Chemotherapy in Treating Patients With Newly Diagnosed Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Trial 4: A Randomized Comparison of Chlorambucil, Fludarabine and Fludarabine Plus Cyclophosphamide

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. It is not yet known which regimen of chemotherapy is more effective for chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying chlorambucil to see how well it works compared to fludarabine and cyclophosphamide or fludarabine alone in treating patients with newly diagnosed chronic lymphocytic leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: vincristine sulfate; Drug: fludarabine phosphate; Drug: doxorubicin hydrochloride; Drug: chlorambucil; Drug: prednisolone

Detailed Description

OBJECTIVES:

• Compare the survival rate of patients with newly diagnosed chronic lymphocytic leukemia treated with chlorambucil alone vs fludarabine with or without cyclophosphamide.
• Compare the response rate and duration of remission in patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.
• Determine the impact of the drug response information provided by the DiSC assay on response rate and survival in relapsed or nonresponding patients.
• Assess the prognostic value of five genetic markers: trisomy 12 and deletions at 11q23, 13q14, p53, and 6q21 in patients treated with these regimens.

OUTLINE: This is a randomized study. Patients enter one of three treatment arms in the first randomization. Depending on response, some patients may also participate in a second randomization to one of two treatment arms.

• First randomization:

  • Arm I: Patients receive oral chlorambucil daily for 7 days. Treatment repeats every 4 weeks until maximum response or up to 1 year.
  • Arm II: Patients receive fludarabine IV or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.
  • Arm III: Patients receive cyclophosphamide IV and fludarabine IV for 3 days or orally daily for 5 days. Treatment repeats every 4 weeks for 3-8 courses.

Patients who relapse after being in remission for at least 1 year may repeat the initial therapy or may participate in a second randomization. Patients who experience progressive disease or relapse within 1 year after treatment proceed to a second randomization.

• Second randomization:

  • Arm I: Treatment is guided by the results of the DiSC assay. Treatment may be one of the first-line treatments with fludarabine or standard CHOP chemotherapy repeated every 4 weeks (cyclophosphamide IV, doxorubicin IV, vincristine IV, and oral prednisolone on days 1-5) or any other therapy guided by the results of the DiSC assay.
  • Arm II: Treatment is physician's choice, which may include any of the options in arm I.

Quality of life is assessed prior to initial therapy; at 3, 6, and 12 months; and then annually thereafter.

Patients are followed annually for survival.

