Neutrophil to Lymphocyte Ratio Is an Independent Prognostic Marker in Myelodysplastic Syndromes

Introduction

Neutrophil to lymphocyte ratio (NLR) is simple biomarker reflecting the balance between the inflammatory and immune responses. Several studies have demonstrated its utility as a predictor marker for overall mortality in several conditions including infection, cardiac, cancer, COVID, and surgery (Song et al., Scientific Reports2021). The pathogenesis of Myelodysplastic syndromes (MDS) is an interplay of stem cell somatic mutations, inflammatory milieu, and immune deregulation. Thus, we sought to interrogate the impact of NLR and outcomes in MDS patients (pts).

Methods

We quantified the NLR ratio in a large comprehensive MDS database. NLR was calculated dividing absolute neutrophils to lymphocyte count among those who had complete blood counts at time of diagnosis. Prior studies have defined range of normal NLR in general population as a range between 1-4. We divided pts into 2 groups: normal NLR (<4) and high NLCR (>=4). We compared demographics, baseline characteristics, response to treatment and outcomes among these 2 groups.

Results

Among 4347 MDS pts with quantified NLR, 466 pts (11%) had high NLR. The demographics and baseline characteristics were similar between those with high NLR and normal NLR except more t-MDS (29% vs 20%, p<.005), and more classified as lower risk by IPSS-M (i.e. very low to moderate low; 53% vs 20%, p< 0.005) for MDS pts with high NLR. There were differences in the somatic mutation profile of MDS pts with high vs normal NLR: ASXL-1 (29% vs 21%, p=0.006), CBL (6% vs 2%, 0.006), SETBP1 (7% vs 4%, p=0.035), and JAK-2 (10% vs 4%, p<0.005).

There was no difference in response to erythroid stimulating agents or lenalidomide based on NLR. However, the response rate to azacitidine was less among those with high NLR ratio, HI or better (HI+) was 24% vs 40%, p=0.02, and similar to decitabine treated pts (HI+ 21% vs 29% for high NLR compared to normal NLR, p=0.049)

The rate of acute myeloid leukemia (AML) transformation was 16.5 % for pts with high NLR and 31% for normal NLR, p<.005.

The median overall survival (mOS) was 31 mo (95%CI 24.5-37.9) for high NLR MDS pts compared to 34.7 mo for normal NLR pts (95% CI 32.7-36.7; p=0.017). Among pts who proceeded to allo-SCT, the mOS was 42 mo for pts with high NLR (n=32) compared to 59.7 mo with normal NLR (n=664; p=0.36).

In multivariable analysis adjusting for age and IPSS-M, high NLR was associated with worse OS (HR 1.6 (95% CI 1.33-2.0) (p= 0.005).

Conclusions

High NLR is a negative, independent prognostic factor in MDS. A proliferative genomic phenotype was observed among those with high NLR. Response to hypomethylating agents was inferior. The mOS was inferior with high NLR in MDS pts despite 50% less chance of progression to AML which warrants further investigation. Our future steps include assessing utility of NLR as biomarker for response to anti-inflammatory and immune based MDS treatments.

Komrokji:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Keros: Membership on an entity's Board of Directors or advisory committees; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy; Janssen: Consultancy; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chan:Novartis: Honoraria; Jazz: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Aptitude Health: Honoraria. Kuykendall:PharmaEssentia: Honoraria; Protagonist Therapeutics: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Research Funding. Lancet:Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board; Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board. Sallman:Agios: Consultancy; Abbvie: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding.