Introduction: Red cell distribution width (RDW) provides a quantitative measure of anisocytosis and it is associated with the presence of subclinical systemic inflammation and a poor outcome in a variety of diseases when elevated. Anisocytosis is a feature of primary myelofibrosis (PMF) but it’s prognostic role in PMF has not yet been evaluated. ----- Patients and methods: 33 newly-diagnosed patients with PMF were analyzed. Baseline RDW values were obtained in addition to CRP, LDH, complete blood count, iron metabolism parameters and JAK2 V617F mutational status. Patients were staged according to IPSS prognostic scoring system, liver and spleen size were assessed by palpation. ----- Results: Median RDW was 19.0% (15.2%-22.5%). RDW correlated significantly with hemoglobin level (p=0.005), CRP (p=0.031), spleen size (p=0.036) and IPSS score (p=0.003). Patients with more pronounced anisocytosis had an inferior overall survival (OS) – very-high RDW (≥19.0%) vs. high RDW (15.1%-18.9%) subgroup, HR 5.37, p=0.002. RDW remained significantly associated with OS (p=0.002) in a multivariate model including IPSS score, hemoglobin level and CRP. ----- Conclusion: A higher degree of anisocytosis is associated with more advanced disease features and a decreased overall survival. RDW encompasses standard prognostic score and may help in the rapid detection of patients with an unfavorable prognosis

Hariš, Višnja

Jakšić, Ozren

Kušec, Rajko

Lucijanić, Marko

Mitrović, Zdravko

Pejša, Vlatko

Piršić, Mario

Prka, Željko

Tomasović-Lončarić, Čedna

Vasilj, Tamara

Štoos-Veić, Tajana

Marko Lucijanic

Vlatko Pejsa

Ozren Jaksic

Zdravko Mitrovic

Cedna Tomasovic-Loncaric

Tajana Stoos-Veic

Zeljko Prka

Mario Pirsic

Visnja Haris

Tamara Vasilj

Rajko Kusec

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Acta Haematologica

The Degree of Anisocytosis Predicts Survival in Patients with Primary Myelofibrosis

Veterinary medicine - Repository of PHD, master's thesis

The degree of anisocytosis predicts survival in patients with primary myelofibrosis

