TNFα) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNFα (MAK 195F). Blood 1995;86:890–9.PubMedGoogle Scholar
  23. 23.
    Levine JE, Uberti JP, Ayash L, et al. Lowered-intensity preparative regimen for allogeneic stem cell transplantation delays acute graft-versus-host disease but does not improve outcome for advanced hematologic malignancy. Biol Blood Marrow Transplant 2003;9:189–97.PubMedCrossRefGoogle Scholar
  24. 24.
    Boiron JM, Lerner D, Pigneux A, et al. Allogeneic transplantation for patients with advanced acute leukemia: a single center retrospective study of 92 patients. Leuk Lymphoma 2001;41:285–96.PubMedCrossRefGoogle Scholar
  25. 25.
    Newland A. Progress in the treatment of acute myeloid leukaemia in adults. Int J Hematol 2002;76(Suppl 1):253–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Witherspoon RP, Deeg HJ, Storer B, et al. Haematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol 2001;19:2134–41.PubMedGoogle Scholar
  27. 27.
    Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukaemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008;26:577–84.PubMedCrossRefGoogle Scholar
  28. 28.
    Matthews DC, Appelbaum FR, Eary JF, et al. Development of a marrow transplantation regimen for acute leukemia using targeted haematopoietic irradiation delivered by I-131-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood 1995;85:1122–31.PubMedGoogle Scholar
  29. 29.
    Buchmann I, Bunjes D, Kotzerke J, et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-Antibody for conditioning of high-risk leukemia patients prior to stem cell transplantation. Cancer Biother Radiopharm 2002;17:151–63.PubMedCrossRefGoogle Scholar
  30. 30.
    Richman CM, Denardo SJ, O'Donnell RT, et al. High-dose radioimmunotherapy combined with fixed, low-dose paclitaxel in metastatic prostate and breast cancer by using a MUC-1 monoclonal antibody, m170, linked to indium-111/yttrium-90 via a cathepsin cleavable linker with cyclosporine to prevent human anti-mouse antibody. Clin Cancer Res 2005;11:5920–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Behr TM, Griesinger F, Riggert J, et al. High-dose myeloablative radioimmunotherapy of mantle cell non-Hodgkin lymphoma with the iodine-131-labeled chimeric anti-CD20 antibody C2B8 and autologous stem cell support. Results of a pilot study. Cancer 2002;94(4 suppl):1363–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Nademanee A, Forman S, Molina A, et al. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 2005;106:2896–902.PubMedCrossRefGoogle Scholar
  33. 33.
    Bunjes D, Buchmann I, Duncker C, et al. Re-188-labeled anti-CD 66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukaemia or myelodysplastic syndrome: results of a phase I-II study. Blood 2001;98:565–72.PubMedCrossRefGoogle Scholar
  34. 34.
    Loevinger R, Berman MA. A revised schema for calculating the absorbed dose from biologically distributed radionuclides. Society of Nuclear Medicine, New York; 1976, MIRD Pamphlet No. 1.Google Scholar
  35. 35.
    Camera L, Kinuya S, Garmestani K, et al. Evaluation of the serum stability and in vivo biodistribution of CHX-DTPA and other ligands for yttrium labeling of monoclonal antibodies. J Nucl Med 1994;35:882–9.PubMedGoogle Scholar
  36. 36.
    Zenz T, Schlenk RF, Glatting G, et al. Bone marrow transplantation nephropathy after an intensified conditioning regimen with radioimmunotherapy and allogeneic stem cell transplantation. J Nucl Med 2006;47:278–86.PubMedGoogle Scholar
  37. 37.
    Frilling A, Weber F, Saner F, et al. Treatment with (90)Y- and (177)Lu-DOTATOC in patients with metastatic neuroendocrine tumors. Surgery 2006;140:968–76.PubMedCrossRefGoogle Scholar
  38. 38.
    Ratei R, Karawajew L, Schabath R, et al. Differential expression of the carcinoembryonic antigen-related cell adhesion molecules panCD66, CD66a, CD66c and of sialyl-Lewis x (CD15s) on blast cells of acute leukemias. Int J Hematol 2008;87:137–43.PubMedCrossRefGoogle Scholar
  39. 39.
