Myelodysplastic Syndromes
Summary of Key Points
Etiology
• The myelodysplastic syndromes (MDS) are a group of clonal marrow failure syndromes originating in a hematopoietic progenitor or stem cell. Approximately 25% to 30% of MDS cases progress to acute myeloid leukemia (AML), which is defined by 20% or more marrow blasts.
• Approximately 50% of MDS cases are associated with a karyotypic abnormality, usually chromosomal aneuploidy.
• Recurrent MDS-associated somatic mutations are now recognized in more than 25 genes. Some of these mutations have prognostic value independent of existing risk stratification tools.
Epidemiology
• The most important risk factor for MDS is aging. The risk of developing MDS increases greatly after age 65 years. The median age at diagnosis in the United States is approximately 71 years.
• Approximately 10% to 15% of MDS cases arise as a consequence of therapeutic or environmental exposure to a DNA damaging agent; these are termed secondary or therapy-related MDS. In patients who had been exposed to ionizing radiation or alkylating agents, abnormalities of chromosomes 5 and 7 are common. Patients treated with topoisomerase II inhibitors may develop rearrangements of the MLL gene at 11q23 or the MECOM (MDS1/EVI1) locus on chromosome 3q21q26.
• Patients who develop MDS before age 40 years without a recognized toxin exposure may have a germline DNA repair defect or congenital marrow failure syndrome, such as Fanconi anemia or dyskeratosis congenita. Chromosome breakage analysis and telomere length analysis is appropriate in such patients.
Pathology
• The 2008 World Health Organization (WHO) classification of MDS, refined from the 2001 WHO and 1982 French–American–British (FAB) MDS classifications, defines several subtypes of MDS with varying risk of AML progression or death. The specific diagnosis depends on the proportion of marrow blasts, the number of cell lineages involved by disease, and the presence or absence of ring sideroblasts or chromosome 5q deletion.
• Minimal diagnostic criteria for MDS (after exclusion of other causes of cytopenias) include either: 10% or more dysplastic cells in one or more myeloid lineages, increased marrow blasts (≥5%), or the presence of a cytogenetic abnormality or another marker of clonal hematopoiesis.
Differential Diagnosis
• Not all marrow dysplasia represents MDS. Other causes of cytopenias and abnormal cell morphology must be considered in the initial evaluation of patients, such as nutritional deficiency (e.g., vitamin B12, folate, copper), inflammation, excessive alcohol use, human immunodeficiency virus infection, and non-MDS neoplasms.
• In ambiguous cases, the presence of an MDS-associated cytogenetic abnormality, such as deletion of chromosome 5q, can confirm the diagnosis.
Prognosis
• Several prognostic tools, including the 2012 Revised International Prognostic Scoring System (IPSS-R), are in widespread use and aid in risk stratification and therapy choice. In general, older patients with higher blast proportion, more severe cytopenias, and higher-risk cytogenetic results have a poorer outlook.
• Complications of peripheral blood cytopenias and functional cell defects, including infection and hemorrhage, are the most common causes of death in MDS. Progression to AML following MDS occurs in 25% to 30% of cases and is usually fatal.
Primary Therapy
• In lower-risk cases, supportive care alone may be appropriate. Epoetin or darbepoetin may alleviate MDS-associated anemia.
• Anemia of MDS associated with chromosome 5q deletion frequently responds to lenalidomide. Thrombocytopenic patients respond less well.
• Chronic red blood cell transfusion can lead to iron overload and is an adverse prognostic marker. The appropriate use of iron chelation therapy in MDS is controversial.
• Azacitidine has been demonstrated to improve survival compared with supportive care in higher-risk MDS. Another DNA methyltransferase inhibitor, decitabine, can also induce hematologic and cytogenetic responses.
• Allogeneic stem cell transplantation is the only potentially curative therapy, and should be considered for patients with higher-risk MDS who are younger than age 75 years and have a matched donor.
Second- or Third-Line Therapies
• Once azacitidine or decitabine fail the patient, or if relapse occurs after a stem cell transplantation, the outlook is very poor, with a median survival less than 6 months. There is currently no established second-line therapy for MDS. Clinical trial enrollment is especially important for this patient group.
1. In the Revised International Prognostic Scoring System (IPSS-R) for MDS, which of the following parameters is weighted the most heavily?
2. Which of the following somatic mutations is associated with better outcomes in MDS than would be predicted by the IPSS?
3. You have been asked to consult in the case of a 42-year-old woman with a 2-month history of fatigue and stumbling gait. Other than bariatric surgery for morbid obesity 4 years ago, after which she successfully lost 45 pounds, her history is unremarkable. Her medications include folate, ferrous sulfate, and fluoxetine.
Absolute neutrophil count 0.96 × 109/L
Serum B12 level is 426 pg/mL, folate level is 13.6 ng/mL, and ferritin is 144 ng/mL
Which of the following tests is most likely to yield an abnormal result?
4. An 81-year-old man with a history of congestive heart failure and chronic obstructive pulmonary disease (most recent echocardiogram showed a left ventricular ejection fraction of 25% to 30%) was discovered to have abnormal blood counts during a routine follow-up evaluation in the thoracic diseases clinic. A complete blood count is as follows:
A chemistry group is unremarkable. Serum vitamin B12 and folate levels are within normal limits.
Which of the following is the most appropriate treatment for this patient?
1. Answer: B. The 2012 Revised International Prognostic Scoring System (IPSS-R) for MDS includes three components for calculating a risk score: blast proportion, karyotype, and degree and number of cytopenias. Compared to the original 1997 IPSS, the IPSS-R weights karyotype more heavily and the fastest way to a high risk IPSS-R score is to have a very poor-risk karyotype. Age and comorbidity are important prognostic factors, but are not included in the IPSS-R. The IPSS-R, like the IPSS, only applies to patients with de novo MDS, not secondary disease.
2. Answer: F. More than 25 different acquired gene mutations have been described in patients with MDS. Most of these have no clear effect on prognosis, either because they are present in too few patients to calculate their independent risk, or because their effect on outcomes is neutral. In an analysis of more than 400 patients with MDS, Bejar and colleagues showed that mutations in ASXL1, RUNX1, NRAS, EZH2, and TP53 were associated with poorer outcomes than would be predicted by the IPSS (Bejar R, Stevenson K, et al. N Engl J Med 2011;364(26):2496-506). Other investigators subsequently showed an IPSS-independent adverse effect of SRSF2 and DNMT3A mutations. Thus far, none of the point mutations described has been associated with better outcomes than would be predicted by the IPSS.
3. Answer: A. Not all that is dysplastic represents MDS. Copper deficiency can mimic features of MDS, and may or may not be associated with neuropathy. Neutropenia is common in copper deficiency and anemia is also often seen, whereas thrombocytopenia is very rare. The typical marrow findings associated with copper deficiency include erythroid and myeloid dysplasia, cytoplasmic vacuolization in hematopoietic precursor cells, and occasionally ring sideroblasts. Risk factors for copper deficiency include gastric bypass surgery, malabsorption syndromes such as celiac disease, and zinc supplementation (e.g., the “health fanatic” who takes high doses of zinc supplements chronically in an attempt to ward off the common cold).
4. Answer: C. This older patient with a poor performance status and several serious comorbid conditions illustrates a common problem encountered in MDS patients: the inability to definitively treat the underlying disease because of the poor general health of the patient. The only therapy that has been shown to increase survival in patients with higher-risk MDS, when compared to conventional care (i.e., supportive care, low-dose cytarabine, or AML-style induction chemotherapy) is azacitidine. Therefore, azacitidine (in combination with good supportive care) is considered first-line therapy for higher-risk patients with MDS, especially those who are not allogeneic stem cell transplantation candidates, such as this patient.
