Myelodysplastic Syndrome (MDS) Guidelines

Myelodysplastic Syndrome (MDS) Classification

In 2016, the World Health Organization (WHO) released a revision to its 2008 classification scheme for myelodysplastic syndrome (MDS). ^{[51, 17]}  The National Comprehensive Cancer Network  (NCCN) has included the revised WHO classification system in its 2017 updated guidelines. ^[23]

The two systems are compared in the table below..

Table. 2008 and 2016 World Health Organization (WHO) classifications of myelodysplastic syndromes (Open Table in a new window)

For the workup in patients with suspected MDS (eg, because of cytopenias), the NCCN recommends the following ^[23] :

• History and physical examination
• Complete blood count (CBC) with differential
• Reticulocyte count
• Examination of peripheral blood smear
• Bone marrow aspiration with iron stain plus biopsy and cytogenetics by standard karyotyping; consider testing for fibrosis
• Serum erythropoietin (prior to red blood cell [RBC] transfusion)
• RBC folate, serum vitamin B12
• Serum ferritin, iron, total iron-binding capacity (TIBC)
• Documentation of transfusion history
• Thyroid-stimulating hormone (TSH)
• Lactate dehydrogenase (LDH)
• Genetic testing for somatic mutations (ie, acquired mutations) in genes associated with MDS is highly recommended
• Recommend additional molecular and genetic testing for hereditary hematologic malignancy predisposition in a subset of patients, particularly in younger patients
• HIV testing if clinically indicated
• Consider evaluation of copper deficiency in patients with GI malabsorption, severe malnutrition, gastric bypass surgery, or patients on zinc supplementation
• Consider distinction from congenital sideroblastic anemia (CSA)

ESMO recommendations are as follows ^[52] :

• Diagnosis is based on blood count, marrow aspirate and marrow karyotype.
• Bone marrow biopsy is recommended at diagnosis.
• Molecular biology is useful for diagnosis if blood and marrow tests are inconclusive
• Flow cytometry of blood and marrow cells is useful for diagnosis in experienced hands.

The NCCN utilizes the WHO classification system for diagnosis and distinguishes subtypes on the basis of blood and bone marrow findings. ^{[23, 51]}

MDS with single-lineage dysplasia (MDS-SLD) criteria are as follows:

• Blood: single cytopenia or bicytopenia
• Bone marrow: dysplasia in ≥ 10% of one cell line, < 5% blasts

MDS with ring sideroblasts (MDS-RS) criteria are as follows:

• Blood: anemia, no blasts
• Bone marrow: ≥ 15% of erythroid precursors with ring sideroblasts, or ≥ 5% blasts ring sideroblasts if SF3B1 mutation is present

MDS with multilineage dysplasia (MDS-MLD) criteria are as follows:

• Blood: cytopenia(s), < 1 × 10 ⁹/L monocytes
• Bone marrow: dysplasia in ≥ 10% of cells in ≥ 2 hematopoietic lineages; < 15% ring sideroblasts (or < 5% ring sideroblasts if SF3B1 mutation present), < 5% blasts

MDS with excess blasts-1 (MDS-EB-1) criteria are as follows:

• Blood: cytopenia(s) ≤2-4% blasts, < 1 × 10 ⁹/L monocytes
• Bone marrow: unilineage or multilineage dysplasia, no Auer rods, 5-9% blasts

MDS with excess blasts-2 (MDS-EB-2) criteria are as follows:

• Blood: cytopenia(s), 5-19% blasts, < 1 × 10 ⁹/L monocytes
• Bone marrow: unilineage or multilineage dysplasia, ±Auer rods, 10-19% blasts

Myelodysplastic syndrome–unclassified (MDS-U) criteria are as follows:

• Blood: cytopenias, ±1% blasts on at least 2 occasions
• Bone marrow: unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, < 5% blasts

Myelodysplastic syndrome associated with isolated del(5q) criteria are as follows:

• Blood: anemia, platelet levels normal or increased
• Bone marrow: unilineage erythroid dysplasia, isolated del(5q), < 5% blasts ± one other abnormality except -7/del(7q)

The following prognostic scoring systems are most commonly used:

• International Prognostic Scoring System (IPSS and IPSS-R)
• WHO Prognostic Scoring System (WPSS)
• Lower-Risk Prognostic Scoring System (LR-PSS)

NCCN guidelines prefer the IPSS-R, because it provides more accurate risk stratification than the IPSS or WPSS, but note that the LR-PSS may be useful in identifying patients with lower-risk disease who have a poorer prognosis and require earlier treatment.. ^[23]  The 2021 European Society for Medical Oncology (ESMO) guidelines consider the IPSS-R to be required for prognostic evaluation, but note that molecular analysis may add prognostic value, especially for TP53 mutations in del(5q) MDS and SF3B1 mutations in patients with < 5% blasts. ^[52] The 2013 European LeukemiaNet (ELN) guidelines recommend that all patients be risk stratified using IPSS. ^[53]

International Prognostic Scoring System

The IPSS has been the most widely used prognostic scoring system for MDS. First published in 1997, it was intended for use with the French-American-British (FAB) classification system which has since been largely supplanted by the World Health Organization (WHO) classification system. The following three factors are rated ^[18] :

• The percentage of blasts in the bone marrow (scored on a scale from zero to 2)
• Karyotype (scored from zero to 1)
• Cytopenias (scored as zero or 0.5)

Each factor is given a score and totaled and the patient’s risk is classified according to the following:

• 0 = Low risk
• 0.5-1 = Intermediate risk - 1
• 1.5-2 = Intermediate risk - 2
• ≥2 = High risk

In 2012, a revised IPSS (IPSS-R) was released with five risk groups (very low, low, intermediate, high and very high). It refined the original model by incorporating more detailed cytogenetic prognostic categorization and cut-offs for hemoglobin levels, platelet counts and neutrophil count. The prognostic score is now weighted according to the severity of cytopenias in addition to the bone marrow blast percentage. ^[19]

WHO Prognostic Scoring System (WPSS)

The WHO Prognostic Scoring System (WPSS) was developed in 2005 based on the 2001 WHO classifications and refined most recently in 2011. ^{[54, 55]} In contrast to the IPSS and IPSS-R, which are applied only at the time of diagnosis, the WPSS is dynamic, and patients can be reassigned categories as their disease progresses. The WHO score is calculated on the basis of the following three factors ^[55] : 

• WHO disorder classification (0-3)
• Karyotype (0-2)
• Presence or absence of severe anemia (0-1)

Based on the total score, risk classification is as follows:

• 0 = Very Low
• 1 = Low
• 2 = Intermediate
• 3-4 = High
• ≥5 = Very High

Lower-Risk Prognostic Scoring System (LR-PSS)

In 2008, researchers at MD Anderson Cancer Center developed the Lower-Risk Prognostic Scoring System (LR-PSS) to identify patients with very low or low risk with a poorer prognosis. The model is a refinement of IPSS and included the following factors that were independent predictors of survival outcomes ^[56] :

• Unfavorable cytogenetics
• ≥60 years old
• Decreased hemoglobin level
• Decreased platelet count
• Higher percentage of bone marrow blasts

Each factor was given a weighted score and based on the total, patients were assigned to one of the following risk categories:

Guidelines for the management of MDS have been issued by the following organizations:

• National Comprehensive Cancer Network (NCCN) ^[23]
• European LeukemiaNet (ELN) ^[53]
• European Society for Medical Oncology (ESMO) ^[52]
• British Society for Haematology (BSH) ^[57]

The NCCN guidelines recommend supportive care as the standard of care for patients with lower-risk MDS. Supportive care includes the following ^[23] :

