Guideline sources The following summarized guidelines for the evaluation and management of myelodysplastic syndrome (MDS) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2021), the European Society of Medical Oncology (ESMO 2021), and the Blood and Marrow Transplant Clinical Trial Group (BMT CTN/IMDSF/EBMT/ELN 2017). 1 2 3 4 Calculator Calculator Calculator Eastern Cooperative Oncology G International Prognostic Scoring Karnofsky https://web.pathway.md/diseases/recccYKJkOFVVCHMo 1/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway Guidelines 1. Screening and diagnosis Diagnosis: As per BSH 2021 guidelines: Suspect MDS in patients with otherwise unexplained cytopenias or macrocytosis. A Recognize that the initial assessment of a patient with unexplained cytopenias may not confirm a diagnosis of MDS. Consider obtaining further follow-up and reassessment to reach a firm diagnosis. B As per ESMO 2021 guidelines, diagnose MDS based on blood count, bone marrow aspirate, and bone marrow karyotype. A As per EBMT 2017 guidelines, suspect MDSs originating from inherited germ-line mutations in young patients (< 40-50 years) with a (family) history of dyskeratosis congenita, Fanconi anemia, Shwachman-Diamond Syndrome, Diamond-Blackfan anemia, and GATA2 mutations. B 2. Classification and risk stratification Classification: classify all cases of MDS according to the WHO classification. A Prognosis: As per BSH 2021 guidelines, use the IPSS-R and the International Prognostic Scoring System at diagnosis to assess prognosis in all patients with MDS. B Show 2 more As per ESMO 2021 guidelines: Use the IPSS-R for prognostic evaluation of patients with MDS. A Obtain molecular analysis to add prognostic value, B especially for TP53 in del 5q MDS and SF3B1 mutations in patients with MDS with < 5% blasts. A 3. Diagnostic investigations Initial evaluation: Evaluate patients with suspected MDS with a minimum set of investigations and for alternative causes of marrow dysplasia. A Elicit a detailed clinical and family history to identify potential cases of MDS with germline predisposition. 4. Diagnostic procedures Biopsy and cytogenetic analysis: https://web.pathway.md/diseases/recccYKJkOFVVCHMo 2/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway As per BSH 2021 guidelines, obtain bone marrow cytogenetic analysis in all patients with suspected MDS undergoing a bone marrow examination. A Show 3 more As per ESMO 2021 guidelines, obtain molecular biology testing to diagnose MDS if blood and bone marrow tests are inconclusive. A Show 2 more 5. Medical management Erythropoiesis-stimulating agents: As per BSH 2021 guidelines, consider offering a trial of ESAs in patients with International Prognostic Scoring System low or intermediate-1 (or IPSS-R very low, low, or intermediate with a score up to 3.5) MDS with symptomatic anemia, or asymptomatic anemia and Hgb < 100 g/L fulfilling the criteria for a high or intermediate predictive Nordic score for response. B Show 5 more As per ESMO 2021 guidelines, initiate ESAs (especially epoetin alfa) as first-line therapy for anemia in patients with lower-risk MDS without del(5q). A Thrombopoietin receptor agonists: As per BSH 2021 guidelines, consider administering thrombopoietin receptor agonists to reduce bleeding events in patients with thrombocytopenia with low or intermediate-1 risk MDS. B As per ESMO 2021 guidelines, consider administering thrombopoietin receptor agonists (romiplostim, eltrombopag) for the treatment of severe thrombocytopenia in patients with MDS only with bone marrow blasts < 5%. C Lenalidomide: As per BSH 2021 guidelines: Consider administering lenalidomide 10 mg/day for 21 days, repeated every 28 days after careful discussion with the patient about risks and benefits, in transfusion-dependent patients with International Prognostic Scoring System low or intermediate-1 MDS with del(5q) unsuitable for, not responding, or losing their response to ESAs. B Do not use lenalidomide in patients with del(5q) and bone marrow blasts > 5% or multiple (complex) cytogenetic abnormalities in addition to del(5q) or patients with International Prognostic Scoring System intermediate-2/high MDS. D As per ESMO 2021 guidelines: Administer lenalidomide for the treatment of transfusion-dependent anemia in patients with lower-risk MDS with del(5q). A Consider administering lenalidomide, with or without ESAs, as second-line therapy for anemia in patients with MDS after failure of ESAs. C Hypomethylating agents: As per BSH 2021 guidelines, discuss therapy options with a hypomethylating agent versus intensive chemotherapy carefully in fit older patients lacking an adverse karyotype. B https://web.pathway.md/diseases/recccYKJkOFVVCHMo 3/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway Show 5 more As per ESMO 2021 guidelines: Administer azacitidine in patients with higher-risk MDS without major comorbidities not immediately eligible for allo-SCT. A Consider administering hypomethylating agents as second-line therapy for anemia in patients with MDS after failure of ESAs. C High-intensity chemotherapy: As per BSH 2021 guidelines, discuss therapy options with a hypomethylating agent versus intensive chemotherapy carefully in fit older patients lacking an adverse karyotype. Offer standard acute myeloid leukemia induction regimens where intensive chemotherapy outside a clinical trial is planned. B As per ESMO 2021 guidelines, offer acute myeloid leukemia-like chemotherapy in fit patients (generally < 70 years old) with favorable cytogenetics according to the International Prognostic Scoring System and bone marrow blasts 10%, preferably as a bridge to allo-SCT. B Antithymocyte globulin: consider administering antithymocyte globulin, with or without cyclosporine, in specific younger patients with lower-risk MDS after failure of ESAs. C Luspatercept: administer luspatercept in patients with RBC transfusion-dependent MDS with ring sideroblasts after the failure of ESAs. A Iron chelation therapy: As per BSH 2021 guidelines, consider initiating iron chelation therapy in all suitable lower-risk patients (International Prognostic Scoring System low and intermediate-1; IPSS-R low and very low) at the time they have received 20 units of RBCs or when the ferritin is > 1,000 g/L. B Show 3 more As per ESMO 2021 guidelines: Initiate iron chelation therapy for the treatment of transfusion iron overload in patients with MDS eligible for allo-SCT. B Initiate iron chelation therapy for the treatment of major iron overload, such as significantly reduced cardiac T2-star by MRI, in patients with lower-risk MDS ineligible for stem cell transplantation, B but take into account that its use is more controversial in patients without major iron overload. B As per EBMT 2017 guidelines, initiate appropriate iron chelation therapy before conditioning for transplantation in patients with MDS with a transfusion history of > 20 units of RBCs being potential candidates for HSCT. B Supportive care: provide supportive care to all patients with MDS and symptomatic cytopenias. A 6. Nonpharmacologic interventions https://web.pathway.md/diseases/recccYKJkOFVVCHMo 4/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway Psychosocial support: assess and address emotional health needs continually. Re-iterate disease-specific information regularly. Offer information regarding how to access MDS patient support groups. 7. Therapeutic procedures Red blood cell transfusion: administer RBC transfusions to improve symptomatic anemia. A Show 3 more Platelet transfusion: do not offer prophylactic platelet transfusions in patients with stable MDS not receiving intensive chemotherapy and without signs of bleeding. D Stem cell transplantation, indications: As per BSH 2021 guidelines, consider offering allo-SCT in the following patients with MDS with del(5q) and International Prognostic Scoring System low or intermediate-1 (or IPSS-R with a score < 3.5) lenalidomide-treated patients failed to achieve transfusion independence patients losing their response patients with transfusion dependence unsuitable for lenalidomide. C Show 3 more As per ESMO 2021 guidelines, offer allo-SCT in all < 70 years old patients with higher-risk MDS without major comorbidities and with a donor. A As per BMT CTN/IMDSF/ELN/EBMT 2017 guidelines, consider offering HSCT in all fit patients without comorbidities, provided that disease-related factors allow for HSCT. C Show 9 more Stem cell transplantation, timing: As per BSH 2021 guidelines: Discuss all transplant-eligible patients with MDS with a transplant physician at a multidisciplinary team meeting both at diagnosis and at disease progression. B Assess additional prognostic factors, such as transfusion burden, depth of cytopenias, cytogenetics, and bone marrow fibrosis, when considering the optimal transplant timing in patients with lower-risk MDS. B As per BMT CTN/IMDSF/ELN/EBMT 2017 guidelines, do not rely on the deterioration of cytopenias (which does not affect the IPSS-R classification) to decide on performing HSCT. D Show 3 more Stem cell transplantation (donor selection): take into consideration the age, gender, and CMV status of donors during the donor selection process and follow the recently formulated donor suitability criteria. B Show 2 more Stem cell transplantation, pre-transplant management: As per BSH 2021 guidelines: https://web.pathway.md/diseases/recccYKJkOFVVCHMo 5/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway Consider administering cytoreductive therapy or hypomethylating agents before transplantation in higher-risk patients with > 10% blasts. C Use performance status and age to inform the choice of myeloablative or reduced-intensity conditioning. B As per ESMO 2021 guidelines, consider administering acute myeloid leukemia-like chemotherapy or hypomethylating agents to reduce the bone marrow blast count before allo- SCT when bone marrow blasts are 10%, especially for non-myeloablative allo-SCT. B As per BMT CTN/IMDSF/ELN/EBMT 2017 guidelines, insufficient evidence to recommend continuing hypomethylating agents or proceeding with HSCT when patients reach complete remission after hypomethylating agent therapy. Consider offering HSCT in patients with stable disease after 6 courses of hypomethylating agent therapy. I Show 4 more Stem cell transplantation (post-transplant management): taper immunosuppression rapidly followed by prophylactically donor lymphocyte infusion in case of absent GvHD in patients with MDS with mixed (< 90% donor cells) or increasing recipient chimerism (> 10% recipient) after HSCT. B Show 2 more 8. Follow-up and surveillance Indications for specialist referral: As per BSH 2021 guidelines: Review cases of MDS with a hematologist with a specialist interest in MDS and refer them for a second opinion if the patient or clinician desires. B Refer patients with MDS with suspected germline predisposition to a clinical geneticist. As per EBMT 2017 guidelines, refer patients with MDSs associated with inherited germ-line mutations, such as young patients (< 40-50 years) with a (family) history of dyskeratosis congenita, Fanconi anemia, Shwachman-Diamond Syndrome, Diamond-Blackfan anemia, and GATA2 mutations, to specialist centers in view of the specific sensitivity to conditioning for HSCT in some of these syndromes (such as Fanconi anemia) and the selection of family donors who may carry the involved mutation. B 9. Quality improvement Reporting: report all cases of MDS to the national cancer registry and MDS-specific registries if available. Clinical findings Patient demographics Symptoms https://web.pathway.md/diseases/recccYKJkOFVVCHMo 6/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway Elderly Bone pain Male sex Easy bleeding Easy bruising Past medical history Exertional dyspnea Fatigue Congenital neutropenia Fever Diamond-blackfan anemia Shortness of breath Down's syndrome Weakness Exposure to chemotherapy Exposure to radiation therapy Family history Fanconi anemia Relapsing polychondritis Acute myeloid leukemia Repeated infections Aplastic anemia Trisomy 8 Familial platelet disorder Vasculitis Myelodysplastic syndrome Social history Integument exam Long-term exposure to benzene Pallor Long-term exposure to insecticides Purpura Genetic testing Long-term exposure to pesticides Chromosome 5q deletion Tobacco use Hematological findings Anemia Pancytopenia MCV blood blast cells blood leukocyte count blood neutrophil count blood platelet count Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. 2009 AZA-001 https://web.pathway.md/diseases/recccYKJkOFVVCHMo 7/8 6/30/23, 1:06 AM Myelodysplastic syndrome Pathway In patients with higher-risk myelodysplastic syndromes, azacitidine was superior to conventional care with respect to overall survival. Fenaux P et al. Lancet Oncol. 2009 Mar. References 1. Sally B Killick, Daniel H Wiseman, Lynn Quek et al. British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes. Br J Haematol. 2021 Jul;194 2 282 293. Open 2. Sally B Killick, Wendy Ingram, Dominic Culligan et al. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes. Br J Haematol. 2021 Jul;194 2 267 281. Open 3. P Fenaux, D Haase, V Santini et al. Myelodysplastic syndromes: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021 Feb;32 2 142 156. Open 4. Theo de Witte, David Bowen, Marie Robin et al. 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