Clinical Presentation, Diagnosis, and Prognosis of Myelodysplastic Syndromes

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1 Review Clinical Presentation, Diagnosis, and Prognosis of Myelodysplastic Syndromes James M. Foran, MD, FRCPC, a and Jamile M. Shammo, MD, FASCP, FACP b a Mayo Clinic, Jacksonville, Florida, USA; and b Rush University Medical Center, Chicago, Illinois ABSTRACT Myelodysplastic syndromes (MDS) comprise a group of underrecognized hematologic clonal malignancies with variable propensity for leukemic transformation that can present a diagnostic challenge because they lack hallmark symptoms. MDS can present with varying degrees of anemia, neutropenia, and thrombocytopenia, and at presentation can range from indolent to life threatening. The clinician should have a heightened level of suspicion when treating elderly patients and those with prior exposure to chemotherapy, radiation, and environmental toxins in the presence of unexplained cytopenias. Chronic anemia should not be considered a natural consequence of aging. Approximately 1 in 6 patients with unexplained anemia may have findings compatible with MDS, suggesting that MDS should be considered higher in the differential diagnosis. Primary care physicians are encouraged to conduct comprehensive evaluations to exclude non-mds-related causes for persistent cytopenias. Patients with pancytopenia, bicytopenia, or any persistent and unexplained isolated cytopenia (and particularly unexplained macrocytic anemia) should be referred to a specialist to establish a diagnosis Elsevier Inc. All rights reserved. The American Journal of Medicine (2012) 125, S6 S13 KEYWORDS: Anemia; Cytopenias; Diagnosis; Elderly; Myelodysplastic syndromes; Specialist referral Myelodysplastic syndromes (MDS) are an underrecognized group of hematopoietic myeloid stem cell disorders; they represent a hematologic malignancy with a significant impact on quality of life and survival. 1,2 Increased awareness of MDS and appropriate workup and referral are necessary to achieve a timely diagnosis and optimal disease management. The primary objective of this review is to summarize the clinical presentation, risk factors, and diagnosis of patients with MDS, and to provide guidance to primary care physicians (PCPs) on when to perform a full workup and when to refer a patient to a specialist. CLINICAL PRESENTATION The MDS represent a heterogeneous group of clonal disorders in which the hematopoietic progenitor cells have a reduced ability to differentiate and are more likely to undergo apoptosis. This leads to bone marrow hyperplasia in most cases, as well as ineffective hematopoiesis that manifests with varying degrees of peripheral cytopenias. 3 Anemia (typically macrocytic) is the most common Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to James M. Foran, MD, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida address: foran.james@mayo.edu. peripheral blood abnormality, occurring in approximately 80% to 85% of patients. 4 Thrombocytopenia occurs in around 30% to 45% of MDS cases, with approximately 40% of patients found to have neutropenia at diagnosis. 4 The impact of thrombocytopenia is often underappreciated; up to 53% of patients with MDS experience bleeding and up to 25% experience serious bleeding events during the course of disease. 3,5-7 The clinical manifestation of MDS is nonspecific and highly variable, depending on the MDS subtype, and it ranges from indolent to life threatening. 3 Clinical features of MDS overlap with a number of hematologic disorders, including acute myeloid leukemia (AML), aplastic anemia, large granular lymphocytosis, myeloproliferative disorders, and paroxysmal nocturnal hemoglobinuria. 4,8,9 Some patients may present with cytopenias that, upon further workup, cannot be attributed to a specific cause and are thus termed idiopathic cytopenia of uncertain significance. 10 Such entities may represent a forme fruste of MDS or may evolve into frank MDS over time. When to Suspect MDS he risk of MDS increases with advancing age; approximately 86% of patients with newly diagnosed MDS in the United States are 60 years old (median age, 76 years). 11,12 In general, MDS is divided into 2 broad categories: primary (de novo) and secondary. Secondary MDS can be therapy related /$ -see front matter 2012 Elsevier Inc. All rights reserved.

2 Foran and Shammo MDS: Clinical Presentation, Diagnosis, and Prognosis S7 and is diagnosed after exposure to radiotherapy or cytotoxic chemotherapy. 13 Of note, the rates of secondary MDS have been increasing recently owing to both an increasing incidence of other cancers and increased success in treating these diseases. 14 In 1 study of 5,411 patients with Hodgkin s disease treated with chemotherapy and/or radiotherapy, the cumulative relative risk of developing secondary AML or MDS was approximately 1% after a median follow-up of 55 months. 15 In patients with breast cancer, the incidence of secondary AML or MDS was elevated in a cohort receiving high-dose cyclophosphamide compared with patients who received a standard cyclophosphamide dosage. 16 A few reports point to an association between the long-term use of granulocyte colonystimulating factors (G-CSF) and the development of MDS in patients with hematologic diseases, 17,18 and in patients aged 65 years with breast cancer receiving adjuvant G-CSF therapy. 19 Table 1 summarizes risk factors known to be associated with MDS. 1,20-26 Familial histories have been reported, but only rarely However, in 90% of patients the cause is unknown. 1 There should be a high level of suspicion for MDS in elderly patients in the setting of isolated unexplained anemia or unexplained progressive cytopenias, and in those with prior exposure to any chemotherapy, radiotherapy, or environmental toxins such as benzene, pesticides, or herbicides. 1,4,30 There should be a high index of suspicion for MDS in elderly patients with isolated unexplained anemia or unexplained progressive cytopenias, those with prior exposure to any chemotherapy and radiotherapy, as well as those with a history of exposure to environmental toxins. Table 1 Known Heritable and Acquired Factors Associated with the Development of Myelodysplastic Syndromes Hereditable Constitutional genetic disorders (trisomy 21, trisomy 8 mosaicism, familial monosomy 7) Neurofibromatosis Germ cell tumors Congenital neutropenia (Kostmann syndrome or Shwachman Diamond syndrome) DNA repair deficiencies (e.g., Fanconi anemia) Mutagen detoxification enzyme mutation (GSTM1-null, GSTT1-null) Acquired Age Chemotherapy (alkylating agents, topoisomerase inhibitors, nucleoside analogs) and HSCT G-CSF Radiation therapy Environmental/occupational toxins Tobacco Alcohol Aplastic anemia and paroxysmal nocturnal hemoglobinuria G-CSF granulocyte colony stimulating factor; GST glutathione- S-methyltransferase; HSCT hematopoietic stem cell transplantation. Adapted from Abeloff s Clinical Oncology, 1 Br J Haemotol, 20 Haematologica, 21 Leuk Res, 22 Lancet, 23 Ann Hematol, 24 Nat Rev Cancer, 25 and N Engl J Med. 26 Symptoms and Signs of MDS Clinical manifestations of MDS are nonspecific and vary considerably depending on subtype and severity of cytopenias. A diagnostic workup for MDS is often, but not always, triggered by symptoms or signs suggestive of cytopenias, including fatigue and decline in living activities indicative of anemia, infections indicative of neutropenia, and frequent or unexplained bleeding and bruising indicative of thrombocytopenia. 4,31 Many patients with MDS are asymptomatic and therefore are diagnosed during evaluation of other comorbidities, such as heart failure or renal disease, when peripheral blood and bone marrow features typical of MDS are incidentally found. 4,31 The lack of hallmark symptoms is among the major challenges PCPs consistently experience when evaluating patients with a suspicion of lower-risk MDS. Patients with higher-risk MDS, who comprise around 30% of the entire MDS population and have both a worse prognosis and a greater propensity to progress to AML, 32,33 are often more straightforward to diagnose. Their clinical status at presentation is typically more severe, with frequent unexplained infections and bleeding, and circulating immature myeloid cells or blasts. 31 At presentation, the most common laboratory finding, present in nearly all adult patients with MDS, is anemia with an inadequate reticulocyte response. 31 The anemia is typically macrocytic but may also be normocytic. Microcytic anemia is rarely associated with MDS. 2,31,34 Anemia may be accompanied by neutropenia and/or thrombocytopenia, with pancytopenia found in approximately 50% of all cases. Isolated neutropenia or thrombocytopenia is reported in 5% of cases. 