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LRF CLL4 trial team

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. 


The LRF CLL4 Trial background

This study compared conventional chlorambucil therapy versus 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. 

Between 1999 and 2004, a total of 777 patients were enrolled in the trial. With follow-up of patients still continuing, LRF 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 level, CD38 and ZAP-70 expression, mutation of the Notch1 and SF3B1 genes and expression of CLLU1. Long-term data from the study have been used in an overview of international studies resulting in a robust prognostic system for CLL (CLL-IPI). 


Publications reporting the trial results 

  1. Young E, Noerenberg D, Mansouri L, Ljungström V, Frick M, Sutton LA, Blakemore SJ, Galan-Sousa J, Plevova K, Baliakas P, Rossi D, Clifford R, Roos-Weil D, Navrkalova V, Dörken B, Schmitt CA, Smedby KE, Juliusson G, Giacopelli B, Blachly JS, Belessi C, Panagiotidis P, Chiorazzi N, Davi F, Langerak AW, Oscier D, Schuh A, Gaidano G, Ghia P, Xu W, Fan L, Bernard OA, Nguyen-Khac F, Rassenti L, Li J, Kipps TJ, Stamatopoulos K, Pospisilova S, Zenz T, Oakes CC, Strefford JC, Rosenquist R, Damm F. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia. Leukemia. 2016 Nov 28. doi: 10.1038/leu.2016.359. [Epub ahead of print].

  2. Larrayoz M, Rose-Zerilli MJ, Kadalayil L, Parker H, Blakemore S, Forster J, Davis Z, Steele AJ, Collins A, Else M, Catovsky D, Oscier DG, Strefford JC. Non-coding NOTCH1 mutations in chronic lymphocytic leukemia; their clinical impact in the UK CLL4 trial. Leukemia. 2016 Oct 24. doi: 10.1038/leu.2016.298. [Epub ahead of print]

  3. International CLL-IPI working group. An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol. 17(6):779-90; 2016. doi: 10.1016/S1470-2045(16)30029-8 Show Abstract

  4. Oscier D, Else M, Matutes E, Morilla R, Strefford JC, Catovsky D. The morphology of CLL revisited: the clinical significance of prolymphocytes and correlations with prognostic/molecular markers in the LRF CLL4 trial. Br J Haematol. 2016 May 6. doi: 10.1111/bjh.14132. Oscier et al: Br J Haematol. 2016 Sep;174(5):767-75 Show Abstract

  5. Johnson N, De Ieso P, Migliorini G, Orr N, Broderick P, Catovsky D, Matakidou A, Eisen T, Goldsmith C, Dudbridge F, Peto J, Dos-Santos-Silva I, Ashworth A, Ross G, Houlston RS, Fletcher O. Cytochrome P450 allele CYP3A7*1C associates with adverse outcomes in chronic lymphocytic leukemia, breast, and lung cancer. Cancer Res. 76(6):1485-93; 2016  Show Abstract

  6. Pratt G, Thomas P, Marden N, Alexander D, Davis Z, Hussey D, Parry H, Harding S, Catovsky D, Begley J, Oscier D. Evaluation of serum markers in the LRF CLL4 trial: β2m but not serum free light chains, is an independent marker of overall survival. Leuk Lymphoma. 2016 Jan 6:1-31. Pratt et al: Leuk Lymphoma. 2016 Oct;57(10):2342-50 Show Abstract

  7. Davis Z, Forconi F, Parker A, Gardiner A, Thomas P, Catovsky D, Rose-Zerilli M, Strefford JC, Oscier D. The outcome of chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity. Br J Haematol. 173(1):127-36; 2016 doi: 10.1111/bjh.13940. Show Abstract

  8. Else M, Wade R, Oscier D, Catovsky D. The long-term outcome of patients in the LRF CLL4 trial: the effect of salvage treatment and biological markers in those surviving 10 years. Br J Haematol. 172:228–237; 2016. Show Abstract

  9. Strefford JC, Kadalayil L, Forster J, Mjj RZ, Parker A, Lin TT, Heppel N, Norris K, Gardiner A, Davies Z, Gonzalez de CD, Else M, Steele AJ, Parker H, Stankovic T, Pepper C, Fegan C, Baird D, Collins A, Catovsky D, Oscier DG. Telomere length predicts progression and overall survival in chronic lymphocytic leukemia: data from the UK LRF CLL4 trial. Leukemia. 29(12):2411-4; 2015. Show Abstract

  10. Catovsky, D., Wade, R. & Else, M. (2014) The clinical significance of patient sex in chronic lymphocytic leukemia. Haematologica, Vol.99(6), pp.1088-1094, Show Abstract