PROJECTED ACCRUAL: A total of 750 patients will be accrued for this study within 6-7 years.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Hospital Alvarez
  • Buenos Aires, Argentina, CP1181ACH
    • Hospital Italiano de Buenos Aires
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Rebro
• Greece
  • Ioannina, Greece, GR-45110
    • University of Ioannina
  • Rio Patras, Greece, GR-26500
    • University of Patras Medical School
• Ireland
  • Dublin, Ireland, 8
    • St. James' Hospital
  • Galway, Ireland
    • Galway University Hospital
• Italy
  • Bergamo, Italy, 24100
    • Ospedali Riuniti di Bergamo
• New Zealand
  • Christchurch, New Zealand
    • Canterbury Health Laboratories
• Russian Federation
  • Moscow, Russian Federation, 115478
    • Russian Academy of Medical Sciences Cancer Research Center
• United Kingdom
  • England
    • Aylesbury-Buckinghamshire, England, United Kingdom, HP21 8AL
      • Stoke Mandeville Hospital
    • Banbury, England, United Kingdom, OX16 9A
      • Horton Hospital
    • Basingstoke, England, United Kingdom, RG24 9NA
      • North Hampshire Hospital
    • Birmingham, England, United Kingdom, B9 5SS
      • Birmingham Heartlands Hospital
    • Birmingham, England, United Kingdom, B29 6JD
      • Selly Oak Hospital at University Hospital NHS Trust
    • Blackpool, England, United Kingdom, FY3 8NR
      • Blackpool Victoria Hospital
    • Bournemouth, England, United Kingdom, BH7 7DW
      • Royal Bournemouth Hospital
    • Bradford, England, United Kingdom, BD9 6RJ
      • Bradford Hospitals NHS Trust
    • Brighton, England, United Kingdom, BN2 5BE
      • Royal Sussex County Hospital
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital at Cambridge University Hospitals NHS Foundation Trust
    • Carshalton, England, United Kingdom, SM5 1AA
      • St Helier Hospital
    • Chester, England, United Kingdom, CH2 1UL
      • Countess of Chester Hospital
    • Chesterfield, England, United Kingdom, S44 5BL
      • Chesterfield Royal Hospital
    • Chichester, England, United Kingdom, P019 4SE
      • Saint Richards Hospital
    • Darlington, England, United Kingdom, DL3 6HX
      • Darlington Memorial
    • Dartford Kent, England, United Kingdom, DA1 5PL
      • Dartford & Gravesham NHS Trust, Joyce Green Hospital
    • Doncaster, England, United Kingdom, DN2 5LT
      • Doncaster Royal Infirmary
    • Dudley, England, United Kingdom, DY1 2HQ
      • Russells Hall Hospital
    • Durham, England, United Kingdom
      • Bishop Auckland Hospital
    • Epsom Surrey, England, United Kingdom, KT18 7E9
      • Epsom General Hospital
    • Gateshead, England, United Kingdom, NE9 6SX
      • Queen Elizabeth Hospital
    • Gateshead-Tyne and Wear, England, United Kingdom, NE9 6SX
      • Queen Elizabeth Hospital
    • Gloucester, England, United Kingdom, GL1 3NN
      • Gloucester Royal NHS Trust - Glouchester Royal Hospital
    • Guildford, England, United Kingdom, GU2 5XX
      • St. Luke's Cancer Centre at Royal Surrey County Hospital
    • Harrogate, England, United Kingdom, HG2 7SX
      • Harrogate District Hospital
    • Hemel Hempstead, England, United Kingdom
      • Hemel Hempstead General
    • High Wycombe, England, United Kingdom
      • Institute of Oncology and Radiology of Serbia
    • Huddersfield, West Yorks, England, United Kingdom, HD3 3EA
      • Huddersfield Royal Infirmary
    • Hull, England, United Kingdom, HU3 2KZ
      • Hull Royal Infirmary
    • Leeds, England, United Kingdom, LS2 9N9
      • Clinical Trials and Research Unit of the University of Leeds
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • Liverpool, England, United Kingdom, L9 7AL
      • Aintree University Hospital
    • Liverpool, England, United Kingdom, L7 8XP
      • Royal Liverpool and Broadgreen Hospitals
    • Liverpool, England, United Kingdom, L9 1AE
