FCR or BR in Patients With Previously Untreated B-Cell Chronic Lymphocytic Leukemia

Phase III Trial of Combined Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab (FCR) Versus Bendamustine and Rituximab (BR) in Patients With Previously Untreated Chronic Lymphocytic Leukaemia

RATIONALE: Drugs used in chemotherapy, such as fludarabine, cyclophosphamide, and bendamustine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known whether giving fludarabine and cyclophosphamide together with rituximab is more effective than giving bendamustine together with rituximab in treating chronic lymphocytic leukemia.

PURPOSE: This randomized phase III trial is studying fludarabine, cyclophosphamide, and rituximab to see how well they work compared with bendamustine and rituximab in treating patients with previously untreated B-cell chronic lymphocytic leukemia.

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Biological: Rituximab; Drug: Cyclophosphamide; Drug: Fludarabine; Drug: Bendamustine

Detailed Description

OBJECTIVES:

• To compare the therapeutic efficacy of fludarabine phosphate, cyclophosphamide, and rituximab vs bendamustine hydrochloride and rituximab in patients with previously untreated B-cell chronic lymphocytic leukemia.
• To compare the incidence of major side effects (e.g., myelosuppression) associated with these regimens in these patients.
• To compare the rate of infections and secondary neoplasias in patients treated with these regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to country and disease stage. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive fludarabine phosphate IV and cyclophosphamide IV on days 1-3. Patients also receive rituximab IV on day 0 of course 1 and on day 1 of courses 2-6. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive bendamustine hydrochloride IV on days 1 and 2. Patients also receive rituximab as in arm I. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Patients complete quality of life questionnaires (EORTC-C30 and EURO-QOL) at baseline and then at 12, 24, 36, 48, and 60 months.

After completion of study therapy, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year thereafter.

• Study Type: Interventional
• Enrollment (Actual): 564
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Cologne, Germany, D-50924
    • Medizinische Universitaetsklinik I at the University of Cologne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Confirmed diagnosis of B-cell chronic lymphocytic leukemia (CLL) meeting 1 of the following criteria:
• Binet stage C disease or stage B or A disease requiring treatment
• Binet stage B or A disease meeting ≥ 1 of the following:

• B-symptoms (e.g., night sweats, weight loss ≥ 10% within the past 6 months, fevers > 38°C or 100.4°F for ≥ 2 weeks without evidence of infection) or constitutional symptoms (e.g., fatigue)

  • Progressive lymphocytosis, defined as peripheral lymphocyte count > 5 x 10^9/L (i.e., > 50% increase over a 2-month period or doubling of peripheral blood lymphocyte count < 6 months)
  • Evidence of progressive marrow failure as manifested by the development/worsening of anemia and/or thrombocytopenia
  • Massive, progressive, or painful splenomegaly or hypersplenism

  • Massive lymph nodes or lymph node clusters (> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy

    • No 17p deletion by FISH
    • No aggressive B-cell cancer, such as Richter syndrome

PATIENT CHARACTERISTICS:

• WHO performance status 0-2
• Life expectancy ≥ 6 months
• Total bilirubin ≤ 2 times upper limit of normal (ULN) (unless directly attributable to CLL)
• AST and ALT ≤ 2 times ULN (unless directly attributable to CLL)
• Creatinine clearance ≥ 70 mL/min (creatinine clearance is to be calculated only in patients with serum creatinine ≥ 1.1 mg/dL)
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for ≥ 6 months after completion of study therapy
• Hepatitis B and C negative
• HIV negative
• CIRS score > 6 or a single score of 4 for one organ category
• No active secondary malignancy requiring treatment, except basal cell carcinoma or malignant tumor curatively treated by surgery, or successfully treated secondary malignancies in complete remission > 5 years prior to enrollment
• No history of anaphylaxis following exposure to monoclonal antibodies
• No active bacterial, viral, or fungal infection
• No medical condition requiring prolonged use of oral corticosteroids (i.e., > 1 month)
• No cerebral dysfunction or legal incapacity
• No circumstance that would preclude completion of the study or the required follow-up

PRIOR CONCURRENT THERAPY:

• No prior CLL specific-chemotherapy, radiotherapy, and/or immunotherapy

  • Prednisolone administered immediately prior to initiation of study therapy allowed for very high lymphocyte counts
• No concurrent participation in another clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FCR	Biological: Rituximab; cycle 1: 375 mg/m² i.v., day 0, q28d cycle 2-6: 500 mg/m² i.v., day 1, q28d; Other Names: Rituxan; Mabthera; Drug: Cyclophosphamide; cycle 1-6: 250 mg/m² i.v., days 1-3, q28d; Other Names: Endoxan; Drug: Fludarabine; cycle 1-6: 25 mg/m² i.v., days 1-3, q28d; Other Names: Fludura
Experimental: BR	Biological: Rituximab; cycle 1: 375 mg/m² i.v., day 0, q28d cycle 2-6: 500 mg/m² i.v., day 1, q28d; Other Names: Rituxan; Mabthera; Drug: Bendamustine; cycle 1-6: 90mg/m² i.v., day 1-2, q28d; Other Names: Treanda; Levact; Ribomustin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival rate after 24 months	estimated time point when 198 needed events for the final analysis(PD or deaths) have occured.	2008-2015

