Medical Oncology

, Volume 18, Issue 2, pp 99–107 | Cite as

Campath-1H (anti-CD52) monoclonal antibody therapy in lymphoproliferative disorders

A review
  • G. A. Pangalis
  • M. N. Dimopoulou
  • M. K. Angelopoulou
  • Ch. Tsekouras
  • T. P. Vassilakopoulos
  • G. Vaiopoulos
  • M. P. Siakantaris
Review

Abstract

Campath-1H is a humanized monoclonal antibody targeted against the CDw52 membrane antigen of lymphocytes, which causes complement and antibody-dependent cell-mediated cytotoxicity. Campath-1H has been used in B-chronic lymphocytic leukemia (B-CLL), T-prolymphocytic leukemia (T-PLL), and low-grade non-Hodgkin’s lymphoma (LGNHL). Campath-1H is administered intravenously thrice weekly for up to 12 wk, at an initial dose of 3 mg, escalated to 10 and 30 mg. The responses (complete [CR] and partial [PR]) obtained in untreated B-CLL patients are of the order of 90%. In previously treated B-CLL patients, responses are of the order of approximately 40%, with 2–4% CRs. Responses are more prominent in the blood and bone marrow compared to the lymph nodes. The median duration of response is 9–12 mo. Because of the antibody’s higher activity on circulating lymphocytes, it has been used for in vivo purging of residual disease in B-CLL, followed by autologous stem-cell transplantation. In heavily pretreated advanced stage LGNHL, response is achieved only in 14% of cases with B-phenotype; a 50% response rate is noted in mycosis fungoides. In T-PLL, the CR rate is approximately 60%. Promising results have been reported in a small number of patients with refractory autoimmune thrombocytopenia of lymphoproliferative disorders. The main complications of Campath-1H treatment are caused by tumor necrosis factor (TNF)-α and interleukin (IL)-6 release, usually during the first intravenous infusion, and include fever, rigor, nausea, vomiting, and hypotension responsive to steroids. These side effects are usually less severe with subsequent infusions and can be prevented by paracetamol and antihistamines. Immunosupression resulting from normal B- and T-lymphocyte depletion is frequent, resulting in an increased risk for opportunistic infections. More clinical trials in a larger number of patients are necessary to determine the exact role and indications of Campath-1H in lymphoproliferative disorders.

