The Prognostic Significance of Monocytopenia in Patients with Myelodysplastic Syndrome
Authors: Diamantopoulos Panagiotis T , Pappa Vassiliki , Viniou Nora-Athina , Kotsianidis Ioannis , Kourakli Alexandra , Symeonidis Argiris , Papageorgiou Sotirios , Solomou Elena E. , Pouli Anastasia , Panagiotidis Panagiotis , Dimou Maria , Zafeiropoulou Kalliopi , Karakatsanis Stamatis J. , Vardi Anna , Vassilakopoulos Theodoros P. , Tsokanas Dimitrios , Drakos George , Hontropoulos Spyros , Hatzimichael Eleftheria , Megalakaki Aikaterini , Repousis Panagiotis , Kotsopoulou Maria , Kaiafa Georgia , Papoutselis Menelaos Konstantinos , Sioni Anastasia , Charchalakis Nikolaos , Bouronikou Eleni , Vasilopoulos Georgios , Lazaris Vasileios , Spiliotopoulou Maria , Kontopidou Flora , Kontos Christos K. , Kalyva Stamatina , Hatzitolios Apostolos , Papadaki Helen A. , Anagnostopoulos Achilles , Anagnostopoulos Nikolaos , Galanopoulos Athanasios 
Published: November 2019

Background: The currently used prognostic systems for myelodysplastic syndromes (MDS) do not consider the prognostic role of monocytopenia, although monocytes may participate in the prognosis of the disease as part of the host immunity. Aim: We studied the prognostic significance of monocytopenia in patients with MDS registered in the Hellenic National MDS registry. Methods: We analyzed clinicopathological data from patients with MDS recorded in a large retrospective national registry. Patients with MDS/MPN were excluded, while patients treated with allogeneic hematopoietic cell transplantation were censored for overall survival (OS) and leukemia-free survival (LFS). IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results. Kaplan-Meier survival analysis and Cox regression analysis were performed for LFS and OS. Results: The study comprised 1719 patients with MDS per the 2008 WHO classification for MDS. The main characteristics of the patients are shown in Table 1. At the time of data cut-off, 818 patients were deceased and the median follow-up for the remaining 901 patients was 23.0 months. The median absolute monocyte count (AMC) was 0.30 x 109/L (0.00 - 0.99 x 109/L). Patients with excess blasts (RAEB1/2) tended to have lower AMCs (median 0.19 versus 0.32 for patients without excess blasts, p<0.0001) and lower AMCs were found in higher IPSS-R categories (very low, 0.37 x 109/L; low, 0.30 x 109/L; intermediate, 0.25 x 109/L; high, 0.16 x 109/L; very high, 0.20 x 109/L) while there was a highly significant difference between lower risk (very low and low) and higher risk (intermediate, high, very high) MDS (0.33 x 109/L vs 0.21 x 109/L, p<0.0001). In univariate analysis, patients with AMCs below 0.2 x 109/L had a median OS of 34.0 months vs 63.0 months for patients with higher AMCs (p<0.0001) with a hazard ratio (HR) for death of 1.57 (95% CI 1.37 - 1.81, p<0.0001). In a multivariate Cox regression model including hemoglobin below 10 g/dL, absolute neutrophil count (ANC) below 1.0 x 109/L, and platelet count below 100 x 109/L (all of them being prognostic for OS in univariate analysis), monocytopenia retained its prognostic significance (HR, 1.16; 95% CI, 1.00 - 1.36, p=0.049). There was a positive correlation between the AMC and the ANC (Pearson Correlation 0.393, p<0.0001). Nevertheless, in a model comprising of AMC and ANC, both variables were independently correlated to OS. Moreover, in a model including AMC below 0.2 x 109/L, the cytogenetic risk score per the IPSS-R, the number of cytopenias, and bone marrow blasts (categorized per the IPSS-R), no additional prognostic impact was found for AMC (HR, 1.01; 95% CI, 0.86 - 1.17; p=0.957). After stratification per the IPSS-R categories, low AMC was prognostic for low OS only in patients with low IPSS-R (median OS, 57 months for patients with low AMC vs 75 months for those with high AMC, p=0.039), but there was no additional prognostic impact after multivariate analysis. Moreover, AMC was prognostic for LFS, since patients with low AMCs (<0.2 x109/L) had a median LFS of 57.0 months, while the median LFS for patients with higher AMCs was not reached (HR, 2.47, 95% CI, 2.01 - 2.47, p<0.0001). In a Cox regression model including the above stated factors (cytopenias, bone marrow blasts, cytogenetic risk, and AMC), AMC retained its prognostic significance for LFS (HR, 1.27; 95% CI, 1.02 - 1.58; p=0.031).
In a subgroup of 162 patients treated with hypomethylating agents (HMAs), monocytopenia was not predictive or response to treatment, but low AMC was correlated to a shorter median progression free survival (27.0 months vs not reached for patients with higher AMC, p=0.001). This correlation was not translated into a survival benefit (survival after HMA initiation, 27.0 vs 28.0 months respectively, log rank p=0.213). Conclusions: Based on a large patient cohort, we found that patients with MDS with excess blasts as well as higher risk patients per the IPSS-R have low AMCs. Moreover, we showed that low AMCs are prognostic of lower OS in univariate analysis and of lower LFS in both univariate and multivariate analysis, highlighting a possible pathogenetic role for AMCs in MDS. Further analysis is needed to define the exact prognostic role of AMC in MDS.

Disclosures
Pappa: Amgen: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding. Symeonidis:MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.