Anemia is present years before myelodysplastic syndrome diagnosis: Results from the pre-diagnostic period
Authors: Jakob Werner Hansen, Håkon Sandholdt, Volkert Siersma, Andreas Due Ørskov, Staffan Holmberg, Ole Weis Bjerrum, Hans Carl Hasselbalch, Niels de Fine Olivarius, Kirsten Grønbæk, Christen Lykkegaard Andersen
Journal: American Journal of Hematology (2017)

Myelodysplastic syndromes (MDS) are clonal hematological neoplasms characterized by peripheral blood cytopenia(s) and dysplastic bone marrow features. Anemia is the most frequently observed cytopenia at the time of diagnosis whereas neutropenia and thrombocytopenia are less common.1 Since MDS is a disease of the elderly population, where the prevalence of anemia due to various benign and other malignant conditions has been estimated to approximately 10% with an age above 65,2 the predictive value of isolated anemia for MDS is poor.3 In order to assess the clinical significance of the duration of prediagnostic cytopenia(s), we used The Copenhagen Primary Care Differential Count (CopDiff) database, which contains prospectively collected and routinely analyzed complete blood cell counts (CBCs) from more than 500 000 Danish citizens over a ten-year-period (2000-2010). We chose to focus primarily on anemia as neutrophil- and platelet cell counts are more affected by infections and other extrinsic factors resulting in more volatile patterns. The aim of the present study was therefore to scrutinize the pre-diagnostic phase in MDS patients in order to investigate the duration of pre-diagnostic anemia and its potential relation to gender, MDS subtype, and clinical outcome. The study was approved by the National Board of Health (3-3013-884/1). Between 2000 and 2010, general practitioners (GPs) in the Copenhagen area were all served by one laboratory, The Elective Laboratory of the Capital Region (ELCR). The CopDiff database is based on ELCR data and contains all CBCs requested by GPs for 555 039 individuals in the period. For the present study, we included adult (≥18 years) MDS (ICD-10 code D46) patients diagnosed between 2000 and 2010. A total of 284 patients were identified (Supporting Information Figure 1). Of these, 63 were excluded as laboratory workup was only performed after the MDS diagnosis. For the remaining 221 patients, we reviewed medical records from secondary care to ensure correct MDS diagnosis, and furthermore reviewed the pathology reports and registered disease morphological categories; 17 were excluded due to misdiagnosis (Supporting Information Figure 1). Of the 204, 145 (Supporting Information Table 1a and 1b) all had three or more CBCs registered, and were included in the multivariable linear mixed effect model. We also grouped these patients according to WHO morphological categories and the occurrence of blast excess; and furthermore into low-, intermediate-, and high risk groups (Supporting Information Table 2). We defined lower thresholds for hemoglobin, platelets, neutrophils, and mean corpuscular volume (MCV) as follows: hemoglobin men, 12.9 g/dL (8 mmol/L) and women, 11.3 g/dL (7 mmol/L); platelets: 150 × 109/L; neutrophils: 1.8 × 109/L; and MCV: 80 fL (upper threshold was defined as 100 fL). We used a multivariable linear mixed effect model to estimate the mean level of hemoglobin prior to diagnosis. To make the model more robust we only included patients with a minimum of three measurements prior to diagnosis (n = 145, Supporting Information Table 1b). The model was used on the log-transformed hemoglobin levels, and also the time variable was log-transformed to capture accelerated loss of hemoglobin close to the diagnosis. The model included an interaction term of time and gender allowing for sex-dependent declines and additive effects of sex, age, Charlson comorbidity index, and number of blood transfusions. Of the 204 patients, 110 were men and 94 were women. The median age was 76 and 77, respectively (P = .12). We observed no significant differences between men and women at time of diagnosis in regard to WHO category (Supporting information Table 1a ) and the overall distribution was similar to what could be expected from a population-based MDS study. Thirty-eight percent of the men and 55% of the women (P = .002) had received at least one pre-diagnostic blood transfusion. Transfused patients received a median of five blood transfusions prior to MDS diagnosis with no gender differences (P = .65). For the 204 patients, a total of 981 pre-diagnostic CBCs were analyzed in the study period, with a median of 4 (range 2-24) per individual. There were no gender differences in this distribution. The proportion of samples below anemic threshold in the years prior to MDS diagnosis is shown in Figure 1. Women exhibited a steady increase whereas men exhibited a more fluctuating pattern; however, both groups demonstrated a proportion of samples below the anemic threshold of ∼80% just prior to MDS diagnosis. The proportions of neutrophil and platelet counts below threshold prior to MDS diagnosis are shown in Supporting Information Figure 2. In order for our model to robustly ascertain the time correlation between anemia and diagnosis we included 863 CBCs from the 145 patients (of the 204 original patients) with a median (range) of 4 (3-24) CBCs per individual. These CBCs accounted for 90% of the total CBCs in the entire cohort, and patient distribution according to WHO categories for the 145 patients was similar to the total cohort (Supporting Information Table 1). Proportion of samples with a hemoglobin count below the lower threshold in the years prior to diagnosis of MDS for women (A) and men (B). Overall, male patients became anemic with a median of 1063 days (IQR, 832-1393) prior to MDS diagnosis as compared to 280 (IQR, 208-316) days for women (P = .002). Changing the lower hemoglobin threshold level to the WHO defined of 12 g/dL for women increased the pre-diagnostic anemic period to 979 days (IQR, 793-1240). When we included WHO morphology categories in the model, we observed the shortest duration of pre-diagnostic anemia in the high risk group; 1 month (IQR, 1-2) and 18 (IQR, 12-30) months in women and men, respectively (Supporting Information Figure 3). There was a clear stepwise decrease in the duration of anemia in women which was longest in the low risk group (median 29 months [IQR, 21-42]), followed by 5 months (IQR, 3-6) in the intermediate risk group and shortest in the high risk group with 1 month (IQR, 1-2). In men, we observed no significant differences between groups with duration of 35 months (IQR, 24-50), 40 months (IQR, 30-50), and 18 months (12-30) in low-, intermediate-, and high risk groups, respectively. Fifty percent of CBCs analyzed at time of MDS diagnosis exhibited macrocytosis, whereas only one percent displayed microcytosis (Supporting Information Figure 4). When combining hemoglobin and MCV measurements it also became evident that MCV was often abnormally high even when the hemoglobin concentration was within normal range (Supporting Information Figure 5). In conclusion, anemia is present years before the diagnosis of MDS. Women with intermediate- and high risk MDS display the shortest duration of pre-diagnostic anemia, which may point to the existence of pathogenically different conditions with phenotypes unaffected by disease duration since the majority of patients do not seem to risk progression during the pre-diagnostic period. Many patients receive multiple blood transfusions before diagnosis emphasizing the difficulties in proper MDS diagnosis and that many patients have a prodromal phase before MDS diagnosis.4 Future research should focus upon early identification of the minority of low risk MDS patients at risk of progressing to high risk MDS or overt AML. J.W.H., K.G., and C.L.A. designed the study; J.W.H., H.S., and V.S. analyzed the data and performed statistical analyses. S.H., O.W.B., A.D.Ø., H.C.H., and N.F.O. all provided clinical data. All authors helped analyze and interpret the data; J.W.H. and C.L.A. wrote the manuscript, and all authors revised and approved the final version of the manuscript. Nothing to report. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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