31 Highlighting the difficulties in diagnosing MDS, anemia is prevalent in the elderly population; an estimated 11% of men and 10.2% of women aged 65 years have anemia. 35 Among patients with the disease, approximately one third have evidence of nutrient deficiency, one third have anemia of chronic inflammation or chronic renal disease, and one third have unexplained anemia. 35 An estimated 1 in 6 patients with unexplained anemia have findings compatible with MDS in the peripheral blood. 35 PCPs should approach any patient with a macrocytic unexplained anemia with a heightened degree of suspicion for MDS. An estimated 1 in 6 older patients with unexplained anemia has findings compatible with MDS in the peripheral blood. 35 Laboratory values of hemoglobin, platelets, and neutrophils seen in patients with newly diagnosed MDS are not usually dramatically low, but can vary broadly. The findings of an analysis of 6 cross-sectional physician surveys revealed that in recently diagnosed patients, a majority were anemic and had mild thrombocytopenia and neutropenia. 33 In a study relating cytopenias to clinical outcomes in MDS, 57% of patients had a hemoglobin level of 10.0 g/dl (27% with severe anemia); 38% of patients had an absolute neutrophil count of 1,500 cells/ L (6% with severe neu-

3 S8 The American Journal of Medicine, Vol 125, No 7A, July 2012 tropenia); and 37% patients had a platelet count of 100,000/ L (5% with severe thrombocytopenia). 36 At presentation and after diagnosis, many patients with MDS require red blood cell (RBC) and platelet transfusions. 33 Among patients with lower-risk MDS, 22% are dependent on RBC transfusions and another 35% require occasional RBC transfusions. In contrast, 68% of newly diagnosed patients with higher-risk MDS are dependent on RBC transfusions, with another 21% requiring occasional RBC transfusion support. Platelet transfusions are also prevalent in patients with newly diagnosed MDS: 6% of patients with lower-risk disease and 33% of those with higher-risk disease are dependent on platelet transfusions; and 31% of patients with lower-risk and 26% of patients with higher-risk disease require occasional platelet transfusions. 33 Therefore, significant transfusion requirements at presentation may be a signal of higher-risk disease. DIAGNOSIS There is no doubt that MDS presents a diagnostic challenge. The minimum diagnostic criterion chosen by pathologists for MDS is dysplasia in 10% of any of the myeloid lineages, unless there are cytogenetic abnormalities suggestive of the diagnosis of MDS as per the World Health Organization (WHO) 2008 revision. 9,26,37 However, not all patients with MDS necessarily present with overt dysplasia. 9 The need to demonstrate morphologic features of dysplasia for diagnosis is further complicated by the inexact nature of assessing cellular atypia, which is subject to interobserver variability and might show artifacts associated with specimen handling and processing. 31,38 Moreover, such features are also seen in other myeloid neoplasms, as well as certain metabolic and nonmalignant hematologic disorders. 31 As a consequence, the diagnosis of MDS often requires the exclusion of other disorders that may share in some of the features of dysplasia. Diagnosis is especially difficult in patients with early and lower-risk MDS because the dysplasia may be mild and they are more likely to have normal cytogenetics. Hence, a proper diagnostic workup is required in all cases where MDS is suspected in order to make an accurate diagnosis. Figure 1 Morphologic features of dysgranulopoiesis can be seen in either a blood or bone marrow aspirate smear: nuclear hyposegmentation, so-called pseudo-pelger-huet or Pelgeroid anomaly. (Reprinted with permission from Hematol Oncol Clin North Am. 31 ) Diagnostic Workup The diagnostic workup should begin with a standard history and physical examination, paying special attention to any toxic exposure (including heavy metals and prior chemotherapy or radiotherapy), medications, smoking, alcohol, and a history of fatigue, infection, or bruising. For patients with 1 cytopenia and suspected MDS, National Comprehensive Cancer Network (NCCN) guidelines 39 recommend several components for a thorough evaluation of MDS. The required components of this evaluation are as follows: a comprehensive history and physical examination; a complete blood count with platelets, differential, and reticulocyte counts; a peripheral blood smear examination; a bone marrow aspiration and biopsy with iron stain and cytogenetics; a check of serum erythropoietin level prior to RBC transfusion; evaluation of RBC folate and serum vitamin B 12 levels; assessment of serum ferritin levels (with or without iron and total iron-binding capacity); and documentation of transfusion history. Of note, PCPs may routinely order blood tests that include an automated differential count, yet they are less likely to order an evaluation of peripheral blood smear. A peripheral blood smear is always warranted in patients with features suggestive of anemia, unexplained jaundice, or both, and also in patients with features suggestive of thrombocytopenia or neutropenia. 40 Dysgranulopoiesis with typical nuclear hyposegmentation in neutrophils represents 1 of the morphologic characteristics that can be recognized in a blood or bone marrow aspirate smear (Figure 1). 31 For patients with isolated thrombocytopenia, the workup might include an abdominal ultrasound to evaluate for splenomegaly. 2 Blood tests for immune-related mechanisms should also be considered. 2 When to Refer to a Hematologist and/or Oncologist Pancytopenia, in the absence of peripheral sequestration, almost always indicates abnormal bone marrow function and patients should be referred to a specialist. 2 Many cases of MDS, however, involve isolated cytopenias and are more difficult to diagnose. A PCP caring for such patients should ask the following questions: (1) How much workup should I do?; (2) When should I refer this patient?; and (3) What is my threshold for referral? Additionally, PCPs should consider a comprehensive workup to exclude non-mds-related causes for observed isolated cytopenias (Figure 2). A patient with isolated anemia should be assessed for nutritional

4 Foran and Shammo MDS: Clinical Presentation, Diagnosis, and Prognosis S9 Figure 2 Flow-chart: diagnosis workup and referral of patients with myelodysplastic syndromes (MDS). AI autoimmune; BM bone marrow; CBC complete blood count; EPO erythropoietin; GI gastrointestinal; ITP idiopathic thrombocytopenic purpura; NCCN National Comprehensive Cancer Network; RBC red blood cell.

5 S10 The American Journal of Medicine, Vol 125, No 7A, July 2012 deficiency and occult gastrointestinal bleeding, as well as renal, cardiac, and other inflammatory causes. 2 It must be stressed that although the incidence of anemia increases with age, it is not a normal consequence of aging. 35 Chronic anemia should not be considered as a natural consequence of aging. A patient with isolated thrombocytopenia should be assessed for pseudothrombocytopenia, idiopathic thrombocytopenic purpura, and hypersplenism. 31 An isolated neutropenia may also be suggestive of T-cell large granular lymphocytic leukemia, medication use, autoimmune disorder, familial or cyclic neutropenia, hypersplenism, or toxic exposure. 31 Of note, copper deficiency (caused by parenteral hyperalimentation, or zinc supplementation, which may interfere with copper absorption) can also result in bicytopenia or pancytopenia, with bone marrow features mimicking MDS (typically lower-risk disease). 41,42 The PCP should consider referral to a specialist when a patient has any of the following conditions: any progressive or symptomatic cytopenia; unexplained macrocytic anemia; pancytopenia; and any bicytopenia of persistent and unexplained nature. Clear guidelines with specific cutoffs for each cytopenia should be established to facilitate referral. In this regard, we propose the following cutoffs for referral for isolated cytopenias: anemia (hemoglobin level 10 g/dl); neutropenia (neutrophil count 1,500 cells/ L); and thrombocytopenia (platelet count 100,000/ L). A thorough workup may be conducted for any patient with a borderline cytopenia depending on the clinical scenario. PCPs should consider a comprehensive workup and referral to a specialist when they have a patient with progressive or symptomatic cytopenia, unexplained macrocytic anemia, pancytopenia, or any bicytopenia of persistent and unexplained nature. The specialist workup will include a review of the peripheral blood smear, bone marrow aspiration/biopsy looking at iron stores, morphology and cytogenetics, and specialized tests for evaluation for specific clonal disorders. 2 Importance of Bone Marrow Assessment In a survey of Medicare beneficiaries diagnosed with MDS, almost 20% of patients were diagnosed on the basis of clinical impression in the absence of bone marrow biopsy. 