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LRF CLL4 trial

Chronic Lymphocytic Leukaemia Trial 4 (LRF 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 closed in September 2008. Follow-up was to September 2016 for patients already recruited into the trial.

Retention/archiving of patient records

All patient records for this trial can now be archived.

See information about file retention in clinical trials

The best practice is to retain the archived files for 15 years from the date the trial was closed (i.e. until at least September 2023).

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 a number of factors, including four genetic markers by FISH analysis, IGHV gene mutation status, beta2 microglobulin level, CD38 and ZAP-70 expression, mutation of the Notch1, SF3B1 and EGR2 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. Pepper AGS, Zucchetto A, Norris K, Tissino E, Polesel J, Soe Z, Allsup D, Hockaday A, Ow PL, Hillmen P, Rawstron A, Catovsky D, Bulian P, Bomben R, Baird DM, Fegan CD, Gattei V, Pepper C. Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies. Leukemia. 2021 Jun 19. doi: 10.1038/s41375-021-01322-1. Online ahead of print. Free access

  2. Else M, Blakemore SJ, Strefford JC, Catovsky D. The association between deaths from infection and mutations of the BRAF, FBXW7, NRAS and XPO1 genes: a report from the LRF CLL4 trial. Leukemia. 2021 Sep;35(9):2563-2569 Free access

  3. Catovsky D, Else M. Early clinical trials in chronic lymphocytic leukaemia in the UK. Br J Haematol. 2020 Nov;191(4): 535-541 Free access

  4. Blakemore SJ, Clifford R, Parker H, Antoniou P, Stec-Dziedzic E, Larrayoz M, Davis Z, Kadalyayil L, Colins A, Robbe P, Vavoulis D, Forster J, Carr L, Morilla R, Else M, Bryant D, McCarthy H, Walewska RJ, Steele AJ, Chan J, Speight G, Stankovic T, Cragg MS, Catovsky D, Oscier DG, Rose-Zerilli MJJ, Schuh A, Strefford JC. Clinical significance of TP53, BIRC3, ATM and MAPK-ERK genes in chronic lymphocytic leukaemia: data from the randomised UK LRF CLL4 trial. Leukemia. 2020 Jul;34(7): 1760-1774. doi: 10.1038/s41375-020-0723-2 Free access 

  5. 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. 2017 Jul;31(7): 1547-1554 Show abstract

  6. 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. 2017 Feb;31(2):510-514 Free access

  7. 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

  8. 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 Sep;174(5):767-75 Free access

  9. 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  Free access

  10. 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

  11. 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. Free access

  12. 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. Free access

  13. 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. Free access

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

  15. 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, Free access
  16. 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, Free access
  17. 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
  18. 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, Free access
  19. 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, Free access 
  20. 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, Free access 
  21. 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, Free access 
  22. 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 
  23. 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, Free access 
  24. 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
  25. 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, Free access
  26. 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, Free access 
  27. 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, Free access
  28. 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, Free access 
  29. 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, Free access 
  30. 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 
  31. 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, Free access
  32. 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, Free access 
  33. 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 

If you require further information please email the trial sponsor Professor Daniel Catovsky at the Institute of Cancer Research.