University of Zagreb Repository

University of Zagreb Medical School Repository

      Središnja medicinska knjižnica     Lucijanić M., Pejša V., Jakšić O., Mitrović Z., Tomasović-Lončarić Č., Štoos-Veić T., Prka Ž., Piršić M., Hariš V., Vasilj T., Kušec R. (2016) The degree of anisocytosis predicts survival in patients with primary myelofibrosis. Acta Haematologica, 136 (2). pp. 98-100. ISSN 0001-5792   https://www.karger.com/Journal/Home/223829  http://dx.doi.org/10.1159/000445247     http://medlib.mef.hr/2756     University of Zagreb Medical School Repository http://medlib.mef.hr/ Title:  The degree of anisocytosis predicts survival in patients with primary myelofibrosis  Auhors:  Marko Lucijanica, Vlatko Pejsaa, b, Ozren Jaksica, b, Zdravko Mitrovica, Cedna Tomasovic-Loncaricc, Tajana Stoos-Veicd, e, Zeljko Prkaa, Mario Pirsica, Visnja Harisa, Tamara Vasilja, Rajko Kuseca, b, f  Affiliations:  a Department of Hematology, University Hospital Dubrava, Zagreb, Croatia b University of Zagreb, School of Medicine, Zagreb, Croatia  c Department of Pathology, University Hospital Dubrava, Zagreb, Croatia d Department of Clinical Cytology and Cytometry, University Hospital Dubrava, Zagreb, Croatia e University of Osijek, School of Medicine, Osijek, Croatia f Clinical Institute of Laboratory Diagnosis, Divison of Molecular Diagnosis and Genetics, University Hospital Dubrava, Zagreb, Croatia   Corresponding author:  Marko Lucijanic; Department of Hematology, University Hospital Dubrava, Avenija Gojka Suska 6, 10000 Zagreb, Croatia; email: markolucijanic@yahoo.com   Conflicts of interest: None Funding: None Informed consent:  All subjects in whom molecular studies were performed provided written informed consent. Ethical approval: The study was approved by the University Hospital Dubrava’s review board. Abstract: Introduction: Red cell distribution width (RDW) provides a quantitative measure of anisocytosis and it is associated with the presence of subclinical systemic inflammation and a poor outcome in a variety of diseases when elevated. Anisocytosis is a feature of primary myelofibrosis (PMF) but it’s prognostic role in PMF has not yet been evaluated.  Patients and methods: 33 newly-diagnosed patients with PMF were analyzed. Baseline RDW values were obtained in addition to CRP, LDH, complete blood count, iron metabolism parameters and JAK2 V617F mutational status. Patients were staged according to IPSS prognostic scoring system, liver and spleen size were assessed by palpation.  Results: Median RDW was 19.0% (15.2%-22.5%). RDW correlated significantly with hemoglobin level (p=0.005), CRP (p=0.031), spleen size (p=0.036) and IPSS score (p=0.003). Patients with more pronounced anisocytosis had an inferior overall survival (OS) – very-high RDW (≥19.0%) vs. high RDW (15.1%-18.9%) subgroup, HR 5.37, p=0.002. RDW remained significantly associated with OS (p=0.002) in a multivariate model including IPSS score, hemoglobin level and CRP.  Conclusion: A higher degree of anisocytosis is associated with more advanced disease features and a decreased overall survival. RDW encompasses standard prognostic score and may help in the rapid detection of patients with an unfavorable prognosis. Keywords:  Anaemia; Hemogram; Inflammation; Myelofibrosis; Splenomegaly   Dear editor,  Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm driven by clonal expansion of pluripotent hematopoietic stem cell[1]. An abundance of pro-inflammatory cytokines released by tumor cells leads to reactive fibrosis in bone marrow, production of often bizarre-shaped red cells (dacryocytes) and activation of extramedullary hematopoiesis, mostly in the spleen and the liver. The survival of PMF patients varies from several months to several years and the risk stratification is achieved by several prognostic scoring systems; International Prognostic Scoring System (IPSS)[2] is preferred at the time of diagnosis. IPSS evaluates the initial presence of five risk factors (one point for each: age over 65 years, a hemoglobin level below 100 g/l, white blood cells (WBCs) elevated above 25x10^9/L, 1% or more of circulating blasts and the presence of constitutional symptoms). Red cell distribution width (RDW) is a measure of variability of erythrocyte volume [3] and it is routinely reported by automated cell counters as a part of red blood cell count. It represents a quantitative measure of anisocytosis. The upper normal limit commonly approximates at 15% and this value is also used as a cut-off in our laboratory. An elevated RDW is associated with an increase in mortality and more advanced disease features in the wide spectrum of benign (most notably cardiovascular) and malignant disorders[4-6]. It is reflecting an increase in levels of circulatory cytokines such as IL-6 and hepcidin[7,8] as well as CRP and ESR[9], thus is being recognized as a marker of subclinical systemic inflammation. Anisocytosis is a feature of PMF (where disease pathogenesis supersedes inflammation as its only cause). However the prognostic role of anisocytosis has not yet been studied in patients with PMF or other chronic myeloproliferative neoplasms. In this study, we present the association of increased RDW values with a decreased overall survival in newly diagnosed PMF patients and provide a correlation with disease features and established prognostic score (IPSS).   We analyzed a group of 33 newly diagnosed patients with PMF who presented in our institution in period from 2004 to 2015. The diagnosis was established according to the WHO criteria[10]. Patients with leukemic transformations at time of diagnosis were excluded from this study. Baseline RDW values were obtained in addition to other routine blood analyses (CRP, LDH, complete blood count, serum iron, UIBC, TIBC and ferritin) and JAK2 V617F mutational status. Patients were staged according to IPSS prognostic scoring system, spleen and liver size were assessed by palpation. The Mann Whitney U test, the Pearson correlation and the Χ2 test/ the Fisher test were used where appropriate. Survival analyses[11] were performed using methods of Kaplan and Meier, the log-rank test and the Cox regression analysis. All statistical tests were two-sided and P values <0.05 were considered significant. Patients’ characteristics are shown in Table 1.  