Disease overview: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy.
Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is complementary but not diagnostic.
Risk-stratification: Prognosis of patients with MDS can be calculated 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 commonly used system is the International Prognostic Scoring System (IPSS). IPSS is likely to be replaced by a new revised score (IPSS-R) and by the incorporation of new molecular markers recently described.
Risk-adapted therapy: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-Azacitidine and decitabine have activity in higher risk MDS. 5-Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation.
Myelodysplastic (MDS) comprises a very heterogeneous group of myeloid malignancies with very distinct natural histories [1, 2]. MDS occurs in 3–4 individuals per 105 in the US population . Prevalence increases with age. For instance in individuals age 60 and above, prevalence is 7–35 per 105 . Other series have reported higher rates  but those studies were based on Medicare reporting that is not based on histopathological diagnosis. MDS affects more frequently males than females . Exposure to prior chemo or radiation therapy is a risk for the development of MDS.
MDS is usually suspected by the presence of cytopenia on a routine analysis of peripheral blood. This prompts evaluation of bone marrow cell morphology (aspirate) and cellularity (biopsy). A manual count of bone marrow blasts is fundamental for risk assessment. Cytogenetic analysis helps in predicting risk and in selecting therapy. Once this information is collected, the risk of the patient can be calculated. Currently, the International Prognostic Scoring System (IPSS)  is still the most commonly used score. Natural history and therapeutic decisions are different for patients with lower risk disease (low and INT-1) versus those with higher (INT-2 and high). In lower risk disease, interventions have been traditionally developed to improve transfusion needs; whereas higher risk options have been modeled following therapy of acute myelogenous leukemia (AML) with remission induction being the goal. This concept is being modified by the better understanding of the natural progression of MDS and the development of new therapies. Another important concept is that a large majority of patients with MDS die from causes intrinsic to the disease and not due to progression to AML . This has important implications for the development of therapies in MDS. A revised IPSS score (IPSS-R) was published in 2012 . The new IPSS-R includes a new cytogenetic risk classification of the disease that divides patients into five cytogenetic categories (Fig. 1) . At this point, it is unclear how the IPSS-R is going to be used in clinical practice and in drug development. It should be noted that the latest version of the American NCCN guidelines already include this prognostic model .
The diagnosis of MDS is suspected based on the presence of an abnormal CBC. Diagnosis is confirmed by performing a bone marrow aspiration and biopsy. Both procedures provide different information. The bone marrow aspirate allows for detailed evaluation of cellular morphology and evaluation of percent of blasts. The bone marrow biopsy allows for determination of bone marrow cellularity and architecture. There is some controversy regarding the utility of bone marrow biopsy. In my practice, we treat patients with hypocellular MDS (those with bone marrow cellularity <20–30% depending on age) with specific forms of therapies (immune based approaches) and do not routinely use cytotoxic forms of therapy in that setting. Recently, a prognostic model for patients with hypoplastic MDS has been proposed (Tables 1 and 2) . Therefore, I believe that is fundamental to have access to bone marrow biopsy. Diagnosis is confirmed by the presence of dysplasia. A number of morphological classifications are in place to classify patients with MDS. The most recent one being the 2008 WHO version .
Table 1. A Prognostic Model of Hypoplastic MDS 
Hemoglobin < 10 (g/dl)
Performance status ≥ 2
Bone marrow blast ≥ 5%
Serum LDH > 600 (IU/l)
Table 2. Estimated Survival According to Independent Risk Factors for patients with hypoplastic MDS
A number of additional tests are needed to complete the laboratory evaluation of a patient with MDS. These include analysis of bone marrow cytogenetics. It is well established that cytogenetic patterns are very heterogeneous . As will be discussed below, cytogenetics are of importance to calculate prognosis of patients and in some subsets of patients to select the most effective form therapy. Recently, a new cytogenetic risk classification in MDS has been proposed. These include 5 different subgroups including 20 different alterations (Fig. 1) . Recent data has indicated that cytogenetic patterns are not stable in MDS and that a significant fraction of patients acquired additional cytogenetic changes. This phenomenon is associated with increased risk of transformation to AML and worse survival . This data has implications for the follow up of patients at risk for clonal cytogenetic acquisition.
