Hem 125 Rar
processing.... Drugs & Diseases > Hematology Myelodysplastic Syndrome (MDS) Updated: Oct 01, 2022 Author: Emmanuel C Besa, MD; Chief Editor: Sara J Grethlein, MD, MBA, FACP more...
Share Print Feedback Close Facebook Twitter LinkedIn WhatsApp Email webmd.ads2.defineAd(id: 'ads-pos-421-sfp',pos: 421); Sections Myelodysplastic Syndrome (MDS) Sections Myelodysplastic Syndrome (MDS) Overview Practice Essentials
Pathophysiology Etiology Epidemiology Prognosis Show All Presentation History
Physical Examination Show All DDx Workup Approach Considerations
Complete Blood Count and Peripheral Blood Smear Bone Marrow Studies Cytogenetic Studies Histologic Findings Staging Laboratory Studies Show All Treatment Approach Considerations
Supportive Care Pharmacologic Therapy Bone Marrow Transplantation Surgical Care Show All Guidelines Guidelines Summary
Diagnosis Prognostic Scoring Systems Treatment Show All Medication Medication Summary
Retinoid-lilke Agents Hematopoietic Growth Factors Antineoplastic Agent, Methylation Inhibitors Immunomodulators Antineoplastic agents, Miscellaneous Erythroid Maturation Agents Show All Questions & Answers Media Gallery Tables References Overview Practice Essentials Myelodysplastic syndrome (MDS) refers to a heterogeneous group of closely related clonal hematopoietic disorders commonly found in the aging population. All are characterized by one or more peripheral blood cytopenias. Bone marrow is usually hypercellular, but rarely, a hypocellular marrow mimicking aplastic anemia may be seen. Bone marrow cells display aberrant morphology and maturation (dysmyelopoiesis), resulting in ineffective blood cell production.
Hem 125 rar
MDS affects hematopoiesis at the stem cell level, as indicated by cytogenetic abnormalities, molecular mutations, and morphologic and physiologic abnormalities in maturation and differentiation of one or more of the hematopoietic cell lines. [1, 2, 3] See the image below.
Patients with MDS may present with clinical manifestations of anemia, thrombocytopenia, and/or neutropenia (see Presentation). The workup in patients with possible MDS includes a complete blood count with differential, peripheral blood smear, and bone marrow studies (see Workup).
Standard care for MDS is constantly changing, but it typically includes supportive therapy, including transfusions, and may include bone marrow stimulation and cytotoxic chemotherapy or hypomethylating agents. Bone marrow transplantation has a limited role. (See Treatment.)
MDS develops when a clonal mutation predominates in the bone marrow, suppressing healthy stem cells. The clonal mutation may result from genetic predisposition or from hematopoietic stem cell injury caused by exposure to any of the following:
MDS can be classified as primary (de novo) or secondary to aggressive treatment of other cancers, with exposure to radiation, alkylating agents, or topoisomerase II inhibitors; it also occurs in heavily pretreated patients with autologous bone marrow transplants.
In the early stages of MDS, the main cause of cytopenias is increased apoptosis (programmed cell death). As the disease progresses and converts into leukemia, further gene mutation occurs, and a proliferation of leukemic cells overwhelms the healthy marrow.
Patients with complex karyotypes constitute 30% of primary MDS cases (only 20% of de novo AML) and up to 50% of therapy-related MDS and AML cases. These patients have a worse prognosis and response to treatment.
Balanced translocation abnormalities lead to the generation of fusion oncogenes such as Bcr-Abl in chronic myelogenous leukemia (CML) and PML-Rar alpha in acute promyelocytic leukemia (APL). Unbalanced recurrent aberrations, most commonly -5, 5q-,-7, 7q-, +8, 11q-, 13q-, and 20q-, suggest that genes within these regions have a role in the pathogenesis of MDS or myeloproliferative disorder (MPD), which is based on loss of tumor suppressor genes or haploinsufficiency of genes necessary for normal myelopoiesis.
Secondary MDS after treatment with a topoisomerase II inhibitors such as an anthracycline or etoposide occurs 1-3 years after exposure to these agents. The chromosomal abnormalities commonly involve the MLL gene (11q23).
MDS may also develop after exposure to certain chemicals (eg, benzene). Insecticides, weed killers, and fungicides are also possible causes of MDS and secondary leukemia. [4] Viral infections have also been implicated. Less evidence supports genetic predisposition, but familial incidences have been described. Some of the congenital platelet disorders with RUNX1 and GATA2 mutations can predispose to MDS.
Although familial cases of myelodysplastic syndromes are rare, they are immensely valuable for the investigation of the molecular pathogenesis of myelodysplasia in general. [5] The best-characterized familial MDS is familial platelet disorder with propensity to myeloid malignancy, which is caused by heterozygous germline RUNX1 mutations. The incidence of MDS/AML in affected pedigrees is over 40%, with a median age of onset of 33 years. Familial monosomy 7; unusually short telomeres in dyskeratosis congenita; and four pedigrees with inherited MDS caused by heterozygous mutations in GATA2 have been reported. [6] These familial forms may occasionally be found in the course of screening family members of a patient with MDS as bone marrow transplant donors.
A study by Kristinsson et al found that chronic immune stimulation is a trigger for acute leukemia and MDS development. The underlying mechanisms may also be caused by a genetic predisposition or treatment for infections or autoimmune conditions. [7]
The actual incidence of MDS in the United States is unknown. MDS was first considered a separate disease in 1976, and its occurrence was estimated at 1500 new cases every year. At that time, only patients with less than 5% blasts were considered to have this disorder. MDS was not classified as neoplastic and included in cancer registries until 2001. [8] Current estimates of the incidence of MDS in the United States vary widely, from 10,000 to 30,000-55,000 new cases each year. [8, 9, 10, 11] The higher figures have been questioned as possible overestimates resulting from inclusion of other hematopoietic conditions. [12]
The incidence of MDS has appeared to be increasing. The apparent rise is believed to reflect the increase in the elderly population, but may also reflect improvements in recognition and criteria for the diagnosis. [9]
Although MDS may occur in persons of any age, including children, MDS primarily affects elderly people, with the median onset in the seventh decade of life. Data from 2001 through 2003 of the first National Cancer Institute's Surveillance, Epidemiology & End Reports (SEER) indicate 86% of MDS cases were diagnosed in individuals who were 60 years of age or older (median age: 76y).
A review of United Kingdom population-based data from September 2004 to August 2013 found marked variations in MDS incidence, depending on the standard population used to calculate rates. For example, using the 1996 world standard, the population with the greatest weighting towards younger groups, the incidence rate was 1.67 per 100,000 population; using the 2013 European Standard Population, which has the greatest weighting towards older ages, the rate was 4.4 per 100,000 population. [14]
In some patients, MDS is an indolent disease. Other patients develop significant cytopenias; the resulting complications (eg, bleeding and infections) account for almost all the mortality related to MDS. In the remainder of cases the disease follows an aggressive course and converts into an acute form of leukemia.
Risk classification systems to estimate prognosis in patients with MDS have been developed by the French-American-British (FAB) Cooperative Group, the World Health Organization (WHO), and the MDS Risk Analysis Workshop.
RA and RARS are characterized by 5% or less myeloblasts in bone marrow. RARS is defined morphologically as having 15% erythroid cells with abnormal ringed sideroblasts (see the image below), reflecting an abnormal accumulation of iron in the mitochondria. Both RA and RARS have a prolonged clinical course and a low prevalence of progression to acute leukemia. In a review of United Kingdom population-based data, with followup of 2 to 11 years, progression to acute leukemia occurred in 5% of RARS cases, compared with 25% of RAEB cases. [14]
RAEB and RAEB-T (see the image below) are characterized by greater than 5% myeloblasts. The higher the percentage of myeloblasts present, the shorter the clinical course and the closer the disease is to acute myelogenous leukemia.
Transition from early to more advanced stages may occur, which indicates that these subtypes are merely stages of disease rather than distinct entities. Elderly patients with MDS who progress to acute leukemia are often considered to have a poor prognosis because their disease response to chemotherapy is worse than that of de novo acute myeloid leukemia patients.
The 1999 WHO classification proposed including all cases of RAEB-T in the category of acute leukemia because these patients have similar prognostic outcomes. [16] However, the response to therapy is worse than in patients with de novo or more typical AML or acute nonlymphocytic leukemia.
The fifth type of MDS, CMML, is the most difficult to classify. This subtype can have any percentage of myeloblasts but manifests as a monocytosis of 1000/μL or more, a total white blood cell (WBC) count of less than 13,000/μL, and trilineage dysplasia.
CMML may be associated with splenomegaly. This subtype overlaps with myeloproliferative disease (MPD) and may have an intermediate clinical course. CMML must be differentiated from classic chronic myelocytic leukemia, which is characterized by a negative Ph chromosome. 041b061a72