Table of Contents
Definition of Myelodysplasia
Myelodysplasias are a group of malignant myeloid stem cell disorders characterized by dysplastic and ineffective bone marrow myeloid line cell production and an increased risk of transformation to acute leukemia. It usually presents in older patients, greater than 60 years of age.
It manifests as pancytopenia, thrombocytopenia, anemia, neutropenia and dysfunctional granulocytes, despite a hypercellular bone marrow. Most patients with myelodysplasia do not develop acute myelogenous leukemia because complications of infection and bleeding lead to death before leukemia occurs.
Classification of Myelodysplasia
Marrow blasts (%)
Anemia, greater or equal to 15 % ringed sideroblasts in erythroid precursors
Refractory anemia with sideroblasts
Anemia, normal platelets
Myelodysplasias with isolated del (5q) (5q syndrome)
Bicytopenia or pancytopenia
Refractory cytopenia with multi-lineage dysplasia
Cytopenias with or without peripheral blood blasts (<5 %)
Refractory anemia with excess blasts -1
Cytopenias, peripheral blood blasts present
Refractory anemia with excess blasts -2
Neutropenia or thrombocytopenia
Myelodysplastic syndrome, unclassified
Pathogenesis of Myelodysplasia
The pathogenesis of myelodysplasias is not completely understood but like other neoplasms, it, too, involves oncogenic mutations that may arise spontanously or after exposure to certain forms of chemotherapy like alkylating agents, environmental toxins like benzene, and radiations.
Clinical features of Myelodysplasia
The majority of patients are asymptomatic and are brought to the doctor’s attention when cytopenias are detected on a routine complete blood count. Some patients present with symptoms of the abnormalities like
- fatigue from anemia,
- bleeding or bruising from thrombocytopenia or
- fever from bacterial infection due to neutropenia.
Anemia is the most common cytopenia found in myelodysplasia and presents as fatigue, exercise intolerance, chest pain or vertigo. Cognitive impairment or altered sensorium can also result from anemia.
Systemic symptoms including weight loss are uncommon, and mostly present in the late stages of disease.
Decreased neutrophils and abnormal granulocytes lead to infection, with bacterial infections being the most common and the skin being the most common site, while fungal, viral, and mycobacterial infections are rare and mostly occur when there is concurrent administration of immunosuppressive drugs.
Abnormalities of the adaptive immune system can also be found in myelodysplasias, although in most cases there is no dysplasia of the lymphoid lineage. Decreased lymphocytes are largely due to a reduced number of CD4+ T cells. Antibody production is also affected with hypogammaglobulinemia, polyclonal hypergammaglobulinemia and monoclonal gammopathy found in many patients.
Autoimmune diseases, although not very common, complicate the course of myelodysplasias. The most common autoimmune diseases are
- chronic rheumatic heart disease,
- rheumatoid arthritis,
- pernicious anemia,
- and polymyalgia rheumatica.
Others may also occur:
- Sweet syndrome
- pleural effusions
- skin ulcerations
- peripheral neuropathy
- pure red cell aplasia
Acquired alpha thalassemia is found in eight percent of patients with myelodysplasias. It results in microcytosis, hypochromia and hemoglobin H containing red blood cells. It is due to an acquired somatic mutation of the ATRX gene.
Skin lesions like Sweet sydrome or myeloid sarcoma of the skin are uncommon in patients with myelodysplasias, but if present, indicate conversion of myelodysplasia to acute leukemia. In fact, the presence of myeloid sarcoma of the skin, also called granulocytic sarcoma may be the first sign of progression to acute leukemia.
Investigations of Myelodysplasia
Complete blood count
Anemia with an increased MCV, nucleated red blood cells and a small number of blast cells, <20 %. The greater the percentage of blast cells, the more severe the disease.
Presence of ringed sideroblasts
Ringed sideroblasts are erythroblasts with iron loaded mitrochondria. They can be seen with prussian blue stain.
Pelger huet cells
These are hyposegmented neutrophils. They are the most distinct abnormality found in myelodysplasias.
Chromosome 5q deletion
It is the most charachteristic abnormality seen in myelodysplasias. Patients with 5q deletion have a better prognosis than those without it and such patients have an excellent response to lenalidomide.
Differential diagnosis of Myelodysplasia
Myeodysplasias should be differentiated from other conditions that may also present with cytopenias and/or dysplasia.
Idiopathic cytopenia of undetermined significance
The term ‘idiopathic cytopenia of undetermined significance’ describes the cases of persistent cytopenia without evident dysplasia, without cytogenetic abnormalities found in myelodysplasia and without a related hematologic or non hematologic disorder.
