To the editor:

The recent article by Arber et al1  detailing the 2016 revision of the World Health Organization (WHO) classification of myeloid malignancies and AML was timely and germane. Regarding myelodysplastic syndromes (MDS), the authors indicate diagnostic criteria that include levels of dysplasia and cytopenias. They further indicated that ethnic variation should be taken into consideration in patients with borderline low neutrophil counts and that a diagnosis of MDS may still be made in “rare cases with milder levels of cytopenia” when definitive morphologic and/or cytogenetic features are present.1,2  The necessity of clarifying these criteria has major relevance, particularly with the advent of a recently described group of indolent hematopoietic disorders that may represent precursor states of MDS such as idiopathic cytopenia of unknown significance (ICUS),3-5  idiopathic dysplasia of unknown significance (IDUS),5,6  clonal hematopoiesis of unknown potential (CHIP),7  and clonal cytopenia of unknown significance (CCUS)4,8,9  that require distinction from MDS. It is recognized that ICUS is not necessarily myeloid (unrecognized lymphoid or plasma cell neoplasms may cause idiopathic cytopenias that may be classified initially as ICUS, and some patients with ICUS may eventuate into nonhematopoietic/reactive disorders such as immune dysregulation), whereas IDUS is a morphological alteration with many potential causes that do not necessarily influence hematopoiesis in terms of the number of generated cells. These entities have been reviewed in the current National Comprehensive Cancer Network MDS Practice Guidelines 1.2017.10 

However, although the WHO perspective indicates that “cytopenia is a sine qua non for any MDS diagnosis,1 ” the recommended threshold levels of cytopenias it proposes for this purpose are those previously reported in the International Prognostic Scoring System (IPSS) risk stratification categorization that were used for prognostic but not diagnostic purposes (hemoglobin [Hb] 10 g/dL, absolute neutrophil count [ANC] 1.8 × 109/L, platelets 100 × 109/L).11 Table 1 provides data from the International Working Group for Prognosis in MDS (IWG-PM) database that was used to generate the Revised-IPSS12 ; if these cytopenia levels were used to diagnose MDS, 18% of MDS patients and 23% of those with <5% marrow blasts would lack any cytopenia and thus would not be classifiable as MDS. Using standard laboratory values for cytopenias (Hb <13 g/dL [males], <12 g/dL [females], ANC <1.8 × 109/L, platelets <150 × 109/L), the data demonstrated that only 1.8% patients evaluated in that study of 7012 MDS subjects would lack a cytopenia (1.3% of patients when nonproliferative chronic myelomonocytic leukemia patients were excluded). Of note, and relevant predominantly for patients with low marrow blast counts in the IWG-PM cohort, the patient's blood counts also needed to demonstrate ≥2 months of stable disease as a potential means of excluding other causes for the cytopenias.

Table 1

Cytopenias in MDS

Cytopenias 
Marrow blasts None, n None, % 1, n 1, % 2, n 2, % 3, n 3, % Total 
Less than normal* 
 <5% 106 2.3 1946 43 1543 34 950 21 4545 
 ≥5% 19 0.8 421 17 927 38 1100 45 2467 
 Total 125 1.8 2367 34 2470 35 2050 29 7012 
Less than normal, without CMML* 
 <5% 73 1.7 1814 43 1395 33 912 22 4194 
 ≥5% 0.4 318 15 792 37 1047 48 2165 
 Total 81 1.3 2132 34 2187 34 1959 31 6359 
WHO categorization 
 <5% 1040 23 1988 44 1064 23 453 10 4545 
 ≥5% 197 776 32 922 37 572 23 2467 
 Total 1237 18 2764 39 1986 28 1025 15 7012 
Cytopenias 
Marrow blasts None, n None, % 1, n 1, % 2, n 2, % 3, n 3, % Total 
Less than normal* 
 <5% 106 2.3 1946 43 1543 34 950 21 4545 
 ≥5% 19 0.8 421 17 927 38 1100 45 2467 
 Total 125 1.8 2367 34 2470 35 2050 29 7012 
Less than normal, without CMML* 
 <5% 73 1.7 1814 43 1395 33 912 22 4194 
 ≥5% 0.4 318 15 792 37 1047 48 2165 
 Total 81 1.3 2132 34 2187 34 1959 31 6359 
WHO categorization 
 <5% 1040 23 1988 44 1064 23 453 10 4545 
 ≥5% 197 776 32 922 37 572 23 2467 
 Total 1237 18 2764 39 1986 28 1025 15 7012 

Percent values rounded off except for values <3%. Data obtained from Greenberg et al.12 

CMML, chronic myelomonocytic leukemia.

*

Standard values: Hb <13 g/dL (males), <12 g/dL (females), ANC <1.8 × 109/L, platelets <150 × 109/L.

IPSS values: Hb <10 g/dL, ANC <1.8 × 109/L, platelets <100 × 109/L.

Regarding our main point, it is of relevance that the MDS database (n = 816) used to generate the IPSS (Table 1)11  similarly demonstrated that 19% of these patients lacked a cytopenia if defined by the prognostic level cutpoints used by the WHO and also incorrectly would not have been considered to have MDS. Similar findings were found in an independent study using these cytopenic cutpoints.13  Prior investigations have demonstrated ethnic-, age-, and altitude-related differences in normal Hb levels14,15 ; ethnic-, age-, and sex-related differences in platelet levels16,17 ; and ethnic- and sex-related differences in platelet and white counts.18  Thus, being cognizant of these conditional blood count variations, we recommend that standard hematologic values be used to define cytopenias in MDS and believe a modification of the WHO definition of cytopenias as 1 of the criteria (in addition to definitive morphologic and/or cytogenetic findings) to diagnose MDS would be valuable and most accurate.

Authorship

Contribution: P.L.G. and H.T. designed the study, analyzed the data, and wrote the report; A.A.v.d.L., D.H., J.M.B., P.F., M.C., and U.G. critically reviewed and modified the manuscript and contributed data to the IWG-PM database; and the remaining authors contributed data to the IWG-PM database and critically reviewed and approved the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Peter L. Greenberg, Stanford University Cancer Institute, 875 Blake Wilbur Dr #2335, Stanford, CA 94305-5821; e-mail: peterg@stanford.edu.

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