Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Relapsed/Refractory Acute Myeloid Leukemia
Authors: Mushtaq Muhammad Umair , Chaudhary Sibgha Gull , Guru Murthy Guru Subramanian , Hall Aric C. , Atallah Ehab L. , Mattison Ryan J. 
Published: October 2019

Abstract
Background
The inflammatory and immune response in tumor microenvironment plays a critical role in cancer progression. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor in solid and lymphoid malignancies. We explored the association of NLR with response to chemotherapy and overall survival (OS) in patients with relapsed/refractory acute myeloid leukemia (RR-AML).
Methods
A single-center retrospective study was conducted, including 63 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. Refractory AML was defined as failure to achieve remission and <50% reduction in myeloblasts after one or more courses of induction chemotherapy according to the Center for International Blood and Marrow Transplant Research (CIBMTR) reporting criteria. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and Kaplan-Meier analyses, using log-rank test, were performed. Cox regression analyses were conducted to correlate factors with OS. Hazard ratios (HR) and adjusted HR (aHR) with 95% confidence intervals (CI) were obtained. Statistical significance was considered at P<0.05.
Results
The study included 63 patients with relapsed (57%) or refractory (43%) AML. Median age was 58 years and 59% of patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (25%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (6%) and AML not otherwise specified (43%). Cytogenetics were good (5%), intermediate (68%) and poor (27%) with normal (46%), complex (17.5%) and trisomy (14%) being common karyotypes. Frequent molecular abnormalities were NPM1 (21%), FLT3-ITD (17.5%), FLT3-TKD (8%), DNMT3A (6%) and CEBPA (5%). AML risk status was good (19%), intermediate (36.5%) and poor (44.5%), based on cytogenetic and molecular abnormalities as defined by the ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 11% of patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% of patients. Median values for clinical factors were: hemoglobin 9.2 g/dL, platelets 43 K/uL, leukocytes 1.7 K/uL, neutrophils 262 /uL, lymphocytes 820 /uL and LDH 211 U/L. Median bone marrow cellularity was 50% with 35% myeloblasts. Median NLR was 0.22 (mean 1.54) and 11% patients had NLR of 3 or more. Salvage chemotherapy included MEC (71%), CLAG-M (24%) and CLAG (5%). Complete remission (CR) was noted in 36.5% patients, 8% of patients had CR with incomplete hematologic recovery (CRi) and 55.5% patients were refractory. Thirty patients (48%) received HSCT, of which 40% (n=12/30) were refractory or relapsed. After index salvage regimen, about half of patients received one (33%) or two (16%) lines of further chemotherapy. At last follow-up, 32% of patients were in CR and 62% had relapsed or refractory disease. Nineteen (30%) patients were alive at last follow-up with a median OS of 8.1 months (95% CI 5.0-11.1). Significant correlates of poor OS included MDS-related AML (HR 2.19, 95% CI 1.13-4.27, P=0.021) and therapy-related AML (HR 4.02, 95% CI 1.16-13.90, P=0.028) compared to de-novo AML, poor-risk AML (HR 3.09, 95% CI 1.18-8.10, P=0.022) compared to good-risk AML, refractory to salvage chemotherapy (HR 7.04, 95% CI 3.51-14.14, P<0.001) and high NLR (HR 1.13, 95% CI 1.04-1.23, P=0.003) while HSCT (HR 0.25, 95% CI 0.13-0.48, P<0.001) predicted better OS. Relapsed vs refractory AML was not associated with OS. In age- and gender-adjusted multivariate model, MDS-related AML (aHR 3.85, 95% CI 1.68-8.87, P=0.002), therapy-related AML (aHR 4.72, 95% CI 1.10-20.31, P=0.037), refractory to salvage chemotherapy (aHR 12.93, 95% CI 4.95-33.78, P<0.001), HSCT (aHR 0.12, 95% CI 0.05-0.27, P<0.001) and high NLR (aHR 1.14, 95% CI 1.05-1.25, P=0.004) independently predicted OS. Median OS in patients with NLR of 3 or more was 3.4 months (95% CI 3.2-3.7) versus 9.2 months (95% CI 7.1-11.3) in those with NLR <3 (P=0.040).
Conclusion
High NLR independently predicts poor OS in RR-AML patients. Our findings warrant further studies with a large prospective cohort to explore the prognostic significance of NLR and incorporate it in AML risk assessment.

Disclosures
Atallah: BMS: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy; Pfizer: Consultancy.