Alemtuzumab as First-line Treatment for Progressive B-cell Chronic Lymphocytic Leukaemia

Alemtuzumab as First-line Treatment for Progressive B-cell Chronic Lymphocytic Leukaemia

Claire Dearden
European Oncological Disease 2007
Published: October 2008
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Chronic lymphocytic leukaemia (CLL) is the commonest of the adult leukaemias in the western world. The clinical course is highly variable with some patients surviving decades without requiring therapy while others have more aggressive disease requiring immediate treatment and associated with a shortened survival. Conventional treatment has relied on alkylating agents such as chlorambucil and, more recently, purine analogues such as a fludarabine. As single agents these therapies achieve good overall response (OR) rates of up to 80%, but complete remission (CR) rates of <10% for chlorambucil and 15–20% for single-agent fludarabine. Combinations of these drugs, such as fludarabine together with cyclophosphamide, have shown an increase in CR rates up to 40% with a prolongation of progression-free survival (PFS). However, none of the randomised studies has shown any survival advantage.

This latter observation is largely due to the ability to successfully re-treat relapsed patients. However, patients who become refractory to alkylator- and fludarabine-based treatments have traditionally had a poor response (<20%) to salvage therapy and a greatly shortened survival (median 10 months).1 Over the past decade this bleak situation for patients has been improved by the introduction of novel agents, including monoclonal antibodies. Alemtuzumab is a fully humanised monoclonal antibody directed against the CD52 antigen, which is widely expressed on B and T lymphocytes. It is licensed for the treatment of fludarabine refractory CLL and has been shown to induce remissions in 33–53% of patients in this setting.2,3 The standard dosing schedule is 30mg given three times a week intravenously for 12 weeks.

Table 1: Response Rates for Single Agent Front-line Therapy inChronic Lymphocytic Leukaemia

* CAM307 phase III prospective randomised trial comparing chlorambucil and alemtuzumab.CR = complete response; IV = intravenous; OR = overall response; SC = subcutaneous.


Alemtuzumab Monotherapy
The first report of the use of alemtuzumab as front-line therapy was in 1996 by Osterborg et al.4 Nine patients received the standard treatment, although in four patients the antibody was administered subcutaneously, and therapy was continued in all patients up to 18 weeks. The OR rate was 89% with three patients achieving CR. This group expanded the patient cohort and reported a further 41 patients treated with subcutaneous alemtuzumab as first-line therapy for a total of 18 weeks.5 The OR rate was maintained at 81% in 38 evaluable patients. Nineteen per cent of patients achieved CR and 68% a partial remission (PR). At the time of publication in 2002 the time to treatment failure had not been reached at 18+ months. These results are comparable to those observed for single-agent fludarabine6 and superior to those for single-agent rituximab7 (see Table 1). Interestingly, complete responders required 18 weeks of therapy to achieve their best response, with significant improvement in bone marrow clearance between the 12- and 18-week evaluation points. Furthermore, patients with low-volume lymphadenopathy also achieved complete remissions in contrast to the observation in relapsed refractory patients that lymphadenopathy predicted a poor response to single-agent antibody treatment. Ten per cent of patients developed cytomegalovirus (CMV) reactivation that responded rapidly to treatment with intravenous ganciclovir. There was no increase in bacterial sepsis. Although transient injection site reactions were observed with the subcutaneous administration in the majority of patients, many of the initial reactions associated with intravenous administration such as rigours, nausea and hypertension were not seen. One in five patients had a transient grade 4 neutropaenia, but other side effects were rare.

