Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial.
Despite promising results with targeted drugs, chemoimmunotherapy with fludarabine, cyclophosphamide (FC), and rituximab (R) remains the standard therapy for fit patients with untreated chronic lymphocytic leukemia (CLL). Herein, we present the long-term follow-up of the randomized CLL8 trial reporting safety and efficacy of FC and FCR treatment of 817 treatment-naïve patients with CLL. The primary end point was progression-free survival (PFS). With a median follow-up of 5.9 years, median PFS were 56.8 and 32.9 months for the FCR and FC group (hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.50-0.69, P < .001). Median overall survival (OS) was not reached for the FCR group and was 86.0 months for the FC group (HR, 0.68; 95% CI, 0.54-0.89, P = .001). In patients with mutated IGHV (IGHV MUT), FCR improved PFS and OS compared with FC (PFS: HR, 0.47; 95% CI, 0.33-0.68, P < .001; OS: HR, 0.62; 95% CI, 0.34-1.11, P = .1). This improvement remained applicable for all cytogenetic subgroups other than del(17p). Long-term safety analyses showed that FCR had a higher rate of prolonged neutropenia during the first year after treatment (16.6% vs 8.8%; P = .007). Secondary malignancies including Richter's transformation occurred in 13.1% in the FCR group and in 17.4% in the FC group (P = .1). First-line chemoimmunotherapy with FCR induces long-term remissions and highly relevant improvement in OS in specific genetic subgroups of fit patients with CLL, in particular those with IGHV MUT. This trial was registered at www.clinicaltrials.gov as #NCT00281918.
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Kirsten
K
Fischer
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Jasmin
J
Bahlo
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Anna Maria
AM
Fink
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Valentin
V
Goede
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Carmen Diana
CD
Herling
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Paula
P
Cramer
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Petra
P
Langerbeins
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Julia
J
von Tresckow
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Anja
A
Engelke
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Christian
C
Maurer
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Gabor
G
Kovacs
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Marco
M
Herling
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
Eugen
E
Tausch
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Karl-Anton
KA
Kreuzer
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany;
Barbara
B
Eichhorst
Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Kiel, Germany;
Sebastian
S
Böttcher
Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia;
John F
JF
Seymour
Division of Experimental Oncology and Department of Onco-Hematology, Università Vita-Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Scientifico San Raffaele, Milano, Italy;
Paolo
P
Ghia
Princess Alexandra Hospital, Brisbane, Australia; University of Queensland, Brisbane, Australia;
Paula
P
Marlton
Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Kiel, Germany;
Michael
M
Kneba
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany; Department of Hematology, Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical Medicine, Klinikum Schwabing, Munich, Germany; and.
Clemens-Martin
CM
Wendtner
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
Hartmut
H
Döhner
Department of Internal Medicine III, University of Ulm, Ulm, Germany;
Stephan
S
Stilgenbauer
Department I for Internal Medicine and Center of Integrated Oncology, University of Cologne, Cologne, Germany; Cluster of Excellence Cellular Stress Responses in Aging Associated Diseases, University of Cologne, Cologne, Germany.
Michael
M
Hallek
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects / Q000379:methods; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000453:epidemiology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D000069283:Rituximab / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014740:Vidarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*
D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine