Impact of red blood cell transfusion dose density on progression-free survival in patients with lower-risk myelodysplastic syndromes

Louise de Swart, Simon Crouch, Marlijn Hoeks, Alex Smith, Saskia Langemeijer, Pierre Fenaux, Argiris Symeonidis, Jaroslav Cermâk, Eva Hellström-Lindberg, Reinhard Stauder, Guillermo Sanz, Moshe Mittelman, Mette Skov Holm, Luca Malcovati, Krzysztof Mądry, Ulrich Germing, Aurelia Tatic, Aleksandar Savic, Antonio Medina Almeida, Njetocka Gredelj-Simec, Agnes Guerci-Bresler, Odile Beyne-Rauzy, Dominic Culligan, Ioannis Kotsianidis, Raphael Itzykson, Corine van Marrewijk, Nicole Blijlevens, David Bowen, Theo de Witte, EUMDS Registry Participants, Louise de Swart, Simon Crouch, Marlijn Hoeks, Alex Smith, Saskia Langemeijer, Pierre Fenaux, Argiris Symeonidis, Jaroslav Cermâk, Eva Hellström-Lindberg, Reinhard Stauder, Guillermo Sanz, Moshe Mittelman, Mette Skov Holm, Luca Malcovati, Krzysztof Mądry, Ulrich Germing, Aurelia Tatic, Aleksandar Savic, Antonio Medina Almeida, Njetocka Gredelj-Simec, Agnes Guerci-Bresler, Odile Beyne-Rauzy, Dominic Culligan, Ioannis Kotsianidis, Raphael Itzykson, Corine van Marrewijk, Nicole Blijlevens, David Bowen, Theo de Witte, EUMDS Registry Participants

Abstract

Progression-free survival (PFS) of patients with lower-risk myelodysplastic syndromes (MDS) treated with red blood cell transfusions is usually reduced, but it is unclear whether transfusion dose density is an independent prognostic factor. The European MDS Registry collects prospective data at 6-monthly intervals from newly diagnosed lower-risk myelodysplastic syndromes patients in 16 European countries and Israel. Data on the transfusion dose density - the cumulative dose received at the end of each interval divided by the time since the beginning of the interval in which the first transfusion was received - were analyzed using proportional hazards regression with time-varying co-variates, with death and progression to higher-risk MDS/acute myeloid leukemia as events. Of the 1,267 patients included in the analyses, 317 died without progression; in 162 patients the disease had progressed. PFS was significantly associated with age, EQ-5D index, baseline World Health Organization classification, bone marrow blast count, cytogenetic risk category, number of cytopenias, and country. Transfusion dose density was inversely associated with PFS (P<1×10-4): dose density had an increasing effect on hazard until a dose density of 3 units/16 weeks. The transfusion dose density effect continued to increase beyond 8 units/16 weeks after correction for the impact of treatment with erythropoiesis-stimulating agents, lenalidomide and/or iron chelators. In conclusion, the negative effect of transfusion treatment on PFS already occurs at transfusion densities below 3 units/16 weeks. This indicates that transfusion dependency, even at relatively low dose densities, may be considered as an indicator of inferior PFS. This trial was registered at www.clinicaltrials.gov as #NCT00600860.

Copyright© 2020 Ferrata Storti Foundation.

Figures

Figure 1
Figure 1
Distribution of dose densities of all transfused patients in the interval preceding the 1-year landmark. Frequency: number of patients in each dose density ranging from >0 to 0.2 units per month to >6 units per mont.
Figure 2
Figure 2
Progression-free survival and risk of progression according to transfusion status at the landmark of visit 3 (1 year after registration). (A) Kaplan-Meier plot of progression-free survival (PFS) of patients who did or did not receive transfusions by the landmark (visit 3). (B) Kaplan-Meier plot of PFS of patients who received transfusions at a low density (0.87 units/month) by the landmark versus PFS of patients who did not receive transfusions; (C) Kaplan-Meier plot of time to progression of patients surviving until progression subdivided according to transfusion burden or not as in panel B; (D) Kaplan-Meier plot of PFS of patients receiving transfusions at densities according to the revised International Working Group criteria: low dose density: >0– <0.75 units per month; mid dose density: 0.75 - 1.75 units per month; high dose density >1.75 units per month.
Figure 3
Figure 3
Influence of dose density on progression-free survival. (A) Dose density effect on progression-free survival (PFS) in an univariate analysis. (B) Dose density effect on PFS in a multivariate regression model unadjusted for the three treatment variables. (C) Dose density effect on PFS in a multivariate regression model adjusted for treatment with either erythropoiesis-stimulating agent, Iron chelation or lenalidomide.

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