Myelodysplastic syndromes

para>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

RA with ring sideroblasts 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 " 7 years after treatment with alkylating agents and/or radiotherapy
Evolves to AML over ’ Ό6 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 " 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)

Diagnosis

History

Fatigue
Fever
Easy bruising

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(17), 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 aspirate 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

Diagnostic Procedures/Other

Review peripheral blood smear
Bone marrow aspiration, biopsy, and cytogenetics
Myeloid gene mutation array

Test Interpretation

Ineffective hematopoiesis with dysplasia in 1 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 ’ Ό10%.
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.

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/d 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, ’ Ό1 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.

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 ’ Ό1 year; 50% of patients evolve to AML and the other 50% die of infection or bleeding.

Complications

Infection
Bleeding
Complications of anemia and transfusions

References

1.Malcovati L, Hellstr Άm-Lindberg E, Bowen D, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European Leukemia Net. Blood. 2013;122(17):2943 " 2964. [View Abstract]2.Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 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 " 885. [View Abstract]4.Larson RA. Myelodysplasia: when to treat and how. Best Pract Res Clin Haematol. 2006;19(2):293 " 300. [View Abstract]5.Fenaux P, Ad ¨s L. How we treat lower-risk myelodysplastic syndromes. Blood. 2013;121(21):4280 " 4286. [View Abstract]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. [View Abstract]7.Koreth J, Pidala J, Perez WS, et al. Role of reduced-intensity 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. [View Abstract]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. [View Abstract]

Additional Reading

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. [View Abstract]
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. [View Abstract]
Larson RA, Le Beau MM. Therapy-related myeloid leukaemia: a model for leukemogenesis in humans. Chem Biol Interact. 2005;153 " 154:187 " 195. [View Abstract]
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. [View Abstract]

Codes

ICD10

D46.9 Myelodysplastic syndrome, unspecified
D46.4 Refractory anemia, unspecified
D46.B Refract cytopenia w multilin dysplasia and ring sideroblasts
D64.3 Other sideroblastic anemias
D46.1 Refractory anemia with ring sideroblasts
D46.A Refractory cytopenia with multilineage dysplasia
D46.C Myelodysplastic syndrome w isolated del(5q) chromsoml abnlt
D46.20 Refractory anemia with excess of blasts, unspecified
D46.Z Other myelodysplastic syndromes
D46.22 Refractory anemia with excess of blasts 2
D46.21 Refractory anemia with excess of blasts 1

ICD09

238.75 Myelodysplastic syndrome, unspecified
238.72 Low grade myelodysplastic syndrome lesions
285.0 Sideroblastic anemia
238.74 Myelodysplastic syndrome with 5q deletion
238.73 High grade myelodysplastic syndrome lesions

SNOMED

109995007 myelodysplastic syndrome (disorder)
109996008 Myelodysplastic syndrome: Refractory anemia, without ringed sideroblasts, without excess blasts (disorder)
415285009 Refractory cytopenia with multilineage dysplasia (disorder)
276448005 Idiopathic sideroblastic anemia
109998009 Refractory anemia with ringed sideroblasts (disorder)

Clinical Pearls

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 disease evolves as cellular maturation becomes more arrested and blast cells accumulate.

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