Diagnostic Red Blood Cell Distribution Width As a Prognostic Factor in Acute Myeloid Leukemia
Authors: Vucinic Vladan , Ruhnke Leo , Sockel Katja , Röhnert Maximilian Alexander , Backhaus Donata , Brauer Dominic , Franke Georg-Nikolaus , Niederwieser Dietger , Bornhäuser Martin , Rollig Christoph , Platzbecker Uwe , Schwind Sebastian , Jentzsch Madlen 
Published: November 2021

Abstract
Introduction: A high red blood cell distribution width (RDW) mirrors dysregulated erythrocyte homeostasis and is associated with a higher mortality in several solid cancers and myelodysplastic syndrome (MDS). A high RDW may also identify individuals more likely to develop a MDS or an acute myeloid leukemia (AML). The prognostic relevance of the RDW in patients diagnosed with AML has not been previously evaluated.
Methods: We analyzed 294 newly diagnosed AML patients (median age at diagnosis 61, range 14-77 years [y]) that underwent an allogeneic hematopoietic stem cell transplantation (HSCT) at the University Hospital Leipzig in complete remission (CR, 63%), CR with incomplete peripheral recovery (CRi, 18%) or with active disease (19%). The RDW was measured at diagnosis and a cut-off of 20.7% was determined using the R package "OptimalCutpoints" to define patients with a low (87%) or high (13%) diagnostic RDW. Disease risk was assessed according to European LeukemiaNet (ELN) 2017. Median follow up after HSCT was 3.0 y. To verify the results irrespective of the consolidating therapy, a validation set of 392 AML patients (median age at diagnosis 63, range 18-87 years) treated at the University Hospital Dresden was analyzed. Here, 46% of patients received chemotherapy alone and patients that underwent allogeneic HSCT were censored at the time of HSCT.
Results: The diagnostic RDW was above the local upper limit of normal (&gt; 15%) in the majority (73%) of AML patients. The RDW as continuous parameter was higher in patients with AML developing from an antecedent myeloid disorder (sAML, after MDS, MPN, or MDS/MPN) than in patients with de novo (P=.01) or treatment-related AML (tAML, after lymphatic or solid neoplasm, P=.02, Figure 1A). A higher RDW was also observed in patients harboring gene mutations previously linked to AML of secondary origin (i.e. mutated JAK2 [P=.03], ASXL1 [P=.004], or spliceosome mutation [P=.03, compromising SF3B1, SRSF2, U2AF1, and ZRSR2, Figure 1B], which was particularly driven by SRSF2 mutations [P=.002]). Adapting an optimal cut, a higher RDW (&gt; 20.7%) was associated with a higher non-relapse mortality (NRM, P=.02), shorter overall survival (OS, P=.009, Figure 1C), but similar relapse incidence (P=.96). In multivariate analyses, the RDW retained its prognostic significance for a higher NRM after adjustment for age at diagnosis. A RDW &gt; 20.7% was also associated with lower hemoglobin levels at diagnosis and a trend for lower incidence of NPM1 mutations (P=.06), which are enriched in de novo AML. In contrast, RDW levels were not associated with chromosomal abnormalities (P=.72) or ELN2017 disease risk (P=.55). Despite known association of a high RDW with a higher cardiovascular/inflammatory risk, neither the comorbidity index at HSCT (HCT-CI, P=.77) nor the incidence of an acute (P=1) or chronic (P=.63) graft-versus-host disease differed according to the diagnostic RDW. Comparably, in the validation set, higher RDW levels were observed in patients with sAML compared to de novo (P=.02) or tAML (P=.02). Introducing the established 20.7% cut into the validation set, patients with high RDW levels again had lower hemoglobin levels at diagnosis (P&lt;.001), less NPM1 mutations (P=.005) and no different ELN2017 disease risk (P=.25). A high RDW in the validation set was associated with a significantly shorter OS (P&lt;.001, Figure 1D) and shorter event-free survival (P=.05).
Conclusions: Our study is the first to evaluate the diagnostic RDW in AML patients. Patients with a secondary AML or secondary AML-associated gene mutations had higher diagnostic RDW levels. The presence of a high diagnostic RDW identifies patients with worse outcomes, irrespective of the ELN2017 risk classification and the applied consolidation therapy. This cost-effective and fast to assess parameter may help to personalize AML patient treatment.
Figure 1 Figure 1.

Disclosures
Vucinic: Gilead: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; MSD: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Janssen: Honoraria, Other: Travel Sponsoring. Backhaus: Bayer: Other: Current Employment of Family Member. Franke: BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; MSD: Honoraria; Jazz Pharmaceuticals: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Geron: Honoraria. Schwind: Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Jentzsch: Astellas: Honoraria; Jazz Pharmaceuticals: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.