43 Despite the significant percentage of patients who are being diagnosed on this basis in clinical practice, bone marrow aspiration and biopsy are not only essential to establish a diagnosis of MDS but also are important for prognostication and selection of therapy. Clearly, there are circumstances where it might be difficult or inappropriate to obtain a bone marrow biopsy, and some patients may be reluctant to undergo such a procedure. If patients are asymptomatic, PCPs may be particularly hesitant to refer them to a specialist for bone marrow assessment, because aspiration and biopsy are perceived to be invasive and possibly painful. However, it should be noted that many procedures routinely performed for the purpose of health assessments are associated with some degree of pain and discomfort. Ultimately, the decision to perform bone marrow aspiration and biopsy should be discussed by the specialist and the patient in the overall clinical context. If the specialist decides not to perform bone marrow aspiration and biopsy, diagnosis could be determined on the basis of a peripheral blood smear evaluated by a specialist. However, bone marrow aspiration and biopsy are required to confirm the diagnosis definitively, fully assess the patient s clinical and cytogenetic risk (as well as determine the bone marrow blast percentage), and to choose optimal and tailored therapeutic options for individual patients. CLASSIFICATION AND PROGNOSIS The understanding of MDS has advanced in recent years, and the terminology to classify it has similarly evolved to adjust to the increasing knowledge. As a result, several classification systems are currently used for the diagnosis of MDS. The French-American-British (FAB) classification is based on morphology and bone marrow blast count (Table 2). 13 The WHO classification modifies the FAB system by also taking cytogenetic and immunophenotypic characteristics into consideration, in addition to morphology and blast count (Table 2). 9,44 Together with the FAB and WHO classification systems, 2 prognostic scoring systems are also commonly used in clinical decision making. The International Prognostic Scoring System (IPSS) uses percentage of bone marrow blasts, cytogenetic abnormalities, and number of cytopenias to separate patients into distinct subgroups based on survival outcome and risk of progression to AML (Table 3). 32 Median survival varies from 0.4 years in patients with IPSS-defined high-risk disease to 5.7 years in patients with low-risk disease. 32 The WHO-based Prognostic Scoring System (WPSS) is a dynamic and time-dependent scoring system that also predicts the probabilities of leukemic evolution and survival, based on a combination of WHO subgroup classification, cytogenetic risk according to IPSS, and transfusion requirement. 45 Additional factors such as performance status and the degree of cytopenias are included in updated models. 46 Both the IPSS and WPSS are currently being revised in light of increasing knowledge about the disease. 47,48 Clonal cytogenetic abnormalities are present in almost 50% of all patients and, in addition to being helpful in diagnosis, can be indicative of prognosis when used in conjunction with FAB and WHO classification systems. 49 A deletion of the long arm of chromosome 5, known as del(5q), is the most common chromosomal alteration. 49 Patients with MDS who have del(5q) as the sole cytogenetic abnormality have characteristic features of macrocytic anemia, normal or elevated platelets with megakaryocytic anomalies, 50 and typically a better prognosis

6 Foran and Shammo MDS: Clinical Presentation, Diagnosis, and Prognosis S11 Table 2 (MDS) French-American-British (FAB) and World Health Organization (WHO) classification systems of myelodysplastic syndromes Classification Peripheral Blood Findings Bone Marrow Findings FAB subtype RA 1% blasts 5% blasts RARS 1% blasts 5% blasts; 15% RS RAEB 5% blasts 5% 20% blasts RAEB-t 5% blasts 21% 30% blasts CMML 5% blasts 20% blasts WHO subtype RCUD (RA, RN, RT) 1% blasts; uni- or bicytopenia 5% blasts; unilineage dysplasia*; 15% RS RARS No blasts; anemia 5% blasts; erythroid dysplasia; 15% RS RCMD 1% blasts; cytopenia(s); no Auer rods 5% blasts; bi- or multilineage dysplasia ; 15% RS; no Auer rods RAEB-1 5% blasts; cytopenia(s); no Auer rods 5% 9% blasts; uni- or multilineage dysplasia; no Auer rods RAEB-2 5% 