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Diagnosis and Management of Myelodysplastic Syndromes

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Diagnosis and Management of Myelodysplastic Syndromes

  1. 1. www.i3Health.com Clinical Tools and Resources for Self-Study and Patient Education Myelodysplastic Syndromes Reference Guide The clinical tools and resources contained herein are provided as educational adjuncts to the CME/NCPD-approved online activity Diagnosis and Management of Myelodysplastic Syndromes. It has been reviewed by David Steensma, MD, Reza Nejati, MD, and Ilene Galinsky, BSN, MSN, ANP-C (April 2020). To access the activity and earn CME/NCPD credit, visit: www.i3Health.com/myelodysplastic-syndromes Contents I. 2016 WHO Classification of Myelodysplastic Syndromes......................................................................... 3 II. Prognostic Scoring Systems and Risk Groups.......................................................................................... 4 III. MDS Scoring Systems ............................................................................................................................. 5 IV. Risk Groups: Lower-Risk Versus Higher-Risk MDS .................................................................................. 6 V. Algorithm for Treatment of Symptomatic Low-Risk MDS........................................................................ 7 VI. Treatment for Lower-Risk MDS With Anemia ......................................................................................... 8 VII. Treatment for Lower-Risk MDS Without Anemia................................................................................... 9 VIII. Treatment for High-Risk MDS ............................................................................................................. 10 IX. HCT Comorbidity Index (HCT-CI)......................................................................................................... 11 X. Initial Care for Anemia........................................................................................................................... 12
  2. 2. 114MDS Reference Guide | Page 2 of 16 www.i3Health.com XI. Treatment for Symptomatic Anemia..................................................................................................... 13 XII. Proposed Modified IWG Response Criteria for Hematological Improvement .................................... 14 XIII. Proposed Modified IWG Response Criteria for Altering Natural History of MDS .............................. 15
  3. 3. 114MDS Reference Guide | Page 3 of 16 www.i3Health.com I. 2016 WHO CLASSIFICATION OF MYELODYSPLASTIC SYNDROMES Subtype Blood Bone Marrow MDS with single lineage dysplasia (MDS-SLD) Single or bicytopenia Dysplasia in ≥10% of 1 cell line, <5% blasts MDS with ring sideroblasts (MDS-RS) Anemia, no blasts ≥15% of erythroid precursors with ring sideroblasts, or ≥5% ring sideroblasts if SF3B1 mutation present MDS with multilineage dysplasia (MDS-MLD) Cytopenia(s), <1 x 109 /L monocytes 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) Cytopenia(s), ≤2%-4% blasts, <1 x 109 /L monocytes Unilineage or multilineage dysplasia, 5%-9% blasts, no Auer rods MDS with excess blasts-2 (MDS-EB-2) Cytopenia(s), 5%-19% blasts, <1 x 109 /L monocytes Unilineage or multilineage dysplasia, 10%-19% blasts, ± Auer rods MDS, unclassifiable (MDS-U) Cytopenias, ±1% blasts on at least 2 occasions Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, <5% blasts MDS with isolated del(5q) Anemia, platelets normal or increased Unilineage erythroid dysplasia, isolated del(5q), <5% blasts ± 1 other abnormality except -7/del(7q) Refractory cytopenia of childhood (provisional WHO category) Cytopenias, <2% blasts Dysplasia in 1-3 lineages, <5% blasts WHO = World Health Organization; MDS = myelodysplastic syndromes. National Comprehensive Cancer Network (2020). Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Version 2.2020. Available at: http://www.nccn.org
  4. 4. 114MDS Reference Guide | Page 4 of 16 www.i3Health.com II. PROGNOSTIC SCORING SYSTEMS AND RISK GROUPS System Prognostic Factors That Are Scored Risk Groups Based on Total Risk Score IPSS • Percent of blast cells in bone marrow (score of 0, 0.5, 1.5, or 2 points) • Chromosome changes (score of 0, 0.5, or 1 point) • Number of low blood counts (score of 0 or 0.5 point) Low IPSS risk score = 0 Intermediate-1 IPSS risk score = 0.5-1 Intermediate-2 IPSS risk score = 1.5-2 High IPSS risk score = 2.5 or higher IPSS-R • Percent of blasts in the bone marrow (score of 0, 1, 2, 3, or 4 points • Chromosome changes (score of 0, 1, 2, 3, or 4 points) • Hemoglobin level (score of 0, 1, or 1.5 points) • Platelet count (score of 0, 0.5, or 1 point) • Neutrophil count (score of 0 or 0.5 points) Very low IPSS-R risk score = 1.5 or lower Low IPSS-R risk score = 2-3 Intermediate IPSS-R risk score = 3.5-4.5 High IPSS-R risk score = 5-6 Very high IPSS-R risk score = 6.5 or higher WPSS • MDS subtype (score of 0, 1, 2, or 3 points) • Chromosome changes (score of 0, 1, or 2 points) • Presence of severe anemia (score of 0 or 1 point) Very low WPSS risk score = 0 Low WPSS risk score = 1 Intermediate WPSS risk score = 2 High WPSS risk score = 3-4 Very high WPSS risk score = 5-6 IPSS = International Prognostic Scoring System; IPSS-R = IPSS-Revised; WPSS = WHO Prognostic Scoring System. National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  5. 5. 114MDS Reference Guide | Page 5 of 16 www.i3Health.com III. MDS SCORING SYSTEMS International Prognostic Scoring System (IPSS) Prognostic Variable Score Value 0 0.5 1.0 1.5 2.0 Marrow blasts (%) <5 5-10 – 11-20 21-30 Karyotype Good Intermediate Poor – – Cytopenia 0/1 2/3 – – – National Comprehensive Cancer Network (2020). Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Version 2.2020. Available at: http://www.nccn.org Revised International Prognostic Scoring System (IPSS-R) Prognostic Variable Score Value 0 0.5 1 1.5 2 3 4 Cytogenetic Very good – Good – – Poor Very poor Marrow blasts (%) ≤2 – >2-<5 – 5-10 >10 – Hemoglobin ≥10 – 8-<10 <8 – – – Platelets ≥100 50-<100 <50 – – – – ANC ≥0.8 <0.8 – – – – – ANC = absolute neutrophil count. National Comprehensive Cancer Network (2020). Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Version 2.2020. Available at: http://www.nccn.org WHO-Based Prognostic Scoring System (WPSS) Prognostic Variable Variable Scores 0 1 2 3 WHO category RCUD, RARS, MDS with isolated del(5q) RCMD RAEB-1 RAEB-2 Karyotype Good Intermediate Poor _ Severe anemia (hemoglobin <9 g/dL in males or <8 g/dL in females) Absent Present – – RCUD = refractory cytopenia with unilineage dysplasia; RARS = refractory anemia with ring sideroblasts; RCMD = refractory cytopenia with multilineage dysplasia; RAEB = refractory anemia with excess blasts. National Comprehensive Cancer Network (2020). Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Version 2.2020. Available at: http://www.nccn.org
  6. 6. 114MDS Reference Guide | Page 6 of 16 www.i3Health.com IV. RISK GROUPS: LOWER-RISK VERSUS HIGHER-RISK MDS Scoring System Lower-Risk MDS Higher-Risk MDS IPSS Low Intermediate-2 Intermediate-1 High IPSS-R Very low Intermediate Low High Intermediate Very high WPSS Very low High Low Very high Intermediate National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  7. 7. 114MDS Reference Guide | Page 7 of 16 www.i3Health.com V. ALGORITHM FOR TREATMENT OF SYMPTOMATIC LOW-RISK MDS Allogeneic SCT EPO ± G-CSF High-Quality Transfusion and Chelation Therapy Immuno- suppressive Treatment Lenalidomide Experimental Treatment Within a Clinical Trial Consider for patients with IPSS-R Intermediate, in particular in the case of additional risk factors (high-risk genetic features, bone marrow fibrosis, transfusion need, severe thrombocytopenia or neutropenia, mutated p53, etc) Consider for patients with anemia and a predictive score of 0-1 When indicated Evaluate patients with MDS-SLD and MDS-MLD For patients with IPSS-R low- and intermediate- risk MDS with isolated del(5q) who have failed growth factor treatment or are not eligible for this treatment according to the predictive model, and who are not p53- positive by immunohistochemistry. Use extreme precaution with lenalidomide treatment in younger patients who may be eligible for SCT Patients with severe cytopenia and/or transfusion dependency who have failed other relevant therapies should be considered SCT = stem cell transplantation; EPO = erythropoietin; G-CSF = granulocyte colony-stimulating factor. Nordic MDS Group (2019). Guidelines for the diagnosis and treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. 9th update. Available at: https://www.nmds.org/
  8. 8. 114MDS Reference Guide | Page 8 of 16 www.i3Health.com VI. TREATMENT FOR LOWER-RISK MDS WITH ANEMIA Initial Treatment Test Results Treatment Options del(5q) ± 1 other chromosome change Lenalidomide No del(5q) ± other chromosome changes; serum EPO ≤500 mU/mL Epoetin alfa ± G-CSF or darbepoetin alfa ± G-CSF No del(5q) ± other chromosome changes; serum EPO >500 mU/mL If likely to respond to IST: ATG (equine) + cyclosporine A If not likely to respond to IST: Azacitidine Decitabine Consider lenalidomide Clinical trial ATG = anti-thymocyte globulin; IST = immunosuppressive therapy. National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org Next Treatment Prior Treatment Treatment Options Epoetin alfa ± G-CSF Darbepoetin alfa ± G-CSF Lenalidomide + epoetin alfa ± G-CSF Lenalidomide + darbepoetin alfa ± G-CSF ATG (equine) + cyclosporine Azacitidine Decitabine Consider lenalidomide Clinical trial Azacitidine Decitabine Clinical trial Consider allogeneic HCT for certain patients G-CSF = granulocyte-stimulating colony factor; HCT = hematopoietic cell transplantation. National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  9. 9. 114MDS Reference Guide | Page 9 of 16 www.i3Health.com VII. TREATMENT FOR LOWER-RISK MDS WITHOUT ANEMIA Treatment Options Disease Progression/No Response Next Options Azacitidine Decitabine IST for certain patients Clinical trial Consider azacitidine or decitabine (if not treating with already) Clinical trial Consider allogeneic HCT for select lower-risk patients National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  10. 10. 114MDS Reference Guide | Page 10 of 16 www.i3Health.com VIII. TREATMENT FOR HIGH-RISK MDS Initial Treatment Assessment Before Treatment Treatment Options Allogeneic HCT is a good option and a well-matched donor is available Allogeneic HCT Azacitidine or decitabine followed by allogeneic HCT High-intensity chemotherapy followed by allogeneic HCT Allogeneic HCT may be a good option but a well- matched donor is not available Azacitidine (preferred) Decitabine Clinical trial Allogeneic HCT is not a good option or a well- matched donor is not available Azacitidine (preferred) Decitabine Clinical trial National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org Next Treatment Prior Treatment Results Treatment Options Next Options Allogeneic HCT Azacitidine or decitabine followed by allogeneic HCT High-intensity chemotherapy followed by allogeneic HCT Relapse after HCT or no response Consider second HCT or DLI Azacitidine or decitabine Clinical trial If response, continue treatment If relapse or no response, clinical trial or supportive care Azacitidine (preferred) Decitabine Clinical trial Response Continue treatment Relapse or no response Clinical trial Supportive care DLI = donor lymphocyte infusion. National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  11. 11. 114MDS Reference Guide | Page 11 of 16 www.i3Health.com IX. HCT COMORBIDITY INDEX (HCT-CI) Comorbidity Definition of Comorbidity HCT-CI Weighted Score Arrhythmia Atrial fibrillation or flutter, sick sinus syndrome, or ventricular arrhythmia 1 Cardiac Coronary artery disease, congestive heart failure, myocardial infarction, or EF ≤50% 1 Inflammatory bowel disease Crohn disease or ulcerative colitis 1 Diabetes Requiring treatment with insulin or oral hypoglycemic but not diet alone 1 Cerebrovascular disease Transient ischemic attack or cerebrovascular accident 1 Psychiatric disturbance Depression or anxiety requiring psychiatric consult or treatment 1 Hepatic, mild Chronic hepatitis, bilirubin >ULN to 1.5 x ULN, or AST/ALT >ULN to 2.5 x ULN 1 Obesity Patients with a body mass index >35 kg/m2 1 Infection Requiring continuation of antimicrobial treatment after day 0 1 Rheumatologic SLE, RA, polymyositis, mixed CTD, or polymyalgia rheumatica 2 Peptic ulcer Requiring treatment 2 Moderate/severe renal Serum creatinine >2 mg/dL (178 mmol/l), on dialysis, or prior renal transplantation 2 Moderate pulmonary DLCO and/or FEV1 66%-80% or dyspnea on slight activity 2 Prior solid tumor Treated at any time point in the patient’s past history, excluding non-melanoma skin cancer 3 Heart valve disease Except mitral valve prolapse 3 Severe pulmonary DLCO and/or FEV ≤65% dyspnea at rest or requiring oxygen 3 Moderate/severe hepatic Liver cirrhosis, bilirubin >1.5 x ULN, or AST/ALT >2.5x ULN 3 EF = ejection fraction; ULN = upper limit of normal; AST = aspartate aminotransferase; ALT = alanine aminotransferase; SLE = systemic lupus erythematosus; RA = rheumatoid arthritis; CTD = connective tissue disease; DLCO = diffusion capacity of carbon monoxide; FEV = forced expiratory volume. Nordic MDS Group (2019). Guidelines for the diagnosis and treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. 9th update. Available at: https://www.nmds.org/
  12. 12. 114MDS Reference Guide | Page 12 of 16 www.i3Health.com X. INITIAL CARE FOR ANEMIA First Steps of Care Rule out and treat other possible causes of anemia Replace iron, folate, or vitamin B12 if needed Red blood cell transfusions Supportive care National Comprehensive Cancer Network (2018). NCCN Guidelines for Patients: myelodysplastic syndromes. Available at: http://www.nccn.org
  13. 13. 114MDS Reference Guide | Page 13 of 16 www.i3Health.com XI. TREATMENT FOR SYMPTOMATIC ANEMIA Test Results Treatment Options Response and Next Options Del(5q) ± 1 other cytogenetic abnormality (except those involving chromosome 7) Lenalidomide If response, stay on lenalidomide or decrease dose to tolerance If no response, see Initial Treatment for Lower-Risk MDS With Anemia Serum EPO ≤500 mU/mL and <15% ring sideroblasts (or <5% ring sideroblasts without an SF3B1 mutation) Epoetin alfa Darbepoetin alfa If response, stay on treatment or decrease dose to tolerance If no response, consider adding G-CSF or lenalidomide, then see Initial Treatment for Lower-Risk MDS With Anemia if needed Serum EPO ≤500 mU/mL and ≥15% ring sideroblasts (or ≥5% ring sideroblasts with an SF3B1 mutation) Epoetin alfa + G-CSF Darbepoetin alfa + G-CSF If response, stay on treatment and lower the dose if needed If no response, try luspatercept or see Initial Treatment for Lower-Risk MDS With Anemia if needed Serum EPO >500 mU/mL and <15% ring sideroblasts (or <5% ring sideroblasts without an SF3B1 mutation) See options in Initial Treatment for Lower-Risk MDS With Anemia Serum EPO >500 mU/mL and ≥15% sideroblasts (or ≥5% ring sideroblasts with an SF3B1 mutation) Luspatercept National Comprehensive Cancer Network (2020). Clinical Practice Guidelines in Oncology: myelodysplastic syndromes. Version 2.2020. Available at: http://www.nccn.org