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minimal residual disease, complete response rates, and partial response rates	done within the final analysis	2008-2015
Duration of remission	done within the final analysis	2008-2015
Event-free survival	done within the final analysis	2008-2015
Overall survival	done within the final analysis	2008-2015
Overall response rate	done within the final analysis	2008-2015
Response rates in and survival times in biological subgroups	done within the final analysis	2008-2015
Toxicity rates	done within the final analysis	2008-2015
Quality of life	done within the final analysis	2008-2015
Standard safety analysis	done within the final analysis	2008-2015

Collaborators and Investigators

• Sponsor: German CLL Study Group
• Collaborators: Mundipharma Pte Ltd.; Roche Pharma AG
• Investigators: Principal Investigator: Barbara Eichhorst, MD, Medizinische Universitaetsklinik I at the University of Cologne

Publications and helpful links

General Publications

• Al-Sawaf O, Robrecht S, Bahlo J, Fink AM, Cramer P, von Tresckow J, Maurer C, Bergmann M, Seiler T, Lange E, Kneba M, Stilgenbauer S, Dohner H, Kiehl MG, Jager U, Wendtner CM, Fischer K, Goede V, Hallek M, Eichhorst B, Hopfinger G. Impact of gender on outcome after chemoimmunotherapy in patients with chronic lymphocytic leukemia: a meta-analysis by the German CLL study group. Leukemia. 2017 Oct;31(10):2251-2253. doi: 10.1038/leu.2017.221. Epub 2017 Jul 12. No abstract available.
• Kurtz DM, Esfahani MS, Scherer F, Soo J, Jin MC, Liu CL, Newman AM, Duhrsen U, Huttmann A, Casasnovas O, Westin JR, Ritgen M, Bottcher S, Langerak AW, Roschewski M, Wilson WH, Gaidano G, Rossi D, Bahlo J, Hallek M, Tibshirani R, Diehn M, Alizadeh AA. Dynamic Risk Profiling Using Serial Tumor Biomarkers for Personalized Outcome Prediction. Cell. 2019 Jul 25;178(3):699-713.e19. doi: 10.1016/j.cell.2019.06.011. Epub 2019 Jul 4.
• Dimier N, Delmar P, Ward C, Morariu-Zamfir R, Fingerle-Rowson G, Bahlo J, Fischer K, Eichhorst B, Goede V, van Dongen JJM, Ritgen M, Bottcher S, Langerak AW, Kneba M, Hallek M. A model for predicting effect of treatment on progression-free survival using MRD as a surrogate end point in CLL. Blood. 2018 Mar 1;131(9):955-962. doi: 10.1182/blood-2017-06-792333. Epub 2017 Dec 18.
• Kutsch N, Robrecht S, Fink A, Lange E, Weide R, Kiehl MG, Sokler M, Schlag R, Vehling-Kaiser U, Kochling G, Ploger C, Gregor M, Plesner T, Clausen MR, Oschlies I, Ritgen M, Herling M, Fischer K, Dohner H, Wendtner CM, Kreuzer KA, Stilgenbauer S, Hallek M, Bottcher S, Klapper W, Eichhorst B. The role of trephine bone marrow biopsies in the era of measurable residual disease-Results from the CLL10 trial of the German CLL Study Group (GCLLSG). Hemasphere. 2024 Jul 24;8(7):e126. doi: 10.1002/hem3.126. eCollection 2024 Jul. No abstract available.
• Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, Lange E, Koppler H, Kiehl M, Sokler M, Schlag R, Vehling-Kaiser U, Kochling G, Ploger C, Gregor M, Plesner T, Trneny M, Fischer K, Dohner H, Kneba M, Wendtner CM, Klapper W, Kreuzer KA, Stilgenbauer S, Bottcher S, Hallek M; international group of investigators; German CLL Study Group (GCLLSG). First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016 Jul;17(7):928-942. doi: 10.1016/S1470-2045(16)30051-1. Epub 2016 May 20.
• Kovacs G, Robrecht S, Fink AM, Bahlo J, Cramer P, von Tresckow J, Maurer C, Langerbeins P, Fingerle-Rowson G, Ritgen M, Kneba M, Dohner H, Stilgenbauer S, Klapper W, Wendtner CM, Fischer K, Hallek M, Eichhorst B, Bottcher S. Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group. J Clin Oncol. 2016 Nov 1;34(31):3758-3765. doi: 10.1200/JCO.2016.67.1305.

Helpful Links

• Click here for more information about this study: CLL10 (German CLL Study Group)

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2008
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: October 8, 2008
• First Submitted That Met QC Criteria: October 8, 2008
• First Posted (Estimated): October 9, 2008

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 30, 2024
• Last Verified: December 1, 2024

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; stage IV chronic lymphocytic leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Bendamustine Hydrochloride; Rituximab; Cyclophosphamide; Fludarabine
• Other Study ID Numbers: CLL10; CDR0000616169 (Other Identifier: Clinical Data Repository); 2007-007587-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO