CLL4 Trial
LRF CLL4 Trial
Chronic Lymphocytic Leukaemia Trial 4 (CLL4) is an LRF-funded trial from the NCRI Haematological Oncology Clinical Studies Group. MREC (1) 98/101 A RANDOMISED COMPARISON OF CHLORAMBUCIL, FLUDARABINE AND FLUDARABINE PLUS CYCLOPHOSPHAMIDE. ISRCTN number: 58585610. EUDRACT Number: 2004.000105-21.
LRF CLL4 is now closed for both first and second randomisations. However, follow-up continues for patients already recruited into this trial. Investigators are requested to continue to return follow-up form (C) to the CTSU on an annual basis and to notify the CTSU on 2nd line treatment form (D) about all treatments given to LRF CLL4 participants after relapse.
Annually in October the CTSU sends a short follow-up form with one line per patient to each investigator. Please return this form promptly each year, even if a form C or form D has recently been completed. This follow-up form allows statistically reliable use of each additional year of follow-up in presentations and publications from the trial.
The LRF CLL4 Trial Background
This study compared conventional therapy with chlorambucil versus the newer agent fludarabine, used alone or in combination with cyclophosphamide. End points of the trial were: survival, response to therapy, duration of response, toxicity and quality of life. For patients who required further treatment after relapse or second line therapy for non-responders, a second randomisation compared treatment guided by the protocol versus guided by the in-vitro drug sensitivity DiSC assay.
CLL4 has also provided an opportunity to investigate the prognostic value of four genetic markers by FISH analysis and other factors such as IgVH mutational status, beta2 microglobulin and CD38 and ZAP-70 expression. Between 1999-2004 a total of 777 patients were enrolled in the study.
Publications Reporting the Trial Results
- Else M, Cocks K, Crofts S, Wade R, Richards SM, Catovsky D, Smith AG. Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial. Leuk Lymphoma. 2012. [Epub ahead of print].
- Gonzalez D, Martinez P, Wade R, Hockley S, Oscier D, Matutes E, Dearden CE, Richards SM, Catovsky D, Morgan GJ. Mutational status of the TP53 gene as a predictor of response and survival in patients with chronic lymphocytic leukemia: results from the LRF CLL4 trial. J Clin Oncol. 2011; 29:2223-2229.
- Wade R, Di Bernardo MC, Richards S, Rossi D, Crowther-Swanepoel D, Gaidano G, Oscier DG, Catovsky D, Houlston RS. Association between SNP-genotype and chronic lymphocytic leukemia outcome in a randomized chemotherapy trial. Haematologica 2011; 96:1496-1503.
- Dearden C, Richards S, Else M, Catovsky D, Hillmen P. A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial. Cancer 2011; 117:2452–2460.
- Oscier D, Wade R, Davis Z, Morilla A, Best G, Richards S, Else M, Matutes E,and Catovsky D, for the UK National Cancer Research Institute (NCRI) Chronic Lymphocytic Leukaemia Working Group. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica 2010; 95:1705-1712
- Bosanquet AG, Richards SM, Wade R, Else M, Matutes E, Dyer MJS, Rassam SMB, Durant J, Scadding SM, Raper SL, Dearden CE, Catovsky D. Drug cross-resistance and therapy-induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing. Br J Haematol. 2009; 146:384-395.
- Else M, Smith AG, Cocks K, Richards SM, Crofts S, Wade R, Catovsky D; UK NCRI CLL Trials Group. Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol. 2008; 143:690-697.
- Rudenko HC, Else M, Dearden C, Brito-Babapulle V, Jones C, Dexter T, Fenwick K, Mackay A, Ashworth A, Matutes E, Gonzalez D, Catovsky D, Morgan GJ. Characterising the TP53-deleted subgroup of chronic lymphocytic leukemia: an analysis of additional cytogenetic abnormalities detected by interphase fluorescence in situ hybridisation and array-based comparative genomic hybridisation. Leuk Lymphoma 2008; 49:1879-1886.
- Dearden C, Wade R, Else M, Richards S, Milligan D, Hamblin T, Catovsky D. The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia - a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 2008; 111:1820-1826
- Sellick GS, Wade R, Richards S, Oscier DG, Catovsky D, Houlston RS. Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis. Blood 2008; 111:1625-1633.
- Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, Pettitt AR, Hamblin T, Milligan DW, Child JA, Hamilton MS, Dearden CE, Smith AG, Bosanquet AG, Davis Z, Brito-Babapulle V, Else M, Wade R, Hillmen P; UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370:230-239.
Further LRF CLL4 papers in preparation
- Report of the second randomisation
- Long-term follow-up
Other papers planned include gene expression studies and a comparison of outcomes by gender.
Forms
Trial Forms Still Currently in Use
Follow-up form (C) (16 KB)
2nd line treatment form (D) (12 KB)
Documentation
Trial Closure Documentation
(please note: follow-up of patients continues indefinitely)
Declaration of the End of Trial (108 KB)
Previous MREC Documentation
MREC Application (110 KB)
MREC letter dated 27 November 1998 (116 KB)
MREC letter dated 15 December 1999 (160 KB)
MREC letter dated 18 November 1999 (36 KB)
CLL4 MREC DDX letter (471 KB)
Other Forms for Historical Documentation Purposes Only
CLL4 protocol revised 27/2/2001 (114 KB) This protocol should not be used as an aide-memoire or guide for the treatment of other patients.
CLL4 patient information sheet (23 KB)
CLL4 consent form (9 KB)
CLL4 forms A, B, C, D (33 KB)
Entry form (A) (14 KB)
First treatment form (B) (16 KB)
CLL4 SAE Reporting form (16 KB)
CLL4 SAE Flow Chart (103 KB)
CLL4 SAE Definitions (75 KB)
Quality of life questionnaire (12 KB)
Quality of life investigator form (11 KB)
Contact
The CTSU address is as follows:
CTSU
Richard Doll Building
Old Road Campus
Roosevelt Drive
OXFORD
OX3 7LF
Freepost address (for leukaemia trial forms):
Freepost RLUJ-UUUU-UUAC
CTSU
Richard Doll Building
Old Road
Headington
OXFORD
OX3 7LF
Telephone: 01865 765615
Fax forms to: 01865 743986
For general enquiries contact:
Email: randomisation@ctsu.ox.ac.uk
Web: www.ctsu.ox.ac.uk
If you require further information please email Monica Else at the ICR
