Chapter 5: Myelodysplastic Syndromes: The MD Anderson Cancer Center Approach

Myelodysplastic syndromes (MDS) refer to a group of hematopoietic disorders characterized by ineffective hematopoiesis and increased risk of transformation to acute myelogenous leukemia (AML). Most patients with MDS succumb to causes related to the disease. The median age of patients with MDS is 70 to 75 years. It is likely that environmental factors play an important role in the pathogenesis of this disease. Myelodysplastic syndromes are classified according to the World Health Organization (WHO) criteria, and a number of prognostic scores can be used to calculate survival and risk of transformation. Cytogenetic, genomic, and epigenetic alterations are common in MDS and help in the prediction of prognosis and potentially in the selection of therapy. Over the last decade, we have witnessed significant improvements in supportive care and therapeutic modalities for patients with MDS. These include growth factors, immune modulatory agents (lenalidomide), and hypomethylating agents (5-azacitidine and decitabine). We also better understand patient subgroups, such as those with hypomethylating failure disease. In this chapter, we summarize our knowledge of MDS and the treatment approach we use at MD Anderson Cancer Center.

Every year, approximately 350 to 400 patients are referred to our center with a diagnosis of MDS. Nearly 20% of patients referred with a diagnosis of MDS receive a different diagnosis in our center. In most instances, the final diagnosis is that of AML or a form of higher-risk MDS. Other benign and malignant conditions can also be observed. In a study of 915 patients referred between 2005 and 2009 and using very strict criteria, 12% were reclassified when initially evaluated here (¹). This justifies our practice to repeat a confirmatory bone marrow aspiration and biopsy at the time of initial MDS evaluation at MD Anderson.

Once the diagnosis is confirmed, the next important step is to calculate the “risk” of the patient. Most clinicians and investigators still use the International Prognostic Scoring System (IPSS) (²) score to perform such analysis, but newer potentially more precise models, such as the Revised International Prognostic Scoring System (IPSS-R), have been developed (^3,4,5). In general, patients with low or intermediate-1 risk by the IPSS or those with less than 10% blasts in the bone marrow are considered as having “lower” risk disease, whereas those with excess blasts or intermediate-2 or high-risk disease are considered as having “higher” risk disease.

Patients with lower risk disease can be candidates for a wide range of interventions, depending on their specific characteristics and transfusion needs. Patients with minimal cytopenias, who are transfusion independent, who have a low percentage of blasts in the bone marrow, and have diploid cytogenetics are more frequently observed, as their 4-year survival is close to 80% (⁴). At the end of the spectrum, older patients with significant cytopenias and transfusion needs can have very poor prognosis, particularly if their cytogenetics are abnormal (⁴). The median survival of these patients is less than 12 months; around 60% to 70% of patients with MDS are in this category, but there are few interventions known to alter the natural history of these patients. Transfusion and growth factor support are usually started. Interventions such as lenalidomide have significant activity in improving red cell counts in patients with deletion of chromosome 5 (⁶) but are significantly less active in patients without this alteration (⁷). The role of the hypomethylating agents 5-azacitidine or decitabine is less clear in this situation, although they are frequently used. Allogeneic stem cell transplantation (alloSCT) is not frequently used up front in patients with lower risk disease (⁸). It is currently accepted that delaying transplantation until the time of progression is associated with longer survival even if transplant outcomes are poorer when performed at that time. A new subset of patients has emerged that is constituted by patients with lower risk disease but with hypomethylating failure. We recently described their natural history (⁹). New investigational strategies are needed for this subset of patients.

Treatment decisions are relatively simpler for patients with higher risk MDS. The data with the hypomethylating agents indicate that treatment with these agents improves survival significantly when compared to supportive care or low-dose chemotherapy approaches. The optimal approach for younger (those less than 60 to 65 years) patients with MDS is unclear. These patients can be treated with hypomethylating agents or an AML-like induction therapy or can be considered for up-front alloSCT. No study has compared these treatments in younger patients. An approach followed by our group is to stratify patients based on cytogenetics. Younger patients with normal karyotype are usually offered induction therapy with an AML-like approach followed when possible by alloSCT. In contrast, younger patients with abnormal karyotypes are offered hypomethylating agent-based therapy followed by alloSCT. It is not our routine to proceed with transplant up front in patients with excess blasts. Older patients benefit significantly from the use of hypomethylating agents, and there is basically no upper age limit that may contraindicate their use (¹⁰). Finally, the group of patients with higher risk disease and hypomethylating failure constitute a major medical need (¹¹).

A comprehensive review of current knowledge in MDS is provided next. Current areas of intense research are the development of newer forms of therapy for patients with newly diagnosed disease and strategies for patients who have relapsed or not responded to hypomethylating agent-based therapy.

The incidence of MDS increases with age. Most patients diagnosed with this condition are more than 60 years old; the median age at diagnosis is 75 years (¹²). The incidence is higher in males than females, with a 2:1 ratio (¹²). The incidence in the United States is 30 to 35 individuals per million per year with a relative yearly increase in the reported incidence, probably related to increase awareness of the disease and reporting efforts (¹³).

The risk of developing MDS is related to the individual's racial background. In the United States, the incidence is highest in the white population (¹²). Patients with MDS from Asia present at a younger age (¹⁴). The underlying cause of this phenomenon is not known but may reflect genetic differences between different racial groups. Asian patients have a similar frequency of karyotype abnormality as European and American cohorts, although they may have less frequent alterations of chromosomes 5 and 7 (^14,15,16). The combination of younger age at diagnosis and lack of chromosome 7 alterations can explain the longer survival observed in patients from Asia.

There is no known cause of MDS. Genetic or environmental risk factors may contribute to MDS. Genetic syndromes, such as Down syndrome, Bloom syndrome, and Fanconi anemia, are associated with an increased risk of MDS, which often presents earlier in life (^17,18). Genetic polymorphisms that influence the activity of enzymes responsible for metabolizing toxic chemicals or chemotherapy drugs may influence an individual's predisposition to MDS. Polymorphisms have been described in the cytochrome p450 3A, glutathione-S-transferase, and NAD(P)H quinine oxidoreductase enzyme systems that increase the risk of developing myeloid malignancy (^19,20,21).

Environmental agents may contribute to the development of MDS by causing toxic damage to hematopoietic stem cells. A causal relationship between occupational exposures to benzene and radiation and the development of myeloid malignancy has been demonstrated (²²). Exposure to organic solvents and pesticides has also been implicated in the development of MDS (^23,24,25). There is no correlation between MDS and socioeconomic status (²⁴).

The most significant risk factor for the development of MDS is previous exposure to chemotherapy or radiotherapy used to treat other cancers. Treatment-related MDS (t-MDS) constitutes a minority of MDS diagnoses but may be increasing in prevalence with improved survival rates after successful cancer therapies for tumors. Usually, t-MDS presents 5 to 6 years after initial cancer treatment and generally has a poor prognosis (²⁶). Patients treated for lymphoma are at risk of this long-term complication (²⁷). Patients who undergo autologous hematopoietic stem cell transplantation have a higher risk (10%-15%) of developing treatment-related MDS or AML, with incidence rates in some centers of up to 10% (²⁸). In our experience with t-MDS at MD Anderson in 281 patients, most of the risk was associated with complex cytogenetics or presence and alteration of chromosome 7 (²⁹).

Most patients with MDS are diagnosed incidentally during routine complete blood cell count (CBC) analysis or because of nonspecific symptoms. Anemia is the most common cytopenia in MDS and is associated with fatigue. A lower percentage of patients presents with bleeding or bruising secondary to thrombocytopenia or with infections related to neutropenia. Physical examination is often normal. Hepatosplenomegaly may be present in patients with chronic myelomonocytic leukemia (CMML) or overlap myeloproliferative neoplasms. A change in the severity of cytopenia or rapid worsening of symptoms may indicate disease transformation. Patients suspected to have MDS transformation require prompt investigation because 20% to 30% of patients will develop acute leukemia throughout their disease course (²).

Initial assessment should include a CBC, reticulocyte count, and serum chemistry, including evaluation of B₁₂ and folate, iron studies (ferritin), and erythropoietin level examination. Other causes of cytopenias or MDS-mimicking syndromes (eg, HIV [human immunodeficiency virus], other infections, autoimmune disorders, or copper deficiency) should be ruled out through appropriate tests. A bone marrow aspirate and biopsy with samples taken for an iron stain and cytogenetic studies are required. Morphological assessment of the disease is still required for MDS. Cytogenetic studies may confirm the presence of clonal hematopoiesis and provide additional important prognostic information. Analysis of specific gene mutations, such as TET2, DNMT3A, ASXL1, TP53, splicing factors, NRAS, FLT-3, IDH1, IDH2, and JAK2 may improve our prognostic and predictive evaluation and may in time allow for the use of targeted interventions using selective inhibitors (eg, FLT3, JAK2, or IDH1/2 inhibitors) or allow earlier consideration of alloSCT. However, it should also be noted that these molecular abnormalities (³⁰) may be present in older individuals with or without cytopenias and may not necessarily point to an MDS diagnosis (^31,32). In general, no patient should be diagnosed as having MDS without knowledge of the clinical and drug history or while on growth factor therapy, including erythropoietin.

Morphological classification of MDS is based on a 500-cell differential count on the bone marrow aspirate and leukocyte differential performed on the blood smear (³³). Table 5-1 shows the different subsets of MDS under the newly revised WHO MDS classification. This analysis determines the percentage of blasts present in the blood and bone marrow and provides an assessment of the number of myeloid lineages involved in the dysplastic process, and the iron stain determines the presence and number of ring sideroblasts (Fig. 5-1) (³³).

Blood cell abnormalities on the peripheral blood smear are variable (³³) (see Fig. 5-1). Red cells may be macrocytic and frequently display anisopoikilocytosis. Polychromasia or basophilic stippling may be present. Dysplastic granulocytes may show abnormal folding of the nucleus, and cytoplasmic granules are often reduced or absent. Platelets are of variable size and may also be hypogranular. The presence of circulating blast cells or an excess of monocytes is important for the classification of high-risk MDS and CMML, respectively.

Definitive diagnosis requires a bone marrow aspirate and biopsy. The bone marrow is usually normocellular or hypercellular, reflecting that hematopoiesis is ineffective. Abnormal maturation of hematopoietic cells results in a variable proportion of myeloblasts that are significantly increased in the more aggressive MDS. Morphological abnormalities found in the nucleus of erythroblasts include nuclear budding, internuclear bridging, karyorrhexis, multinuclearity, and megaloblastoid changes (see Fig. 5-1). Cytoplasmic features include the presence of ring sideroblasts and abnormal vacuolization. Abnormal or absent granulation is a common feature of dysplastic granulocyte series. Aberrant nuclear folding of the neutrophil precursor can produce a dysplastic bilobed nucleus, the pseudo–Pelger-Huet anomaly. Megakaryocytes may have a very variable morphology, and a small dysplastic form called the micromegakaryocyte is a typical finding. A normal megakaryocyte has a polyploid nucleus that can be altered with dysplasia to produce hypolobulation or nuclei that are dispersed throughout the cell. The bone marrow biopsy provides the best assessment of the overall cellularity and allows examination of the architecture of the marrow and surrounding bone (Fig. 5-2). The presence of fibrosis can be assessed on biopsy with specific stains for reticulin and collagen. In normal bone marrow, the immature blast cells are frequently located near the endosteal surface. In MDS, these cells may be distant to this site and form aberrant clusters referred to as abnormal localization of immature precursors (ALIP). Immunohistochemical staining of biopsies can aid diagnosis, with CD34 staining to identify blast and progenitor cells and CD42 or CD62 for quantitation and assessment of megakaryocytes (³⁴) (see Fig. 5-2).

Nonclonal diseases may cause dysplastic morphological changes in blood cells. Secondary causes of dysplasia should be excluded in the initial assessment and can potentially complicate the diagnosis. Blood cell dysplasia is seen with exposure to heavy metals or antituberculous therapies, B₁₂ and folate deficiency, HIV infection, excessive alcohol consumption (³³), and occasionally normal aging (³⁵). Dysplastic features are commonly observed after chemotherapy or with the therapeutic use of granulocyte colony-stimulating factor (G-CSF). These diagnoses should be assessed in the history and may require exclusion with further laboratory testing. Diagnostic difficulties may occur in patients with marked hypocellularity of the bone marrow and in patients with prominent fibrosis as there are often very few cells in the aspirate sample to allow morphological assessment of dysplasia. For patients with prominent hypocellularity of the marrow, it may be difficult to distinguish from aplastic anemia, for which morphological dysplasia of the erythroid lineage may also be observed. In cases of marked fibrosis, bone marrow aspiration is often unsuccessful. Some patients with mild dysplastic changes in the bone marrow and a diploid karyotype may be difficult to definitively diagnose at initial presentation and may require a period of observation to confirm the underlying diagnosis. These patients require review with repeat investigations performed in 3 to 6 months.

A cytogenetic abnormality is found in 40% to 50% of patients with primary MDS and lower risk disease; it is higher in patients with more advanced MDS. Cytogenetic analysis of hematopoietic cells derived from the bone marrow aspirate provides important prognostic and predictive information and may direct therapy (eg, lenalidomide therapy with deletion 5q or earlier alloSCT with complex or adverse karyotypes). A karyotypic abnormality provides evidence for the presence of a clonal blood disorder, which may be particularly important if the morphological changes are not clear. Typically, cytogenetic analysis will assess 20 bone marrow metaphases (³⁴). Multiple different cytogenetic abnormalities have been described (³⁶). These are summarized in Table 5-2. No specific cytogenetic abnormalities characterize MDS. Unlike AML and chronic myeloid leukemia, genetic translocations are rare in MDS, but deletions are common.

The presence or absence of a cytogenetic abnormality has a marked influence on prognosis (³⁶). Median survival of patients with normal karyotypes is approximately 53 months, compared to less than 12 months for patients with three or more cytogenetic abnormalities (complex). Del(5q) and del(20q) are associated with a favorable prognosis. However, when these abnormalities are present in association with other cytogenetic abnormalities, especially as a component of a complex karyotype, the prognosis is poor. Abnormalities of chromosome 7, usually deletions, are associated with poor prognosis regardless of the presence or absence of other abnormalities. Complex cytogenetic abnormalities are more frequently observed in patients with increased marrow blasts. A progressively worse prognosis is observed with increasing complexity. Patients with six or more abnormalities have a very poor median survival of 5 months (³⁶). In 2012, a new comprehensive scoring cytogenetic system was developed using data from 2,902 patients (³⁷). This analysis resulted in 19 new cytogenetic categories and 5 prognostic subgroups (Fig. 5-3). This scoring system serves as the basis for the IPSS-R (⁵).

Treatment-related MDS has a particularly high incidence of cytogenetic abnormalities, with karyotypic changes observed in 70% to 90% of cases (^26,29,36). A high incidence of abnormalities is associated with an unfavorable prognosis for this group of patients. Abnormalities of chromosomes 5 and 7 are frequently observed after exposure to alkylating agents (^38,39). Translocations involving 11q23 are seen after treatment with topoisomerase II inhibitors (³⁸).

The high frequency of chromosomal deletions has prompted interest in the identification of epigenetic repressive alterations, such as aberrant DNA methylation in MDS. Aberrant DNA methylation of multiple promoter CpG islands has been associated with poor prognosis in MDS (⁴⁰). At this point, we do not have evidence of specific molecular pathways that are epigenetically inactivated in MDS.

An association between a genetic abnormality and disease phenotype was reported in a few specific subsets of MDS. An example is the 5q- syndrome. A minority of patients with an interstitial deletion of chromosome 5q display an indolent anemia with relative preservation of the platelet count associated with hypolobated megakaryocytes in the bone marrow. This array of findings is called the 5q- syndrome (⁴¹) and is recognized as a separate diagnostic entity in the current WHO classification. The genetic defect within the deleted region that is responsible for the disease is not known. Research has focused on one candidate gene, SPARC, that may potentially contribute to the malignant phenotype (⁴²). CTNNA1 is another gene on chromosome 5q identified to be important in MDS and AML but without specific features of the 5q- syndrome (⁴³). Ebert et al. reported the identification of RPS14 as haploinsufficient in 5q- MDS. RPS14 is involved in ribosomal biogenesis, and its deficiency has a role in anemia in this syndrome (⁴⁴). It is likely that a complex network of genes cooperate in the pathogenesis of this syndrome. Indeed, microRNA 145 and 146a have been found to be involved in the biology of 5q- syndrome (⁴⁵).

A small number of patients have been described with a deletion of 17p associated with abnormalities in the p53 gene. This specific disorder has a poor prognosis and may be suspected when morphological characteristics of prominent dysgranulopoiesis, including neutrophils exhibiting the Pelger-Huet anomaly and abnormal vacuolization, are present (⁴⁶). Acquired hemoglobin H disease produces red cell changes on the blood smear reminiscent of α-thalassemia. This red cell phenotype is secondary to decreased expression of α-globin within the bone marrow MDS clone and is associated with a mutation in the ATRX gene in most cases (⁴⁷). These rare syndromes represent a small minority of patients with MDS, and specific gene defects are not identified in most patients.

