Calculator‐free point‐of‐care prognostication in myelodysplastic syndromes
Authors: Ayalew Tefferi, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat
Journal: American Journal of Hematology (2019)

Contemporary prognostication in primary myelodysplastic syndromes (MDSs) began with the 1997 publication of the International Prognostic Scoring System (IPSS).1 The particular model was subsequently revised in 2012 (IPSS-R). Both IPSS and IPSS-R employ multiple categories of bone marrow (BM) blast percentage, karyotype and cytopenias. BM blast categories in IPSS include <5%, 5%-10%, 11%-20% and 21%-29% and in IPSS-R ≤ 2%, >2 and <5%, 5%-10% and >10%. Cytogenetic risk groups in IPSS include good (normal, -Y, 20q-, 5q-), poor (chromosome 7 anomalies or complex karyotype with ≥3 abnormalities) and intermediate (all other abnormalities) and in IPSS-R very good (-Y, 11q-), good (normal, 5q-, 20q-, 12p- or two abnormalities including 5q-), intermediate (+8, 7q-, i[17q], +19, +21, other single abnormalities, independent clones, two abnormalities not including 5q- or −7/7q-), poor (−7, inv,3 del(3q), two abnormalities including −7/7q-, complex karyotype with ≥3 abnormalities) and very poor (complex karyotype with ≥4 abnormalities). Cytopenias in IPSS included hemoglobin <10 g/dL, platelets <100 × 109/l and absolute neutrophil count (ANC) <1.8 × 109/l and in IPSS-R multiple categories of anemia (hemoglobin 8 to <10 g/dL and <8 g/dL), thrombocytopenia (platelets <50 × 109/l and 50 to <100 × 109/l) and neutropenia (ANC <0.8 × 109/l). IPSS and IPSS-R and more contemporary risk models for MDS2 are generally not easily applicable in routine office practice where immediate access to risk model components and the extra time needed to refer to an online calculator are difficult to secure. With the exception of allogeneic hematopoietic stem cell transplant (HCT), current treatment in MDS has not affected survival, in a substantial manner.3 In other words, the primary purpose of prognostication in MDS is currently to determine whether or not HCT should be considered sooner than later. The question then becomes whether or not one needs a sophisticated and complex prognostic system in order to deliver optimal care or whether that can be accomplished by a simpler and more practical prognostic model. The three variables of interest for the current study were selected based on their consistent prognostic value in MDS. Karyotype and BM blast percentage are generally accepted as the most important prognostic determinants in MDS. However, the current IPSS-R system for classifying cytogenetic and BM blast percentage risk levels is too cumbersome for application in routine clinical practice. Also, in a large Mayo Clinic study, we were unable to reproduce the cytogenetic risk stratification by IPSS-R4; we have since proposed a simpler three-tiered system that considered monosomal karyotype (MK) as “high risk”, normal karyotype or sole/double abnormalities of 5q- as “low risk” and all other abnormalities as “intermediate risk”.2 We were able to do the same with BM blast percentage by identifying 10% as the most optimal prognostic threshold.2 Finally, we recently re-visited with sex-adjusted hemoglobin thresholds in MDS and discovered that the presence or absence of red cell transfusion dependency overrides all other definitions of anemia that are based on arbitrary hemoglobin thresholds (eg, 10 g/dL). The current study was approved by our institutional review board. It is important to note that we used the same study population that helped devise the new Mayo Alliance Prognostic Model for MDS; the former was based on both genetic and clinical risk factors (MK, “non-monosomal karyotype abnormalities other than single/double del(5q)”, RUNX1 and ASXL1 mutations, absence of SF3B1 mutations, age > 70 years, hemoglobin <8 g/dL in women or <9 g/dL in men, platelet count <75 × 109/l and BM blasts ≥10%) and the latter only on the genetic components of the Mayo alliance model. Diagnosis of primary MDS was according to the 2008 World Health Organization criteria. Statistical analyses considered clinical and laboratory parameters obtained at time of diagnosis or initial referral to our institution. For analysis of overall survival data, patients receiving HCT were censored at the time of their transplant. Overall survival curves were prepared by the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazard regression model was used for multivariable analysis. P values of less than 0.05 were considered significant. Three hundred and fifty seven consecutive patients (median age 74 years; 70% males) with primary MDS were included. IPSS-R risk distribution included 11% very high, 16% high, 17% intermediate, 40% low, and 16% very low risk categories. Cytogenetic risk groups according to the simplified three-tiered Mayo cytogenetic risk model were: 11% high risk category (ie, displayed MK), 59% low risk category (ie, displayed normal karyotype or single/double abnormalities of 5q-), and 30% to intermediate risk category (ie, neither high nor low). According to the simplified two-tiered Mayo risk stratification for BM blast count, 12% displayed BM blast count of ≥10%. Anemia, defined as a hemoglobin level of below the sex-adjusted reference range, was present in 96% of all study patients; 38% were red cell transfusion dependent, 28% had a hemoglobin level of <10 g/dL but were not transfusion dependent and 34% had anemia with hemoglobin level of ≥10 g/dL. Median leukocyte, absolute neutrophil and platelet counts were 3.8 × 109/l, 1.8 × 109/l and 116 × 109/l, respectively. Multivariable analysis that included our operational parameters of interest yielded HRs (95% CI) of 5.1 (3.2-8.0) for MK (ie, Mayo high risk karyotype), 2.3 (1.6-3.1) for Mayo intermediate risk karyotype, 2.6 (1.9-3.5) for transfusion-dependent anemia and 2.4 (1.5-3.6) for BM blasts ≥10%. HR-weighted risk point assignment was subsequently employed in order to construct a three-tiered risk model that performed equally well in transplant age (≤70 years) and older patients alike (Figure 1). During age-adjusted multivariable analysis that included other genetic and IPSS-R-relevant risk variables, additional independent effect on survival was demonstrated for advanced age, thrombocytopenia and presence of ASXL1 or RUNX1 or absence of SF3B1 mutations; regardless, the additional prognostic contribution of other risk variables, as illustrated with risk distribution comparison with IPSS-R (Supplementary Figure 1), was limited to intermediate-risk patients and not overtly apparent in high or low risk patients designated by the new simpler point-of-care model. The authors have no conflict of interest to declare. All authors have reviewed the manuscript and gave their approval. AT designed the study, contributed patients, helped abstract patient information, performed statistical analysis and wrote the article. AP and NG contributed patients and helped abstract patient information. RPK was in charge of cytogenetic information. CAH was in charge of information on pathology. 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