19% blasts; cytopenia(s); Auer rods 10% 19% blasts; uni- or multilineage dysplasia; Auer rods MDS-U 5% blasts; cytopenias 5% blasts; unequivocal dysplasia ; accompanied by a cytogenetic abnormality common in MDS MDS associated with isolated del(5q) 1% blasts; anemia; normal or increased platelet count 5% blasts; normal to increased megakaryocytes with hypolobated nuclei; isolated del(5q); no Auer rods CMML chronic myelomonocytic leukemia ( 1,000 monocytes/ L); MDS-U MDS, unclassified; RA refractory anemia; RAEB RA with excess blasts; RAEB-t RAEB with excess blasts in transformation; RARS RA with ringed sideroblasts; RCMD refractory cytopenia with multilineage dysplasia; RCUD refractory cytopenia with unilineage dysplasia; RN refractory neutropenia; RS ringed sideroblasts; RT refractory thrombocytopenia. Adapted with permission from Blood by the American Society of Hematology, and Br J Haematol. 13 *In 10% of the cells of 1 myeloid lineage. In 10% of the cells of 2 myeloid lineages. In 10% of the cells of 1 myeloid lineage. Table 3 International Prognostic Scoring System (IPSS) for Myelodysplastic Syndromes IPSS Score Value Prognostic Variable* Bone marrow blast (%) Karyotype Good Intermediate Poor Cytopenias 0/1 2/3 Adapted with permission from Blood by the American Society of Hematology, all rights reserved, and J Clin Oncol. 45 *IPSS risk score groups: Low 0, Intermediate ; Intermediate ; High 2.5. Good normal, Y, del(5q), del(20q); Poor complex ( 3 abnormalities) or chromosome 7 abnormalities; Intermediate other abnormalities. than patients with complex abnormalities. 9 It is crucial to obtain information about a patient s cytogenetics in order to establish an accurate prognosis. Recently, a large multicenter analysis confirmed that IPSS-defined poor-risk cytogenetics negatively affect the survival prognosis for patients with MDS to the same degree as high bone marrow blast counts ( 20%). 51 In addition, several genetic mutations were found to be predictive of poor survival outcome in patients with MDS, independently of established cytogenetic risk factors. 52 Although this study seems to suggest that the outcome of MDS may be governed by certain genetic associations, the specific contribution of such point mutations to disease biology, and their potential therapeutic significance, remains to be determined. 52 SUMMARY As a heterogeneous disease with a nonspecific and highly variable clinical presentation, MDS presents a diagnostic challenge that requires careful assessment by the PCP and a comprehensive workup. PCPs should use a high degree of clinical suspicion for MDS when treating elderly patients and those patients with a history of prior exposure to chemotherapy, radiotherapy, or environmental toxins. At presentation, most patients have anemia with or without other cytopenias; however, isolated neutropenia or thrombocytopenia does not exclude a diagnosis of MDS and the impact of thrombocytopenia should not be underestimated. Indeed, many patients have substantial platelet as well as RBC transfusion requirements at the time of diagnosis. PCPs should be mindful that chronic anemia is not a natural consequence of aging, but rather highlights an underlying problem that requires thorough investigation. They should, therefore, perform a comprehensive workup of any patient with unexplained anemia regardless of comorbidities. Referral to a specialist also is required for patients with a progressive or symptomatic cytopenia, pancyto-

7 S12 The American Journal of Medicine, Vol 125, No 7A, July 2012 penia, bicytopenia, or any persistent and unexplained isolated cytopenia. ACKNOWLEDGMENTS The authors received editorial/writing support provided by Nikki Moreland and Marianne Eyholzer of Excerpta Medica in the preparation of this manuscript, funded by Celgene Corporation. The authors are fully responsible for content and editorial decisions for this manuscript. AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: James M. Foran, MD, has received research support and honoraria from Celgene Corporation. Jamile M. Shammo, MD, has received research support and honoraria from Celgene Corporation. References 1. Foran JM, Sekeres MA. Myelodysplastic syndromes. In: Abeloff MD, Armitage JO, Neiderhuber JE, Kastan MB, McKenna WG, eds. Abeloff s Clinical Oncology. 4th ed. Philadelphia: Churchill Livingstone, 2008: Barzi A, Sekeres MA. 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