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Myelodysplastic Syndromes
Richard A. Larson, MD
image BASICS
DESCRIPTION
Myelodysplastic syndromes (MDSs) constitute a heterogeneous group of acquired hematopoietic stem cell disorders characterized by cytologic dysplasia in the bone marrow and blood and by various combinations of anemia, neutropenia, and thrombocytopenia.
  • The natural progression of disease evolves as cellular maturation becomes more arrested and blast cells accumulate. There is an overlap between arbitrary diagnostic subgroups (1)[C],(2)[A],(3)[C].
  • World Health Organization (WHO) classification
    • Refractory cytopenia with unilineage dysplasia
      • Refractory anemia (RA); refractory neutropenia; refractory thrombocytopenia
      • <5% blasts and <15% ring sideroblasts in marrow; <1% blasts in blood
    • Refractory anemia with ring sideroblasts (RARS)
      • <5% blasts in marrow; ≥15% of erythroid precursors are ring sideroblasts; no blasts in blood
      • Also known as acquired idiopathic sideroblastic anemia
    • RARS and marked thrombocytosis
    • Refractory cytopenia with multilineage dysplasia:
      • Marked trilineage dysplasia but without excess blasts in marrow; no Auer rods; <1% blasts in blood
    • Refractory cytopenia with multilineage dysplasia and ring sideroblasts
    • RA with excess blasts-1 (RAEB-1):
      • 5-9% blasts in marrow; no Auer rods; <5% blasts in blood; <1,000 monocytes/mm3
    • RAEB-2
      • 10-19% blasts in marrow; 5-19% blasts in blood; ± Auer rods; <1,000 monocytes/mm3
    • MDS associated with isolated del(5q)
      • RA with erythroid hyperplasia, increased megakaryocytes with hypolobated nuclei, and normal or increased platelets; <5% blasts in marrow; <1% blasts in blood
    • Acute MDS with sclerosis:
      • RAEB with marked myelosclerosis
    • Chronic myelomonocytic leukemia (CMMoL) is now grouped with myelodysplastic/myeloproliferative disorders:
      • <20% blasts and promonocytes in marrow and blood with >1,000 monocytes/mm3
    • RAEB in transformation is now considered acute myeloid leukemia (AML):
      • 20-30% blasts in marrow; >20% blasts in blood
      • Incidence: 2:1 (female > male)
    • Therapy-related MDS (t-MDS):
      • Seen 3 to 7 years after treatment with alkylating agents and/or radiotherapy
      • Evolves to AML over ˜6 months
      • Classified by the WHO as therapy-related myeloid neoplasm
  • System(s) affected: hematologic, lymphatic, immunologic
  • Synonym(s): dysmyelopoietic syndrome; hemopoietic dysplasia; preleukemia; smoldering or subacute myeloid leukemia
Pediatric Considerations
Pediatric presentations of MDS
  • Monosomy 7 syndrome
  • Juvenile chronic myelogenous leukemia
EPIDEMIOLOGY
  • Predominant age: median age, >65 years; uncommon in children and young adults
  • Predominant sex: male = female
Incidence
Apparent increased incidence (1 to 2/100,000 per year) in recent years may be due to improved diagnosis; incidence increases markedly with older age.
Genetics
  • Most are clonal neoplasms by cytogenetics, G6PD isoenzyme analysis, or restriction fragment length polymorphism analysis.
  • Mutations in RAS oncogene
  • Mutations in RPS14 gene on chromosome 5q
  • Mutations in TET2, SF3B1, SRSF2, U2AF1, DNMT3A, ASXL1
RISK FACTORS
  • Primary MDS is associated with older age, occupational exposure to petroleum solvents (benzene, gasoline), and smoking.
  • Secondary (therapy-related) MDS is associated with prior treatment with alkylating agents or radiotherapy.
COMMONLY ASSOCIATED CONDITIONS
  • Anemia
  • Neutropenia
  • Thrombocytopenia
  • Pancytopenia
  • Opportunistic infections
  • Bleeding, bruising
  • Sweet syndrome (neutrophilic dermatosis)
image DIAGNOSIS
PHYSICAL EXAM
  • Anemia
    • Fatigue
    • Shortness of breath
    • Light-headedness
    • Angina
  • Leukopenia
    • Fever
    • Infection
  • Thrombocytopenia
    • Ecchymoses
    • Petechiae
    • Epistaxis
    • Purpura
  • Splenomegaly (uncommon)
    • Mild to moderate enlargement may be encountered, particularly in CMMoL.
  • Skin infiltrates
    • Sweet syndrome
DIFFERENTIAL DIAGNOSIS
  • Other malignant disorders
    • Evolving AML or erythroleukemia
    • Chronic myeloproliferative disorders
    • Polycythemia vera
    • Myeloid metaplasia with myelofibrosis
    • Malignant lymphoma
    • Metastatic carcinoma
  • Nonmalignant disorders
    • Aplastic anemia
    • Autoimmune disorders (Felty syndrome, lupus, hemolytic anemia)
    • Nutritional deficiencies (vitamin B12, pyridoxine, copper, protein malnutrition)
    • Heavy metal intoxication
    • Alcoholism
    • Chronic liver disease
    • Hypersplenism
    • Chronic inflammation
    • Recent cytotoxic therapy or irradiation
    • HIV infection
    • Paroxysmal nocturnal hemoglobinuria
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC with differential and peripheral smear
  • Reticulocyte count and serum erythropoietin level if anemia were present
  • Review of the peripheral blood smear for the presence of dysplasia
  • Liver/spleen scan or CT, although rarely necessary, may disclose occult splenomegaly or lymphadenopathy.
  • Cytogenetics
    • At least 50% of patients with primary MDS and nearly all with t-MDS have clonal chromosomal abnormalities: + 8, -7, del(5q), del(7q), del(20q), iso(17p), various others, and complex karyotypes.
    • Detection of clonal abnormality establishes a diagnosis of neoplasm and rules out a nutritional, toxic, or autoimmune disorder.
    • Cytogenetic analysis of metaphase cells from a bone marrow aspiration provides more information than fluorescence in situ hybridization analysis on blood cells.
  • Granulocyte function tests: abnormal in 50% (decreased myeloperoxidase activity, phagocytosis, chemotaxis, and adhesion)
  • Platelet function tests: impaired aggregation
  • Marrow colony assays in vitro
    • Results are variable and correlate poorly with clinical course.
    • Poor clonal growth may suggest more rapid evolution to AML.
  • Immunophenotyping
    • Nonspecific myeloid markers are present.
    • Occasionally, evidence can be found for concomitant lymphoproliferative disorder.
    • Loss of CD59 expression suggests paroxysmal nocturnal hemoglobinuria (PNH).
Follow-Up Tests & Special Considerations
  • Anemia: often macrocytic; occasional poikilocytosis, anisocytosis; variable reticulocytosis
  • Granulocytopenia: hypogranular or agranular neutrophils with poorly condensed chromatin; Pelger-Huet anomaly with hyposegmented nuclei
  • Thrombocytopenia: occasionally giant platelets or hypogranular platelets
  • Fetal hemoglobin may be elevated.
  • Flow cytometry to detect loss of CD59 on RBCs, CD16 on granulocytes, and CD14 on monocytes; typical of PNH
  • Direct antiglobulin (Coombs) test
  • Paraprotein: present in some
  • Erythropoietin: usually normally elevated given the degree of anemia unless renal failure is present
  • Increased serum and tissue iron (ferritin), especially if anemia has been long-standing
  • Serum copper level
P.699

Diagnostic Procedures/Other
  • Review peripheral blood smear.
  • Bone marrow aspiration, biopsy, and cytogenetics
  • Myeloid gene mutation array
Test Interpretation
  • Ineffective hematopoiesis with dysplasia in one or more cell lineages dominates the bone marrow picture in MDS.
  • Marrow cellularity usually is normal or increased for the patient's age but may be hypoplastic in ˜10%.
  • Reticulin fibrosis usually is minimal except in t-MDS and acute MDS with sclerosis.
  • Myeloblasts may be clustered in the intertrabecular spaces with abnormal localization of immature precursors.
image TREATMENT
GENERAL MEASURES
  • Immunize for pneumococcal pneumonia, pertussis, influenza, and hepatitis B (4)[C].
  • RBC transfusions to alleviate symptoms
  • Platelet transfusions only for bleeding or before surgery to avoid alloimmunization
  • Early use of antibiotics for fever, even while culture results are pending, due to quantitative and qualitative granulocyte disorder
  • Iron chelation therapy to avoid iron overload from chronic transfusions
MEDICATION
First Line
  • Epoetin alfa or darbepoetin can increase hemoglobin levels in MDS patients who have low serum erythropoietin levels at baseline (5)[C].
  • Only azacitidine, decitabine, and lenalidomide have been approved by the FDA for MDS.
  • Azacitidine and decitabine have been proven in randomized controlled trials to be more effective for these heterogeneous disorders than only supportive care, with antibiotics, and transfusions.
  • Vitamins, iron, corticosteroids, androgens, or thyroid hormone are rarely helpful, unless evidence of a specific deficiency exists.
  • Clinical trials show azacitidine, 75 mg/m2/day SC for 7 days and repeated every 28 days, decreases RBC transfusion requirements, yields longer times to AML or death, and improves quality of life.
  • Decitabine was approved with a continuous IV schedule that usually requires hospitalization. More commonly, it is given at 20 mg/m2 IV over 1 hour daily for 5 days as an outpatient, repeated every 4 weeks.
  • Lenalidomide, 10 mg PO daily for 21 days every 4 weeks has yielded complete remission in patients with MDS and del(5q). It is less effective in patients with MDS without del(5q) (6)[B].
  • Intensive chemotherapy
    • Younger patients with MDS may benefit from AML chemotherapy, especially if Auer rods are present, but toxicity may be severe for older patients.
    • Remission durations are variable (median, ˜1 year).
  • Allogeneic hematopoietic stem cell transplantation:
    • Recommended for younger patients with HLA antigen-matched donors to eradicate the malignant clone and resupply normal hematopoietic stem cells (7)[A].
  • Aminocaproic acid (epsilon-aminocaproic acid) or tranexamic acid may benefit patients with chronic, severe thrombocytopenia and bleeding.
  • Contraindications: Cytotoxicity of chemotherapy may increase the risk of bleeding and infection and the need for transfusion support.
  • Precautions: Aspirin, salicylates, and NSAIDs should be avoided.
Second Line
  • Danazol or prednisone may be of benefit for concomitant autoimmune thrombocytopenia.
  • Investigational agents
    • Low doses of cytarabine, tretinoin (all-trans retinoic acid), 13-cis retinoic acid, arsenic trioxide, histone/protein deacetylase inhibitors, interferon, cyclosporine, antithymocyte globulin, filgrastim, and interleukin-3
    • Agents, such as thalidomide, that inhibit the production of tumor necrosis factor in the marrow.
  • Amifostine may stimulate the proliferation of normal hematopoiesis.
ISSUES FOR REFERRAL
  • Refer younger adults for allogeneic hematopoietic cell transplantation.
  • Refer patients with symptoms or transfusion requirements for clinical trials.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Usually outpatient, except when necessary to hospitalize for the treatment of infection, blood transfusions, or intensive chemotherapy
Patient Monitoring
  • At least monthly during supportive care
  • More frequently if receiving treatment
DIET
Reduce alcohol use and iron intake (unless patient is iron-deficient).
PATIENT EDUCATION
  • Stop smoking.
  • Seek early medical attention for fever, bleeding, or symptoms of anemia.
  • Advise about the risks of chronic transfusion therapy.
PROGNOSIS
  • Median survival for RA and RARS is 5 years, but it may extend much longer (8)[B].
  • RA with del(5q) syndrome is favorable.
  • Median survival for RAEB, RCMD, and CMMoL is ˜1 year; 50% of patients evolve to AML and the other 50% die of infection or bleeding.
REFERENCES
1. Malcovati L, Hellström-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964.
2. Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: IARC Press; 2008.
3. Greenberg PL. The multifaceted nature of myelodysplastic syndromes: clinical, molecular, and biological prognostic features. J Natl Compr Canc Netw. 2013;11(7):877-884.
4. Larson RA. Myelodysplasia: when to treat and how. Best Pract Res Clin Haematol. 2006;19(2):293-300.
5. Fenaux P, Adès L. How we treat lower-risk myelodysplastic syndromes. Blood. 2013;121(21):4280-4286.
6. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355(14):1456-1465.
7. Koreth J, Pidala J, Perez WS, et al. Role of reducedintensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: an international collaborative decision analysis. J Clin Oncol. 2013;31(21):2662-2670.
8. Voso MT, Fenu S, Latagliata R, et al. Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database. J Clin Oncol. 2013;31(21):2671-2677.
Additional Reading
&NA;
  • Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419-425.
  • Larson RA, Le Beau MM. Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. Chem Biol Interact. 2005;153-154:187-195.
  • Nybakken GE, Bagg A. The genetic basis and expanding role of molecular analysis in the diagnosis, prognosis, and therapeutic design for myelodysplastic syndromes. J Mol Diagn. 2014;16(2):145-158.
  • Singh ZN, Huo D, Anastasi J, et al. Therapy-related myelodysplastic syndrome: morphologic subclassification may not be clinically relevant. Am J Clin Pathol. 2007;127(2):197-205.
Codes
&NA;
ICD10
  • D46.9 Myelodysplastic syndrome, unspecified
  • D46.4 Refractory anemia, unspecified
  • D46.B Refract cytopenia w multilin dysplasia and ring sideroblasts
Clinical Pearls
&NA;
  • MDS constitutes a heterogeneous group of acquired, hematopoietic stem cell disorders characterized by cytologic dysplasia in the bone marrow and blood and by various combinations of anemia, neutropenia, and thrombocytopenia.
  • The natural progression of this malignant disease evolves as cellular maturation becomes more arrested and blast cells accumulate.