Myelodysplastic Syndromes

Medical Experts

Contributor

Li

Associate Professor of Pathology (Clinical), University of Utah

Medical Director, Hematopathology, ARUP Laboratories

Myelodysplastic syndromes (MDSs) are heterogeneous blood cancers characterized by ineffective hematopoiesis, cytopenia(s), and dysplasia(s).^,^,^, MDSs may progress to acute myeloid leukemia (AML).^,^,^, MDSs may also be associated with inherited genetic abnormalities or other hematologic conditions. Cytogenetic and molecular studies play a key role in the evaluation of patients with MDSs; results are used in diagnosis and classification, prognosis, medical management, and monitoring.

Quick Answers for Clinicians

Which conditions must be distinguished from myelodysplastic syndromes?

Myelodysplastic syndromes (MDSs) may present similarly to other conditions associated with cytopenias, dysplasias, or clonality. Dysplasia or cytopenia may be induced by nutritional deficiencies (eg, of vitamin B₁₂, folate, or copper), toxins (eg, arsenic, lead, zinc, or alcohol), drugs (eg, chemotherapeutic agents), infections (eg, HIV), congenital disorders (eg, congenital dyserythropoietic anemia), paroxysmal nocturnal hemoglobinuria (PNH), chronic inflammation (eg, VEXAS syndrome), and anemias secondary to another etiology (eg, sideroblastic anemia, aplastic anemia). These conditions can be distinguished from MDSs using a combination of morphologic findings, clinical presentation, detailed history, and laboratory testing, including cytogenetics and molecular testing.

Clonal disorders that must be distinguished from MDSs include clonal hematopoiesis of indeterminate potential (CHIP) and acute myeloid leukemia (AML). CHIP will exhibit somatic mutations associated with hematologic malignancy but will not meet the diagnostic criteria for MDSs or other disorders. AML can be distinguished from MDSs by the percentage of blasts and/or the presence of characteristic cytogenetic and molecular features associated with AML. For more information, refer to the ARUP Consult Acute Myeloid Leukemia topic.

Finally, an MDS in the presence of prominent myeloproliferative features (eg, thrombocytosis, megakaryocytic proliferation, or leukocytosis) is more appropriately characterized as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).

What are the criteria for diagnosing myelodysplastic syndromes?

The minimal diagnostic criteria for a myelodysplastic syndromes (MDSs) vary by organization.^,^, Both the International Consensus Classification (ICC) and World Health Organization (WHO) offer diagnostic and classification criteria that consider cytopenias, dysplasias, cytogenetic findings, and the exclusion of other disorders.^,^, Refer to the Criteria for Diagnosis and Classification section for more information.

What are the differences between pediatric and adult myelodysplastic syndromes, and how do they affect testing?

Most myelodysplastic syndromes (MDSs) occur in adults.^,^, Childhood MDSs and related syndromes are classified separately from adult MDS,^,^, and recommendations for adult MDS may not apply to children. Many cases of pediatric MDS are associated with hereditary syndromes; therefore, germline genetic testing, including testing for such syndromes and additional genetic testing, should be considered in children.^, However, it should be noted that the concept that hereditary MDS manifests at younger ages has been recently revised. In addition, some patients with hereditary MDS may not exhibit syndromic extramedullary manifestations, regardless of age.

There may also be differences between adult and pediatric testing for specific hereditary syndromes; for example, serum trypsinogen is tested in the evaluation of suspected Shwachman-Diamond syndrome in children, but not in adults.

What is the role of human leukocyte antigen (HLA) testing in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms?

Human leukocyte antigen (HLA) typing is recommended for individuals with myelodysplastic syndromes (MDSs) or myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) for whom hematopoietic stem cell transplantation is being considered. For more information, refer to the ARUP Consult HLA Testing topic.

What is the role of minimal residual disease testing in myelodysplastic syndromes?

The role of minimal residual disease (MRD) has not been established in myelodysplastic syndromes (MDSs); however, it is an area of current research. MRD may be assessed by flow cytometry or next generation sequencing (NGS) in the context of clinical trials. MRD should be reported regularly in clinical trials and may be used as a provisional response category, although specification of the definition of MRD is recommended to aid in future validation of MRD in MDSs.

