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Myelodysplastic Syndrome

posted Mar 5, 2015, 4:56 PM by Kevin Hauck
Better late than never!  A Monte Minute brought to you by Shubha Bhar from Firm 3!

Review of Myelodysplastic Syndrome

During our last crs case, we discussed a 72 yo M(pmh of multiple skin abscesses and folate deficiency) who presented with 5 weeks of persistent violaceous lesions of bilateral hands after recent L hand dog bite.  On routine labs he was found to have anemia and thrombocytopenia.  The patient was ultimately diagnosed with atypical pyoderma gangrenosum with association with myelodysplastic syndrome which was initiated by a pathergic stimulus (dog bite). 

In this monte minute, I will review myelodysplastic syndrome including its pathogenesis, clinical presentation, diagnosis, and treatment.    

Myelodysplastic Syndrome: 

Definition:  Myelodysplastic syndrome is an ineffective maturation of the myeloid blood cells.  It can affect red blood cells, neutrophils, and platelets, thus putting patients at risk for anemia, infection, and bleeding.  There is variable risk for progression to acute myeloid leukemia. 

Population:  The median age at diagnosis is greater than 65 yo, it rarely affects individuals younger than 50.  Incidence rates are 1.8 higher in men than women. Median age of diagnosis is 71 years, 72% of patients are 70 or older.

Risk factors:  male age, prior treatment with chemotherapy or radiation, tobacco use, occupational exposure to chemicals (benzene).  The risk is also higher in certain genetic syndromes including Diamond-Blackfan syndrome, ataxia telengiectasia, Fanconi’s anemia, Down’s Syndrome, and certain blood disorders including paroxysmal nocturnal hemoglobinuria and congenital neutropenia.  There is also a rare autosomal dominant familial MDS.

Pathogenesis:  The majority of cases are de novo, about 10% of cases are secondary to radiation or chemotherapy.  Secondary MDS has a worse prognosis than primary MDS, typically MDS develops 5 years after tx with chemotherapy or radiation.  MDS develops from a series of mutations in the hematopoietic stem cell, affecting growth and differentiation, and leading to abnormal, immature myeloid cells in the bone marrow.  Multiple mutations in MDS have been found including chromosomal abnormalities and those affecting DNA methylation, histone modification, RNA splicing, transcription factors, and cytokine signaling pathways.  Many of these mutations have also been found in patients with AML.  The inciting cause is often unknown for most cases.  Detection of certain chromosomal and genetic abnormalities aids in MDS classification and prognostication. 

Clinical Presentation: Many patients diagnosed with MDS are asymptomatic and are diagnosed with routine blood screening.  Other patients will be diagnosed with non-specific symptoms.  As anemia is the most common cytopenia in MDS (present in approximately 80-85% of patients), patients can present with fatigue, weakness, palpitations, sob/cp on exertion.  Patients may present with recurrent infection due to neutropenia and impaired granulocyte dysfunction.  Bacterial infections are most common, and the skin is most commonly affected.  Fungal, viral, and mycobacterial infections are less common. Additionally patients presenting with thrombocytopenia may present with petechial/purpura, bleeding of mucosal services, and easy bleeding. 

Physical exam rarely shows splenomegaly and lymphadenopathy, and should raise suspicion for a myeloproliferative or lymphoproliferative neoplasm.  Skin lesions in MDS are uncommon but can occur. Sweet’s syndrome (aka acute febrile neutrophilic dermatosis) is an inflammatory disorder characterized by painful, edematous, and erythematous papules, plaques, or nodules of the skin, often accompanied by fever and leukocytosis.  Biopsy shows neutrophilic infiltration.  Myeloid sarcoma is an extramedullary collection of immature myeloblasts, it can occur in any organ or tissue, and may be a sign of transformation into aml.  The most common area for involvement is the skin ad the gingiva.  Lesions are typically violaceous, raised, nontender plaques or nodules.  Biopsy shows myeloblast infiltration. 

Autoimmune abnormalities may be associated with mds.  This includes cutaneous vasculitis, psoriasis, rheumatoid arthritis, polymyalgia rheumatica, and pernicious anemia.  Additionally patients can develop acquired Hb H disease.

Classification:  There are two major classification systems for MDS, the FAB classification and the WHO classification systems.  While aiding in diagnosis, they are not as helpful in prognostication.

Below is the WHO classification for myelodysplastic syndromes:

1. Refactory cytopenia with unilineage dysplasia (refractory anemia, neutropenia, or thrombocytopenia

2. Refractory anemia with ring sideroblasts (ring  sideroblast >= 15% bone marrow)

3. Refractory cytopenia with multilineage dysplasia

4. Refractory anemia with excess blasts (RAEB.  RAEB 1: 2-4% circulating blasts, or 5-9% marrow blasts; RAEB 2: 5-19% circulating blasts or 10-19% marrow blasts or Auer rods)

5. Myelodysplastic syndrome with isolated del(5q)

6. Myelodysplastic syndrome (unclassifiable

There are three prognostic systems which include the international prognostic scoring system (IPSS), WHO prognostic scoring system, and MD Anderson Cancer Center MDS model.  The IPSS is the simplest and most commonly used.  The IPSS takes into account the percentage of blast cells, the karyotype, and number of blood cell lineages involved. Prognosis worsens with percentage of blast cells and number of cell lines affected.

Diagnosis:  Diagnosis is based on peripheral blood smear, bone marrow bx, and certain genetic abnormalities

- in evaluating a patient for cytopenias/dysplastia, should obtain the following for further workup:  iron studies, b12, folate, copper, hiv, tsh, lfts, hiv, hepatitis panel.  Medications should be reviewed.

- CBC: isolated or multilineage cytopenia.  Consider MDS in elderly patients with persistent macrocytic anemia, multiple cytopenia, or dysplastic peripheral blood cells after exclusion of other conditions. 

a.       Anemia: typically macro or normocytic.  RDW is generally increased

b.      Leukopenia: present in ½ of pts, fewer than 20% blasts

c.       Thrombocytopenia:  present in ¼ pts

-          Peripheral smear/BM bx:  erythroid, granulocyte, or megakaryocytes are > 10% dysplastic on visual inspection.  Generally bm bx reveals hypercellular bone marrow, but about 5-10% of patients can have hypocellular bone marrow.  Less than 20% blasts should be present, cases with >20% are considered to have AML.  Patients with certain genetic abnormalities are diagnostic of AML regardless of the blast cell count.

Treatment:  Low risk disease, especially for anemia is tx with growth factors, lenalidomide, and transfusions.  Higher risk patients are tx with hypomethylating agents and if possible allogenic stem cell transplant.

a.       supportive care:  with rbc transfusions as needed for anemia

b.      erythropoiesis stimulating agents for anemia at Hb of <10

c.       hypocellular or immune mediated MDS:  tx with immunosuppressive therapy with thymoglobulin

d.       MDS with isolated chromosome 5q deletion: tx with lenalidomide

e.       advanced MDS (excess blasts) or pancytopenia unresponsive to other therapy: azacitidine or dacogen

f.       Stem cell transplant

 

“Myelodysplastic Syndromes” N Engl J Med 2009;361:1872-85.

“Myelodysplastic Syndromes: A practical guide to diagnosis and treatment.” Cleveland Clinic Journal of Medicine January 2010 vol. 77 1 37-44

“Myelodysplastic Syndrome” The Lancet, Volume 383, Issue 9936, Pages 2239 - 2252, 28 June 2014

up to date 

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