Myelodysplastic syndromes
Introduction
Hello, welcome to this 10th class of the Hematology course provided by the University of Guanajuato. In this class we are going to review some basic concepts of myelodysplastic syndromes. These syndromes are considered bone marrow failures, where hematopoietic cells present several alterations, which will be reviewed in this class, recalling the cells we already discussed In the 3rd class, In order to compare normal vs altered cells.
It Is Important to review the first classification made by the French-American-British association In order to understand the changes made by the WHO organization.
A special attention must be paid to the chronic and juvenile myelomonocytic leukemia, as they present features of myelodysplastic and myeloproliferative syndromes.
Some treatment options will be reviewed and a special prognostic system will be learned In order to predict the evolution of the patient. So, let’s start with this really Interesting class, hope will full your expectations.
Content development
Myelodysplastic and myeloproliferative diseases
They are disorders of clonal myeloid origin, with both dysplastic and proliferative characteristics but are not correctly classified as either myelodysplastic syndromes or chronic myeloproliferative disorders.
- Myeloproliferative disorders: these are diseases in which there is an overproduction of specific blood cells in the bone marrow.
- Myelodysplastic syndromes: Also called preleukemic or «latent» leukemia, these are diseases in which the bone marrow does not function normally and not enough normal blood cells are produced.
EMD / EMP are divided into four categories:
- Atypical chronic myeloid leukemia
- Unclassifiable myelodysplastic / myeloproliferative diseases
- Chronic myelomonocytic leukemia
- Juvenile myelomonocytic leukemia
Atypical chronic myeloid leukemia:
A clonal hematopoietic disorder characterized by dysplastic and myeloproliferative features, including persistent granulocytosis with immature forms, hypercellularity of the bone marrow with dysplastic hematopoiesis, and myeloid preponderance.
It occurs in older adults with no apparent preference for sex.
Hypogranulated granulocytes, hypolobulated nuclei and Pseudo Pelger-Huet.
Unclassifiable myelodysplastic / myeloproliferative diseases:
They have similar characteristics or presentations of myelodysplastic syndromes or myeloproliferative disorders but do not meet the criteria for being part of the main types of DME / EMP.
Patients with splenomegaly without increased erythrocyte mass, absence of Ph chromosome, absence of leuko-erythroblastic reaction, and non-significant myelofibrosis. Some cases may be early stages of one of the other diseases.
Philadelphia chromosome:
It consists of a phenomenon known as translocation.
Parts of two chromosomes, 9 and 22 (translocation 9-22), swap their positions.
The result is that part of the Breakpoint Cluster Region (BCR) gene on chromosome 22 (region q11) is fused with part of the ABL gene on chromosome 9 (region q34).
The ABL gene takes its name from «Abelson», the name of a virus that causes leukemia, the precursor of a protein similar to that produced by this gene.
Synthesizes an altered tyrosine kinase that causes the cell to divide indefinitely.
Leuko-erythroblastic reaction
It is defined as the presence in peripheral blood of nucleated erythroid cells together with immature myeloid cells. Dacrocytes can also be seen.
- Hematological diseases: acute and chronic lymphoproliferative and myeloproliferative syndromes, myelodysplastic syndromes, myelofibrosis, hemolytic anemia (crisis) and hemorrhages.
- Metastatic tumors: breast, prostate, lung and neuroblastoma cancer.
- Infections: tuberculosis and deep mycoses.
Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) begin with one or more acquired changes (mutations) in monocyte DNA.
CMML: The average age at diagnosis varies between 65 and 75 years. Common symptoms include weakness, fatigue, unexplained bruising or bleeding, liver infections, or an enlarged spleen.
JMML: Most often diagnosed in infants and children under six years of age. Common symptoms include paleness, developmental delays, decreased appetite, irritability, an enlarged abdomen, a dry cough, a rash, an enlarged liver or spleen, and enlarged lymph nodes.
CMML diagnosis
Blood tests and bone marrow aspiration with biopsy to verify.
- Persistently elevated blood monocyte count (greater than 1,000 / µl)
- Less than 20% blasts in the blood or bone marrow
- Dysplasia of hematopoietic cells of the three cell lines
Between 20% and 40% of patients with CMML have chromosomal abnormalities.
In CMML, translocation (5:12 translocation) involves the PDGFR-β (platelet-derived growth factor receptor) and TEL (one of the ETS transcription factors that participate in cell differentiation) genes.
Other chromosomal abnormalities associated with CMML include:
- Monosomy 7 and trisomy 8, which are the most common chromosomal abnormalities in patients with CMML.