Indications for Testing

MDS should be suspected in individuals with persistent cytopenia(s) (values lower than standard values based on age, sex, ethnicity, and altitude of patient residence) on sequential CBCs that cannot otherwise be explained and/or other morphologic changes consistent with myelodysplasia.

Criteria for Diagnosis and Classification

The diagnosis and classification of MDSs, also referred to as myelodysplastic neoplasms, are based on the results of bone marrow examination, peripheral blood examination, cytogenetic testing, and molecular genetic tests.^, These tests are used to determine the percentage of blasts and identify cytopenias, morphologic dysplasias, and genetic abnormalities—findings which define and distinguish between MDSs, myelodysplastic/myeloproliferative neoplasms (MDS/MPNs), AMLs, and other conditions^, such as clonal cytopenia of unknown significance (CCUS). The World Health Organization (WHO) and International Consensus Classification (ICC) vary in their classifications of MDSs and related entities, although both increasingly emphasize genetic/genomic features.^,^, The National Comprehensive Cancer Network (NCCN) does not advocate for one classification system over the other.

Response Criteria

The therapeutic response criteria for MDSs are based on the results of bone marrow examination (including blast enumeration), peripheral blood counts, and cytogenetic testing, among other factors. Molecular genetic testing is now included in the response criteria, and the molecular International Prognostic Scoring System (IPSS-M) has been widely implemented in clinical practice.

Laboratory Testing

Initial Workup

In addition to a history and physical examination with particular attention to cytopenias, recommended laboratory testing in the initial workup of suspected MDS includes a CBC with differential, platelet count, and reticulocyte count; peripheral smear with at least 200 cells; red blood cell (RBC) folate and serum B₁₂ tests; serum ferritin, iron, and total iron-binding capacity or transferrin saturation tests; and thyroid-stimulating hormone, haptoglobin, creatinine, and lactate dehydrogenase tests.^, These tests identify cytopenia(s) and dysplasia(s) and rule out other conditions (eg, anemia or thyroid disease) that may present similarly to MDSs or MDS/MPNs.^, In some cases, the results of these tests may be useful in prognosis.

Additional Tests

Consider testing for copper deficiency in individuals who have malabsorption or malnutrition, have had gastric bypass surgery, or are taking zinc supplements. HIV tests are recommended if clinically indicated. Testing for paroxysmal nocturnal hemoglobinuria (PNH) may also be useful.

Bone Marrow Aspirate and Biopsy

Bone marrow aspiration with iron staining and biopsy are recommended at diagnosis.^, At least 500 cells should be evaluated. This number allows for blast enumeration, evaluation of fibrosis, hematopoiesis, marrow cellularity, and ring sideroblast identification.^, For follow-up testing purposes, aspiration is generally recommended in Europe, whereas biopsy is commonly used in the United States.

In some cases, MDSs can be morphologically defined. Morphologic factors considered in the classification of MDSs include^,:

Bone marrow blast percentage
Hypoplasia
Auer rods
Fibrosis
Ring sideroblasts

Bone marrow aspiration also provides material for cytogenetic and molecular testing.

Testing for Cytogenetic Abnormalities

Cytogenetic testing is recommended as part of the evaluation of suspected MDSs and is used to classify MDSs and identify abnormalities relevant to prognosis and therapeutic decision-making.^, Chromosome analysis (karyotyping) should be performed, and if 20 or more metaphases cannot be obtained, chromosomal microarray or fluorescence in situ hybridization (FISH) may be performed.^, Consideration of chromosomal microarray, next generation sequencing (NGS), or FISH is also recommended if karyotyping is normal.^, If FISH is performed at diagnosis, use of probes for 5q31, 7q31, 20q, cen7, cen8, cenY, and TP53 is recommended.

Somatic gene rearrangements/abnormalities that define MDSs and/or are important in prognosis and therapeutic decision-making include 17p, complex karyotype, del(5q), del(7q), and monosomy 7.^,^,^,

Polymerase chain reaction (PCR) testing for TCR and testing for STAT3 mutations may, in conjunction with flow cytometry, be useful to evaluate for large granular lymphocytes (LGLs) and PNH, which are usually considered morphologic MDS mimics.