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References:
  1. Keating MJ, O Brien S, Kantarjian H, et al., Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukaemia, Leuk Lymphoma, 2002;43: 1755-62.
  2. Keating MJ, Flinn I, Jain V, et al., Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study, Blood, 2002;99:3554-61.
  3. Moreton P, Kennedy B, Lucas G, et al., Eradication of minimal residual disease in B-cell chronic lymphocytic leukaemia after alemtuzumab therapy is associated with prolonged survival, J Clin Oncol, 2005;23(13):2971-9.
  4. Osterborg A, Fassas AS, Anagnostopoulos A, et al., Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukaemia, Br J Haematol, 1996;93: 151-3.
  5. Lundin J, Kimby E, Bjorkholm M, et al., Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL), Blood, 2002;100: 768-73.
  6. Rai KR, Peterson BL, Appelbaum FR, et al., Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukaemia, N Engl J Med, 2000;343:1750-57.
  7. Hainsworth JD, Litchy S, Barton JH, et al., Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network, J Clin Oncol, 2003;21:1746-51.
  8. Hillmen P, Skotnicki A, Roback T, et al., Alemtuzumab (Campath, MabCampath) has superior progression free survival (PFS) vs chlorambucil as front-line therapy for patients with progressive B-cell chronic lymphocytic leukaemia (BCLL), Blood, 2006;11:p93a, a301.
  9. Rawstron AC, Kennedy B, Evans PA, et al., Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy, Blood, 2001;98: 29-35.
  10. Esteve J, Villamor N, Colomer D, et al., Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status, Leukemia, 2001;15:445-51.
  11. Bosch F, Ferrer A, Lopez-Guillermo A, et al., Fludarabine, cyclophosphomide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia, Br J Haematol, 2002;119:976-84.
  12. Weirda W, O Brien S, Wen Sijin, et al., Chemo-immunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukaemia, J Clin Oncol, 2005;23:4070-78.
  13. Wendtner CM, Ritgen M, Schweighofer CD, et al., Consolidation with alemtuzemab in patients with chronic lymphocytic leukemia (CLL) in first remission-experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG), Leukemia, 2004;18:1093-1101.
  14. O Brien, SM, et al., Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukaemia, Cancer, 2003;98:2657-63.
  15. Rai KR, Byrd JC, Peterson B, et al., Alemtuzumab following fludarabine for previously untreated patients with chronic lymphocytic leukaemia (CLL). CALGB study 19901, Blood, 2003;102:676A, a2506.
  16. Montillo M, Tedeschi A, Miqueleiz S, et al., Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukaemia, J Clin Oncol, 2006;24(15):2337-42.
  17. Schweighofer M, Ritgen B, Eichorst R, et al., Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission long-term follow-up of a randomized phase III trial of the German CLL study group (GCLLSG), Blood, 2006;108:p14, a33.
  18. Dohner H, Fischer K, Bentz M, et al., p53 gene deletion predicts for poor survival and non-response to therapy with purine analogs in chronic B-cell leukemias, Blood, 1995;85:580-89.
  19. Stilgenbauer S, Dohner H, Campath-1H-induced complete remission of chronic lymphocytic leukemia despite p53 gene mutation and resistance to chemotherapy, N Engl J Med, 2002;347:452-3.
  20. Lozanski G, Heerema NA, Flinn IW, et al., Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions, Blood, 2004;103:3278-81.
  21. Osuji N, Del Giudice I, Matutes E, et al., The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53, Haematologica, 2005;90:1435-36.
  22. Thornton PD, Hamblin M, Treleaven JG, et al., High dose methyl prednisolone in refractory chronic lymphocytic leukaemia, Leuk Lymphoma, 1999;34:167-70.
  23. Pettitt AR, Matutes E, Oscier D, Alemtuzumab in combination with high-dose methylprednisolone: a rational approach for CLL patients with p53 defects, Leuk Lymphoma, 2005;46 (Suppl. 1): S92.
  24. Elter T, Borchmann P, Schulz H, et al., Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial, J Clin Oncol, 2005;23: 7024-31.
  25. Weirda WG, O Brien S, Faderl S, et al., Combined cyclophosphomide, fludarabine, alemtuzumab and rituximab (CFAR), an active regimen for heavily treated patients with CLL, Blood, 2006;108:p14, a31.

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