A number of other assays can be used to help in the diagnosis of MDS. These include the use of flow cytometry and fluorescent in situ hybridization (FISH). Flow cytometry can help in the identification of abnormal phenotypic patterns and can be of help in cases of minimal dysplasia. Because the heterogeneity of cytogenetic alterations in MDS, there is no evidence that a panel of FISH probes could replace routine 20 metaphase cytogenetic analysis. Thus, in my opinion FISH and flow cytometry should not be considered part of the standard work up evaluation procedure of the patient with MDS and should be used in specific situations.
Diagnostic problems in MDS
Because diagnosis of MDS is based on morphological assessment, it can be subjective particularly in patients with early low risk disease. It is calculated that diagnostic discrepancy can occur at the time of initial presentation in 20–30% of patients. At MD Anderson Cancer Center (MDACC) we compared the final MDACC diagnosis with that of the referral center and found a discrepancy of close to 20%. This discrepancy affected 50% of IPSS calculations, usually going from a lower to a higher risk score . This has obvious implications for therapeutic decision making and patient counseling. In general, diagnosis is obvious in patients with excess blasts. The problem is in patients without excess blasts were diagnosis is based on dysplasia. This can affect one line or all of three and can be minimal. Clinical assessment is therefore needed in those patients. The presence of a cytogenetic alteration can also aid in confirming diagnosis. In these cases, it is recommended that other causes of cytopenia be excluded. Routine test include the analysis of anemia and thrombocytopenia, exclude cause of blood loss and inflammatory processes. When suspected, evaluation of GI tract needs to be considered. I recommend GI and gynecological evaluation in all patients referred to our group that are not up to date on their respective screening follow up based on accepted guidelines.
Another subset of patients are those without evidence of dysplasia but with presence of unexplained cytopenia and those with evidence of abnormal karyotype without evidence of dysplasia. These two situations can be encountered in the evaluation of patients with cytopenia. Once other potential causes of cytopenia are excluded, these patients are considered in the subset of idiopathic cytopenia of unknown significance. The natural history of this group of patients is not well known and observation is recommended at this time. Recently, the presence of clonal somatic mutations have been reported in hematopoietic cells from older individuals .
Finally, there are two subsets of patients with overlap features of importance. Those are patients with evidence of a myeloproliferative component (with or without fibrosis) and patients with evidence of a paroximal nocturnal hemoglobinuria (PNH) clone. At this time, we do not fully understand the natural history of patients with MDS/MPN features. In our center, they are currently treated as MDS but studies are ongoing to clarify this issue. Second, although it has been reported that PNH clones can be identified in up to 30% of patients with MDS , in the majority of the patients these are of no significance .
The prognosis of patients with MDS is very heterogeneous and thus the need to develop prognostic systems that allow risk stratification and help in the timing and choice of therapy. Apart from the intrinsic prognostic value of morphological classifications , a number of prognostic scores are currently in use in MDS.
The most commonly used one if the International Prognostics Scoring System (IPSS) . This system has been in place since 1997. The prognostic score includes percent of blasts, number of cytopenias, and cytogenetics. IPSS is of fundamental importance as it has allowed the prognostication of patients over 2 decades. This system is highly reproducible and very simple to use. The system has several limitations that have become evident over the years. The most important one is that it is not a very precise predictor of prognosis in patients with lower risk disease and that it attributes relatively little weight to cytogenetics. A new revised international score (IPSS-R) was published in 2012 . The IPSS-R includes different cut off for cytopenias and incorporates a new cytogenetic score. It is expected that the IPSS-R will be incorporated by most centers until the role of molecular information is better understood in the prognostication of patients with MDS.
Another commonly used system is the WPSS . This system was developed after the realization 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 main limitations of the WPSS are that it requires WHO classification of the disease and requires prior information of 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. Patients with proliferative features and CMML or that have received prior therapy were excluded . To overcome these limitations, the global MDACC model was developed . This model is summarized in Table 3. This model has now been validated by at least one independent group . The importance of the global MDACC model is that allows evaluation of all patients that are considered as MDS at any time during their course of their disease without needed WHO evaluation.
Table 3. The Global MDACC MDS Prognostic Model 
BM: bone marrow; PS: performance status; WBC: white blood cell count.
