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 was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610.


RESULTS
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(H)) 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.


CONCLUSIONS
Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.
Catovsky
D
D
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK. Electronic address: daniel.catovsky@icr.ac.uk.
Richards
S
S
Clinical Trial Service Unit, Oxford, UK.
Matutes
E
E
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK.
Oscier
D
D
Royal Bournemouth Hospital, Bournemouth, UK.
Dyer
Mjs
M
Leicester Royal Infirmary, Leicester, UK.
Bezares
R F
RF
Hospital Alvarez, Buenos Aires, Argentina.
Pettitt
A R
AR
University of Liverpool, Liverpool, UK.
Hamblin
T
T
Royal Bournemouth Hospital, Bournemouth, UK.
Milligan
D W
DW
Heartlands Hospital, Birmingham, UK.
Child
J A
JA
Leeds General Infirmary, Leeds, UK.
Hamilton
M S
MS
Good Hope Hospital, Sutton Coldfield, UK.
Dearden
C E
CE
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK.
Smith
A G
AG
Southampton General Hospital, Southampton, UK.
Bosanquet
A G
AG
Bath Cancer Research, Bath, UK.
Davis
Z
Z
Royal Bournemouth Hospital, Bournemouth, UK.
Brito-Babapulle
V
V
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK.
Else
M
M
Section of Haemato-Oncology, Institute of Cancer Research, Sutton, UK.
Wade
R
R
Clinical Trial Service Unit, Oxford, UK.
Hillmen
P
P
Leeds General Infirmary, Leeds, UK.
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002699:Chlorambucil / Q000008:administration & dosage / Q000009:adverse effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016019:Survival Analysis; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives
D002699:Chlorambucil; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine