Estimated Glomerular Filtration Rate Is an Independent Predictor of Outcome in High-Risk Myelodysplastic Syndrome (MDS) and Low Blast Count Acute Myeloid Leukaemia (AML) Patients Treated with Azacytidine (AZA). a Retrospective Study from the MDS Registry of the Hellenic MDS Study Group
Authors: Papageorgiou Sotirios , Papadopoulos Vasileios , Menelaos Papoutselis , Bouhla Anthi , Symeonidis Argiris , Galanopoulos Athanasios , Viniou Nora-Athina , Hatzimichael Eleftheria , Gogos Dimitrios , Zikos Panagiotis , Vassilakopoulos Theodoros P. , Kourakli Alexandra , Giannoulia Panagiota , Vrachiolias George , Megalakaki Aikaterini , Diamantopoulos Panagiotis T , Poulakidas Elias , Vardi Anna , Anagnostopoulos Achilles , Mparmparousi Despoina , Papaioannou Maria , Mpouronikou Eleni , Papadaki Helen A. , Dimou Maria , Panayiotidis Panayiotis , Pappa Vassiliki , Kotsianidis Ioannis 
Published: November 2019

Introduction. Myelodysplastic Syndrome (MDS) is a disease of the elderly. Apart from IPSS, IPSS-R and WPSS, several indexes incorporating patient comorbidities (such as the MDS CI index- Della Porta et al Haematologica 2011, the HCT-CI index - Sorror et al Blood 2005) and performance status (the GFM index- Itzykson et al Blood 2011) have been used to predict outcome in MDS patients treated with azacytidine (AZA). We sought to investigate the effect of comorbidities on the outcome after AZA in a large group of patients from the MDS registry of the Hellenic MDS Study Group.
Methods. The present study has been conducted as a retrospective observational cohort one. It included high-risk MDS and low blast count AML patients treated with AZA from 26 centers in Greece from 2007 to 2018. T-test and ANOVA were used to compare scale variables between two or more groups respectively. Univariate analysis of nominal and scale survival data was performed using Kaplan-Meier survival curves and Cox regression respectively. All variables achieving p<0.05 at univariate analysis were considered eligible for multivariate analysis; the latter was based on Cox regression method.
Results. We analyzed 536 consecutive patients. Patient characteristics are depicted in Table 1. The median follow-up period was 27.5±4.8 months. 371 patients received at least four cycles of AZA and 165 patients received less than 4 cycles of AZA. Patients who received ≥4 cycles of AZA did not differ from those who received <4 cycles regarding gender, age, estimated Glomerular Filtration Rate (eGFR), cardiovascular, renal, and tumor comorbidities. Significantly higher IPSS-R and GFM scores at baseline were found in the group of patients receiving < 4 cycles of AZA compared to patients who received ≥ 4 cycles of AZA (p=0.042 and 0.05 respectively), while transfusion dependence at baseline occurred more often in patients who received ≥ 4 cycles of AZA (p=0.039).
To assess the prognostic significance of risk factors on leukemia free survival (LFS) and overall survival (OS), univariate and multivariate analysis for the whole population was performed, as well as a landmark analysis for patients who were treated with at least 4 cycles of AZA. ECOG performance status and the presence of peripheral blasts were independent prognostic factors for LFS and OS for the whole cohort analysis while response to AZA and the presence of peripheral blasts were independent prognosticators for LFS and OS in the landmark analysis. In addition, prior low dose cytarabine was an independent adverse prognostic factor for LFS in the landmark analysis. As regards comorbidities, neither of MDS-CI, HCT-CI and GFM systems independently predicted LFS or OS in either analysis, but eGFR with a cut-off of 45 ml/min was a strong and independent prognosticator for LFS and OS in both the standard and the landmark analysis. Kaplan-Meier survival curves regarding LFS and OS at AZA initiation and landmark analysis after 4th cycle of AZA in relation with eGFR are shown in Figure 1.
Conclusion. This is the first study to demonstrate the importance of eGFR at baseline as a prognostic marker for LFS and OS in high-risk MDS and low-blast AML patients treated with AZA. The role of comorbidities and PS needs to be further evaluated in this patient group.

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