      • Walton General Hospital
    • London, England, United Kingdom, SW17 0QT
      • St. George's Hospital
    • London, England, United Kingdom, SE1 9RT
      • Guy's and St. Thomas' Hospitals NHS Foundation Trust
    • London, England, United Kingdom, SW3 6JJ
      • Royal Marsden NHS Foundation Trust - London
    • London, England, United Kingdom, E11 1NR
      • Whipps Cross Hospital
    • London, England, United Kingdom, NW1 2QG
      • Royal Free and University College Medical School
    • Middlesex, England, United Kingdom, N18 1QZ
      • West Middlesex Hospital
    • Newcastle-Upon-Tyne, England, United Kingdom, NE27 OQJ
      • Northern Cancer Network
    • Northampton, England, United Kingdom, NN1 5BD
      • Northampton General Hospital NHS Trust
    • Nottingham, England, United Kingdom, NG5 1PB
      • Nottingham City Hospital NHS Trust
    • Nottinghamshire, England, United Kingdom, S81 3SA
      • Bassetlaw Hospital & Community Services NHS Trust
    • Orpington Kent, England, United Kingdom, BR6 8ND
      • Farnborough Hospital
    • Otley, England, United Kingdom, LS21 7AA
      • Wharfdale General Hospital
    • Pontefract West Yorkshire, England, United Kingdom, WF8 1PL
      • Pontefract General Infirmary
    • Reading, England, United Kingdom, RG1 5AN
      • Berkshire Cancer Centre at Royal Berkshire Hospital
    • Romford, England, United Kingdom, RM7 OBE
      • Oldchurch Hospital
    • Rotherham, England, United Kingdom, S60 2UD
      • Rotherham District General Hospital - NHS Trust
    • Saint Leonards-on-Sea, England, United Kingdom, TN37 7RD
      • Conquest Hospital
    • Scunthorpe, England, United Kingdom, DN15 7BH
      • Scunthorpe General Hospital
    • Southampton, England, United Kingdom, SO16 6YD
      • Southampton General Hospital
    • Southampton, England, United Kingdom, SO14 0YG
      • Royal South Hants Hospital
    • Stafford, England, United Kingdom, ST16 3SA
      • Staffordshire General Hospital
    • Stoke-On-Trent, England, United Kingdom, ST4 7LN
      • North Staffs Royal Infirmary
    • Surrey, England, United Kingdom, KT 16 OPZ
      • St. Peter's Hospital NHS Trust
    • Torquay Devon, England, United Kingdom, TQ2 7AA
      • Torbay Hospital
    • West Bromwich, England, United Kingdom, B71 4HJ
      • City Hospital - Birmingham
    • West Midlands, England, United Kingdom, B75 7RR
      • Good Hope Hospital Trust
    • Worthing, England, United Kingdom, BN11 2DH
      • Worthing Hospital
    • York, England, United Kingdom, Y031 8HE
      • Cancer Care Centre at York Hospital
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 7AB
      • Belfast City Hospital Trust
    • Dundonald, Northern Ireland, United Kingdom, BT16
      • Ulster Hospital
    • Portadown, Craigavon, Northern Ireland, United Kingdom, BT63 5QQ
      • Craigavon Area Hospital
  • Scotland
    • Aberdeen, Scotland, United Kingdom, AB25 2ZN
      • Aberdeen Royal Infirmary
    • Airdrie, Scotland, United Kingdom, ML6 0JF
      • Monklands General Hospital
    • Dumfries, Scotland, United Kingdom, DG1 4AP
      • Dumfries Royal Infirmary
    • Edinburgh, Scotland, United Kingdom, EH4 2XU
      • Western General Hospital
    • Glasgow, Scotland, United Kingdom, G51 4TF
      • Southern General Hospital
    • Inverness, Scotland, United Kingdom, 1V2 3UJ
      • Raigmore Hospital
    • Kirkcaldy, Scotland, United Kingdom, KY2 5AH
      • Victoria Hospital
    • Paisley, Scotland, United Kingdom
      • Royal Alexandra Hospital
  • Wales
    • Bangor, Wales, United Kingdom, LL57 2PW
      • Ysbyty Gwynedd
    • Gwent, Wales, United Kingdom
      • Nevill Hall Hospital
    • Swansea, Wales, United Kingdom, SA 2 8QA
      • Singleton Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Diagnosis of B-cell chronic lymphocytic leukemia (CLL) requiring therapy and meeting the following criteria:

  • Previously untreated disease
  • Peripheral blood morphology, excluding other leukemia and low-grade lymphoma in leukemic phase
  • Cell markers: CD5+, CD23+, SmIg (weak), CD79b-, FMC7-
  • Persistent lymphocytosis (greater than 10,000/mm^3)
  • At least 40% bone marrow infiltration

• Stage 0 or I progressive disease indicated by at least one of the following:

  • Persistent rise in lymphocyte count with doubling time less than 12 months
  • Downward trend in hemoglobin and/or platelet count
  • At least 50% increase in size of liver and/or spleen and/or lymph nodes
  • Appearance of lymphadenopathy, hepatomegaly, or splenomegaly

  • Constitutional symptoms caused by disease

    • Pyrexia
    • Night sweats
    • Weight loss OR
• Stage II or III

PATIENT CHARACTERISTICS:

Age:

• Not specified

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Bilirubin no greater than 2 times upper limit of normal (ULN)*
• SGOT/SGPT no greater than 2 times ULN* NOTE: * Unless due to CLL

Renal:

• Creatinine clearance at least 30 mL/min

Other:

• No other cancer or life-threatening disease
• Not pregnant
• Fertile patients must use effective contraception during and for 6 months after study therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• Not specified

Endocrine therapy

• No concurrent corticosteroids (e.g., dexamethasone) as antiemetics

Radiotherapy

• Not specified

Surgery

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

Collaborators and Investigators

• Sponsor: Leukemia Research Fund
• Collaborators: Medical Research Council
• Investigators: Study Chair: Daniel Catovsky, MD, Royal Marsden NHS Foundation Trust

Publications and helpful links

General Publications

• Else M, Cocks K, Crofts S, Wade R, Richards SM, Catovsky D, Smith AG; UK National Cancer Research Institute (NCRI) Chronic Lymphocytic Leukaemia Trials Group. Quality of life in chronic lymphocytic leukemia: 5-year results from the multicenter randomized LRF CLL4 trial. Leuk Lymphoma. 2012 Jul;53(7):1289-98. doi: 10.3109/10428194.2011.649479. Epub 2012 Mar 1.
• 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 Jun 1;29(16):2223-9. doi: 10.1200/JCO.2010.32.0838. Epub 2011 Apr 11.
• Wade R, Di Bernardo MC, Richards S, Rossi D, Crowther-Swanepoel D, Gaidano G, Oscier DG, Catovsky D, Houlston RS. Association between single nucleotide polymorphism-genotype and outcome of patients with chronic lymphocytic leukemia in a randomized chemotherapy trial. Haematologica. 2011 Oct;96(10):1496-503. doi: 10.3324/haematol.2011.043471. Epub 2011 Jun 9.
• Oscier D, Wade R, Davis Z, Morilla A, Best G, Richards S, Else M, Matutes E, Catovsky D; Chronic Lymphocytic Leukaemia Working Group, UK National Cancer Research Institute. Prognostic factors identified three risk groups in the LRF CLL4 trial, independent of treatment allocation. Haematologica. 2010 Oct;95(10):1705-12. doi: 10.3324/haematol.2010.025338. Epub 2010 May 29.
• Else M, Smith AG, Cocks K, Richards SM, Crofts S, Wade R, Catovsky D. Patients' experience of chronic lymphocytic leukaemia: baseline health-related quality of life results from the LRF CLL4 trial. Br J Haematol. 2008 Dec;143(5):690-7. doi: 10.1111/j.1365-2141.2008.07407.x. Epub 2008 Oct 18.
• Catovsky D, Richards S, Matutes E, Oscier D, Dyer M, 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 Jul 21;370(9583):230-239. doi: 10.1016/S0140-6736(07)61125-8.
• Dearden CE, Wade RL, Else M, et al.: The combination of fludarabine and cyclophosphamide has a beneficial effect on the incidence of hemolytic anemia in chronic lymphocytic leukemia: results from the UK LRF CLL4 trial. [Abstract] Blood 110 (11): A-2044, 2007.
• 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 Dec 20;30(36):4524-32. doi: 10.1200/JCO.2011.41.0852. Epub 2012 Oct 22.

Study record dates

Study Major Dates

• Study Start: October 1, 1999
• Study Completion (Actual): July 1, 2007

Study Registration Dates

• First Submitted: January 28, 2000
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): December 18, 2013
• Last Update Submitted That Met QC Criteria: December 17, 2013
• Last Verified: January 1, 2006

More Information

Terms related to this study

• Keywords: B-cell chronic lymphocytic leukemia; stage 0 chronic lymphocytic leukemia; stage I chronic lymphocytic leukemia; stage II chronic lymphocytic leukemia; stage III chronic lymphocytic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Prednisolone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Fludarabine; Fludarabine phosphate; Vincristine; Chlorambucil
• Other Study ID Numbers: CDR0000067454; LRF-CLL4; LRG-MRC-LEUK-CLL4; EU-99030; MRC-LEUK-CLL4; EUDRACT-58585610; ISRCTN58585610