  11. Rose-Zerilli, MJ., Forster, J., Parker, H., Parker, A., Rodriguez, AE., Chaplin, T., Gardiner, A., Steele, AJ., Collins, A., Young, BD., et al. (2014) ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia, data from the UK LRF CLL4 trial. Haematologica, Vol.99(4), pp.736-742, Show Abstract
  12. Johnson, GG., Lin, K., Cox, TF., Oates, M., Sibson, DR., Eccles, R., Lloyd, B., Gardiner, L-J., Carr, DF., Pirmohamed, M., et al. (2013) CYP2B6*6 is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukaemia. Blood, Vol.122(26), pp.4253-4258, Show Abstract
  13. Skowronska, A., Parker, A., Ahmed, G., Oldreive, C., Davis, Z., Richards, S., Dyer, M., Matutes, E., Gonzalez, D., Taylor, AM., et al. (2012) Biallelic inactivation Significantly Reduces Survival in Patients Treated on the United Kingdom Leukemia Research Fund Chronic Lymphocytic Leukemia 4 Trial. J Clin Oncol, Vol.30, pp.4524-4532, Show Abstract
  14. Oscier, DG., Rose-Zerilli, MJJ., Winkelmann, N., Gonzalez de Castro, D., Gomez, B., Forster, J., Parker, H., Parker, A., Gardiner, A., Collins, A., et al. (2013) The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial. Blood, Vol.121, pp.468-475, Show Abstract 
  15. Gonzalez, D., Else, M., Wren, D., Usai, M., Buhl, AM., Parker, A., Oscier, D., Morgan, G. & Catovsky, D. (2013) CLLU1 expression has prognostic value in CLL after first-line therapy in younger patients and those with mutated IGHV genes. Haematologica, Vol.98, pp.274-278, Show Abstract 
  16. Matutes, E., Bosanquet, AG., Wade, R., Richards, SM., Else, M. & Catovsky, D. (2013) 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, Vol.27, pp.507-510, Show Abstract 
  17. Lin, K., Adamson, J., Johnson, GG., Carter, A., Oates, M., Wade, R., Richards, S., Gonzalez, D., Matutes, E., Dearden, C., et al. (2012) 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, Vol.18, pp.4191-4200, Show Abstract 
  18. Else, M., Cocks, K., Crofts, S., Wade, R., Richards, SM., Catovsky, D. & Smith, AG. (2012) Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial. Leuk Lymphoma, Vol.53, pp.1289-1298, Show Abstract 
  19. Gonzalez, D., Martinez, P., Wade, R., Hockley, S., Oscier, D., Matutes, E., Dearden, CE., Richards, SM., Catovsky, D. & Morgan, GJ. (2011) 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, Vol.29, pp.2223-2229, Show Abstract 
  20. Catovsky, D., Else, M. & Richards, S. (2011) Chlorambucil--still not bad: a reappraisal. Clin Lymphoma Myeloma Leuk, Vol.11 Suppl 1, pp.S2-S6, Show Abstract
  21. Wade, R., Di Bernardo, MC., Richards, S., Rossi, D., Crowther-Swanepoel, D., Gaidano, G., Oscier, DG., Catovsky, D. & Houlston, RS. (2011) Association between SNP-genotype and chronic lymphocytic leukemia outcome in a randomized chemotherapy trial. Haematologica, Vol.96, pp.1496-1503, Show Abstract
  22. Dearden, C., Richards, S., Else, M., Catovsky, D. & Hillmen, P. (2011) A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial. Cancer, Vol.117, pp.2452–2460, Show Abstract 
  23. Oscier, D., Wade, R., Davis, Z., Morilla, A., Best, G., Richards, S., Else, M., Matutes, E. & Catovsky D, for the UK National Cancer Research Institute (NCRI) Chronic Lymphocytic Leukaemia Working Group. (2010) Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica, Vol.95, pp.1705-1712, Show Abstract
  24. Bosanquet, AG., Richards, SM., Wade, R., Else, M., Matutes, E., Dyer, MJS., Rassam, SMB., Durant, J., Scadding, SM., Raper, SL., et al. (2009) Drug cross-resistance and therapy-induced resistance in chronic lymphocytic leukaemia by an enhanced method of individualised tumour response testing. Br J Haematol, Vol.146, pp.384-395, Show Abstract 
  25. Else, M., Smith, AG., Cocks, K., Richards, SM., Crofts, S., Wade, R., Catovsky, D.; UK NCRI CLL Trials Group. (2008) Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol, Vol.143, pp.690-697, Show Abstract 
  26. Rudenko, HC., Else, M., Dearden, C., Brito-Babapulle, V., Jones, C., Dexter, T., Fenwick, K., Mackay, A., Ashworth, A., Matutes, E., et al. (2008) 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, Vol.49, pp.1879-1886, Show Abstract 
  27. Dearden, C., Wade, R., Else, M., Richards, S., Milligan, D., Hamblin, T. & Catovsky, D. (2008) 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, Vol.111, pp.1820-1826, Show Abstract
  28. Sellick, GS., Wade, R., Richards, S., Oscier, DG., Catovsky, D. & Houlston, RS. (2008) Scan of 977 nonsynonymous SNPs in CLL4 trial patients for the identification of genetic variants influencing prognosis. Blood, Vol.111, pp.1625-1633, Show Abstract 
  29. Catovsky, D., Richards, S., Matutes, E., Oscier, D., Dyer, MJ., Bezares, RF., Pettitt, AR., Hamblin, T., Milligan, DW., Child, JA., et al. (2007) Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet, Vol.370, pp.230-239, Show Abstract


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 February 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)
Second 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: [email protected]
Web: www.ctsu.ox.ac.uk 

If you require further information please email Monica Else at the ICR

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