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

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.

Sex

All

Minimum age

18 Years

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

• BACKGROUNDKurtz 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. PMID 31280963
• BACKGROUNDDimier 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. PMID 29255066
• BACKGROUNDKutsch 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. PMID 39050548
• BACKGROUNDEichhorst 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. PMID 27216274
• 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.