Myelodysplastic Syndromes. Not yet a leukemia but can be fatal.

In 1982, “myelodysplasia” was used by the French–American–British (FAB) group to describe the morphologic abnormalities of the myeloid cell lines of hematopoiesis in preleukemic conditions, which were named myelodysplastic syndromes (MDS). MDS occur mainly, but not exclusively, in patients with a median age of about 70 years, and the crude incidence is 4 to 5 cases per 100,000 persons per year. Probably under reported. Hematopoeitic stem cells cloSeveral mutation-driver genes, belonging to different biologic pathways, can lead to MDS, and most patients have combinations of pathway mutations, accounting for the heterogeneity of these disorders.ne, usually one clone having a developmental advantage. Chromosome 5 seems to be affected with a C to T conversion by spontaneous deamination of cytosine. The deletion on the long arm of chromosome 5 is the initiating driver mutation that leads to haploinsufficiency of multiple genes and, in turn, to clinical manifestations.

It is the growth and spread of a somatically mutated clone represent the pathophysiological process that leads to MDS. Several mutation-driver genes, belonging to different biologic pathways, can lead to MDS, and most patients have combinations of pathway mutations, accounting for the heterogeneity of these disorders.

When most of the bone marrow hematopoietic cells are clonally derived, the disease is clinically manifested as cytopenia and morphologic dysplasia. After the common causes of cytopenia have been ruled out a bone marrow aspiration biopsy is done to detect morphologic dysplasia and blasts, bone marrow biopsy to assess marrow cellularity and fibrosis, and conventional cytogenetics to detect nonrandom chromosomal abnormalities.

Clinical manifestations.

Anemia is the most common cytopenia associated with MDS and it may be manifest as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment, or an altered sense of well-being. Fatigue is nearly ubiquitous and often may be out of proportion to the degree of anemia. Less commonly, complications associated with leukopenia (eg, infections, gingivitis) or thrombocytopenia (eg, easy bruising, bleeding) are present. Systemic symptoms such as fever, sweats, or weight loss are uncommon and generally represent late manifestations of MDS or transformation to acute leukemia. Physical findings of MDS are nonspecific but may include pallor, petechiae, purpura, mucosal ulceration/gingivitis, or stigmata of infections. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon.

Patients with MDS may develop infections related to neutropenia and granulocyte dysfunction (eg, impaired chemotaxis and microbial killing). Bacterial infections predominate, with the skin being the most common site involved.

The most common autoimmune conditions in patients with MDS are chronic rheumatic heart disease (7 percent), rheumatoid arthritis (6 percent), pernicious anemia (6 percent), psoriasis (2 percent), and polymyalgia rheumatica (2 percent). 

 Other autoimmune abnormalities include Sweet syndrome, pericarditis, pleural effusions, skin ulcerations, iritis, myositis, peripheral neuropathy, and pure red cell aplasia. Sweet syndrome (acute febrile neutrophilic dermatosis) may herald transformation to acute leukemia

Assessment.

Complete blood count — Complete blood count (CBC) with leukocyte differential usually demonstrates anemia, but neutropenia and thrombocytopenia are more variable. While isolated anemia is often seen, few patients present with isolated neutropenia, thrombocytopenia, or monocytosis without anemia. Pancytopenia (ie, anemia, leukopenia, and thrombocytopenia) is present in up to half of patients at the time of diagnosis. Thrombocytosis may be associated with abnormalities of chromosome 5q and in MDS/MPN with ring sideroblasts and thrombocytosis,

The peripheral blood smear usually demonstrates dysplasia in the red and white blood cell series and may reveal platelet abnormalities

Bone marrow examination is an essential component of the evaluation, diagnosis, and classification of MDS.

Characteristic morphologic features of MDS in the bone marrow examination include:

  1. Blasts – Myeloblasts are increased, but by definition, the blast percentage is <20 percent.
  2. Myeloid cells – Impaired myeloid maturation is often readily apparent; there may be a variable percentage of granulocytic precursors and a relative maturation arrest at the myelocyte stage.
  3. Erythroid cells – Although erythroid hyperplasia (associated with ineffective erythropoiesis) is usually seen, red cell aplasia and/or hypoplasia also rarely occur.
  4. Megakaryocytes are usually normal or increased in number and sometimes occur in clusters. Abnormal megakaryocytes, including large or very small mononuclear forms.
  5. Other lineages – Reactive lymphocytosis, lymphoid aggregates, increased histiocytes, and/or pseudo-Gaucher histiocytes may be seen. Increases of mast cells or spindled or clustered mast cells may be a manifestation of systemic mastocytosis, which may accompany MDS and other myeloid neoplasms (ie, systemic mastocytosis with associated hematologic neoplasm)
  6. Flow cytometry — Multiparameter flow cytometry is not required for the diagnosis of MDS but can be useful for assessing diagnostic and prognostic features of MDS.

MDS with ring sideroblasts — MDS with ring sideroblasts (MDS-RS) was previously called refractory anemia with ring sideroblasts. This category is further characterized by the number of dysplastic lineages (ie, single lineage versus multilineage).

The differential diagnosis of dysplasia also includes nonmalignant causes, including nutritional deficiencies, toxic exposures, and medications. Deficiency of vitamin B12, folic acid, or copper, or zinc excess should be excluded by clinical evaluation and laboratory testing.

Idiopathic cytopenia of undetermined significance (ICUS) and clonal cytopenia of undetermined significance (CCUS) – ICUSrefers to persistent cytopenias without significant dysplasia, evidence of other hematologic or nonhematologic cause for cytopenia, and none of the specific cytogenetic abnormalities that are considered presumptive evidence of MDS. 

Treatment.

The treatment of choice or definitive treatment is allogeneic stem cell transplant. Whereas only a portion of patients with lower-risk MDS are potential candidates for transplantation at the clinical onset of disease, all patients with higher-risk MDS should be assessed for eligibility at the time of diagnosis. Patients with good performance status and no or few coexisting conditions are the best candidates for transplantation, whereas those with poor performance status or multiple coexisting conditions should be preferentially considered for medical treatments. A complete blood count should be performed every 3 to 6 months, with a marrow examination once a year or whenever there is a clinically significant drop in blood counts.

Managing anemia.

Administration of erythropoiesis-stimulating agents can increase red-cell production and ameliorate anemia in patients with lower-risk MDS; this is the first therapeutic option for most such patients with anemia. A serum erythropoietin level below 200 mU per milliliter is the most reliable predictor of a response, whereas a high transfusion requirement predicts treatment failure.

Lenalidomide induces transfusion independence in about two thirds of patients with lower-risk MDS and isolated del(5q), and many patients with a response to lenalidomide have a cytogenetic remission, clearly indicating that this is a true targeted therapy.

Luspatercept is a recombinant fusion protein that binds transforming growth factor β superfamily ligands to enhance late-stage erythropoiesis. In a study involving transfusion-dependent patients who had MDS with ring sideroblasts, luspatercept treatment resulted in transfusion independence in 38% of cases.

In a subgroup of transfusion-dependent patients with hypoplastic MDS, transfusion independence can be achieved with immunosuppressive therapy, primarily antithymocyte globulin combined with cyclosporine. 

The vast majority of patients with MDS become dependent on regular red-cell transfusions during their clinical course.Although a hemoglobin level of 8 g per deciliter is generally used as a transfusion threshold, a more liberal regimen may promote a better quality of life. Transfusion dependence can lead to parenchymal iron overload and its clinical consequences. so chelation therapy is required.

Several drugs can modulate myelodysplastic hematopoiesis, but available treatments fail to eradicate it, mainly because their selective pressure leads to the emergence of resistant subclones.

The use of a hypomethylating agent, azacitidine or decitabine, currently represents the most common initial treatment in patients with higher-risk MDS who are ineligible for transplantation. About half the patients treated with azacitidine have a hematologic response, including some with a complete response. Treatment is associated with prolonged survival, although the survival benefit observed in real-life studies is on the order of a few months, which is shorter than the survival in the registration study.

With the advent of hypomethylating agents, AML-type chemotherapy is used less frequently in patients with MDS. Nonetheless, it may be considered in patients below the age of 60 years who have 10% or more bone marrow blasts without adverse cytogenetic characteristics and are ineligible for transplantation.

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shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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