Effect of FCGR2A and FCGR3A variants on CLL outcome.
Polymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 [0.37-0.8 CI]; P = .0017 and hazard ratio = 0.63 [0.44-0.9 CI]; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 [0.4-1.84 CI]; P = .7 and hazard ratio = 0.7 [0.41-1.18 CI]; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 [0.56-1.29 CI]; P = .44 and hazard ratio = 0.82 [0.47-1.42 CI]; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC.
Dornan
David
D
Molecular Diagnostics and Cancer Cell Biology, Genentech Inc, South San Francisco, CA, USA. dornan.david@gene.com
Spleiss
Olivia
O
Yeh
Ru-Fang
RF
Duchateau-Nguyen
Guillemette
G
Dufour
Annika
A
Zhi
Jianguo
J
Robak
Tadeusz
T
Moiseev
Sergey I
SI
Dmoszynska
Anna
A
Solal-Celigny
Philippe
P
Warzocha
Krzysztof
K
Loscertales
Javier
J
Catalano
John
J
Afanasiev
Boris V
BV
Larratt
Loree
L
Rossiev
Viktor A
VA
Bence-Bruckler
Isabelle
I
Geisler
Christian H
CH
Montillo
Marco
M
Wenger
Michael K
MK
Weisser
Martin
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived / Q000493:pharmacokinetics / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D017452:Receptors, IgG / Q000235:genetics*; D000069283:Rituximab; D016896:Treatment Outcome; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use
D058846:Antibodies, Monoclonal, Murine-Derived; C445323:FCGR2A protein, human; C496124:FCGR3A protein, human; D017452:Receptors, IgG; D000069283:Rituximab; D003520:Cyclophosphamide; D014740:Vidarabine; C024352:fludarabine