title: Neutrophil to Lymphocyte Ratio is Associated With Outcome During Ipilimumab Treatment.
abstract: BACKGROUND
  Ipilimumab (IPI) and BRAF inhibitors (BRAFi) improve survival in melanoma, but not all patients will benefit and toxicity can be significant. Pretreatment neutrophil to lymphocyte ratio (NLR) has been associated with outcome in IPI-treated patients, but has not been studied during treatment or in BRAFi-treated patients.
  
  
  METHODS
  Using a prospectively maintained database, patients with unresectable stage III or IV melanoma treated with IPI or a BRAFi (vemurafenib or dabrafenib as monotherapy) from 2006 to 2011 were identified. NLR was calculated before treatment and at 3-week intervals after treatment initiation until 9weeks. Baseline NLR was tested for association with overall survival (OS), progression free survival (PFS), and clinical response to treatment. On-treatment NLRs were tested for association with the same outcomes using landmark survival analyses and time-dependent Cox regression models. The association of relative change of NLR from baseline with outcomes was also examined. A multivariate model tested the association of NLR and OS/PFS with additional clinical factors.
  
  
  RESULTS
  There were 197 IPI patients and 65 BRAFi patients. In multivariable analysis adjusting for M stage, and disease type (in OS)/gender (in PFS), an NLR value of 5 or above at every timepoint was associated with worse OS (HR 2.03-3.37, p<0.001), PFS (HR 1.81-2.51, p<0.001), and response to therapy (OR 3.92-9.18, p<0.007), in the IPI cohort. In addition, a >30% increase in NLR above baseline at any timepoint was associated with a worse OS and PFS (HR 1.81 and 1.66, p<0.004). In BRAFi patients, NLR was not consistently associated with outcomes.
  
  
  CONCLUSIONS
  A high NLR, whether measured prior to or during treatment with IPI, is associated with worse OS, PFS, and clinical response in patients with advanced melanoma. An increasing NLR from baseline during treatment was correlated with worse OS and PFS in IPI-treated patients. In comparison, as NLR was not associated with outcomes in BRAFi patients, NLR may have a uniquely predictive value in patients treated with immunotherapy.
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States. Electronic address: cassidym@mskcc.org.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Cassidy
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Wolchok
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Junting
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
authors.forename: Katherine S
authors.initials: KS
authors.lastname: Panageas
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY, United States.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Coit
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States; Weill Cornell Medical College, New York, NY, United States.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ariyan
mesh_terms: D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D000074324:Ipilimumab / Q000627:therapeutic use*; D008214:Lymphocytes / Q000166:cytology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009504:Neutrophils / Q000166:cytology; D010091:Oximes / Q000627:therapeutic use; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000074322:Antineoplastic Agents, Immunological; D007093:Imidazoles; D000074324:Ipilimumab; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib
keywords: BRAF inhibitors; Immunotherapy; Melanoma; NLR; Neutrophil to lymphocyte ratio