Patients with 0–4 points had a median survival of 54 months and a 3 year 63% survival. Patients with 5 and 6 points had a median survival of 23–30 months and 3-year survival of 30–40%. Patients with 7–8 points had a median survival of 13 months and a 3-year survival rate of 13–19%. Patients with 9 or more points had a median survival of 5–10 months and a 2% 3-year survival. Adapted from Ref. .
PS ≥ 2
Platelets × 109/L
Hemoglobin <12 g/dL
BM blast (%)
WBC > 20 × 109/L
Alteration of chromosome 7 or ≥ 3 alterations
It has become apparent that the natural history of patients with lower risk disease is very heterogeneous . We evaluated outcomes in a large series of patients with low or int-1 disease by IPSS. We found that expected prognosis varied significantly in patients with lower risk MDS and were able to develop a lower risk MDS specific prognostic score (Tables 4 and 5). This has significant implications for the development of specific interventions for patients with lower risk disease. In the future, and if confirmed, this model will allow identification of patients with poor prognosis lower risk disease that could be candidates for early alloSCT or other therapies. Recently, Bejar et al has presented data confirming the reproducibility of this model and indicating that genetic alterations may be different in “poor prognosis” lower risk patients versus those in a more bening category . This data provides a molecular bases for the identification of this group of patients and very high risk .
Table 4. MDACC MDS Lower Risk Prognostic Model 
Characteristics were selected from multivariate analysis model in patients with lower risk MDS. Each characteristic is associated with a number of points.
Score is calculated by adding all points. Each score allows calculation of median survival (in months) and probability of survival at 4 years. Adapted from Ref. .
MDS occurs in older patients that suffer from comorbidities more frequently. None of the systems discussed above include impact of comorbidity to the calculation of the natural history of MDS patients. To study this issue, we used a comprehensive comorbidity score known as ACE-27in a cohort of 500 patients with MDS . Presence of comorbidity had a significant independent impact on survival and a prognostic score could be developed that included age, IPSS, and ACE-27 score. This data indicates the need to add comorbidity scores in MDS. Recently, other groups have confirmed the importance of comorbidity scores in MDS .
New Cytogenetic and Molecular Data in MDS
Over the last 12 months, a number of very important studies have been published describing comprehensive analysis of the incidence and clinical impact of multiple genetic lesions in MDS . Bejar et al. published an analysis of 18 genes using different techniques on 439 patients . Frequency of mutations is shown in Table 6 and distribution of mutational events in Fig. 2. This data confirmed prior reports of individual gene distributions  and demonstrated that addition of molecular information has significant impact on our ability to prognosticate patients with MDS and potentially in selecting therapy. For instance, it has been reported that patients with TET2 mutations may have higher response rates to azacitidine than those without mutation . This has very significant practical implications because is going to require that centers develop clinical assays to test for these genes using next generation sequencing techniques. These are not widely available at most centers. Recently, a number of mutations in genes involved in regulation of DNA splice have been described in MDS . The clinical implications of this new subgroup of mutations have been recently described . Recently, European consortium has reported an analysis of mutations in 111 genes using next generation sequencing technology in a cohort of 738 patients . This data will be summarized once full access to paper is available. This effort and that of other centers ongoing using whole genome sequencing approaches should clarify the role of genomic alterations in the prognosis and management of patients with MDS.
Table 6. Reported Frequency of Genetic Lesions in MDS [27, 29, 80, 81]
Control of cytosine hydroxymethylation
Polycomb group protein
Cell metabolism, epigenetic regulation
Cell cycle control
Risk adapted therapy
Currently, we still use IPSS to decide the choice of therapy for an individual patient. Below is a summary of options and recommendations for specific subsets of patients . A treatment algorithm is shown in Fig. 3. Once IPSS-R becomes an accepted tool, it is likely that this algorithm will be modified.
Options for newly diagnosed patients with lower risk MDS
Therapy in this subset of patients is based on the transfusion needs of the patients. Patients that are transfusion independent are usually observed until they become transfusion dependent. Below is a list of agents currently available for patients with lower risk MDS. A new important concept in lower risk MDS is the idea of early intervention in patients with “poor prognosis” lower risk MDS. The identification of these patients is going to be fundamental to improve on the natural history of the disease. The development of new molecular information and prognostic score for these patients is going to allow this.
Erythroid growth factor support
The use of erythroid stimulating agents (ESA) is common practice in the community . It should be noted that no randomized study has ever proven than this intervention positively affects the natural history of patients with MDS. A number of ESAs are available. Reported response rates range from 30 to 60% depending on study . Data from the Swedish group has indicated that addition of G-CSF to erythropoietin increases responses rates and in a retrospective observational study that early introduction of this combination in patients with low risk disease and minimally transfusion dependent patients may have an impact of survival . This group has also developed an algorithm to predict response to ESA . The French group has also evaluated the impact of ESA on survival in a retrospective study of 284 patients and compared it to the group of patients that formed the IPSS cohort . In this study, patients exposed to ESA had a better survival (HR for death was 0.43, 95% CI 0.25–0.72) . Recent questions on potential tumorigenic effect of these drugs has resulted in increased scrutiny of their use. G-CSF is not approved by the FDA for patients with anemia of MDS.
I believe that a course of ESA with or without G-CSF is not contraindicated in most patients with low risk MDS and significant anemia without other cytopenia. Data indicates that early incorporation of these agents is more effective than in patients with heavy transfusion burdens. I maintain therapy for at least 3 months to judge efficacy. In responding patients, I continue therapy until transfusion effect is lost. Recent data on the results with romiplostin, questions its use in patients with lower risk MDS, particularly due to complications related to disease transformation and marrow fibrosis. A number of studies are now evaluating eltrombopag in MDS, another TPO agonist, but results are not known at this point.
Lenalidomide is approved in the US for patients with lower risk MDS, anemia and alteration of chromosome 5 . It should be noted that this compound was also recently approved in Europe. Initial phase I study of lenalidomide indicated that a potential group of patients, described above, benefitted significantly from therapy . This was confirmed in a subsequent phase II study of lenalidomide in patients with anemia and alteration of chromosome 5 . In that study 148 patients received 10 mg of lenalidomide for 21 days every 4 weeks or daily. Of those, 112 had decrease need for transfusions (76%; 95% CI 68–82) and 99 patients (67%; 95% CI, 59–74) became transfusion independent. Response was fast: median time 4.6 weeks. The median rise of hemoglobin was 5.4 g/dL. Of interest, cytogenetic responses were observed in close to 50% informative patients. Predictors of response included presence of a platelet count of 100 × 109/L and <4 prior units of red cells transfused. It should be noted that in this study patients with a platelet count of less than 50 × 109/L were excluded.
In a parallel study, lenalidomide was investigated in patients without chromosome 5 alterations . In this study, 214 patients received 10 mg oral lenalidomide daily or 10 mg on days 1 to 21 of a 28-day cycle. Fifty six (26%) patients achieved transfusion independence after a median of 4.8 weeks of therapy. Median response duration was 41.0 weeks. Lenalidomide is not approved for this indication now.
It should be noted that 2 large randomized phase III clinical trials have been conducted in MDS. One known as AZA-004 has completed accrual and studied two different doses of lenalidomide (5 and 10 mg orally daily) versus placebo. This study was also designed to clarify the issue of transformation to AML. This study reported that a dose of 10 mg daily was superior and that there was no increase incidence of transformation to AML in patients treated with lenalidomide . Another phase III is studying the role of lenalidomide in patients with lower risk disease without an alteration of chromosome 5. Results are still pending at this point. Of importance, a recent report from the initial MDS-003 trial of lenalidomide has indicated a longer survival for patients responding to therapy . This is the first evidence that lenalidomide can change the natural history of patients with 5q-MDS.
The degree of response in patients with lower risk MDS, anemia, good platelets, and del5q makes standard of care in my opinion. This is further reinforced by the recent data on survival in responding patients . I do not consider this agent in patients with thrombocytopenia. No recommendation can be made for patients without an alteration of chromosome 5 now. It is likely that a subset of patients with anemia, low risk disease, and diploid cytogenetics could also benefit from this compound. This is being tested in a large phase III trial mention above.
