|Year : 2014 | Volume
| Issue : 4 | Page : 123-132
Management of myelodysplastic syndromes: Expert consensus opinion from the Saudi MDS Working Group
Ahmed Alaskar1, Abdul Kareem Al Momen2, Ahmad Al-Saeed1, Ahmed Al Sagheir3, Amr Hanbali4, Ayman Al-Hejazi1, Hani Al-Hashmi3, Khalid Al-Anazi3, Mohsen Al Zahrani1, Saud Abu Harbesh4, Zayed Al-Zahrani1
1 King Abdullah International Medical Research Center; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
2 King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
3 King Fahad Specialist Hospital, Dammam, Saudi Arabia
4 Security Forces Hospital, Riyadh, Saudi Arabia
|Date of Web Publication||13-Dec-2014|
Dr. Ahmed Alaskar
Division of Adult Hematology and SCT, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, POB 22490, Riyadh 11426
Source of Support: None, Conflict of Interest: None
Myelodysplastic syndromes (MDSs) constitute a heterogeneous group of clonal hematopoietic disorders. A panel of Saudi hematologists representing the Saudi MDS Working Group convened with two international experts to develop the guidelines for MDS diagnosis and treatment. The recommendations were formulated on the basis of a list of real cases and therapy-related questions. The diagnostic procedures should help distinguish MDS from other causes of cytopenia and dysplasia and other clonal stem cell disorders. Blood smear, bone marrow aspirate and biopsy, and cytogenetic testing are among the mandatory diagnostic tests in MDS. Higher resolution genetic testing like mutational analysis and single nucleotide polymorphisms can be suggested for the workup depending on the clinical condition and availability of these technologies. The Working Group stressed that the heterogeneity of MDS strongly withstands a risk-adapted treatment strategy based on the international prognostic scoring system risk group of patients.
Keywords: Consensus, diagnosis, guidelines, myelodysplastic syndromes, Saudi MDS Working Group, treatment
|How to cite this article:|
Alaskar A, Al Momen AK, Al-Saeed A, Al Sagheir A, Hanbali A, Al-Hejazi A, Al-Hashmi H, Al-Anazi K, Al Zahrani M, Harbesh SA, Al-Zahrani Z. Management of myelodysplastic syndromes: Expert consensus opinion from the Saudi MDS Working Group. J Appl Hematol 2014;5:123-32
|How to cite this URL:|
Alaskar A, Al Momen AK, Al-Saeed A, Al Sagheir A, Hanbali A, Al-Hejazi A, Al-Hashmi H, Al-Anazi K, Al Zahrani M, Harbesh SA, Al-Zahrani Z. Management of myelodysplastic syndromes: Expert consensus opinion from the Saudi MDS Working Group. J Appl Hematol [serial online] 2014 [cited 2019 Jul 22];5:123-32. Available from: http://www.jahjournal.org/text.asp?2014/5/4/123/146946
| Introduction|| |
Myelodysplastic syndromes (MDSs) are a heterogeneous group of myeloid neoplasms characterized by peripheral blood cytopenias, dysplastic changes, clonal chromosomal abnormalities and increased risk of leukemic evolution. , Common risk factors for developing MDS include advanced age, male gender, family history of hematopoietic cancers, exposure to solvents and agricultural chemicals, and prior chemo-or radiotherapy for previous solid cancer. , The incidence rate of MDS in the USA and Western European countries is approximately 5/100,000 people. ,,, Data on the incidence of MDS in Kingdom of Saudi Arabia (KSA) is absent in the medical literature. However, unpublished data from previous experts meetings raised the issue of increased refractory anemia (RA) in the elderly patients in KSA who were eventually given a late diagnosis of MDS. The idea of establishing a national MDS registry in KSA is being entertained by a group of hematologists, an endeavor that might give us an idea about the incidence of MDS in KSA.
The pathophysiology of MDS is a multistep process involving genetic mutations detectable by conventional cytogenetic testing or smaller alterations detectable by more advanced methods like sequencing or single nucleotide polymorphism (SNP) array. , MDSs range from indolent (so-called "low risk") conditions with long natural history to subtypes analogous to acute myeloid leukemia (AML) (so-called "high-risk"); this makes the clinical decision concerning treatment modalities and timing of interventions problematic. , Given the importance of fast and accurate diagnosis of MDS, diagnostic criteria needed to be periodically revised and updated in order to incorporate modifications in classification criteria and recent diagnostic methodologies.
| Methods|| |
A panel of Saudi hematologists representing the newly established Saudi MDS Working Group (SMW) convened on two occasions in 2012/2013 to review the diagnostic criteria and treatment option of MDS; the meetings were characterized by discussions and revision of many individual cases. During the second meeting, the SMW met with two international experts over 2 days in a scientific forum that covered the key topics on diagnosis and recent advances in MDS management. The ultimate objectives of the SMW were to establish a consensus and publish the guidelines for the management of MDS reflecting the Saudi experience.
It is quite important that the diagnostic procedures help distinguish MDS from other causes of cytopenia and dysplasia and other clonal stem cell disorders.  Complete information should be collected on symptoms of anemia (palpitations, fatigue), thrombocytopenia (bleeding, bruising, ecchymosis), neutropenia (recurrent infections); chronicity of the symptoms; prior chemotherapy, radiation exposure or therapy, and occupational exposure (especially to agricultural chemicals and benzene). , History taking should gather information on concomitant medications, smoking, alcohol intake, bleeding tendency, autoimmune disorders, previous blood transfusions, previous surgeries particularly bowel resection, and infections. Collection of family history should focus on conditions suggestive of inherited bone marrow failure disorders, like Fanconi anemia. ,
A thorough physical examination should be performed. Among the things that should be examined are: Pallor, petechiae, ecchymosis, mouth ulcers, glossitis, palmar and plantar warts, dysmorphic features to rule out constitutional bone marrow failure syndrome (facial features, "café au lait" spots, and nail dystrophy), jaundice, features of hypothyroidism, lymphadenopathy, features of portal hypertension, skeletal disorders, and hepato-splenomegaly. [Table 1] summarizes the blood tests of value in the diagnostic workup of suspected MDSs.
The next diagnostic approach to suspected MDS includes morphologic studies of peripheral blood film and bone marrow aspirate to evaluate abnormalities of peripheral blood cells and hematopoietic precursors; bone marrow biopsy to assess marrow cellularity, cell morphology and fibrosis; cytogenetic testing to identify clonal chromosomal abnormalities.
Repeated bone marrow examinations are sometimes required to establish the diagnosis and to identify patients with rapid disease progression. Patients might be observed for 3-6 months before repeating bone marrow examination if cytogenetics was normal or nonrevealing and if only unilineage dysplasia is present with no increase in blasts or ring sideroblasts (represent <15% of the erythroid precursors).
Morphology (peripheral blood and bone marrow smears)
It is recommended to follow the World Health Organization (WHO) 2008 classification of myeloid neoplasms for evaluation of morphology and dysplasia in blood and bone marrow.  Counting at least 300 cells in bone marrow smears is recommended. To qualify as significant, the recommended requisite percentage of bone marrow dysplastic cells are ≥10% of the nucleated cells in the lineage under consideration.
Myeloblasts are defined in terms of several nuclear characteristics, including a high nuclear/cytoplasmic ratio, easily visible nucleoli, with or without granules or Auer rods More Details, but no Golgi zone. Myeloblasts in MDS should be classified as agranular (Type I) or granular (Type II). Granular blasts must be distinguished from promyelocytes, the latter having a clearly visible Golgi zone. 
Evaluation of bone marrow smears must include iron staining to evaluate the presence and number of ring sideroblasts. Ring sideroblasts are defined as erythroblasts having a minimum of five siderotic granules covering at least one-third of the nuclear circumference. ,
Note: An increase in white blood cell count with the monocytosis might be seen in chronic myelomonocytic leukemia-1 or -2 when an infection is encountered, and this presentation might be mistaken for acute leukemia transformation especially that the monocytes might look bizarre on blood film. Treatment of the infection will result in resolution of this exaggerated response.
Bone marrow biopsy
A trephine biopsy should be performed in all cases of suspected MDS whenever possible. Bone marrow biopsy is needed to assess marrow cellularity and fibrosis, abnormal localization of immature precursors, blast compartment, and the presence of nonhematologic cells, such as metastases. Immunohistochemistry with antiCD34 (allows the identification of CD34 + blast cells - particularly useful when the aspirate is of suboptimal quality because of bone marrow fibrosis or hypocellularity), antiCD117 and antiCD61 (stains for abnormal megakaryocytes) should be done. An important gene for prognosis in MDS, that is recommended to be stained for in bone marrow samples, is the p53 gene. Almost 85% of cases with p53 mutation can be detected by immunohistochemical stain. If >5% of the cells are p53 positive, then it is a bad prognostic feature and entails shorter survival. 
The best way of estimating cellularity is 100 minus the patient's age. The bone marrow in MDS is usually hyper- or normo-cellular, but in approximately 10% the bone marrow is hypocellular (hypoplastic MDS). , This group needs to be distinguished from aplastic anemia morphologically. An increase in bone marrow CD34 + cells, presence of ring sideroblasts, and dysplasia of either granulocytes or megakaryocytes have been shown to be useful in distinguishing hypoplastic MDS from cases of aplastic anemia. 
A cytogenetic analysis of bone marrow aspirate should be performed in all patients with suspected MDS. Cytogenetic analysis has a major role in determining clonality in patients with suspected MDS. Chromosomal abnormalities are observed in up to 50% of patients with MDS; the most frequent single cytogenetic abnormalities include del (5q), monosomy 7 or del (7q), trisomy 8, and del (20q). ,, At least 20 metaphases should be analyzed whenever possible and described according to most recent International System for Human Cytogenetic Nomenclature recommendations.  The most recent system classifies cytogenetics according to five prognostic subgroups  [Table 2], and this system provided the foundation for the revised international prognostic scoring system (IPSS-R). 
In the case of repeated failure of standard G-banding (absent or poor-quality metaphases) or the setting of a normal metaphase cytogenetics when the clinical suspicion is high for MDS, fluorescence in situ hybridization (FISH) should be done. FISH improves the likelihood of identifying specific gene rearrangements common in MDS. , FISH can be performed on mitotic as well as on interphase cells, which overcomes this limitation of metaphase cytogenetics; thus, it can be quickly performed with high sensitivity and specificity.  When the metaphase cytogenetics is normal or in a situation when divisions have failed to reveal the bands, FISH is recommended to test for 5q, monosomy 7, trisomy 8, 20q, 12p, 4q, and 17p.
High-resolution SNPs can now be applied in karyotypic testing with the advent in microarray technologies. SNP does not depend upon the availability of dividing cells, and consequently can be informative when routine metaphase cytogenetics is not. Due to the higher resolution of SNP array, smaller and previously cryptic deletions and duplications can be detected. A major advantage of SNP over metaphase cytogenetics is the ability to detect copy-neutral loss of heterozygosity, which is caused by uniparental disomy. ,
In a recent study, the combination of metaphase cytogenetics and SNP array karyotyping led to a higher diagnostic yield of chromosomal defects compared with that picked up with metaphase cytogenetics alone, often through detection of novel lesions in patients with normal or noninformative standard cytogenetic results.  Consequently, the concurrent use of SNP array and metaphase cytogenetics in the initial karyotypic testing was shown to affect outcome prediction and improve prognostic stratification of MDS patients.
Acquired somatic mutations have been detected in several genes, including genes that encode signal transduction proteins (CBL, JAK2, KRAS, NRAS, and PTPN11), transcription factors and cofactors (NPM1, RUNX1, and p53) and epigenetic regulators (ASXL1, DNMT3A, EZH2, IDH1, IDH2, and TET2). ,,,,, Recently, mutations in genes encoding for spliceosome components were identified in a high proportion of MDS patients. These genes include SF3B1, SRSF2, U2AF1, and ZRSR2, and SF3A1 [Figure 1].
|Figure 1: Distribution of different molecular markers in myelodysplastic syndromes|
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| Myelodysplastic Syndrome Classification and Scoring Systems|| |
Staging and prognostic scoring systems are important to accurately diagnose, predict outcomes and assist in selecting optimal treatment of MDS patients.  Many scoring systems have been developed and are continuously being refined to become more convenient in evaluating optimal treatments.  The French-American-British (FAB) classification is the oldest scheme for the classification of MDS. It divides MDS into five subtypes based on the bone marrow morphology, including percentage of blasts in the peripheral blood and bone marrow, presence or absence of ring sideroblasts or increased circulating monocytes. 
The WHO classification, which was revised in 2008, is based on the FAB system but better delineates each subtype by adding the criteria of the number of lineages with dysplasia and incorporating a cytogenetic abnormality.  In addition to defining the lower-grade diseases, refractory cytopenia with unilineage dysplasia and RA with ring sideroblasts (RARS) and the addition of a new subtype, refractory cytopenia with multilineage dysplasia, MDS with isolated del (5q) was added. Two subtypes of RA with excess blasts were also recognized. Based on the WHO classification, cytogenetic abnormality pattern, and transfusion requirements, the WHO prognostic scoring system was developed,  which classifies patients into five risk groups [Table 3].
Another scoring system specific for lower risk MDS was established by MD Anderson prognostic scoring system.  Lower risk MDS patients were divided into three risk groups based on age, presence of poor cytogenetics, hemoglobin, platelets, and percent of blasts in the marrow [Table 4].
The IPSS classification was developed in 1997 and it combined clinical, cytogenetic and morphological data in an attempt to improve on previous systems  [Table 5]. The IPSS system assigns scores based on the initial cytogenetics, number of cytopenias and percentage of blasts in bone marrow. The four IPSS risk groups are low risk (score: 0), intermediate-1 risk (score: 0.5-1.0), intermediate-2 risk (score: 1.5-2.0) and high risk (score ≥ 2.5). MDS patients can be stratified into lower risk (corresponding to IPSS low and intermediate-1) and higher risk (corresponding to IPSS intermediate-2 and high).  A new IPSS-R has recently been refined with multiple statistically weighted clinical features used to generate a prognostic categorization model  [Table 6]. Initial cytogenetics, number of cytopenias, and the percentage of blasts in bone marrow remained the basis of the revised system. Changes included: Five rather than three cytogenetic prognostic subgroups with new classifications of a number of less common cytogenetic abnormalities; splitting the low marrow blast percentage in those with <2% blasts and those with 2-4% blasts; and depth of cytopenias. This model defined five rather than the four prognostic categories of the IPSS. Until recently, the most commonly used system is the IPSS. However, IPSS is likely to be replaced by a new IPSS-R and the incorporation of the new molecular markers recently described.
The Working Group stressed that the heterogeneity of MDS strongly withstands a risk-adapted treatment strategy based on the IPSS risk group of patients. The treatment algorithms for MDS patients with low and high IPSS scores are reported in [Figure 2] and [Figure 3].
|Figure 2: Treatment algorithm for patients with lower risk myelodysplastic syndromes. rHuEPO, recombinant human erythropoietin; BM, bone marrow; ATG, antithymocyte globulin; CSA, cyclosporine|
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|Figure 3: Treatment algorithm for patients with higher risk myelodysplastic syndromes. BM, bone marrow; CT, chemotherapy; SCT, stem cell transplantation|
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Adult patients with primary MDS, low IPSS risk, and asymptomatic cytopenia do not need any treatment and should be followed regularly. In addition, patients with intermediate-1 IPSS risk, asymptomatic cytopenia, no blast excess, and no poor-risk cytogenetic abnormality may be followed without specific treatment.  This watchful-waiting strategy might change in the future if safe treatments capable of modifying the natural history of the disease are developed. It must be emphasized that patients should understand that the safety of the watchful-waiting approach is dependent upon regular monitoring. Patients should be regularly monitored for the early recognition of worsening cytopenia (especially transfusion dependence), increasing the number of circulating or bone marrow blasts, and karyotypic evolution.
Hematopoietic growth factors
Patients with IPSS low or intermediate-1 risk, with moderate to severe anemia (hemoglobin below 10 g/dL), serum erythropoietin level below 500 mU/mL, and/or red cell transfusion requirement lower than two red blood cell (RBC) units/month should be considered for therapy with epoetin alfa or beta at an initial dose ranging from 30,000 to 60,000 IU/week. , Those patients who do not respond to epoetin alone after 8 weeks of treatment should be given granulocyte-colony stimulating factor (300 μg/week in 2-3 divided doses) in combination.
Although the scientific evidence on darbepoetin alfa is not comparable to that available for epoetin alfa or beta in terms of number and size of studies, the results suggest that the use of equipotent doses of this agent may result in clinical effects similar to those obtained with epoetin alfa or beta.
The available evidence does not allow any recommendations to be made on the use of thrombopoiesis-stimulating agents (i.e. romiplostim, eltrombopag), which should be restricted to clinical trials.
Red blood cell transfusion and iron chelation therapy
The objective of RBC transfusion therapy is to improve the quality-of-life and to avoid anemia-related symptoms and ischemic organ damage. No single hemoglobin concentration can be recommended as being the optimal level below which red cell support should be given. The decision should be based on the patient's symptoms and comorbidities (especially cardio-vascular risk factors). As a general recommendation, all patients with severe anemia (hemoglobin lower than 8 g/dL) and those with symptomatic milder anemia should receive RBC transfusion. ,
Iron chelation should be considered in transfusion-dependent patients with RA, RARS, or MDS with isolated 5q deletion and a serum ferritin level higher than 1000 ng/mL after approximately 25 units of red cells.  MDS patients who are potentially candidates for allo-stem cell transplantation (SCT) can be considered for appropriate iron chelation therapy prior to the conditioning regimen for transplantation. 
Lenalidomide's development within low-risk MDS patients has been relatively rapid. The first MDS study, MDS-001, a phase I/II clinical trial of 43 patients, 74% of whom were transfusion-dependent at study initiation, and 12 of whom had the 5q deletion abnormality.  Patients received lenalidomide at 10 mg daily, 25 mg daily, or 10 mg daily for 21 days of a 28-day cycle, and 49% had a major erythroid response, 83% of those with 5q deletion. This prompted 2 phase II studies, both for transfusion-dependent, low-risk MDS patients with (MDS-003) or without (MDS-002) 5q deletion. In MDS-003, 148 patients with the 5q deletion were treated with lenalidomide 10 mg daily for 21 or 28 days of a 28-day cycle.  Most (73%) had failed prior erythropoiesis-stimulating agents (ESAs), and 74% had no additional cytogenetic abnormalities. About 67% of patients achieved transfusion independence, with a median duration of response of > 2 years. A complete cytogenetic response was achieved by 45% of evaluable patients. In the MDS-002 study,  26% of patients became transfusion-independent.
