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Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial
Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial
Background: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine.
Methods: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life.
Analysis: This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610.
Findings: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p < 0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p < 0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V,,) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
combination, chlorambucil, alemtuzumab, gene mutation status, fludarabine plus cyclophosphamide, monoclonal antibody, multicenter, quality-of-life, age, cladribine, gene, time, progression-free survival, mutation, 1st-line therapy, monoclonal-antibodies, metaanalysis, survival, regimen, chemoimmunotherapy
0140-6736
230-239
Catovsky, D.
8f2e75e5-9762-456e-b60b-1fd34a67ba82
Richards, S.
231c6be9-3769-47b3-ae97-06ea844e0448
Matutes, E.
1ede5543-9493-4b0b-8d9b-62315bdfd36b
Oscier, D.
c2620a1d-25bb-48f7-9651-f5d023636381
Dyer, M.J.S.
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FBezares, R.
df19e904-0979-49f8-bf6f-710ef8e26d8d
Pettitt, A.R.
2419c472-6d6f-4e71-ac40-d381e78cb7b0
Hamblin, T.
50cc753a-132d-4f62-91a5-a53f6c4c022c
Milligan, D.W.
76b5bb0e-2550-42aa-bd25-207d311cf543
Child, J.A.
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Hamilton, M.S.
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Dearden, C.E.
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Smith, A.G.
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Bosanquet, A.G.
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Davis, Z.
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Brito-Babapulle, V.
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Else, M.
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Wade, R.
a1533eee-e592-45c1-9414-fad86444a3ea
Hillmen, P.
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Catovsky, D.
8f2e75e5-9762-456e-b60b-1fd34a67ba82
Richards, S.
231c6be9-3769-47b3-ae97-06ea844e0448
Matutes, E.
1ede5543-9493-4b0b-8d9b-62315bdfd36b
Oscier, D.
c2620a1d-25bb-48f7-9651-f5d023636381
Dyer, M.J.S.
14dd1a96-2bfb-4583-9c42-4aa54b611273
FBezares, R.
df19e904-0979-49f8-bf6f-710ef8e26d8d
Pettitt, A.R.
2419c472-6d6f-4e71-ac40-d381e78cb7b0
Hamblin, T.
50cc753a-132d-4f62-91a5-a53f6c4c022c
Milligan, D.W.
76b5bb0e-2550-42aa-bd25-207d311cf543
Child, J.A.
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Hamilton, M.S.
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Dearden, C.E.
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Smith, A.G.
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Bosanquet, A.G.
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Davis, Z.
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Brito-Babapulle, V.
e8ad17c3-38e1-40e7-b78d-4ff631e1ac7c
Else, M.
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Wade, R.
a1533eee-e592-45c1-9414-fad86444a3ea
Hillmen, P.
a723149d-d8c0-4cc6-9c89-1650cdc53e7b

Catovsky, D., Richards, S., Matutes, E., Oscier, D., Dyer, M.J.S., FBezares, R., Pettitt, A.R., Hamblin, T., Milligan, D.W., Child, J.A., Hamilton, M.S., Dearden, C.E., Smith, A.G., Bosanquet, A.G., Davis, Z., Brito-Babapulle, V., Else, M., Wade, R. and Hillmen, P. (2007) Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. The Lancet, 370 (9583), 230-239. (doi:10.1016/S0140-6736(07)61125-8).

Record type: Article

Abstract

Background: Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine.
Methods: 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life.
Analysis: This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610.
Findings: There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38% vs 15%, respectively; overall response rate 94% vs 80%, respectively; p < 0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p < 0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V,,) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. Interpretation Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

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Published date: 2007
Keywords: combination, chlorambucil, alemtuzumab, gene mutation status, fludarabine plus cyclophosphamide, monoclonal antibody, multicenter, quality-of-life, age, cladribine, gene, time, progression-free survival, mutation, 1st-line therapy, monoclonal-antibodies, metaanalysis, survival, regimen, chemoimmunotherapy
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 62701
URI: https://eprints.soton.ac.uk/id/eprint/62701
ISSN: 0140-6736
PURE UUID: 9472d7b1-65b1-4c9f-a5b8-ac9069a25ec7

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Date deposited: 05 Sep 2008
Last modified: 05 Oct 2018 12:03

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Contributors

Author: D. Catovsky
Author: S. Richards
Author: E. Matutes
Author: D. Oscier
Author: M.J.S. Dyer
Author: R. FBezares
Author: A.R. Pettitt
Author: T. Hamblin
Author: D.W. Milligan
Author: J.A. Child
Author: M.S. Hamilton
Author: C.E. Dearden
Author: A.G. Smith
Author: A.G. Bosanquet
Author: Z. Davis
Author: V. Brito-Babapulle
Author: M. Else
Author: R. Wade
Author: P. Hillmen

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