Laboratory and clinical risk assessment to treat myelodysplatic syndromes

Introduction

Myelodisplastic syndromes (MDS) are a group of clonal myeloid disorders characterized by progressive cytopenia due to ineffective hematopoiesis, with a variable risk of transformation into acute myeloid leukemia (AML) [1, 2].

The incidence of MDS is estimated to be around five cases per 100,000 people per year in the general population, but after 60 years it increases up to 50 cases per 100,000 people per year. Typically MDS affect elderly people (median age at diagnosis of 65–70 years), while they occur in <10% of patients under 50 years of age [3]. The annual incidence of MDS increases logarithmically after 20 years of age, from <1.0 per million persons to 20 per 100,000 persons in septuagenarians. Males are affected approximately 1.5 times as often as females. The incidence is widely distributed with no ethnic differences, but in the Asian population MDS occur at an earlier age, as compared to the Western population [3].

MDS are generally suspected in the presence of cytopenia on routine analysis of peripheral blood, which triggers bone marrow evaluation. The evaluation of bone marrow cells morphology and cellularity generally shows hypercellular bone marrow, with variable grades of dysplasia, with or without immature blood cells. Parameters such as the percentage of blasts in the bone marrow, the number of cell lines involved in peripheral cytopenia, and karyotype abnormalities can significantly affect the natural course of the disease and its prognosis [4]. The International Prognostic Scoring System (IPSS) on the basis of the above mentioned parameters identifies four risk groups of patients with different prognosis: low, intermediate-1, intermediate-2, and high risk [5]. The median overall survival of MDS intermediate-2 or high-risk patients is 1.2 and 0.4 years, respectively; these patients are at high risk of developing AML, which means that the aim of the treatment is to modify the natural history of the disease and extend survival. Over the years more accurate prognostic scores, including an evaluation of transfusion requirement and assessment of patients’ comorbidities, have been developed, in order to obtain a deeper risk assessment to guide treatment in MDS patients [5–12].

The available therapies range from the treatment of symptomatic cytopenias in the low-risk group of MDS patients, to immunomodulatory agents, chemotherapy or allogenic stem cell transplantation in high-risk patients. The aim of this article is to review the role of oldest and newer laboratory assays in association with clinical and hematological parameters in stratifying the risk of MDS patients.

Materials and methods

We reviewed the medical literature for published studies evaluating “Myelodysplastic syndromes and risk assessment, and laboratory evaluation and Therapy and Prognosis”. The PubMed electronic database was searched without temporal limits using an English language restriction. The key words used were: myelodysplastic syndromes, risk assessment, laboratory evaluation, therapy and prognosis. References of most recent papers on myelodysplastic syndromes were also cross-referenced to identify potentially relevant papers not captured in our initial literature search. Data of pediatric patients are not considered in the present paper. Search terms were also applied to abstracts from the latest international hematological and oncological congresses.

The reference lists of the trials as well as articles were reviewed for additional publications.

When there was duplication of publications, we reviewed each article and included only the most recent or the complete version of the trial for analysis. In situations in which there was a discrepancy in the data, we considered the safety report from the most recent package insert to be the most accurate and used that report instead of the original publication for our review article.

Clinical and laboratory diagnosis

MDS patients complain about symptoms which are usually consistent with the type and severity of the peripheral blood cytopenias. They commonly report fatigue and decreased exercise tolerance due to anemia. Less often, patients show bleeding, easy bruisability, or recurrent bacterial infections as initial complaint [4]. Hepatomegaly or splenomegaly occur in approximately 5 or 10% of patients, respectively.

Variants of myelodysplastic syndromes

Risk stratification

The prognostic score based on the French American British (FAB) classification called IPSS includes percentage of blasts, number of cytopenias, and cytogenetics [5]. This system is highly reproducible and very simple to use. In order to overcome the main limitation of the system (imprecise predictor of prognosis in low-risk patients) a new scoring system called IPSS-R has been developed [7]. Bone marrow cytogenetics, bone marrow blast percentage, and cytopenias remain the basis of the new system but novel components are included (five rather than three cytogenetic prognostic subgroups, splitting the low bone marrow blast percentage value and depth of cytopenias). This model defined five rather than the four major prognostic categories that are present in the IPSS. The WHO classification-based prognostic scoring system (WPSS) represents another commonly used scoring system [8]. This system was developed when it was clear that red cell transfusion dependency is an independent predictor of prognosis in MDS. This system was also developed as time-dependent model, meaning that it can be used sequentially at any time during the course of the disease. The WPSS requires WHO classification of the disease and prior information on transfusion needs. Recently, the WPSS score was modified to include hemoglobin levels instead of transfusion needs. Both the IPSS and WPSS were developed in a very specific subset of patients: newly diagnosed patients at the time of initial presentation. Recently the global MD Anderson Cancer Centre (MDACC) model was developed [9]. Poor performance, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (≥3) abnormalities and prior transfusions are considered the main predictors of prognosis in MDS patients in a multivariate analysis of prognostic factors. The new MDS prognostic model divided patients into four prognostic groups with significantly different outcomes. The model was found applicable to any patient with MDS at any time during the course of MDS. Low-risk MDS patients are challenging due to their heterogeneous prognosis which does not allow to distinguish between longer survival patients and those with intermediate outcome. In a study enrolling 600 MDS patients, the assessment of comorbidities performed with the adult comorbidity evaluation showed that patients with severe diseases had 50% lower survival than did those without co-morbidities, independently of age and IPSS risk group [10]. The impact of comorbidities on prognosis of MDS has been largely underlined also by other groups [11].

Amongst other prognostic factors, age is an important predictor of poor prognosis and bone-marrow fibrosis has been shown to be independently associated with poorer prognosis, in both lower-risk and higher-risk MDS patients [28]. Recurrent mutations in genes encoding components of the splicing machinery, including SF3B1, SRSF2, U2AF1, and ZRSR2, have also been reported in myelodysplastic syndromes [29, 30] SF3B1 mutations are strictly linked with ring sideroblastic subtypes of myelodysplastic syndromes; directly contributing to formation of ringed sideroblasts and abnormal iron retention. Furthermore, SF3B1 mutations seem to be predictors of favorable clinical outcome [31].

Somatic mutations also strongly affect survival. The presence of any of the mutations TP53, RUNX1, EZH2, or ETV6 worsens outcome, independently of IPSS [32, 33]. ASXL1 and SRSF2 mutations are also associated with a poorer outcome according to the literature [33, 34]. These genes can be divided into four main groups: (1) transcription factors (TP53, RUNX1, ETV6); (2) epigenetic regulators and chromatin-remodeling factors (TET2, DNMT3A, ASXL1, EZH2, IDH1/2); (3) pre-mRNA splicing factors (SF3B1, SRSF2, U2AF1, ZRSR2); and (4) signaling molecules (NRAS, CBL, JAK2, SETBP1). The most frequently mutated genes were TET2, SF3B1, ASXL1, DNMT3A, SRSF2, RUNX1, TP53, U2AF1, EZH2, ZRSR2, STAG2, CBL and NRAS, although no single mutated gene was found in more than a third of patients. Several of these gene mutations are associated with adverse clinical features, such as complex karyotypes (TP53), excess bone marrow blast proportion (RUNX1, NRAS, and TP53) and severe thrombocytopenia (RUNX1, NRAS, and TP53). Despite associations with clinical features considered by prognostic scoring systems, mutations in several genes hold independent prognostic value as shown in Table 4. Mutations of TP53, EZH2, ETV6, RUNX1, and ASXL1 have been shown to predict decreased OS in multivariable models adjusted for IPSS or IPSS-R risk groups in several studies. Within IPSS risk groups, a mutation in one or more of these genes identifies patients whose risk resembles that of patients in the next highest IPSS risk group (e.g. the survival curve for INT-1-risk patients with an adverse gene mutation was similar to that of patients assigned to the INT-2-risk group by the IPSS) [35].

When applied to patients stratified by the IPSS-R, the presence of a mutation in one or more of these five genes was associated with shorter OS for patients in the low- and intermediate-risk groups. Other mutated genes have been associated with decreased OS, including DNMT3A, U2AF1, SRSF2, CBL, PRPF8, SETBP1, and KRAS.

Mutations of SF3B1 have been associated with a more favorable prognosis, but this may not be an independent risk factor.

For example, SF3B1 mutated patients are likely to present reduced hemoglobin levels leading to a higher transfusion dependence, while patients harboring SRSF2 mutations clustered in RAEB-1 and RAEB-2 subtypes and had pronounced thrombocytopenias [36]. Table 4 reports the frequency of genetic mutations in MDS [4, 27, 30, 34–38].

Hyperferritininemia and high levels of lactate dehydrogenase are associated with poorer prognosis and higher cardiac or extra hematological mortality [39].

The introduction of new therapies that can modify the clinical course of MDS revealed new factors able to predict the response to these treatments, in addition to the traditional ones.

For example, patients with low levels of blood erythropoietin (EPO) respond better to erythroid stimulating agents (ESA) and an early resistance to ESA seems to be associated with a worse outcome [39–41]. Response to hypomethylating agents can be predicted by performance status, karyotype, erythrocyte transfusion requirements, presence of circulating immature bone marrow elements or TP53 mutations [42, 43]. Although screening for such molecular defects on a routine basis cannot currently be recommended, the spread of massive genotyping technology will allow clinicians to detect a broad range of genetic aberrations in peripheral blood at a reasonable cost in the near future, making it easier to confirm the diagnosis in patients with suspected MDS.

Treatment strategies

In the recent years, despite the improvement of treatment strategies, MDS remain challenging diseases. New drugs such as lenalidomide, demethylating agents and iron chelators, helped slowing the natural history of the disease and improving the quality of life of patients who are not eligible for transplantation [44, 45]. Many factors make identification of an univocal treatment strategy in MDS patients very difficult. First of all, MDS are a heterogeneous group of hematological diseases, with different clinical and prognostic features but they are all linked by a clonal disorder of stem cells, ineffective haematopoiesis and a variable risk of transformation into AML. In addition, the complexity of cytogenetic and molecular abnormalities (except for 5q-) does not allow to identify targeted therapies. Most patients with MDS are old and affected by many comorbidities, therefore less able to tolerate aggressive therapies. Some patients with MDS may have prolonged survival; older patients with low-grade myelodysplasia may be more likely to die of illnesses other than MDS.

Establishing the prognosis for patients with MDS is a key step of their management. In fact, possible benefit from therapy has to be carefully balanced against the risks of complications. Treatment for myelodysplasia has to be highly individualized. An accurate estimate of prognosis drives decisions about timing and choice of the therapeutic options. In low-risk and unfit patients control of symptoms is the primary goal of therapy. In younger or healthier patients with high-risk MDS aggressive therapy in attempt to achieve cure might be warranted.

Treatment strategies in low-risk/intermediate-1 MDS (IPSS), very low, low, intermediate MDS (IPSS-R), very low, low, intermediate MDS (WPSS)

The approach for treatment of low-risk MDS is aimed at correcting cytopenias. Chronic anemia adversely affects the quality of life of MDS patients and the clinical course of disease while transfusion dependence leads to reduced survival [46, 47]. Erythropoietic stimulating agents (ESAs) increase the hemoglobin level in approximately 15%–25% of MDS patients. The multivariate analysis in several studies confirmed that predictive factors of major erythroid response after treatment with ESAs were baseline serum levels of EPO <100 IU/L, favorable cytogenetics, low number of blasts, no or low transfusion requirement [46–48]. Anti-apoptotic effects on erythroid progenitors are probably the most important mechanism of action of ESAs. However, in responding patients the median duration of response is only approximately 2 years [47]. A recent study from our group has shown that biosimilar epoetin-α is effective for the treatment of anemia in MDS patients with comparable efficacy to that of other ESAs [49]. Several studies have shown that ESAs have no effects on the risk of progression to AML [50–52].

In non-responding MDS patients there is some evidence that adding low-dose granulocyte colony stimulating factors (G-CSFs) has a synergistic effect with erythropoiesis stimulating agents (ESAs) [48, 53, 54]. No randomized study has shown improvement in survival for patients with MDS treated with epoetin-α plus G-CSF and further randomized trials are needed to optimize dosing. Greenberg et al. [48] showed that combination of G-CSFs (initial dose 1 μg/kg per day SQ) plus epoetin-α (150–300 units/kg per day SQ) results in a substantial erythroid response (i.e. decreased transfusion requirements and increased hemoglobin concentrations) in approximately 40%–47% of patients.

Lenalidomide directly acts on del5q- clones, inducing hematopoiesis and erythropoiesis stimulation, whereas other effects including immunomodulation, anti-inflammatory activity, and angiogenesis inhibition [55, 56] are similar to those of thalidomide. Based on this evidence lenalidomide has been licensed in the USA and in Europe for transfusion-dependent anemia in MDS patients with documented 5q-abnormality. Cytogenetic responses are reported in 50%–70% of the treated population [57–59]. List et al. [60] showed that lenalidomide was effective in inducing an erythroid response as well as reversing cytological and cytogenetic abnormalities in 148 MDS patients with del5q31 and transfusion-dependency. The response to lenalidomide was rapid and long-lasting, and the median duration of transfusion independence had not been reached after a median of 104 weeks of follow-up. Moderate-to-severe neutropenia (in 55% of the patients) and thrombocytopenia (in 44%) were the most frequent reasons for interrupting treatment or adjusting the dose of lenalidomide. Fenaux et al. [56] carried out a randomized double-blind study of the efficacy and safety of lenalidomide in 205 patients with MDS who were RBC transfusion-dependent and at IPSS low-risk or intermediate-1 risk and carried del5q31. The researchers concluded that lenalidomide is beneficial and has an acceptable safety profile in transfusion-dependent 5q- patients who were with low to intermediate-1-risk. Lenalidomide reverses transfusion dependence in 25%–30% of lower-risk MDS patients resistant to ESAs [56] but it is not approved for this indication outside clinical trials. Preliminary results suggest that the combination of lenalidomide and ESAs can lead to high rates of independence from erythrocyte transfusion in patients resistant to ESAs alone [61, 62]. Treatment of anemia in patients resistant to ESAs (or lenalidomide in patients with deleted 5q) or after relapse remains challenging [21]. Hypomethylating agents in low risk MDS patients [63] are effective and are shown to lead to transfusion independence in about 40% of patients. However, despite these treatments, many low-risk MDS patients eventually need erythrocyte transfusion to control anemia.

In selected younger patients with low-risk MDS, with limited erythrocyte transfusion history, normal karyotype (or possibly trisomy 8), no excess marrow blasts or HLA DR15 genotype, no deleted 5q, limited exposure to previous treatments, and possibly hypocellular marrow, antithymocyte globulins, with or without ciclosporin, can be used to obtain an erythroid response, with response of other cytopenias (especially thrombocytopenia) in 25%–40% of MDS patients [64–67].

The experience gained with thalassemic patients suggests the use of chelation therapy in patients with MDS undergoing transfusion therapy for which prolonged life expectancy is not already affected by leukemic transformation. In lower-risk myelodysplastic patients, receiving more than 20–40 red-blood-cell concentrates, or when serum ferritin rises over 1000 ng/mL [68], iron chelation therapy is considered, in order to prevent iron overload. However, clinically significant iron overload associated with heart failure is quite frequent in MDS patients, especially when elderly, receiving 100 or more red blood cell concentrates. Other papers suggest that potential benefits of iron chelation should be lowering of infection risk, improvement of the outcome of allogeneic hematopoietic stem cell transplantation and delay of leukemic transformation [69]. Deferasirox, an oral iron chelator, has shown efficacy and acceptable tolerability in MDS setting and has also been shown to improve peripheral cytopenia in 10%–20% of MDS patients [70, 71]. However, desferasirox has a potential renal toxicity and is contraindicated in patients with renal failure. According to literature data, we suggest a starting dose of 10–20 mg/kg/per day with dose escalation up to 40 mg/kg. Young MDS patients suitable for bone marrow transplantation need to be especially controlled for iron overload. Several studies have shown that iron overload can affect the outcome of bone marrow transplantation [72–74].

Although MDS patients have a high incidence of infection due to neutropenia and granulocyte dysfunction and infection is the principal cause of death in patients with MDS, the use of granulocyte-colony stimulating factors (G-CSFs) [75–77] or granulocyte macrophage colony stimulating factors (GM-CSFs) [78–80] in efficacy trials, including randomized trials, has been disappointing. Antibiotics are indicated for bacterial infections, but no routine prophylaxis is recommended (with the exception of patients with recurrent infections).

Severe bleeding is a rare problem in low-risk MDS patients and platelet counts below 50×10⁹ cell/L are generally observed in 30%–50% of patients. Rarely and only in advanced stages MDS patients require repeated platelet transfusions. The current availability of thrombopoietin-receptor agonists romiplostim and eltrombopag approved for therapy of autoimmune thrombocytopenia suggested their use in the setting of MDS patients [81–83]. The development of myeloid malignancies is a concern when administering thrombopoietin receptor agonists. Among 168 MDS subjects treated with romiplostim, progression from MDS to AML was observed in 10 (6%) patients [84]. In another clinical trial a transient increase in bone marrow blasts has been reported in 15% [79]. In conclusion thrombopoietin mimetics should be considered in the setting of MDS patients with bleeding due to low platelet counts who do not respond to transfusions. Further studies to evaluate their safety in the setting of MDS patients with thrombocytopenia are ongoing. Figure 1 summarizes the therapeutic approach to this risk class of patients.

Figure 1:

Therapeutic strategies for the treatment of myelodysplastic syndromes.

Treatment strategies for patients with myelodisplastic syndromes according to the International prognostic scoring system (IPSS), WHO Prognostic Scoring System (WPSS) and Revised IPSS (R-IPSS). Anemic very low and low-intermediate myelodisplastic (MDS) patients carrying del 5q should be treated with lenalidomide in order to reduce transfusion request and to obtain cytogenetic response. Lenalidomide should be avoided in patients with a clinically significant decrease in neutophils or platelet count. Although the cost of lenalidomide is higher than that of other treatments, the reduction in the number of transfusions and in transfusion dependence partially offsets the expense. Symptomatic patients with no del(5q) or patients not responding to lenalidomide should be treated according to endogenous levels of eritropoietin (Epo) with erytropoietic stimulating agents (ESAs), eventually associated with granulocyte colony stimulating factors (G-CSFs). Non responding patients should be treated with immusuppressive therapy or with anti-timocytes globulin (ATG) or cyclosporine. Allo hematopoietic stem cell transplantation (allo-HSCT) should be considered in selected fit patients affected by intermediate-1 myelodysplastic syndromes. In selected patients carrying high levels of endogenous Epo who are unlikely to respond to ESAs immunosuppressive therapy should be considered. For patients with poor probability to respond to immunosuppressive therapy alternative therapies with Azacytidine/Decitidine/Lenalidomide should be considered. Red blood cell (leuko-reduced) transfusions are recommended for symptomatic anemia. Platelet transfusions are recommended for thrombocytopenic bleeding. However, they should not be used routinely in patients with thrombocytopenia in the absence of bleeding unless platelet count is <10,000/mm³. Irradiated products are suggested for transplant candidates. If >20 to 30 red blood cells transfusions have been received, consider daily chelation with deferoxamine subcutaneously or deferasirox orally to decrease iron overload, particularly for low/intermediate-1 and for potential transplant patients. Patients with low creatinine clearance (<40 mL/min) should not be treated with deferasirox. IPSS, International Prognostic Scoring System; WPSS, World Health Organization Prognostic Scoring System; IPSS-R, Revised IPSS; EPO, erythropoietin; ATG, anti timocytes globulins; allo HSCT, allo hematopoietic stem cell transplantation; MDS, myelodisplastic syndromes.