Elevated RDW values were present in all PMF patients with median RDW of 19.0% (range from 15.2% to 22.5%). RDW correlated significantly with hemoglobin level (r=-0.48, p=0.005), CRP (r=0.42, p=0.031) and spleen size (r=0.37, p=0.036). Significant correlation was present between RDW and IPSS score (r=0.51, p=0.003). No correlation was found according to the age or sex of the patients, degree of bone marrow fibrosis, JAK2 V617F mutational status, WBC, percentage of circulatory blasts, platelet count, MCV, LDH or iron metabolism parameters. This means that both RDW and IPSS are reflecting similar processes associated with more advanced features of disease. During follow up, considerable variations of RDW in both directions were observed in individual patients and were associated with specific therapy used (hydroxyurea, ruxolitinib, splenectomy, spleen irradiation), disease progression, septic complications, bleeding and transfusion support; thus making RDW an unsuitable parameter to monitor disease activity over time. The median overall survival (OS) was 42 months with the median follow-up of 28 months. The median RDW value of 19.0% was used as a cut-off to discriminate the “very-high RDW” group (≥19.0%)  from the “high RDW” group (15.1%-18.9%) and show significant difference in OS between the two groups (HR 5.37; p=0.002) (Figure 1); the median OS was 23 and 89 months for the “ very-high RDW” and the “high RDW” group, respectively.   In univariate Cox regression analysis, RDW (p=0.0026), IPSS score (p=0.0151), CRP (p=0.0025), LDH (p=0.0285) and hemoglobin level (p=0.04) were significantly associated with OS. RDW remained significantly associated with OS (HR=3.16; p=0.002) in a multivariate Cox regression analysis model including IPSS score, CRP, hemoglobin level and RDW (Table 1) and independently contributed to prognosis; choice of variables is based on associations with RDW and OS. Therefore, RDW represents a good integrative measure of different disease processes and also bears a prognostic significance at the time of PMF diagnosis. It encompasses standard prognostic score (IPSS) and may help in the rapid detection of patients with an unfavorable prognosis. Our preliminary observations are limited by a small number of patients and need to be evaluated by larger studies.   Acknowledgements:  The authors would like to thank Wilma Miletic for help with language editing.   References:  1 Buschle M, Janssen JW, Drexler H, Lyons J, Anger B, Bartram CR: Evidence for pluripotent stem cell origin of idiopathic myelofibrosis: Clonal analysis of a case characterized by a n-ras gene mutation. Leukemia 1988;2:658-660. 2 Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, Vannucchi AM, Mesa RA, Demory JL, Barosi G, Rumi E, Tefferi A: New prognostic scoring system for primary myelofibrosis based on a study of the international working group for myelofibrosis research and treatment. Blood 2009;113:2895-2901. 3 Simel DL, DeLong ER, Feussner JR, Weinberg JB, Crawford J: Erythrocyte anisocytosis. Visual inspection of blood films vs automated analysis of red blood cell distribution width. Archives of internal medicine 1988;148:822-824. 4 Felker GM, Allen LA, Pocock SJ, Shaw LK, McMurray JJ, Pfeffer MA, Swedberg K, Wang D, Yusuf S, Michelson EL, Granger CB, Investigators C: Red cell distribution width as a novel prognostic marker in heart failure: Data from the charm program and the duke databank. Journal of the American College of Cardiology 2007;50:40-47. 5 Seretis C, Seretis F, Lagoudianakis E, Gemenetzis G, Salemis NS: Is red cell distribution width a novel biomarker of breast cancer activity? Data from a pilot study. Journal of clinical medicine research 2013;5:121-126. 6 Perisa V, Zibar L, Sincic-Petricevic J, Knezovic A, Perisa I, Barbic J: Red blood cell distribution width as a simple negative prognostic factor in patients with diffuse large b-cell lymphoma: A retrospective study. Croatian medical journal 2015;56:334-343. 7 de Gonzalo-Calvo D, de Luxan-Delgado B, Rodriguez-Gonzalez S, Garcia-Macia M, Suarez FM, Solano JJ, Rodriguez-Colunga MJ, Coto-Montes A: Interleukin 6, soluble tumor necrosis factor receptor i and red blood cell distribution width as biological markers of functional dependence in an elderly population: A translational approach. Cytokine 2012;58:193-198. 8 Rhodes CJ, Howard LS, Busbridge M, Ashby D, Kondili E, Gibbs JS, Wharton J, Wilkins MR: Iron deficiency and raised hepcidin in idiopathic pulmonary arterial hypertension: Clinical prevalence, outcomes, and mechanistic insights. Journal of the American College of Cardiology 2011;58:300-309. 9 Lippi G, Targher G, Montagnana M, Salvagno GL, Zoppini G, Guidi GC: Relation between red blood cell distribution width and inflammatory biomarkers in a large cohort of unselected outpatients. Archives of pathology & laboratory medicine 2009;133:628-632. 10 Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R, Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman JW: Proposals and rationale for revision of the world health organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel. Blood 2007;110:1092-1097. 11 Lucijanic M, Petrovecki M: Analysis of censored data. Biochemia medica 2012;22:151-155.  Table 1.: Characteristics of newly diagnosed patients with primary myelofibrosis. Values are presented as proportions or as median and range. Associations with overall survival in univariate and multivariate Cox regression analysis are shown. *IPSS score used; **IPSS score, Hemoglobin level, CRP and RDW included in a model.   Univariate survival analysis  **Multivariate survival analysis Total number 33   Sex 25 / 33 (76%) males   8 / 33 (24%) females n.s. - Age 68 (57 – 84) years n.s. - Hemoglobin level (g/L) 115 (78 – 165) HR 0.96; p=0.0409 n.s. RDW value (%) 19.0 (15.2 - 22.5) HR 1.68; p=0.0026 HR 3.16; p=0.0022 WBC (x10^9/L) 11.0 (2.1 – 38.7) n.s. - Platelet count (x10^9/L) 366 (56 - 1046) n.s. - ≥1% of circulatory blasts 11 / 33 (33%) n.s - CRP (mg/L) 5.65 (0.2 – 73) HR 1.06; p=0.0255 n.s. LDH (U/L) 533 (195 – 3400) HR 1.001; p=0.0285 - Ferritin (mcg/L) 152 (10 – 721) n.s. - JAK2 V617F positive 21 / 30 (70%) n.s. - Constitutional symptoms present 12 / 33 (36%) n.s. - International prognostic scoring system (IPSS) Low risk:                  3 (9%) Intermediate-1:   10 (30%) Intermediate-2:     9 *HR 2.03; p=0.0151  *n.s. (27%) High risk:              11 (33%)  Figure 1: More pronounced anisocytosis at the time of diagnosis is significantly associated with a decreased overall survival in patients with primary myelofibrosis. Log-rank test; median RDW value (19.0%) is used as a cut-off.  

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The degree of anisocytosis predicts survival in patients with primary myelofibrosis

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