  14. 14. 114MDS Reference Guide | Page 14 of 16 www.i3Health.com XII. PROPOSED MODIFIED IWG RESPONSE CRITERIA FOR HEMATOLOGICAL IMPROVEMENT Hematological Improvement Response Criteria (Response Must Last at Least 8 Weeks) Erythroid response (pre-treatment <110 g/L) Hb increase by ≥15 g/L Relevant reduction of units of RBC transfusions by an absolute number of at least 4 RBC transfusion/8 weeks compared with the pretreatment transfusion number in the previous 8 weeks. Only RBC transfusion given for Hb ≤90 g/L pre-treatment will count in the RBC transfusion evaluation Platelet response (pre-treatment <100 x109 /L) Absolute increase of ≥30 x 109 /L for patients starting with >20 x 109 /L Increase from <20 x 109 /L to >20 x 109 /L and by at least 100% Neutrophil response (pre-treatment <1.0 x 109 /L) At least 100% increase and an absolute increase >0.5 x 109 /L Progression or relapse after HI At least 1 of the following: At least 50% decrement from maximum response levels in granulocytes or platelets Reduction in Hb by ≥15 g/L Transfusion dependence IWG = International Working Group; RBC = red blood cell; HI = hematological improvement. Nordic MDS Group (2019). Guidelines for the diagnosis and treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. 9th update. Available at: https://www.nmds.org/
  15. 15. 114MDS Reference Guide | Page 15 of 16 www.i3Health.com XIII. PROPOSED MODIFIED IWG RESPONSE CRITERIA FOR ALTERING NATURAL HISTORY OF MDS Category Response Criteria (Response Must Last at Least 4 Weeks) Complete remission Bone marrow ≤5% myeloblasts with normal maturation of all cell lines Persistent dysplasia will be noted Peripheral blood: • Hb ≥110 g/L • Platelets ≥100 x 109 /L • Neutrophils ≥1.0 x 109 /L Blasts 0% Partial remission All CR criteria if abnormal before treatment except: • Bone marrow blasts decreased by ≥50% over pre-treatment but still >5% Cellularity and morphology not relevant Marrow CR BM ≤5% myeloblasts and decrease by ≥50% over pre-treatment Peripheral blood: if HI responses, they will be noted in addition to marrow CR Stable disease Failure to achieve at least PR, but no evidence of progression for >8 weeks Failure Death during treatment or disease progression characterized by worsening of cytopenias, increase in percentage of BM blasts, or progression to a more advanced MDS subtype than pretreatment Relapse after CR or PR At least 1 of the following: • Return to pretreatment BM blast percentage • Decrement of ≥50% from maximum remission/response levels in granulocytes or platelets Reduction in Hb concentration by ≥15 g/L or transfusion dependence Cytogenetic response Complete: disappearance of the chromosomal abnormality without new ones Partial: at least 50% reduction of the chromosomal abnormality Disease progression ≥50 increase in blasts Any of the following: • At least 50% decrement from maximum remission/response in granulocytes or platelets • Reduction of Hb by ≥20 g/L Transfusion dependence
  16. 16. 114MDS Reference Guide | Page 16 of 16 www.i3Health.com Survival End points: • OS: death from any cause • EFS: failure or death from any cause • PFS: disease progression or death from MDS • DFS: time to relapse Cause-specific death: death related to MDS Hb = hemoglobin; CR = complete remission; BM = bone marrow; PR = partial remission; OS = overall survival; EFS = event-free survival; PFS = progression-free survival; DFS = disease-free survival. Nordic MDS Group (2019). Guidelines for the diagnosis and treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. 9th update. Available at: https://www.nmds.org/

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