Treatment strategies in intermediate-2 high-risk MDS (IPSS), intermediate high, very high-risk MDS (IPSS-R)

The median overall survival of MDS intermediate-2 or high-risk patients is 1.2 and 0.4 years, respectively; these patients show high risk of developing AML, which means that the aim of the treatment is to modify the natural history of the disease and extend survival [3].

Allogeneic bone marrow transplant (BMT)

Allogeneic bone marrow transplant (BMT) represents the only potentially curative therapy for MDS. Unfortunately, the use of allogeneic BMT for MDS is limited by the older age of most patients and by the fact that only a minority of patients has histocompatible bone marrow donors. However, the use of allogeneic BMT is being extended to older patients, and the use of a national bone marrow donor registry has allowed matched unrelated transplants. Several trials treating MDS with allogeneic BMT have been performed; ~40% of patients in these trials have long-term disease-free survival and may be cured [93]. Patients with MDS show high transplant-related mortality rates (~30% to 35%) due to infections, graft-vs.-host disease and multi organ failure [94]. It is now generally accepted that AlloSCT with myeloablative conditioning is generally indicated only in few patients with MDS while for most other patients, particularly older patients, a reduced-intensity transplant can be still offered from an HLA-identical donor [95]. Different transplant modalities of different intensities and donor sources are now active. Most of them are still investigational. There are several relevant concerns regarding AlloSCT in MDS. These include timing of transplant and choice of the best approach for patients that achieved a complete response to hypomethylating agents prior to AlloSCT. A study from the International Blood and Bone Marrow Transplant Registry (IBMTR) indicated that early transplantation in higher-risk MDS patients was associated with better outcome [96].

Due to the observation that blast percentage before transplantation (especially if >10%) is clinically associated with higher risk of relapse [97], a cytoreductive regimen (chemotherapy or hypomethylating agents) are generally administered to patients with excess of blasts. Prospective studies on the topic are lacking to drive definitive conclusions.

Regarding the timing of BMT, both in younger higher-risk patients treated with myeloablative conditioning transplantation and in older patients receiving non-myeloablative regimens, early stem-cell transplantation was associated with a survival advantage compared with other therapeutic options [97, 98]. By contrast, early stem-cell transplantation had an adverse effect on survival in lower-risk patients [96, 97].

The evolution of transplantation techniques, today characterized by a better control of graft-vs.-host disease (GVHD) and infectious complications, the consequent increased availability of unrelated donors with the use of peripheral blood stem cells and the overall lower toxicity of the transplant have extended the availability of this procedure to patients older than 60 years if clinically fit [99].

There is no consensus regarding the optimal treatment of patients with intermediate-1 IPSS and intermediate IPSS-R risk and this remains a burning issue in the treatment of MDS patients. Patients who want to focus on quality rather than quantity of remaining years may favor supportive care and hypomethylating agents. In contrast, more intensive chemotherapy with or without transplantation may be chosen by younger, fit patients who prefer to deal with the higher risk of treatment-related mortality and morbidity in order to achieve an increase in survival. The possible role of hypomethylating agents as a bridge therapy to bone marrow transplantation is under consideration. Treatment with hypomethylating agents may delay progression to AML before HSCT. Such a strategy is especially relevant for MDS patients with intermediate-2 or high-risk IPSS disease, for whom the average time to AML progression may be short [100].

