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. However, lifelong follow-up continues for patients already recruited into this trial. 

• Trial background
• Publications
• Forms
• Documentation
• Contact

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 IGHV gene mutation status, beta2 microglobulin, CD38 and ZAP-70 expression, mutation of the Notch1 and SF3B1 genes and expression of CLLU1. Between 1999 and 2004 a total of 777 patients were enrolled in the study.

Publications reporting the Trial results

1. Skowronska A, Parker A, Ahmed G, Oldreive C, Davis Z, Richards S, Dyer M, Matutes E, Gonzalez D, Taylor AM, Moss P, Thomas P, Oscier D, Stankovic T. Biallelic ATM Inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial. J Clin Oncol. 2012 Oct 22. [Epub ahead of print]
2. Oscier DG, Rose-Zerilli MJJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Cross NCP, Else M, Catovsky D and Strefford JC. The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood. 2012 Oct 18. doi: 10.1182/blood-2012-05-429282. [Epub ahead of print].
3. Gonzalez D, Else M, Wren D, Usai M, Buhl AM, Parker A, Oscier D, Morgan G, Catovsky D. CLLU1 expression has prognostic value in CLL after first-line therapy in younger patients and those with mutated IGHV genes. Haematologica. 2012. [Epub ahead of print]
4. Matutes E, Bosanquet AG, Wade R, Richards SM, Else M, Catovsky D. The use of individualized tumor response testing in treatment selection: second randomization results from the LRF CLL4 trial and the predictive value of the test at trial entry. Leukemia. 2012 Jul 19. doi: 10.1038/leu.2012.209. [Epub ahead of print]
5. Lin K, Adamson J, Johnson GG, Carter A, Oates M, Wade R, Richards S, Gonzalez D, Matutes E, Dearden C, Oscier DG, Catovsky D, Pettitt AR. Functional Analysis of the ATM-p53-p21 Pathway in the LRF CLL4 Trial: Blockade at the Level of p21 Is Associated with Short Response Duration. Clin Cancer Res. 18:4191-200; 2012.
6. 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; 53:1289-1298.
7. 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.
8. 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.
9. 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.
10. 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
11. 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.
12. 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.
13. 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.
14. 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
15. 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.
16. 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

Other papers planned include a long-term follow-up and a comparison of outcomes by gender.

Documentation

Trial closure documentation

(please note: follow-up of patients continues for life)

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)

Follow-up form (C) (16 KB)

2nd line treatment form (D) (12 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

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