Two azanuclesoides are approved for MDS: 5-azacitidine  and 5-aza-2′-deoxycitidine (decitabine) . 5-azacitidine is approved for all subsets of MDS whereas decitabine for those with INT-1 disease and above. There is very little data in the use of these compounds in lower risk MDS. None of them have been shown to modify the natural history of patients with lower risk disease.
Different schedules of 5-azacitidine have been explored in MDS. In a community study a 5 day schedule was compared to a 7 day 5-2-2 schedule (weekend off) or a 5-2-5 schedule of 10 days . Fifty patients were assigned to each arm (except 5-2-2 was 51 patients). Most patients had lower risk disease. Hematologic improvement was achieved by 44–56% of patients in each arm. Transfusion independency was documented in 50 to 64% of patients. There was a trend for better response rates and less toxicity with the 5-day schedule of 5-azacitidine. Therefore it is reasonable to use a shorter (5 day schedule) of 5-azacitidine in lower risk MDS. The results of a phase 1 trial of an oral derivative of azacitidine were recently published . Oral azacitidine is currently being tested in an international phase III trial in patients with lower risk MDS and significant cytopenias (NCT01566695).
There is very little data with decitabine in patients with lower risk disease. In the initial randomized trial of decitabine , 31 patients with INT-1 disease were treated. Four of 28 patients achieved some type of response. A randomized phase II trial has been conducted exploring a 3-day subcutaneous schedule versus a weekly × 3 monthly schedules. This study did not find significant differences between both arms, although it declare the daily × 3 schedule an initial winner. Low dose decitabine used in this fashion was associated with close to 60% trilineage transfusion independence with minimal hematopoietic toxicity .
Both 5-azacitidine and decitabine are used in patients with lower risk disease that are transfusion dependent. Most patients treated with these agents have failed or were not candidates for growth factor support or lenalidomide. Further studies of these agents in lower risk MDS are needed. An oral formulation of 5-azacitidine is being studied for patients with lower risk MDS . Lower dose of azacitidine or decitabine can be considered for these patients.
This is an area of controversy. It is accepted that a subset of patients with MDS are characterized by deregulation of immunity [16, 47]. This could explain that features of bone marrow failure that are present in a significant fraction of patients. Based on this it will be logical that the use if immmunemodulatory agents could have therapeutic benefit in MDS. The group at the NIH has pioneered these approaches. Agents studied include antithymocyte globulin (ATG), cyclosporine, steroids. These therapies have been modeled after therapy of aplastic anemia . The group at the NIH has also developed an algorithm to predict response to this classes of agents . These include younger age, HLA-DR15, and shorter duration of transfusion dependency. Using this algorithm, the NIH group has recently reported that alemtuzumab, an antibody against CD52, has significant activity in patients with MDS predicted to response to immune suppressive therapy . Recently, the group at Moffitt Cancer Center has suggested that a CD4/CD8 ratio could be used to predict response . Our group has not been capable to reproduce the data discussed above. Response rates with ATG observed at MDACC are significantly lower than those of the NIH. The most important predictor for response has been the presence of marrow hypocellularity . This is in line of the results of Mufti et al. in London .
Also recently, the impact of this interventions on survival has been questioned. Data from a Swiss study comparing ATG versus supportive care indicated a higher response rate but no survival benefit . In this study, patients were randomized to a combination of horse ATG with cyclosporine versus best supportive care (BSC). Forty-five patients received ATG + CSA and 43 patients received BSC. By month 6, 13, of 45 patients on ATG + CSA had a hematologic response compared with four of 43 patients on BSC (P = 0.0156). Despite higher response rates, no significant effect on survival or transformation was observed.
Recently, the group of the NIH has reported on the clinical activity of eltrombopag in patients with aplastic anemia as salvage therapy . This data was of importance because responses could be multilineage and not just restricted to platelets. A number of studies are investigating this agent in MDS.
This is a particular difficult group of patients. Outcomes in older individuals are not affected by the use of ATG and most patients are treated with some form of supportive care that could include cyclosporine, growth factors, and steroids. Most older patients cannot tolerate this type of approach. The impact of it is not known either. In younger patients with severe hypoplastic MDS, allogeneic stem cell transplantation (alloSCT) should be considered as soon as possible. For those that are not candidates, a combination with equine ATG is recommended. I cannot recommend the use of alemtuzumab at the present time until more data from other clinical trials is reported. The data on eltrombopag is of interest.
Allogeneic stem cell transplantation
AlloSCT is usually not recommended in patients with lower risk disease even if they are young. This is based on data from Cutler et al using a Markov model . The explanation for this effect is based on the expected long survival of this subset of patients. The anticipated early mortality with alloSCT cannot be overcome by the potential beneficial survival effect in relation to survival expectation without therapy. This concept was confirmed by Koreth et al. at recently (Fig. 4) . Using a Markov model, the investigators analyzed the impact of reduced intensity transplant in older patients with MDS. Patients with lower risk disease did not appear to benefit from this less toxic transplant approach .
I generally do not recommend alloSCT in patients with lower risk disease at initial presentation. That said because of time required for donor identification, I refer all potential candidate patients for a transplant consult in anticipation of future needs. Patients that are candidates for alloSCT and that had been exposed to multiple therapies (growth factors, lenalidomide, azanuclesoides, etc.) should be considered for transplantation. These patients are also candidates for clinical trials. Patients with hypoplastic MDS that are young should be considered for alloSCT up front.
Supportive care measures in MDS
A number of interventions can be used in patients with MDS. These include the use of prophylactic antibiotics and iron chelation. No randomized data exists to make formal recommendation for any of these interventions. In my experience, patients with isolated neutropenia and MDS are not at significantly increased risk of infection to support recommendation of prophylactic antibiotics.
The role of iron chelation in MDS is more complicated. Data from thalassemia indicates that iron chelation has an important role in this setting. Iron accumulation is frequent in MDS. The consequences of this are not fully understood in MDS. I do not see in my practice patients with liver cirrhosis or cardiomyopathy as reported by other groups . Iron accumulation could have a role in transformation to AML  and increased infectious complications. The NCCN guidelines recommend the use of chelation therapy in patients with ferritin levels above 2500 ng/ml . A large phase III (NCT00940602) study is evaluating the role of iron chelation in MDS.
I do not routinely recommend antibiotics in patients with isolated neutropenia and MDS that are not receiving some form of cytotoxic or immunosuppressive therapy. I use iron chelation in patients with ferritin levels in excess of 2500 ng/ml but I consider all these patients for a clinical trial of iron chelation.
Options for newly diagnosed patients with higher risk MDS
Options for patients with higher risk MDS have evolved significantly over the last decade. Before that period most patients were treated with some of cytarabine based therapy modeled after AML. The used of azanucleosides has modified this practice(2).
Decitabine was studied in an initial randomized comparing it to BSC . In this study, the dose of decitabine was 15 mg/m2 IV infused over 3 hr every 8 hr for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks. Although there was no clear benefit in terms of survival in this study, the use of decitabine was associated with a complete response rate of 9% and overall response rate of 17%. These results led to the approval of decitabine in the US. Based on the results of a phase I trial of decitabine performed at MDACC, a Bayesian randomized phase II trial of three different doses and schedules of decitabine was conducted . In this study a 5-day schedule of decitabine administered daily at a dose of 20 mg/m2 was shown to be superior to a 10-day or subcutaneous schedule. A multicenter phase II trial of decitabine (ADOPT) using the 5-day schedule confirmed the safety of this schedule although response rates were significantly lower than those reported by the MDACC . In the ADOPT study the median number of courses administered was 5, the CR rate was 17% and the median survival was 19.4 months. No randomized survival study of a 5-day schedule of decitabine has been conducted in MDS. In parallel with this work, European investigators developed a randomized study of decitabine using the initial 3-day schedule. The major objective of the study was survival. Unfortunately, use of decitabine at this dose and schedule was not associated with improved survival in patients with higher risk MDS . Despite all this data, the final dose and schedule of decitabine is not fully understood. Recently, Blum et al have indicated that a 10-day schedule of decitabine has significant activity in AML .