- Mutation of a specific gene within the family of genes known as “RAS”, such as the K-RAS or N-RAS genes. RAS genes and the proteins encoded by them regulate cell growth. When a RAS gene mutation occurs, cells multiply uncontrollably.
This type of mutation occurs in approximately 35% of patients with CMML.
CMML treatment
Decitabine (Dacogen), currently approved for the treatment of CMML, is being studied for use in combination with other agents such as vorinostat (Zolinza®) and arsenic trioxide (Trisenox®) for patients who have not responded to treatment or who have relapsed after initial therapy.
Decitabine belongs to a class of medications called hypomethylating agents. It works by helping the bone marrow make normal blood cells and destroying abnormal cells in it.
Vorinostat is in a class of medications called histone deacetylase (HDAC) inhibitors. It works by killing or stopping the growth of cancer cells.
Arsenic trioxide is a cytotoxic agent that appears to act by inducing apoptosis of leukemic cells in leukemia.
Reduced-intensity allogeneic stem cell transplantation (also known as “non-myeloablative stem cell allogeneic transplantation”) may prove effective for CMML patients who do not respond to drug therapy but are not considered candidates for allogeneic transplantation due to advanced age or other health risks.
Patients who are conditioned for a reduced intensity transplant receive lower doses of chemotherapy or radiation therapy than those given to patients before a stem cell transplant.
Factors that may indicate a less favorable outcome include:
- Severe anemia
- High percentage of blasts
- High total leukocyte (white blood cell) count
- High LDH level
- Larger spleen.
Approximately 20% of patients with CMML have disease that progresses to acute myelogenous leukemia.
JMML treatment
Pharmacotherapy for JMML. Standard chemotherapy, regardless of intensity, has proven effective in only a small number of patients. 13-cis-retinoic acid (Accutane®) has shown some responses that produce a stabilization of the disease and a partial remission rather than a complete remission.
Stem cell transplantation for JMML. Allogeneic stem cell transplantation has been widely used in treatment. While this treatment has been found to achieve long-term survival in up to 50% of patients, relapses (relapses) occur in up to 30% to 40% of patients after transplantation.
However, allogeneic stem cell transplants remain the only known cure for JMML.
Some patients have benefited from second transplants, mainly when used in conjunction with reduced immunosuppression, which supposedly leads to a more substantial graft-versus-leukemia effect.
Myelodysplastic syndromes
Myelodysplastic syndromes (MDS) are clonal proliferations of multipotent medullary germ cells that, although they retain the ability to differentiate to mature stages, do so defectively ineffectively, so that the resulting cells are deficient in number, function, and morphology.
MDS comprise a heterogeneous group of entities of clonal origin, characterized by different degrees of mismatch in the proliferation and differentiation capacity of the hematopoietic progenitor cell, which is expressed with progressive cytopenia, qualitative alterations in the three hematopoietic series, and risk of transformation into acute myeloblastic leukemia (AML).
Normal:
The diagnosis of myelopathy is based, fundamentally, on the presence of qualitative morphological alterations that are described as dyshemopoiesis.
There are two types of SMD:
Primary: is of generally unknown etiology
Secondary: corresponds to 20% of MDS usually associated with the use of antineoplastic drugs, among which the alkylating agents and anthracyclines stand out; in contact with chemical products, mainly those derived from benzene; to exposure to ionizing radiation.
Recently it has been suggested that smoking increases the risk of suffering from MDS.
In childhood, its appearance is associated with the existence of constitutional diseases.
The different types of myelodysplastic syndromes are diagnosed based on certain changes in the blood cells and bone marrow.
French-American-British classification
Presence of dysmyelopoiesis, myeloblasts, and erythroblasts.
The criteria used in this classification are the percentage of blasts in the bone marrow and peripheral blood, the absolute number of monocytes, the presence of Auer rods, and the proportion of ringed sideroblasts, all together with dyshemopoietic morphological features of varying degrees.
The variety of refractory anemia with excess transforming blasts is suppressed, and it is now considered an acute leukemia.
Unilinear dysmorphia of the erythroblastic series is required in refractory anemia and in refractory sideroblastic anemia.
Main contributions of the WHO classification in relation to the FAB classification
There are two types of SMD:
Primary: is of generally unknown etiology
Secondary: corresponds to 20% of MDS usually associated with the use of antineoplastic drugs, among which the alkylating agents and anthracyclines stand out; in contact with chemical products, mainly those derived from benzene; to exposure to ionizing radiation.
Recently it has been suggested that smoking increases the risk of suffering from MDS.
In childhood, its appearance is associated with the existence of constitutional diseases.
5q- syndrome:
The most common breakpoints are 5q 12-14 (proximal breakpoint) and 5q 31-33 (distal breakpoint).