Figure 2 summarizes the approach to treatment in these subgroups of patients.

Figure 2:

Treatment strategies for patients with myelodysplastic syndromes according to the International Prognostic Scoring System (IPSS), WHO Prognostic Scoring System (WPSS) and Revised IPSS (R-IPSS).

Intermediate-2, high or very high risk myelodysplastic patients have different treatment strategies based on patients’ characteristics and their elegibility for high intensity therapy. If they are candidate to bone marrow transplant and a donor is available, patients should be treated with allo hematopoietic stem cell transplantation. A bridging therapy should be considered in order to decrease marrow blasts to an acceptable level prior to transplant. High intensity chemotherapy (only in selected fit patients) or azacytdine/decitabine treatment should be considered for fit patients eligible for high intensity chemotherapy. Not high intensity therapy candidates should be treated with azacytdine/decitabine. Supportive care or clinical trials should be considered for non-responding or relapsing patients. IPSS, International Prognostic Scoring System; WPSS, World Health Organization Prognostic Scoring System; IPSS-R, Revised IPSS; allo HSCT, allo hematopoietic stem cell transplantation.

Conclusions and future directions

The central problem with MDS is their heterogeneity. MDS are a heterogeneous group of hematological diseases, with different clinical and prognostic features. The MDS are challenging for clinicians and pathologists due to the clinicopathologic heterogeneity of the disease and overlapping features with other benign and malignant disorders. Currently, the initial evaluation of a patient with suspected MDS focuses on a detailed medical history, review of the peripheral blood and bone marrow by an expert hematopathologist and risk stratification using laboratory results, morphology and cytogenetics. More sophisticated technologies, including multi-color flow cytometry, FISH, next-generation sequencing, and others are emerging and promise to offer significant refinements in diagnostic, prognostic and, hopefully, therapeutic information.

Since MDS range from indolent conditions with a long natural history to subtypes analogous to AML, clinical decision-making concerning treatment modalities and timing of interventions is challenging. Currently the prognosis of patients with MDS can be predicted using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most common used system was IPSS and tends to shift to IPSS-R. Although parameters such as hemoglobin level, blast count, and high-risk cytogenetic abnormalities will continue to retain strong independent prognostic value, the current era of genomics will provide us with additional parameters including new molecular markers, which may significantly contribute to a refined risk assessment of MDS and allow us to move towards a more patient-tailored therapeutic approach. Newer technologies with next-generation targeted deep sequencing and whole-genome and -exone sequencing have identified several recurrent mutations that play a pivotal role in the pathophysiology of MDS and the impact of these genetic changes on disease phenotype.

In recent years, several gene mutations have been identified among patients with MDS that may, at least partly, explain the clinical heterogeneity of the disease course and may influence prognosis. A large variety of gene mutations will be present in most patients with newly diagnosed MDS, including most patients with normal cytogenetics. Several studies examining large numbers of MDS bone marrow or peripheral blood samples have identified more than 40 recurrently mutated genes, with more than 80% of patients harboring at least one mutation.

Thus, the combined analysis of these gene mutations and the IPSS or IPSS-R may improve the risk stratification provided by these prognostic models alone.

Future molecular analysis could predict not only the risk of disease, but also the response to therapy allowing a molecular based tailored therapy. Other important goals include the determination of the clinical impact of all these mutations on response to therapy and MDS patients’ survival in large cohorts of patients. With the introduction of more sophisticated molecular techniques like gene expression profiling, it might become possible not only to predict the natural course of the disease, but also to identify patient populations that are prone to respond to specific drugs especially designed for specific genetic lesions. Sequencing-based studies suggest that multiple mutations may play a role in the progression of MDS to AML. Further work is necessary to understand the molecular basis of leukemic transformation in MDS syndromes.