5-Azacitidine has been studied in higher-risk MDS in two major randomized multicenter trials: CALGB 9221  and AZA-001 . In the CALGB 9221  study, 191 patients with MDS were randomized between 5-azacitidine (75 mg/m2/day for 7 consecutive days every 28 days) and BSC. Median age was 68 years. Sixty percent of the patients in the 5-azacitidine group, compared with 5% of control arm patients, responded to treatment (P < 0.0001). The median time to leukemic transformation or death was 21 months in patients treated with 5-azacitidine versus 12 months in the BSC arm (P = 0.007). No significant difference in survival was observed. A landmark analysis suggested a survival advantage for patients initially on 5-azacitidine or who had crossed-over to 5-azacitidine within 6 months of inclusion on study (P = 0.03). A significant improvement in quality of life was documented in patients treated with 5-azacitidine compared to BSC . AZA-001 was a randomized study designed to test the concept that treatment with 5-azacitidine resulted in improved survival compared with a menu of standard of care options . These included BSC, low dose cytarabine (ara-C) or AML-like therapy. In AZA-001, 358 patients with higher-risk MDS were randomized to either 5-azacitidine (as per CALGB9221 schedule) or to standard of care. Median age of patients was 69 years. Median survival was significantly better in patients treated with 5-azacitidine versus standard of care options: 24.5 months versus 15 months (P = 0.0001). Progression to AML was significantly delayed, and RBC transfusion requirements and rate of infections were significantly improved with 5-azacitidine. The survival advantage with 5-azacitidine was irrespective of age (including patients older than 75 years), percent of marrow blasts (including patients with 20–30% blasts, now classified as AML using WHO criteria) or karyotype. This effect was significant when compared to BSC and low dose ara-C. The number of patients treated with AML-like therapy was too small to allow comparison with 5-azacitidine.
Because 5-azacitidine has become the standard of care in front line higher risk MDS, a number of studies are being conducted to test the concept that combinations of 5-azacitidine with histone deacetylase inhibitors [67, 68] or lenalidomide are superior to single agent 5-azacitidine. An Intergroup study is comparing 5-azacitidine versus the combination with vorinostat or lenalidomide (NCT01522976). Another study of interest is exploring the combination of azacitidine and pracinostat (NCT01873703) a second generation HDAC inhibitor. This combination was associated with very high rate of response, both morphological and cytogenetically, in a small pilot trial (unpublished).
Biomarkers of response to azanucleosides
An area of active research is the identification of biomarkers predictive of response to azanucleosides. Due to their capacity to induce DNA hypomethylation, a number of groups have focused in the identification of methylation patterns that would predict for response. Now no such profile exists. Two candidate biomarkers and a clinical model have been recently proposed. Levels of miR29b  and mutations on TET2  have been reported to be associated with response to decitabine and azacitidine, respectively. miR29b regulates expression levels of DNMT1 . TET2 is a protein involved in the conversion of 5mC to 5OHmC and could therefore result in passive induction of DNA methylation . None of these two biomarkers have been confirmed in other larger studies. Our group was not able to correlate miRNA29b levels with response . Recently, the French group reported that previous low dose ara-C, bone marrow blasts >15% and abnormal karyotype predicted for lower response rate to 5-azacitidine . Poor performance status, intermediate and poor risk cytogenetics, circulating blasts, and more than four units of red blood cells transfuse every 8 weeks were associated with worse survival . In the near future, a combination of genetic and clinical markers could be used to define who may benefit from this type of therapy. The incorporation of new molecular markers are going to have a profound impact on our ability to prognosticate and select therapy for patients with MDS.
The azanucleosides are the standard of care for most patients with higher risk disease. No study has compared 5-azacitidine versus decitabine. Although response rates appear to be similar, only 5-azacitidine has been associated with improvement of survival in a randomized trial. Based on this, I consider 5-azacitidine standard therapy for front line treatment in higher risk MDS. The combinations are still investigational and should not be used outside the setting of a clinical trial.