• Clinical monitoring
• Psychosocial support
• Quality-of-life assessment
• Transfusion – Red blood cell (RBC) transfusions for symptomatic anemia, platelet transfusions for thrombocytopenic bleeding
• Consider aminocaproic acid or other antifibrinolytic agents for bleeding refractory to platelet transfusions or profound thrombocytopenia
• Antibiotics for bacterial infections; consider prophylaxis in patients with recurrent infections
• Iron chelation, after > 20-30 RBC transfusions, particularly in patients who have lower-risk MDS or are potential transplant candidates, with deferoxamine subcutaneously or deferasirox orally, except in patients with low creatinine clearance (< 40 mL/min)
• Erythropoietin for symptomatic anemia
• Consider  in neutropenic patients with recurrent or resistant infections.
• Consider treatment with a thrombopoietin-receptor agonist in patients with lower-risk MDS who have severe or life-threatening thrombocytopenia.

In lower-risk MDS, all four guidelines recommend lenalidomide for the treatment of symptomatic anemia in patients with del(5q) MDS. ^{[23, 53, 52, 57]} However, the BHS guidelines consider erythropoiesis-stimulating agents (ESAs) first-line therapy, although responses are inferior to those seen in low-risk MDS lacking del(5q). ^[57]

For treatment of symptomatic anemia in patients without del(5q), with or without other cytogenetic abnormalities and with ring sideroblasts < 15% (or ring sideroblasts < 5% with an SF3B1 mutation), NCCN recommendations are as follows ^[23] :

• Serum erythropoietin (EPO) level  ≤500 mU/mL - Recombinant human EPO or darbepoetin
• Serum erythropoietin (EPO) level > 500 mU/mL - Immunosuppressive therapy with equine anti-thymocyte globulin (ATG), with or without cyclosporine, for patients likely to respond (generally, those ≤60 y and with ≤5% marrow blasts, or those with hypocellular marrows, PNH clone positivity, or STAT-3 mutant cytotoxic T-cell clones); for those unlikely to respond to immunosuppressive therapy, azacitadine is preferred

For patients with symptomatic anemia with no del(5q) with or without other cytogenetic abnormalities and with ring sideroblasts ≥15% (or ring sideroblasts ≥5% with an SF3B1 mutation), NCCN recommendations are as follows ^[23] :

• Serum erythropoietin (EPO) level  ≤500 mU/mL - Recombinant human EPO or darbepoetin
• Serum erythropoietin (EPO) level > 500 mU/mL - Luspatercept-aamt

For patients with clinically relevant thrombocytopenia or neutropenia or increased marrow blasts, NCCN guidelines recommend azacitidine (preferred), decitabine, or immunosuppressive therapy in selected cases. ^[23]

For patients with higher-risk MDS who are candidates for transplantation, NCCN guidelines recommend allogeneic hematopoietic stem cell transplantation, alone or preceded by treatment with azacitidine, decitabine, or high-intensity chemotherapy. For patients who are not candidates for transplantation, options are azacitidine (preferred, category 1), decitabine, or clinical trial enrollment. ^[23]

The ESMO, ELN, and BSH guidelines offer similar recommendations. ^{[53, 52, 57]}

In addition, BSH guidelines recommend transplantation for patients with lower-risk MDS and any of the following ^[57] :

• Transfusion dependency (≥2 units of blood/month)
• Significant cytopenias (platelets < 30 × 109/L, neutrophils < 0.3 × 109/L)
• Adverse cytogenetics

Further BSH recommendations regarding transplantation include the following:

• Transplantation in lower-risk MDS should possibly be considered at an early stage before iron overload occurs, or after failure of ESA or lenalidomide treatment, in particular if TP53 mutation coexists with del(5q), or if fibrosis is present.
• In higher-risk MDS, upfront transplantation is recommended if bone marrow blasts are 5-10%, with hypomethylating agents given before transplantation if blasts are > 10%.
• Screen patients who are potential transplantation candidates for mutations of the TP53, RAS, JAK2, DNMT3A, TET2, ASXL1, and RUNX1 genes, which correlate with poorer outcomes.
• Selected older patients (> 70 years) with high-risk MDS who have good performance status and a low transplantation-specific comorbidity index should be presented as candidates for allogeneic transplantation.