title: Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG).
abstract: To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P<0.0001). Univariate Cox regression analysis demonstrated that patients who did receive antibody treatment had a 1.42-fold higher risk of death (hazard ratio, 1.42; 95% confidence interval: 1.185-1.694). Therapies administered at relapse were very heterogeneous. Only 55 of 368 patients (14.9%) who started second-line treatment >24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901.
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany paula.cramer@uk-koeln.de.
authors: Paula
authors: P
authors: Cramer
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany Department for Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, Munich, Germany.
authors: Susanne
authors: S
authors: Isfort
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Jasmin
authors: J
authors: Bahlo
authors: Department III of Internal Medicine, University Hospital Ulm, Munich, Germany.
authors: Stephan
authors: S
authors: Stilgenbauer
authors: Department III of Internal Medicine, University Hospital Ulm, Munich, Germany.
authors: Hartmut
authors: H
authors: Döhner
authors: Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany.
authors: Manuela
authors: M
authors: Bergmann
authors: Specialized Practice for Hematology and Oncology and Day Hospital, Kronach, Germany.
authors: Martina
authors: M
authors: Stauch
authors: Department II of Internal Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Germany.
authors: Michael
authors: M
authors: Kneba
authors: Protestant Hospital Hamm, Clinic for Hematology, Oncology and Palliative Care, Hamm, Germany.
authors: Elisabeth
authors: E
authors: Lange
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Petra
authors: P
authors: Langerbeins
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Natali
authors: N
authors: Pflug
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Gabor
authors: G
authors: Kovacs
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Valentin
authors: V
authors: Goede
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Anna-Maria
authors: AM
authors: Fink
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Thomas
authors: T
authors: Elter
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Kirsten
authors: K
authors: Fischer
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Hospital Munich-Schwabing, Munich, Germany.
authors: Clemens-Martin
authors: CM
authors: Wendtner
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Michael
authors: M
authors: Hallek
authors: Department I of Internal Medicine and Center of Integrated Oncology Cologne-Bonn, University of Cologne, Munich, Germany.
authors: Barbara
authors: B
authors: Eichhorst
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003520:Cyclophosphamide / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000401:mortality* / Q000473:pathology; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage; D011446:Prospective Studies; D000069283:Rituximab / Q000008:administration & dosage; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011239:Prednisolone