AML-like protocols in higher risk MDS have generally used classical anthracycline-araC combinations similar to those used in de novo AML [73, 74]. When used in MDS or AML post-MDS, AML-like therapy results in lower CR rates (40–60%), shorter CR duration (median duration of 10–12 months) and tend to be associated with more prolonged periods of aplasia. In addition, the feasibility of AML-like therapy is also reduced by the advanced median age of patients with MDS. The most important prognostic factor of response to AML-like therapy is karyotype: patients with unfavorable karyotype (−7/del 7q or complex karyotype) have a low CR rate and short duration of response. This is of importance as, at least in the AZA-001 study , patients with alterations of chromosome 7 had a significant benefit with 5-azacitidine versus other therapies. Currently, AML-like therapy is only recommended for relatively younger patients with favorable karyotype that are candidates for alloSCT.
The randomized AZA-001 study was not powered to demonstrate the superiority of 5-azacitidine versus AML-like therapy. The reason for this being that most investigators did not consider their patients candidates for such therapy. Therefore, the question is who may be a candidate for AML therapy. In our practice, this is restricted to younger patients with a high likelihood of response to the therapy, such as diploid patients. I rarely use AML therapy in older patients or in those with poor risk cytogenetics.
AlloSCT is reported to be the only curative treatment of higher-risk MDS. Results from selected studies report prolonged DFS in about 30–50% of the patients . However, its use is mainly restricted to younger patients with an appropriate donor. Different transplant modalities of different intensities and donor sources are now in use. Most of them remain investigational and therefore in my opinion all patients should be transplanted in the setting of a clinical trial. Current advances in transplant technology are allowing the consideration of older patients and alternative donors. This should result in greater number of older patients benefitting from this potentially curative treatment modality. There are several relevant practical questions regarding alloSCT in MDS. These include timing of transplant; and what to do with patients that achieved a complete response to hypomethylating agent prior to alloSCT. A study from the IBMTR indicated that early transplantation in higher-risk MDS was associated with longer life expectancy [55, 56] (Fig. 4). This study was performed before the mature use of hypomethylating agents. Although data suggests longer survival with SCT in patients with higher risk disease, it should be noted that curves cross close to 3 years after initiation of therapy. It will important to identify how are this long term survivors that benefit the most from transplant. A retrospective study of the IBMTR is comparing azanucleosides use with transplant in MDS. In terms of what to do in responding patients, no recommendation can be given at this time. Other questions include whether or not alloSCT should be preceded by a cytoreductive regimen (with chemotherapy or perhaps hypomethylating agents). Many authors consider that when marrow blasts > 10% at the time of transplant, because of the very high relapse risk post transplant, pretransplant therapy is required. A recent report from the EBMTR has indicated that long-term survival of patients with monosomy 7 is very poor with alloSCT . Although this data needs to be validated in more recent series, these results have significant implications for the use of alloSCT in MDS, as this suggests that the current practice of reserving transplant for poor prognostic features may not be indicated. Recent data indicates that the use of hypomethylating agents, either before or after transplantation, can improve results particularly in patients at higher risk for relapse post transplantation .
All patients, potential candidates for alloSCT should be counseled regarding the possibilities of undergoing alloSCT. Optimally, patients will be enrolled in an MDS specific clinical trial of alloSCT. A national study to study this issue is being developed. I consider the use of lower doses of 5-azacitidine in patients at high risk for relapse post transplantation.
Options for patients with relapsed or refractory lower risk MDS
Treatment of patients with relapsed or refractory lower risk MDS is sequential. A common practice is to start growth factor support and then consider lenalidomide or an azanucleoside. Patients that fail either lenalidomide or azanucleoside are candidates for clinical trials or alloSCT. A number of agents are being studied including a MAPKinase inhibitor known as ARRAY614 (NCT00916227).
Options for patients with relapsed or refractory higher risk MDS
At the present time there is no therapy approved for patients with higher risk MDS that fail hypomethylating agents or relapsed after AML-like therapy or alloSCT. The group of patients that failed hypomethylating agents has particularly poor prognosis. In a study from MDACC in patients that had received and responded to decitabine, median survival was 4 months . This has now been confirmed by several groups. In general outcomes were very poor and patients become refractory to alternate azanucleoside. Only patients that received alloSCT had a meaningful outcome. This is an area of active research that is complicated by lack of understanding of what are the mechanisms of resistance to azanucleoside agent. A large phase III study with ON1910  (NCT01241500) was completed in 2013 and results are expected next year.
All patients with higher risk disease that have relapsed or refractory disease should be considered for alloSCT and for clinical trial.