Key Words

Campath-1H monoclonal antibodies LGNHL transplantation 

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References

  1. 1.
    Boussiotis, V.A., Panayiotidis, P.G. and Pangalis, G.A. Prolonged intermittent chlorambucil administration in B-chronic lympghocytic leukemia. Experience from a single hematology Unit. Leuk Lymphoma 5(Suppl.):113–118.Google Scholar
  2. 2.
    Keating, M.J., O’Brien, S., Lerner, S., Koller, C., Beran, M., Robertson, L.E., et al. (1998). Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimen as initial therapy. Blood 92:1165–1171.PubMedGoogle Scholar
  3. 3.
    Montserrat, E. and Rozman, C. (1995). Chronic lymphocytic leukemia: present status. Ann. Oncol. 6:219–235.PubMedGoogle Scholar
  4. 4.
    Pangalis, G.A., Angelopoulou, M.K., Vassilakopoulos, T.P., Siakantaris, M.P., and Kittas, Ch. (1999). Chronic lymphocytic leukemia, small lymphocytic lymphoma and lymphoplasmacytic lymphoma, including Waldenstrom’s macroglobulinemia. A clinical, morphologic and biologic spectrum of similar disorders. Semin. Hematol. 36:104–114.PubMedGoogle Scholar
  5. 5.
    Byrd, J.C., Rai, K.R., Sausville, E.A., Grever, M.R. (1998). Old and new therapies in chronic lymphocytic leukemia: now is the time for a reassessment of therapeutic goals. Semin. Oncol. 25:65–74.PubMedGoogle Scholar
  6. 6.
    Coiffier, B., Thieblemont, C., Felman, P., Salles, G., and Berger, F. (1999). Indolent nonfollicular lymphomas: characteristics, treatment and outcome. Semin. Hematol. 36:198–208.PubMedGoogle Scholar
  7. 7.
    Dyer, M.J.S., Hale, G., Marcus, R., Waldmann, H. (1990). Remission induction in patients with lymphoid malignancies using unconjugated Campath-1H monoclonal antibodies. Leuk. Lymphoma 2:179–193.Google Scholar
  8. 8.
    Rai, K.R. (1999). New biologic therapies. Semin. Hematol. 36(Suppl. 5):12–17.PubMedGoogle Scholar
  9. 9.
    Longo, D.L. (1996). Immunotherapy for non-Hodgkin’s lymphoma. Curr. Opin. Oncol. 8:353–359.PubMedGoogle Scholar
  10. 10.
    Maloney, D.G. (1998). Advances in immunotherapy of hematologic malignancies. Curr. Opin. Haematol. 5:237–243.CrossRefGoogle Scholar
  11. 11.
    Dyer, M.J.S. (1999). The role of Campath-1H antibodies in the treatment of lymphoid malignancies. Semin. Oncol. 26(Suppl. 14):52–57.PubMedGoogle Scholar
  12. 12.
    Hale, G., Xia, M.Q., Tighe, H.P., Dyer, M.J., Waldmann, H. (1990). The Campath-1 antigen (CDw52). Tissue Antigens 35:118–127.PubMedCrossRefGoogle Scholar
  13. 13.
    Xia, M.G., Tone, M., Packman, L., Hale, G., and Waldman, H. (1991). Characterization of the Campath-1H (CDw52) antigen: biochemical analysis and cDNA cloning reveal an unusually small peptide back bone. Eur. J. Immunol. 21:1677–1684.PubMedCrossRefGoogle Scholar
  14. 14.
    Salisbury, J.R., Rapson, N.T., Codd, J.D., Rogers, M.V., Nethersell, A.B.W. (1994). Immunohistochemical analysis of CDw52 antigen expression in non-Hodgkin’s lymphomas. J. Clin. Oncol. 47:313–317.Google Scholar
  15. 15.
    Bindon, C.J., Hale, G. and Waldmann, H. (1988). Importance of antigen specificity for complement-mediated lysis by monoclonal antibodies. Eur. J. Immunol. 18:1507–1514.PubMedCrossRefGoogle Scholar
  16. 16.
    Dyer, M.J.S., Hale, G., Hayhoe, F.G.J., and Waldmann, H. (1989). Effects of Campath-1H antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 73:1431–1439.PubMedGoogle Scholar
  17. 17.
    Ginaldi, L., De Martinis, M., Matutes, E., Farahat, N., Morilla, R., Dyer, M.J.S., et al. (1998). Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. Leuk. Res. 22:185–191.PubMedCrossRefGoogle Scholar
  18. 18.
    Hale, G., Bright, S., Chumbley, G., Hoang, T., Metcalf, D., Munro, A.J., et al. (1983). Removal of T cells from bone marrow for transplantation: a monoclonal antilymphocyte antibody that fixes human complement. Blood 62:873–883.PubMedGoogle Scholar
  19. 19.
    Hale, G., Hoang, T., Prospero, T., Watt, S.M., Waldmann, H. (1983). Removal of T cells from bone marrow for transplantation: comparison of rat monoclonal anti-lymphocyte antibodies of different isotypes. Mol. Biol. Med. 1:305–319.PubMedGoogle Scholar
  20. 20.
    Riechmann, L., Clark, M., Waldmann, H., Winter, G. (1988). Reshaping human antibodies for therapy. Nature 332:323–327.PubMedCrossRefGoogle Scholar
  21. 21.
    Page, M.J. and Sydenham, M.A. (1991). High level expression of the humanized monoclonal antibody Campath-1H in chinese hamster ovary cells. Biotechnology 9:64–68.PubMedCrossRefGoogle Scholar
  22. 22.
    Österborg, A., Dyer, M.J.S., Bunjes, D., Pangalis, G.A., Bastion, Y., Catovsky, D., et al. (1997). Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. J. Clin. Oncol. 15:1567–1574.PubMedGoogle Scholar
  23. 23.
    Rawstron, A.C., Davies, F.E., Morgan, G.J., Haynes, A.P., Russell, N.H., Hale, G., et al. (1998). Monitoring of residual disease after Campath-1H therapy of refractory chronic lymphocytic leukaemia. Blood 92(Suppl. 1):105a (abstract).Google Scholar
  24. 24.
    Dyer, M.J.S., Kelsey, S.M., Mackay, H.J., Emmett, E., Thornton, P., Hale, G., et al. (1997). In vivo “purging” of residual disease in CLL with Campath-1H. Br. J. Hematol. 97:669–672.CrossRefGoogle Scholar
  25. 25.
    Pangalis, G.A., Dimopoulou, M.N., Angelopoulou, M.K., Tsekouras, Ch., and Siakantaris, M.P. (2000). Campath-1H in B-chronic lymphocytic leukemia: report on a patient treated thrice in a 3 year period. Med. Oncol. 17:70–73.PubMedGoogle Scholar
  26. 26.
    Tsekouras, Ch., Angelopoulou, M.K. and Pangalis, G.A. (1994). Treatment of B-chronic lymphocytic leukemia with the monoclonal antibody Campath-1H. Br. J. Haematol. 87(Suppl. 1):237(abstract).Google Scholar
  27. 27.
    Kennedy, B., Rawstron, A.C., Evans, P., English, A., Hoynes, A.P., Russell, N.H., et al. (1999). Campath-1H therapy in 29 patients with refractory CLL: “true” complete remission is an attainable goal. Blood 94(Suppl.1):603a(abstract).Google Scholar
  28. 28.
    Keating, M.J., Byrd, J., Rai, K., Flinn, I., Jain, V., Binet, J.L., et al. (1999). Multicenter study of Campath-1H in patients with chronic lymphocytic leukemia (B-CLL) refractory to fludarabine. Blood 94(Suppl.1):705a(abstract).Google Scholar
  29. 29.
    Mellstedt, H., Österborg, A., Lundin, J., Björkholm, M., Celsing, F., Hogberg, H., et al. (1998). Campath-1H therapy of patients with previously untreated chronic lymphocytic leukemia. Blood 92(Suppl. 1):490a (abstract).Google Scholar
  30. 30.
    Österborg, A., Fessas, A.S., Anagnostopoulos, A., Dyer, M.J., Catovsky, D., Mellstedt, H. (1996). Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukaemia. Br. J. Haematol. 93:151–153.PubMedCrossRefGoogle Scholar
  31. 31.
    Bowen, A.L., Zomas, A., Emmett, E., Matutes, E., Dyer, M.J.S., Catovsky, D. (1997). Subcutaneous Campath-1H in fludarabine-resistant/relapsed chronic lymphocytic and B-prolymphocytic leukaemia. Br. J. Haematol. 96:617–619.PubMedCrossRefGoogle Scholar
  32. 32.
    Pawson, R., Dyer, M.J.S., Barge, R., Matutes, E., Thornton, P.D., Emmett, E., et al. (1997). Treatment of T-cell prolympocytic leukemia with human CD52 antibody. J. Clin. Oncol. 15:2667–2672.PubMedGoogle Scholar
  33. 33.
    Cazin, B., Wettewald, M., Ojeda, M., Matie, B., and Bauters, F. (1999). Campath-1H in the treatment of T-prolymphocytic leukemia (T-PLL). Blood 94(Suppl. 1):125a (abstract).Google Scholar
  34. 34.
    Österborg, A., Lundin, J. and Mellstedt, H. (1998). Campath-1H monoclonal antibody in therapy for advanced low-grade non-Hodgkin’s lymphomas: a phase II study. Blood 92(Suppl. 1):461a (abstract).Google Scholar
  35. 35.
    Lundin, J., Österborg, A., Brittinger, G., Crowther, D., Dombret, H., Engert, A., et al. (1998). Campath-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin’s lymphomas: a phase II multicenter study. J. Clin. Oncol. 16:3257–3263.PubMedGoogle Scholar
  36. 36.
    Kolitz, J.E., O’Mara, V., Willemze, R., Poynton, C.H., Jaeger, U., Brody, J., et al. (1998). Treatment of acute leukemia (ALL) with Campath-1H: initial observations. Blood 92:301a (abstract).Google Scholar
  37. 37.
    Isaacs, J.D., Watts, R.A., Hazleman, B.L., Hale, G., Keogan, M.T., Cobbold, S.P., et al. (1992). Humanized monoclonal antibody treatment for rheumatoid arthritis. Lancet 340:748–752.PubMedCrossRefGoogle Scholar
  38. 38.
    Mathieson, P.W., Cobbold, S.P., Hale, G., Clark, M.R., Oliveira, D.B., Lockwood, C.M., et al. (1990). Monoclonal antibody therapy in systemic vasculitis. N. Engl. J. Med. 323:250–254.PubMedCrossRefGoogle Scholar
  39. 39.
    Isaacs, J.D., Hazleman, B.L., Chakravarty, K., Grant, J.W., Hale, G., Waldmann, H. (1996). Monoclonal antibody therapy of diffuse cutaneous scleroderma with Campath-1H. J. Rheumatol. 23:1103–1106.PubMedGoogle Scholar
  40. 40.
    Lim, S.H., Hale, G., Marcus, R.E., Waldmann, H., and Berlin, T.P. (1993). Campath-1H monoclonal antibody therapy in severe refractory autoimmune thrombocytopenic purpura. Br. J. Haematol. 84:542–544.PubMedGoogle Scholar
  41. 41.
    Lim, S.H. and Ifthikharuddin, J.J. (1994). Autoimmune thrombocytopenic purpura complicating lymphoproliferative disorders. Leuk. Lymphoma 15:61–64.PubMedGoogle Scholar
  42. 42.
    Hale, G., Zhang, M.J., Bunjes, D., Prentice, H.G., Spence, D., Horowitz, M.M., et al. (1998). Imroving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood 92:4581–4590.PubMedGoogle Scholar
  43. 43.
    Boussiotis, V.A., Freedman, A.S. and Nadler, L.M. (1999). Bone marrow transplantation for low grade lymphoma and chronic lymphocytic leukemia. Semin. Hematol. 36:209–216.PubMedGoogle Scholar
  44. 44.
    Hamblin, M., Marsh, J.C., Lawler, M., McCann, S.R., Wickham, N., Dunlop, L., et al. (1996). Campath-1G in vivo confers a low incidence of graft-versus-host disease associated with a high incidence of mixed chimaerism after bone marrow transplantation for severe aplastic anaemia using HLA-identical sibling donors. Bone Marrow Transplant. 17:819–824.PubMedGoogle Scholar
  45. 45.
    Naparstek, E., Or, R., Nagler, A., Cividalli, G., Engelhard, D., Aker, M., et al. (1995) T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1H antibodies and post-transpant administration of donor’s peripheral blood lymphocytes for prevention of relapse. Br. J. Haematol. 89:506–515.PubMedGoogle Scholar
  46. 46.
    Hale, G. and Waldmann, H. (1996). Recent results using Campath-1 to control GVHD and graft rejection. Bone Marrow Transplant. 17:305–308.PubMedGoogle Scholar
  47. 47.
    Hale, G., Cobbold, S. and Waldmann, H. (1988). T-cell depletion with Campath-1 in allogeneic bone marrow transplantation. Transplantation 45:753–759.PubMedCrossRefGoogle Scholar
  48. 48.
    Naparstek, E., Delukina, M., Or, R., Nagler, A., Kapelushnik, J., Varadi, G., et al. (1999). Engraftment of marrow allografts treated with Campath-1 monoclonal antibodies. Exp. Haematol. 27:1210–1218.CrossRefGoogle Scholar
  49. 49.
    Novitzky, N., Thomas, V., Hale, G., and Waldmann, H. (1999). Ex vivo depletion of T cells from bone marrow grafts with Campath-1 in acute leukemia: graft-host disease and graft-versus-leukemia effect. Transplantation 67:620–626.PubMedCrossRefGoogle Scholar
  50. 50.
    Or, R., Aker, M., Cidivalli, G., Rachmilewitz, E.A., Samuel, S., Pugatsch, T., et al. (1999). β-Thalassemia major corrected by marrow allografts and Campath-1H: long-term follow-up. Blood 94(Suppl. 1):425a (abstract).Google Scholar
  51. 51.
    Mehta, J., Powles, R., Treleavan, J., Horton, C., Shepherd, V., Hale, G., et al. (1997). Autologous transplantation with CD52 monoclonal antibody-purged marrow for acute lymphoblastic leukemia: long-term follow-up. Leuk. Lymphoma 25:479–486.PubMedGoogle Scholar
  52. 52.
    Cull, G.M., Haynes, A.P., Byrne, J.L., Carter, G.I., Miflin, G., Rebello, P., et al. (2000). Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM-Campath conditioning: an effective regimen with low procedure-related toxicity. Br. J. Haematol. 108:754–760.PubMedCrossRefGoogle Scholar
  53. 53.
    Wing, M.G., Moreau, T., Greenwood, J., Smith, R.M., Hale, G., Issacs, J., et al. (1996). Mechanism of first-dose cytokine-release syndrome by Campath-1H: involvement of CD16 (FcgammaRIII) and CD11a/CD18 (LFA-1) on NK cells. J. Clin. Invest. 2819–2826.Google Scholar
  54. 54.
    Poynton, C.H., Mort, D. and Maughan, T.S. (1993). Adverse reactions to Campath-1H monoclonal antibody. Lancet 341:1037 (letter).PubMedCrossRefGoogle Scholar
  55. 55.
    Rai, K.R., Hoffman, M., Janson, D., Fuchs, A., Shevde, N., Kollipara, P., et al. (1995). Immunosuppression and opportunistic infections (OI) in patients with chronic lymphocytic leukemia (CLL) following Campath-1H therapy. Blood 86(Suppl. 1):348a.Google Scholar
  56. 56.
    Tang, S.C., Hewitt, K., Reis, M.D., and Berinstein, N.L. (1996). Immunosupressive toxicity of Campath-1H monoclonal antibody in the treatment of patients with recurrent low-grade lymphoma. Leuk. Lymphoma 24:93–101.PubMedGoogle Scholar
  57. 57.
    Hale, G., Dyer, M.J., Clark, M.R., Phillips, J.M., Marcus, R., Riechmann, L., et al. (1988). Remission induction in non-Hodgkin lymphoma with reshaped human monoclonal antibody Campath-1H. Lancet 2(8625):1394–1399.PubMedCrossRefGoogle Scholar
  58. 58.
    Foon, K.A., Schroff, R.W., Bunn, P.A., Mayer, D., Abrams, P.G., Fer, M., et al. (1984). Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia. Blood 64:1085–1093.PubMedGoogle Scholar
  59. 59.
    Byrd, J.C., Shinn, C.A., Jansure, J., Hydom, C., Pearson, M.D., Flinn, I.W., et al. (1999). Campath-1H induces apoptosis in human chronic lymphocytic leukemia cells (CLL) in vitro independent of complement mediated lysis or Fcyreceptor ligation. Blood 94(Suppl. 1):426a (abstract).Google Scholar
  60. 60.
    Österborg, A., Werner, Å., Halopi, E., Lundin, J., Harmenborg, U., Wigzell, H., et al. (1997). Clonal CD8+ and CD52- T cells are induced in responding B cell lymphoma patients treated with Campath-1H (anti-CD52). Eur. J. Haematol. 58:5–13.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • G. A. Pangalis
    • 1
  • M. N. Dimopoulou
    • 1
  • M. K. Angelopoulou
    • 1
  • Ch. Tsekouras
    • 1
  • T. P. Vassilakopoulos
    • 1
  • G. Vaiopoulos
    • 1
  • M. P. Siakantaris
    • 1
  1. 1.1st Department of Internal Medicine, Laikon General HospitalNational and Kapodistrian University of Athens School of MedicineGoudi, AthensGreece

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