Clonal hematopoiesis of indeterminant potential
The term ‘clonal hematopoiesis of indeterminant potential’ describes the cases in which blood cells possess somatic mutations which are also found in hematologic malignancies but there is absence of other diagnostic criteria for hematologic malignancy.
Persons with ‘clonal hematopoiesis of indeterminant potential’ may have normal cell counts, cytopenias that are unrelated to myelodysplasias or cytopenias that are related to myelodysplasia but do not meet the criteria for it.
Another related term, ‘clonal cytopenia of undetermined significance’, describes the cases that have clinically evident, but idiopathic cytopenias plus a mutation that does not meet the criteria for myelodysplasia or another hematologic malignancy.
Acute myeloid leukemia
Acute myeloid leukemia can be differentiated from myelodysplasias by the following crtieria.
- The presence of myeloid sarcoma or any of the following genetic mutations, regardless of blast cell count, is suggestive of acute myeloid leukemia.
- At least 20 % blast cells in the bone marrow or peripheral blood is suggestive of acute myeloid leukemia.
- AML with t (8;21) (q22;q22); RUNX1-RUNX1T1 (previously AML1-ETO)
- AML with inv (16) (p13.1q22) or t (16;16) (p13.1;q22); CBFB-MYH11
- APL with t (15;17) (q24.1;q21.1); PML-RARA
- It may not be possible to differentiate myelodysplasia from early evolving acute myeloid leukemia by checking the blast cell count, and can only be made reliably after at least 30 days of observation.
- As a general rule, the percentage of blast cells should continue to rise in evolving acute myeloid leukemia and remain relatively stable in myelodysplasias.
Myelodysplasia and myeloproliferative syndromes
Myelodysplasia and myeloproliferative syndromes are syndromes in which features of both myelodysplasias and myeloproliferative disorders coexist.
Myeloproliferative features include evident thrombocytosis, for example a platelet count of atleast 450 x 109 per liter, accompanied by megakaryocytic proliferation and leukocytosis (white blood cell count of atleast 13 x 109 per liter), with or without splenomegaly.
Myelodysplasia and myeloproliferative syndromes include:
1. Chronic myelomonocytic leukemia
Chronic myelomonocytic leukemia is characterized by the excessive multiplication of mutated monocytes and sometimes mutated neutrophils, accompanied by anemia and thrombocytopenia.
In chronic myelomonocytic leukemia blood monocyte count is greater than 1000 per microliter while in myelodysplasias borderline or sometimes relative elevations in the monocyte count are present.
Proliferative features such as splenomegaly and leukocytosis may be present in chronic myelomonocytic leukemia but are not found in myelodysplasias. Furthermore, dysplastic features are more subtle in chronic myelomonocytic leukemia as compared to myelodysplasias and are often found in less than ten percent of mononuclear cells counted.
2. Atypical chronic myeloid leukemia (BCR-ABL1 negative)
Atypical chronic myeloid leukemia is characterized by the excessive multiplication of mutated neutrophils accompanied by dysgranulopoiesis.
3. Juvenile myelomonocytic leukemia
Juvenile myelomonocytic leukemia is a rare disorder affecting infants and children. It is characterized by hepatomegally, splenomegaly and lymphadenopathy, with or without dysgranulopoiesis.
4. Myelodysplasia and myeloproliferative syndrome with ring sideroblasts and thrombocytosis
In some cases, patients will have clinical and morphologic charachteristics of myelodysplasias with ring sideroblasts but will also have thrombocytosis and megakaryocytosis. Such cases are termed as ‘myelodysplasia and myeloproliferative syndrome with ring sideroblasts and thrombocytosis’.
The diagnosis of myelodysplasia and myeloproliferative syndrome with ring sideroblasts and thrombocytosis requires all of the following:
- Anemia due to erythroid lineage dysplasia with or without multi lineage dysplasia, atleast 15 % ring sideroblasts, less than 1 % blast cells in the peripheral blood and less than 5 % blast cells in the bone marrow.
- Persistent thrombocytosis with platelet count of atleast 450,000 per microliter
- Presence of a SF3B1 mutation or in the absence of SF3B1 mutation, no recent evidence of cytotoxic or growth factor therapy that could have given rise to features of myelodysplasia and myeloproliferative syndrome.
- No BCR-ABL1 or PCM1-JAK2 fusion gene; no rearrangement of PDGFRA, PDGFRB or FGFR1; no (3;3) (q21;q26), inv(3) (q21;q26), or del(5q).
- No previous history of myeloproliferative neoplasms, myelodysplasia (except for myelodysplasias with ring sideroblasts) or some other type of myelodysplasia and myeloproliferative syndrome.
5. Unclassifiable myelodysplasia & myeloproliferative syndromes
Aplastic anemia is when there are decreased or absent pluripotent stem cells.
Although most myelodysplasias have normal or increased bone marrow cellularity, a minority of cases have lower bone marrow cellularity as compared to the patient’s age. Such myelodysplasia is called hypoplastic myelodysplasia. Hypoplastic myelodysplasia is usually therapy-induced.
To differentiate hypoplastic myelodysplasia from aplastic anemia, the bone marrow cells should be checked. Cells in myelodysplasia have abnormal karyotype and morphology.
Though myelodysplasia can present with mild to moderate fibrosis of bone marrow, severe fibrosis can be seen in a small number of cases, which makes it very difficult to differentiate it from primary myelofibrosis.
Myelodysplasia with severe bone marrow fibrosis is often associated with pancytopenia, dysplasia of all three myeloid lineages and atypical megakaryocyte proliferation.
In most cases, primary myelofibrosis can be differentiated from myelodysplasia by the presence of splenomegaly in primary myelofibrosis.
In some cases, the genotype needs to be seen. Mutations in JAK2, CALR or MPL gene suggest primary myelofibrosis.
Human Immunodeficiency Virus
The most common finding in patients affected by human immunodeficiency virus are dysplasias of bone marrow cells. These are thought to result from medications, opportunistic infections or the direct effect of the virus on progenitor cells.
Other findings may include
- megaloblastic hematopoiesis,
- fibrosis of bone marrow,
- increased bone marrow iron stores,
- lymphocyte aggregates or
Therefore, it is important to rule out human immunodeficiency virus infection in a patient with unexplained cytopenias and/or dysplasia.
Poor nutritional status
Many patients with myelodysplasias have macrocytics, low reticulocytes and pancytopenia.
These findings may also be present in megaloblastic anemias, copper deficiency or zinc excess.
Therefore, these need to be differentiated. For example, hyposegmented neutrophils (pelger-huet cells) are present in myelodysplasia while hypersegmented neutrophils with macrocytes are present in megaloblastic anemia.
Some medicines can cause macrocytosis, hyposegmented neutrophils, neutropenia, thrombocytopenia and dysplasias in all three myeloid lineages of the bone marrow.
These features are reversible on reduction or discontinuation of these medicines, usually within a few weeks.
These medicines include granulocyte colony stimulating factor, valproic acid, mycophenolate mofetil, ganciclovir, alemtuzumab, methotrexate and cyclophosphamide.
Inherited and acquired sideroblastic anemias
Sideroblastic anemias are anemias resulting from abnormal heme synthesis and abnormal mitrochodrial function. Ring sideroblasts that are erythroblasts with iron loaded mitochondria, are a charachteric feature of sideroblastic anemia.
Ring sideroblasts may also be found in myelodysplasias (or ‘myelodysplasia and myeloproliferative syndrome with ring sideroblasts and thrombocytosis’) and it is important to differentiate it from sideroblastic anemias.
For acquired sideroblastic anemia, one should rule out its causes like copper deficiency, medicines or alcohol abuse.
For X linked sideroblastic anemia, either ALAS2 gene mutation should be checked or persistent sideroblasts after a three month trial of vitamin B6 can point to diagnosis. An acquired mutation in SF3B1 or JAK2 gene confirms myelodysplasia and rules out inherited sideroblastic anemia.
Management of Myelodysplasia
Patients with <5 % blast cells in the bone marrow
They are usually managed conservatively with red blood cell and platelet transfusions and antibiotics for infections, as needed. Haemopoietic growth factors like erythropoietin and G-CSF may be useful in some patients.
Patients with >5 % blast cells in the bone marrow
They have a less favourable prognosis, and a number of treatment options.
only suitable for elderly patients with other medical problems.
(low-dose or single-agent like azacytidine) may be useful in patients with high white blood cell counts.
can be tried for patients below the age of 60 with acute myeloblastic leaukemia, but the remission rate is less, and prolonged pancytopenia may occur because of decreased regeneration since there is a defect in pluripotent stem cells.
Lenalidomide (a thalidomide analogue)
has been proven to be remarkably successful in the treatment of early stage myelodysplasia with a chromosome 5q deletion.
Bone marrow transplantation
offers the hope of cure in the small proportion of myelodysplasia patients who are under the age of 50 and who have an HLA-identical sibling or an unrelated HLA-matched donor.
Complications of Myelodysplasia
Myelodysplasias are associated with common complications, such as
- Recurrent infections bleeding
- Petechie, purpura
- Acute myelogenous leukemia