The myelodysplastic syndromes (MDS, formerly known as preleukemia) are a diverse collection of hematological (blood-related) medical conditions that involve ineffective production (or dysplasia) of the myeloid class of blood cells.
Patients with MDS often develop severe anemia and require frequent blood transfusions. In most cases, the disease worsens and the patient develops cytopenias (low blood counts) due to progressive bone marrow failure. In about one third of patients with MDS, the disease transforms into acute myelogenous leukemia (AML), usually within months to a few years.[1]
The myelodysplastic syndromes are all disorders of the stem cell in the bone marrow. In MDS, hematopoiesis (blood production) is disorderly and ineffective. The number and quality of blood-forming cells decline irreversibly, further impairing blood production.
In 1974 and 1975, a group of pathologists from France, the US, and Britain produced the first widely used classification of these diseases. This French-American-British classification was published in 1976,[2] and revised in 1982. Cases were classified into five categories: (ICD-O codes are provided where available)
A table comparing these is available from the Cleveland Clinic.[3]
The best prognosis is seen with refractory anemia with ringed sideroblasts and refractory anemia, where some non-transplant patients live more than a decade (the average is on the order of three to five years, although long-term remission is possible if a bone marrow transplant is successful). The worst outlook is with RAEB-T, where the mean life expectancy is less than 1 year. About one quarter of patients develop overt leukemia. The others die of complications of low blood count or unrelated disease. The International Prognostic Scoring System is another tool for determining the prognosis of MDS, published in Blood in 1997.[4] This system takes into account the percentage of blasts in the marrow, cytogenetics, and number of cytopenias.
The FAB classification was used by pathologists and clinicians for almost 20 years.
In the late 1990s a group of pathologists and clinicians working under the World Health Organization (WHO) modified this classification, introducing several new disease categories and eliminating others. Most recently the WHO has evolved a new classification scheme (2008) which is based more on genetic findings. However, morphology of the cells in the peripheral blood, bone marrow aspirate, and bone marrow biopsy is still the screening test used in order to decide which classification is best and which cytogenetic aberrations may be related.
The list of dysplastic syndromes under the new WHO system includes:
Not all physicians concur with this reclassification. This is because the underlying pathology of the diseases is not well understood. It is difficult to classify things that are not well understood.
WHO proposed criteria for diagnosis and classification of MDS apply to most cases. However, occasional cases are difficult to classify into defined categories because of one or more unusual features: I- Rare cases with less than 5% blast will present with auer rods. These cases usually have the features of RAMD. II- Occasionally cases of MDS present with isolated neutropenia or thrombocytopenia without anemia and with dysplastic changes confined to the single lineage. The term refractory neutropenia and refractory thrombocytopenia have sometimes used to describe these cases. A diagnosis of MDS in patients with neutropenia or thromobocytopenia without anemia should be made with caution. III- Patients with RA or RAEB occasionally present with leukocytosis or thrombocytosis instead of usual cytopenia.
Enlarged spleen due to myelodysplastic syndrome; CT scan coronal section. Spleen in red, left kidney in green.
The median age at diagnosis of a MDS is between 60 and 75 years; a few patients are younger than 50; MDS diagnoses are rare in children. Males are slightly more commonly affected than females. Signs and symptoms are nonspecific and generally related to the blood cytopenias:
Many individuals are asymptomatic, and blood cytopenia or other problems are identified as a part of a routine blood count:
Although there is some risk for developing acute myelogenous leukemia, about 50% of deaths occur as a result of bleeding or infection. Leukemia that occurs as a result of myelodysplasia is notoriously resistant to treatment.
MDS is caused by environmental exposures such as radiation and benzene; other risk factors have been reported inconsistently. Secondary MDS occurs as a late toxicity of cancer treatment, usually with a combination of radiation and the radiomimetic alkylating agents such as busulfan, nitrosourea, or procarbazine (with a latent period of 5 to 7 years) or the DNA topoisomerase inhibitors (2 years). Both acquired aplastic anemia following immunosuppressive treatment and Fanconi's anemia can evolve into MDS.
MDS is thought to arise from mutations in the multi-potent bone marrow stem cell, but the specific defects responsible for these diseases remain poorly understood. Differentiation of blood precursor cells is impaired, and there is a significant increase in levels of apoptotic cell death in bone marrow cells. Clonal expansion of the abnormal cells results in the production of cells which have lost the ability to differentiate. If the overall percentage of bone marrow blasts rises over a particular cutoff (20% for WHO and 30% for FAB) then transformation to acute myelogenous leukemia (AML) is said to have occurred. The progression of MDS to AML is a good example of the multi-step theory of carcinogenesis in which a series of mutations occur in an initially normal cell and transform it into a cancer cell.
While recognition of leukemic transformation was historically important (see History), a significant proportion of the morbidity and mortality attributable to MDS results not from transformation to AML but rather from the cytopenias seen in all MDS patients. While anemia is the most common cytopenia in MDS patients, given the ready availability of blood transfusion MDS patients rarely suffer injury from severe anemia. However, if an MDS patient is fortunate enough to suffer nothing more than anemia over several years, they then risk iron overload. The two most serious complications in MDS patients resulting from their cytopenias are bleeding (due to lack of platelets) or infection (due to lack of white blood cells). Long-term, transfusion of packed red blood cells leads to iron overload.
The recognition of epigenetic changes in DNA structure in MDS has explained the success of two of three commercially available medications approved by the U.S. Food and Drug Administration (FDA) to treat MDS. Proper DNA methylation is critical in the regulation of proliferation genes, and the loss of DNA methylation control can lead to uncontrolled cell growth, and cytopenias. The recently approved DNA methyltransferase inhibitors take advantage of this mechanism by creating a more orderly DNA methylation profile in the hematopoietic stem cell nucleus, and thereby restore normal blood counts and retard the progression of MDS to acute leukemia.
Some authors have proposed that the loss of mitochondrial function over time leads to the accumulation of DNA mutations in hematopoietic stem cells, and this accounts for the increased incidence of MDS in older patients. Researchers point to the accumulation of mitochondrial iron deposits in the ringed sideroblast as evidence of mitochondrial dysfunction in MDS.[6]
According to an online news story article from the Washington University in St. Louis Newsroom, posted by Caroline Arbanas, on Tuesday, December 13, 2011,: "Scientists have uncovered a critical genetic mutation in some patients with myelodysplastic syndromes — a group of blood cancers that can progress to a fatal form of leukemia. The research team at Washington University School of Medicine in St. Louis also found evidence that patients with the mutation are more likely to develop acute leukemia. While this finding needs to be confirmed in additional patients, the study raises the prospect that a genetic test could one day more accurately diagnose the disorder and predict the course of the disease. The research is available online in Nature Genetics. The scientists discovered the mutation in a gene known as U2AF1 when they sequenced the entire genome of a 65-year old man with myelodysplastic syndrome that had progressed to leukemia and compared it with the genome of his tumor cells. They also found the genetic error in other patients with myelodysplastic syndromes, an indication of the mutation’s significance. “The mutation in this gene was not on anyone’s radar screen,” says senior author and hematologist/oncologist Matthew Walter, MD, assistant professor of medicine. “In many cases, the diagnosis of myelodysplastic syndromes is unclear because there isn’t a straightforward diagnostic test. By understanding at the genetic level what is contributing to this disease, we hope to eventually improve the diagnosis and treatment of this disorder.” Myelodysplastic syndromes are a difficult-to-treat family of blood cancers that occur when blood cells in the bone marrow don’t mature properly. About 28,000 Americans are diagnosed with the disorder each year, most of them over age 60. Drugs are available to treat the disease, but none can cure it. In about 30 percent of cases, the disorder progresses to a form of acute myeloid leukemia that usually is fatal because chemotherapy drugs are not effective in these patients. Doctors currently assess the likelihood that a patient with myelodysplastic syndrome will develop leukemia by looking at the chromosomes in the tumor cells to determine the extent to which they have broken apart and rearranged themselves, an indicator of the severity of the disease. “There are chromosomal patterns that indicate high risk and low risk, but the current methods to determine prognosis aren’t perfect,” says first author Timothy Graubert, MD, associate professor of medicine, who specializes in treating patients with myelodysplastic syndromes. After identifying the U2AF1 mutation in three patients through whole-genome sequencing, the researchers scoured the gene for the mutation in another 150 patients with myelodysplastic syndromes. They identified the mutation in 13, or nearly 9 percent. The mutations were acquired during development of myelodysplastic syndromes because they were not present in normal cells obtained from each patient. Patients were almost three times as likely to develop leukemia if they had a mutation in the U2AF1 gene. The disorder progressed to leukemia in 15.2 percent of patients with the mutation, compared with 5.8 percent of those without the genetic error. The most common mutation results in a single letter change in the DNA at a precise location in the U2AF1 gene. Patients with the genetic error were most likely to have the amino acids phenylalanine or tyrosine substituted for a serine. The researchers say that the mutation by itself does not cause myelodysplastic syndromes but appears to be an early event in the course of the disease. ..."[7]
Since at least 1974, the loss of the long arm of chromosome 5 has been associated with dysplastic abnormalities of hematopoietic stem cells.[8][9] By 2005, it was recognized that Lenalidomide was effective in MDS patients with the 5q- syndrome,[10] and in December 2005, the US FDA approved the drug for this indication.
MDS must be differentiated from anemia, thrombocytopenia, and/or leukopenia. Usually, the elimination of other causes of these cytopenias, along with a dysplastic bone marrow, is required to diagnose a myelodysplastic syndrome.
Blood smear from an adult female with a myelodysplastic syndrome related to radiotherapy and chemotherapy for Hodgkin disease. A hypogranular neutrophil with a pseudo-Pelger-Huet nucleus is shown. The red blood cells show marked poikilocytosis, in part related to post-splenectomy status. (Wright-Giemsa stain).
A typical investigation includes:
- Full blood count and examination of blood film. The blood film morphology can provide clues about hemolytic anemia, clumping of the platelets leading to spurious thrombocytopenia, or leukemia.
- Blood tests to eliminate other common causes of cytopenias, such as lupus, hepatitis, B12, folate, or other vitamin deficiencies, renal failure or heart failure, HIV, hemolytic anemia, monoclonal gammopathy. Age-appropriate cancer screening should be considered for all anemic patients.
- Bone marrow examination by a hematopathologist. This is required to establish the diagnosis, since all hematopathologists consider dysplastic marrow the key feature of myelodysplasia.
- Cytogenetics or chromosomal studies. This is ideally performed on the bone marrow aspirate. Conventional cytogenetics requires a fresh specimen, since live cells are induced to enter metaphase to enhance chromosomal staining. Alternatively, virtual karyotyping can be done for MDS,[11] which uses computational tools to construct the karyogram from disrupted DNA. Virtual karyotyping does not require cell culture and has dramatically higher resolution than conventional cytogenetics, but cannot detect balanced translocations.
- Flow cytometry is helpful to establish the presence of any lymphoproliferative disorder in the marrow.
Anemia dominates the early course. Most symptomatic patients complain of the gradual onset of fatigue and weakness, dyspnea, and pallor, but at least half the patients are asymptomatic and their MDS is discovered only incidentally on routine blood counts. Previous chemotherapy or radiation exposure is an important historic fact. Fever and weight loss should point to a myeloproliferative rather than myelodysplastic process. Children with Down syndrome are susceptible to MDS, and a family history may indicate a hereditary form of sideroblastic anemia or Fanconi anemia.
The average age at diagnosis for MDS is about 65 years, but pediatric cases have been reported. Some patients have a history of exposure to chemotherapy (especially alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil) or radiation (therapeutic or accidental), or both (e.g., at the time of stem cell transplantation for another disease). Workers in some industries with heavy exposure to hydrocarbons such as the petroleum industry have a slightly higher risk of contracting the disease than the general population. Males are slightly more frequently affected than females. Xylene and benzene exposure has been associated with myelodysplasia. Vietnam veterans exposed to Agent Orange are at risk of developing MDS.
The features generally used to define a MDS are: blood cytopenias; ineffective hematopoiesis; dyserythropoiesis; dysgranulopoiesis; dysmegakaropoiesis and increased myeloblast.
Dysplasia can affect all three lineages seen in the bone marrow. The best way to diagnose dysplasia is by morphology and special stains (PAS) used on the bone marrow aspirate and peripheral blood smear. Dysplasia in the myeloid series is defined by:
- Granulocytic series
- Hypersegmented neutrophils (also seen in Vit B12/Folate deficiency)
- Hyposegmented neutrophils (Pseudo-Pelger Huet)
- Hypogranular neutrophils or pseudo Chediak Higashi large granules
- Auer rods - automatically RAEB II (if blast count <5% in the peripheral blood and <10% in the bone marrow aspirate) also note Auer rods may be seen in mature neutrophils in AML with translocation t(8;21)
- Dimorphic granules (basophilic and eosinophilic granules) within eosinophils
- Erythroid series
- Binucleated erythroid percursors and karyorrhexis
- Erythroid nuclear budding
- Erythroid nuclear strings or internuclear bridging (also seen in congenital dyserythropoietic anemias)
- Loss of E-cadherin in normoblasts is a sign of aberrancy
- PAS (globular in vacuoles or diffuse cytoplasmic staining) within erythroid precursors in the bone marrow aspirate (has no bearing on paraffin fixed bone marrow biopsy). Note: One can see PAS vacuolar positivity in L1 and L2 blasts (AFB classification; the L1 and L2 nomenclature is not used in the WHO classification)
- Ringed sideroblasts seen on Prussian blue iron stain (10 or more iron granules encircling 1/3 or more of the nucleus and >15% ringed sideroblasts when counted amongst red cell precursors)
- Megakaryocytic series (can be the most subjective)
- Hyposegmented nuclear features in platelet producing megakaryocytes (lack of lobation)
- Hypersegmented (osteoclastic appearing) megakaryocytes
- Ballooning of the platelets (seen with interference contrast microscopy)
Other stains can help in special cases (PAS and napthol ASD chloroacetate esterase positivity) in eosinophils is a marker of abnormality seen in chronic eosinophilic leukemia and is a sign of aberrancy.
On the bone marrow biopsy high grade dysplasia (RAEB-I and RAEB-II) may show atypical localization of immature precursors (ALIPs) which are islands of immature precursors cells (myeloblasts and promyelcytes) localized to the center of intertrabecular space rather than adjacent to the trabeculae or surrounding arterioles. This morphology can be difficult to recognize from treated leukemia and recovering immature normal marrow elements. Also topographic alteration of the nucleated erythroid cells can be seen in early myelodysplasia (RA and RARS), where normoblasts are seen next to bony trabeculae instead of forming normal interstitially placed erythroid islands.
Myelodysplasia is a diagnosis of exclusion and must be made after proper determination of iron stores, vitamin deficiencies, and nutrient deficiencies are ruled out. Also congenital diseases such as congenital dyserythropoietic anemia (CDA I through IV) has been recognized, Pearson's syndrome (sideroblastic anemia), Jordans anomaly - vacuolization in all cell lines may be seen in Chanarin-Dorfman syndrome, ALA (aminolevulinic acid) enzyme deficiency, and other more esoteric enzyme deficiencies are known to give a pseudomyelodysplastic picture in one of the cell lines, however, all three cell lines are never morphologically dysplastic in these entities with the exception of chloramphenicol, arsenic toxicity and other poisons.
All of these conditions are characterized by abnormalities in the production of one or more of the cellular components of blood (red cells, white cells other than lymphocytes and platelets or their progenitor cells, megakaryocytes).
The goals of therapy are to control symptoms, improve quality of life, improve overall survival, and decrease progression to acute myelogenous leukemia (AML).
The IPSS scoring[12] system can help triage patients for more aggressive treatment (i.e. bone marrow transplant) as well as help determine the best timing of this therapy.[13] Supportive care with blood product support and hematopoeitic growth factors (e.g. erythropoietin) is the mainstay of therapy. The regulatory environment for the use of erythropoietins is evolving, according to a recent US Medicare National coverage determination. No comment on the use of hematopoeitic growth factors for MDS was made in that document.[14]
Three agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of MDS:
- 5-azacytidine: 21 month median survival[15][16][17][18]
- Decitabine: Complete response rate reported as high as 43%. A phase I study has shown efficacy in AML when decitabine is combined with valproic acid.[19][20][21][22]
- Lenalidomide: Effective in reducing red blood cell transfusion requirement in patients with the chromosome 5q deletion subtype of MDS[23]
Chemotherapy with the hypomethylating agents 5-azacytidine and decitabine has been shown to decrease blood transfusion requirements and to retard the progression of MDS to AML. Lenalidomide was approved by the FDA in December 2005 only for use in the 5q- syndrome. In the United States, treatment of MDS with lenalidomide costs about US$9,200 per month.[24]
Stem cell transplantation, particularly in younger patients (i.e. less than 40 years of age), more severely affected patients, offers the potential for curative therapy. Success of bone marrow transplantation has been found to correlate with severity of MDS as determined by the IPSS score, with patients having a more favorable IPSS score tending to have a more favorable outcome with transplantation.[25]
Iron overload in MDS, red blood cell (RBC) transfusions are a major part of the supportive care for anemic MDS patients. Although the specific therapies patients receive may alleviate the RBC transfusion need, many MDS patients may not respond to these treatments and may develop iron overload as well as its consequences.
Patients requiring relatively large numbers of RBC transfusions have experienced adverse effect of chronic iron overload on liver, heart, endocrine functions. It is possible that this organ disfunction may result from iron overload in patients with MDS and that transfusional iron overload might be a contributor to increased sickness and death in early stage MDS.
For patients requiring many RBC transfusions, serum ferritin levels, number of RBC transfusions received, and associated organ dysfunction (heart, liver, and pancreas) should be monitored to determine iron levels. Monitoring serum ferritin may also be useful, aiming to decrease ferritin levels to <1000 mcg/L.
There are currently two iron chelators available in the US, deferoxamine (Desferal) for IV use and deferasirox (Exjade) for oral use. These options now provide potentially useful drugs for treating this iron overload problem. A third chelating agent is available in Europe, deferiprone for oral use, but not available in the US.
Clinical trials in the MDS are ongoing with iron chelating agents to address the question of whether iron chelation alters the natural history of patients with MDS who are transfusion dependent. Reversal of some of the consequences of iron overload in MDS by iron chelation therapy have been shown.
Both the MDS Foundation and the NCCN MDS Guidelines Panel have recommended that chelation therapy be considered to decrease iron overload in selected MDS patients. Evidence also suggest there is a potential value to iron chelation in patients who then undergo a stem cell transplant.
Although deferasirox is generally well tolerated (other than episodes of gastrointestinal distress and kidney dysfunction in some patients), recently a safety warning by the FDA and Novartis was added to deferasirox treatment guidelines. Following post-marketing use of deferasirox, there were rare cases of acute kidney failure or liver failure, some resulting in death. Due to this, it is recommended that patients be closely monitored on deferasirox therapy prior to the start of therapy and regularly thereafter.
Currently[citation needed], a large international Phase III clinical trial is ongoing comparing treatment of deferasirox to placebo, which should help to establish the clinical value of deferasirox in iron- overloaded MDS patients.
Indicators of a good prognosis Younger age; normal or moderately reduced neutrophil or platelet counts; low blast counts in the bone marrow(<20%) and no blasts in the blood; no Auer rods; ringed sideroblasts; normal karyotypes of mixed karyotypes without complex chromosome abnormalities and in vitro marrow culture- non leukemic growth pattern.
Indicators of a poor prognosis Advanced age; Severe neutropenia or thrombocytopenia ; high blast count in the bone marrow (20-29%) or blasts in the blood; Auer rods; absence of ringed sideroblasts; abnormal localization or immature granulocyte precursors in bone marrow section all or mostly abnormal karyotypes or complex marrow chromosome abnormalities and in vitro bone emarrow culture-leukemic growth pattern.
Prognosis and karyotype Good: Normal, -Y, del(5q), del(20q)
Intermediate or variable: +8, other single or double anomalies
Poor; Complex (>3 chromosomal aberrations); chromosome 7 anomalies
[26]
The International Prognostic Scoring System (IPSS) is the most commonly used tool in MDS to predict long-term outcome.[27]
Cytogenetic abnormalities can be detected by conventional cytogenetics, a FISH panel for MDS, or Virtual Karyotype.
The exact number of people with MDS is not known because it can go undiagnosed and there is no mandated tracking of the syndrome. Some estimates are on the order of 10,000 to 20,000 new cases each year in the United States alone. The incidence is probably increasing as the age of the population increases, and some authors propose that the incidence in patients over 70 may be as high as 15 cases per 100,000 per year.[28]
Since the early 20th century it began to be recognized that some people with acute myelogenous leukemia had a preceding period of anemia and abnormal blood cell production. These conditions were lumped with other diseases under the term "refractory anemia". The first description of "preleukemia" as a specific entity was published in 1953 by Block et al.[29] The early identification, characterization and classification of this disorder were problematical, and the syndrome went by many names until the 1976 FAB classification was published and popularized the term MDS.
Famous patients with MDS include astronomer Carl Sagan, writer Susan Sontag, writer Roald Dahl, jazz musicians Michael Brecker and Paul Motian, actress Nina Foch, firearms executive Val Forgett, United States Congressmen Joe Moakley and Bob Matsui, actor Pat Hingle, singer and comedienne Fran Allison, radio personality J.P. McCarthy, Danish theoretical physicist Per Bak, first National Spelling Bee winner Frank Neuhauser, and pioneering plant pathologist Jack Bailey.
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