On the basis of the available evidence, it is recommended that patients with 5q deletion without additional chromosomal abnormalities or excess blasts, with a low or intermediate-1 IPSS score and transfusion-dependent anemia, who are not candidates for treatment with or have failed a therapeutic trial with hematopoietic growth factors, should be offered lenalidomide.  The recommended dose is 10 mg given for 21 days every 4 weeks. The median time to response is 6 weeks and the dose might be reduced to 5 mg depending on tolerance. Patients with 5q deletion and an intermediate-1 IPSS score due to additional chromosomal abnormalities or an excess of blasts, who are not candidates for treatment with or have failed a therapeutic trial with hematopoietic growth factors, may be offered lenalidomide within a clinical trial.  Patients with 5q deletion, a low or intermediate-1 IPSS score, and evidence of TP53 mutation have a significantly higher risk of transformation to AML, which should be considered in the choice between lenalidomide and alternative therapeutic options. ,
It should be kept in mind that patients treated with lenalidomide are at risk of cytopenias and thromboembolic events. Patients should be monitored for cytopenias, and given thromboprophylaxis with aspirin or low molecular weight heparin. ,
Two pyrimidine nucleoside analogs, 5-azacytidine and decitabine (5-aza-2Ͳ-deoxycytidine), have been extensively investigated in clinical studies of patients with MDS. The literature on the use of these agents includes prospective randomized trials and prospective or retrospective nonrandomized studies. ,, Although the Working Group agreed that it was not possible to draw a definitive conclusion on the use of one drug with respect to the other from the available evidence, the advantage in overall survival reported for azacytidine makes this agent preferable at present. On the basis of this evidence, patients with IPSS intermediate-2 or high-risk disease who are not eligible for AML-like chemotherapy and/or allogeneic SCT should be treated with azacytidine. In addition, fit patients with IPSS intermediate-2 or high-risk MDS and poor-risk cytogenetics who lack a stem cell donor may receive treatment with azacytidine. This agent may also be offered to fit patients without poor-risk cytogenetics who lack a stem cell donor as an alternative to remission induction chemotherapy. The recommended azacitidine starting dose is 75 mg/m 2 injected subcutaneously for 7 days (28-day treatment cycle) for a minimum of 6 cycles.  Treatment should be continued as long as the patient continues to benefit or until disease progression.
Immunosuppressive therapy with antithymocyte globulin (ATG) plus 6 months of oral cyclosporine should be considered in patients younger than age 60 years, with <5% marrow blasts, normal cytogenetics, and transfusion dependency who are not candidates for treatment with or for whom a therapeutic trial with hematopoietic growth factors has failed. , The use of ATG is highly recommended in the presence of a hypoplastic bone marrow with normal cytogenetics or trisomy 8. 
Remission induction chemotherapy
Induction chemotherapy should be considered for fit patients without a suitable donor who are younger than age 65-70 years and have 10% or more bone marrow blasts without adverse cytogenetic characteristics. All patients who achieve complete remission after induction chemotherapy should receive postremission consolidation chemotherapy. 
Allogeneic stem cell transplantation
Recent data suggest that allogeneic SCT is feasible in carefully selected patients older than 60 years of age, with acceptable morbidity and mortality.  Fit patients up to age 65-70 years with IPSS intermediate-2 or high risk and those with IPSS intermediate-1 risk with excess blasts or poor-risk cytogenetics are all candidates for allogeneic SCT.
Cytoreductive (whether intensive or nonintensive) therapy should be administered to those patients with 10% or more bone marrow blasts who are candidates for allogeneic SCT. The use of hypomethylating agents to prepare MDS patients with an excess of marrow blasts for allogeneic SCT has been reported in retrospective studies , and were being tested in clinical trials. In the case of young and fit patients, the evidence available so far does not allow firm recommendation on the use of hypomethylating agents for this purpose. However, in less young and frail patients, hypomethylating agents are increasingly used and may represent an option.
For MDS patients with a contraindication to a standard myeloablative preparative regimen due to comorbidity, reduced-intensity or reduced-toxicity conditioning allogeneic SCT should be considered, preferably within a clinical trial.
| Conclusion and Future Prospective|| |
These guidelines provide practice recommendations for the diagnosis and management of patients with MDS. They are adopted by the SMW based on international practice guidelines and expert opinion.
Myelodysplastic syndrome is a heterogeneous disease and advances in its understanding and treatment modalities are always in progress. The SMW will work on regularly updating these published guidelines based on international recommendations.
| Acknowledgments|| |
This consensus meeting on MDS was sponsored by Algorithm and Celgene.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]