It predominates in women, presents macrocytosis, erythroid hypoplasia, thrombocytosis, and dysmegakaryopoiesis.
The distinctive and obliged morphological feature is finding the medulla of an increase in micromegakaryocytes, unilobed or unconnected.
Myelodysplastic syndromes often have no signs or symptoms.
They are sometimes found in a routine blood test.
Signs and symptoms can be caused by any myelodysplastic syndrome or by another condition.
- Dyspnea.
- Weakness.
- Paler skin than usual.
- Easy bruising or bleeding.
- Petechiae (flat spots located under the skin caused by bleeding).
The following tests and procedures can be used:
Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems abnormal.
The medical history of the patient’s previous illnesses and treatments is also taken.
Complete blood count (CBC) with differential.
Myelodysplasic syndromes with hypocellular bone marrow
It is not included in the FAB classification.
Some investigators have reported hypoplastic bone marrow with dysplastic hematopoiesis.
It is characterized by severe thrombocytopenia and leukopenia, and macrocytic anemia, without the presence of karyotypic abnormalities.
Other authors consider hypoplastic MDS as a subtype of aplastic anemia; because it can be related to an immune reaction against bone marrow stem cells and does not respond to conventional therapy.
It has been reported that immunosuppressive therapy (Cyclosporine + ATG) can be an alternative treatment.
Multimethodological diagnostic
The diagnosis of an MDS requires integrating multiple parameters that include, apart from the clinical-cytological data, immunocytochemical information, molecular cytogenetics, and, occasionally, cell cultures and medullary biopsy, since no data alone is pathognomonic for MDS.
Cyto and histochemical reactions. Immunocyto and immunohistochemical studies
Iron staining with Prussian blue: detection of pathological sideroblasts, especially ring forms and reactions of myeloperoxidase and nonspecific esterase, to ensure myeloid affiliation of blast cells more accurate identification of rods of Auer.
Detection of CD61 antigen: an excellent marker of megakaryocytic series.
CD34 antigen allows more precise visualization of cell aggregates related to the evolution of acute leukemia.
Ring sideroblasts
Cytogenetics. Molecular studies
The determination of the karyotype in MDS has acquired a progressive diagnostic value.
The observation of specific alterations makes it possible to ensure the diagnosis of these syndromes in patients with morphological abnormalities that are not sufficiently expressive.
The detection of various chromosomal abnormalities has undoubted prognostic significance concerning survival and the risk of leukemic transformation.
In vitro cell cultures
In vitro cultures of bone marrow, especially of the granulomonocytic line, have provided some help in the diagnosis, prognosis, clinical evolution, and pathophysiological understanding of MDS.
Bone marrow granulomonocytic precursors can show a variable in vitro behavior, ranging between the typical growth pattern and that observed in leukemias: decrease or absence of colonies, accompanied by a growth of aggregates.
In low-grade MDS, average growth predominates; on the other hand, in those with a high degree of malignancy, the most characteristic pattern is the leukemic one.
Treatment
Treatment options and recommendations depend on various factors, including subtype and International Prognostic Scoring System (IPSS) classification, risk of developing AML, possible side effects, patient preferences, age, and general health status.
Growth factors
Chemotherapy (decitabine and azacitidine)
Anti-thymocyte globulin with cyclosporine (hypoplastic MDS, immune in origin)
* Lenalidomide, derived from thalidomide, can cause thrombocytopenias, severe congenital disabilities, neutropenia, blood clots, skin reactions. It is given to patients with low risk or 5q syndrome.
* IPSS-R System (International Prognostic Scoring System Revised)
It is used to predict a patient’s risk for developing acute myeloid leukemia and overall survival.
It evaluates the percentage of blasts present in the bone marrow, type and number of chromosomal changes, hemoglobin levels, platelets, and absolute neutrophil count.
Manage five categories:
- Very low risk
- Low risk
- Intermediate risk
- High risk
- Very high risk
ANC: Absolute neutrophil count
Conclusion
Chronic and juvenile myelomonocytic leukemia are considered separated entities as they present myelodysplastic and myeloproliferative features.
Hematopoietic cells are altered in myelodysplastic syndromes causing refractory cytopenia. Percent of blast cells are Important In order to differentiate one entity from another.
Myelodysplastic syndromes are considered preleukemic alterations. The IPSS-R system can help to predict the patient leukemic evolution without a proper treatment.
Information sources
- Atypical chronic myeloid leukaemia – a rare subtype of myelodysplastic / myeloproliferative neoplasm
- Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management
- Myelodysplastic syndrome (myelodysplasia)
- MYELODYSPLASTIC SYNDROME
- Revised International Prognostic Scoring System for Myelodysplastic Syndromes