    Scheinberg DA, Tanimoto M, McKenzie S, et al. Monoclonal antibody M195: a diagnostic marker for acute myelogenous leukemia. Leukemia 1989;3:440–5.PubMedGoogle Scholar
  40. 40.
    Caron PC, Co MS, Bull MK, et al. Biological and immunological features of humanized M195 (anti-CD33) monoclonal antibodies. Cancer Res 1992;52:6761–7.PubMedGoogle Scholar
  41. 41.
    Caron PC, Jurcic JG, Scott AM, et al. A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity. Blood 1994;83:1760–8.PubMedGoogle Scholar
  42. 42.
    Matthews DC, Appelbaum FR, Eary JF, et al. Phase I study of I-131-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 1999;94:1237–47.PubMedGoogle Scholar
  43. 43.
    Buchmann I, Kull T, Glatting G, et al. A comparison of biodistribution and biokinetics of 99mTc-anti-CD66-mAb BW250/183 and 99mTc-anti-CD45-mAb YTH24.5 with regard to suitability for myeloablative radioimmunotherapy. Eur J Nucl Med Mol Imaging 2003;30:667–73.PubMedGoogle Scholar
  44. 44.
    Glatting G, Müller M, Koop B, et al. Anti-CD45 monoclonal antibody YAML568: a promising radioimmunoconjugate for targeted radioimmunotherapy for acute leukemia. J Nucl Med 2006;47:1335–41.PubMedGoogle Scholar
  45. 45.
    Schwartz MA, Lovett DR, Redner A, et al. Dose-escalation trial of M195 labeled with iodine 131 for cytoreduction and marrow ablation in relapsed or refractory myeloid leukemias. J Clin Oncol 1993;11:294–303.PubMedGoogle Scholar
  46. 46.
    Jurcic JG, DeBlasio T, Dumont L, et al. Molecular remission induction with retinoic acid and anti-CD33 monoclonal antibody HuM195 in acute promyelocytic leukemia. Clin Cancer Res 2000;6:372–80.PubMedGoogle Scholar
  47. 47.
    Bunjes D. Re-188-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia. Leuk Lymphoma 2002;43:2125–31.PubMedCrossRefGoogle Scholar
  48. 48.
    Reske SN, Bunjes D, Buchmann I, et al. Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation. Eur J Nucl Med 2001;28:807–15.PubMedCrossRefGoogle Scholar
  49. 49.
    Ringhoffer M, Blumstein N, Neumaier B, et al. 188Re or 90Y-labeled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol 2005;130:604–13.PubMedCrossRefGoogle Scholar
  50. 50.
    Orchard KH, Cooper M, Lewington V, et al. Targeted radiotherapy in haematopoietic stem cell transplantation: results of a phase I trial using a yttrium-90-labelled anti-CD66 murine monoclonal antibody demonstrating consistent BM targeting. Bone Marrow Transplant 2006;37(Suppl), p. 45, O338.Google Scholar
  51. 51.
    Jurcic JG, Caron PC, Nikula TK, et al. Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. Cancer Res 1995;55(Suppl):5908s–10s.PubMedGoogle Scholar
  52. 52.
    Jurcic JG, Larson SM, Sgouros G, et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002;100:1233–9.PubMedGoogle Scholar
  53. 53.
    Buchmann I, Mutschler J, Steinbach G, et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-mAb before stem cell transplantation does not increase cytokine levels (abstract). J Nucl Med 2002;43(Suppl):314P.Google Scholar
  54. 54.
    Buchmann I, Schultz A, Sparber M, et al. Myeloablative radioimmunotherapy with Re-188-anti-CD66-mAb in paediatric leukaemia patients: a phase I-trial. J Nucl Med 2002;43(Suppl):37P.Google Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Inga Buchmann
    • 1
    • 3
  • Ralf G. Meyer
    • 2
  • Walter Mier
    • 1
  • Uwe Haberkorn
    • 1
    • 3
  1. 1.Department of Nuclear MedicineUniversity of HeidelbergHeidelbergGermany
  2. 2.Department of Medicine 3University of MainzMainzGermany
  3. 3.University of LübeckLübeckGermany

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