Molecular Genetic Testing for Other Somatic Variants

Molecular genetic testing for somatic variants (also referred to as acquired mutations) in genes associated with MDSs is recommended and may aid in diagnosis and prognostication. Bone marrow or peripheral blood may be tested.

Somatic gene mutations that define MDSs include but are not limited to SF3B1 and TP53.

Other genes with somatic variants associated with MDSs include ASXL1, CBL, DNMT3A, ETV6, EZH2, IDH1, IDH2, JAK2, KRAS, NRAS, RUNX1, SETBP1, SRSF2, STAG2, TET2, U2AF1, and ZRSR2.^,

Immunophenotyping by Flow Cytometry

Flow cytometry may be considered in the evaluation of suspected MDS, although it is not a substitute for morphologic evaluation to determine blast percentage.^, It is most useful for blast characterization, identification of an abnormal immunophenotype in myeloid cells, including myeloblasts, and the investigation of abnormal lymphoid cell populations. These findings can be used to exclude other diagnoses, as cocriteria to confirm the diagnosis of MDS if the diagnosis is uncertain, and for prognosis. Flow cytometry in conjunction with genetic testing for TCR and STAT3 may also be useful to evaluate for LGLs and PNH.

Hereditary Syndrome Assessment

Genetic testing for hereditary hematologic malignancy predisposition, including bone marrow failure syndromes such as Diamond-Blackfan anemia and Shwachman-Diamond syndrome, may be informative, particularly in individuals who are diagnosed with an MDS before 50 years of age or in families with multiple cases of MDSs, AML, or related conditions.^, Genetic counseling is recommended both before and after testing.

Cultured skin fibroblasts are the recommended specimen type for germline testing because blood contamination may lead to the detection of somatic variants. Furthermore, mosaicism and somatic reversion in blood or bone marrow in patients with germline variants may yield false-negative results. Buccal swab samples, which are easy to obtain, are a potential alternative to cultured fibroblasts; however, leukocyte contamination remains a major issue with buccal swabs.

Panel testing should be considered, including both NGS and genomic array, to detect mutations and copy number variants. Panels should be intended for germline assessment because somatic panels may not include relevant genes. In some cases, additional testing may be useful (eg, FISH testing in short telomere syndromes).

Genes with variants associated with hereditary MDSs include ACD, ANKRD26, CTC1, DDX41, DKC1, DNAJC21, EFL1, ELANE, ERCC6L2, ETV6, FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1/BACH1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANQ/ERCC4, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7/MAD2L2GATA1, G6PC3, GATA2, GFI1, HAX1, NAF1, NHP2, NOP10, PARN, POT1, RPL5, RPL11, RPL15, RPL23, RPL26, RPL27, RPL31, RPL35A, RPS7, RPS10, RPS17, RPS19, RPS24, RPS26, RPS27, RPS28, RPS29, RTEL1, RUNX1, SAMD9, SAMD9L, SBDS, SRP72, TERC, TERT, TINF2, TSR2, WRAP53, and ZCCHC8.^,

Prognosis and Risk Assessment

Results from the CBC, blast enumeration, and cytogenetic and molecular testing may be used in prognosis.^, Prognostic scoring systems include the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), molecular IPSS (IPSS-M), WHO-Based Prognostic Scoring System (WPSS), and Lower-Risk Prognostic Scoring System (LR-PSS).^,

Treatment Planning and Monitoring

Treatment Planning

Cytomegalovirus testing and human leukocyte antigen (HLA) typing should be performed in both the patient and potential donors if the patient is a candidate for hematopoietic stem cell transplantation. Serum erythropoietin should be measured before RBC transfusion or if erythropoiesis-stimulating agents are being considered.^, Genetic testing and flow cytometry for PNH or STAT3-mutant cytotoxic T-cells may be useful to determine potential responsiveness to immunosuppressive therapy.

Monitoring

Regular blood counts should be performed for routine follow-up. If cytopenias worsen or a change in peripheral blasts occurs, bone marrow examination (with or without karyotyping) can be performed. Additional follow-up, such as molecular testing, should be performed as indicated for the specific treatment being used.