Several groups have used large-scale single-nucleotide polymorphism (SNP) arrays in MDS (⁴⁸). This has allowed the identification of areas of microdeletions and uniparenteral disomy in MDS (⁴⁹). It is likely that these genomic regions harbor genes important in MDS, such as c-CBL (⁵⁰). Over the last 5 years, we have accumulated significant information regarding genomic alterations in MDS (^30,51). The data are summarized in Fig. 5-4 from a study reported by a consortium of European investigators (⁵¹). Common mutations affect genes involved in gene splicing, epigenetic regulators (eg, TET2, DNMT3A, ASXL1, and EZH2), and other pathways, such as TP53. The presence of mutations in TP53 and EZH2 is associated with poor prognosis (³⁰). A recent analysis correlated specific genomic alterations with gene expression patterns that may explain some of the phenotypic features of the disease (⁵²).

Flow cytometry is not required for the routine diagnosis of MDS, but it may sometimes provide valuable supplementary information. Flow cytometry can confirm the presence of specific myeloid lineages within the marrow and may also identify aberrant expression of cell surface markers indicative of a clonal cell population. This may have diagnostic significance in confirming abnormal hematopoiesis, particularly in the setting of inconclusive morphological changes and a normal karyotype. Quantitation of the number of CD34-positive cells in the bone marrow may assist in the differentiation of hypoplastic MDS from aplastic anemia. In MDS, the number of CD34 cells is usually normal or increased, compared to aplastic anemia, for which it is frequently reduced (⁵³).

Fluorescent in situ hybridization (FISH) techniques using probes specific for specific chromosomes (ie, covering chromosomes 5, 7, 8, 20) have not been fully standardized in MDS. Their use should not be consider standard of care in MDS and cannot yet replace conventional cytogenetics.

The classification systems used to group different MDS have evolved over time with increased understanding of the biology and genetics of the disease. The first widely accepted classification was that proposed by the French-American-British (FAB) study group (⁵⁴). The FAB categorized MDS primarily on the percentage of blasts in the peripheral blood and bone marrow, with disease entities defined by increased numbers of blasts associated with a more aggressive clinical course. Patients with a bone marrow blast percentage greater than 30% were considered to have acute myeloid leukemia. This classification used only morphological criteria to define disease groups and provided a framework that allowed the study of the natural history of MDS and its response to therapy.

The WHO classification of MDS was developed with the objective of using all features of disease biology, including morphology, cytogenetics, immunophenotype, and clinical behavior (⁵⁵). This classification was updated in 2008 (⁵⁶) (see Table 5-1). Figure 5-5 shows an algorithm for the morphological diagnosis of MDS. In the original WHO classification, the importance of morphological assessment of blast percentage within the bone marrow and peripheral blood was retained, although the threshold level for the diagnosis of acute leukemia was altered. Patients with more than 20% bone marrow blasts were considered to have AML. Patients with 20% to 29% blasts had a similar prognosis as patients with greater than 30% blasts. Within the WHO MDS categories with an increased blast percentage, the magnitude of the blast elevation was quantified between refractory anemia with excess blasts (RAEB) types 1 and 2, reflecting the worse prognosis of patients with an elevated blast count (²). In patients with a normal proportion of blast cells within the bone marrow, the relatively indolent refractory anemia (RA) and RA with ring sideroblasts (RARS) introduced in the FAB system were further delineated by assessment for the presence of multilineage dysplasia. Patients with dysplastic maturation limited to the erythroid lineage have a more favorable prognosis than patients with cytopenia and dysplasia present in multiple myeloid lineages. Also, WHO introduced the 5q- syndrome as a separate diagnostic entity primarily on the basis of a genetic abnormality rather than morphological features alone. Deletions involving chromosome 5q are relatively common in MDS, and the WHO classification tightly defined the syndrome as an isolated del(5q) associated with anemia, a preserved or increased platelet count, and hypolobated megakaryocytes on the bone marrow biopsy (Fig. 5-6). The WHO classification has been validated by a number of independent groups (^57,58). The most recent WHO classification (⁵⁶) included the following changes: (1) specific guidelines for the requirement of specimen collection and blast and blast lineage assessment, as well as for the analysis of genetic alterations; (2) an effort to report new changes in the diagnosis and classification of MDS/MPN; (3) inclusion of patients with cytopenias but not clear morphological evidence of MDS in the bone marrow as presumptive MDS; (4) inclusion of refractory cytopenia with unilineage dysplasia; and (5) disappearance of the category of refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS) (⁵⁶).

The prognosis of patients with MDS is heterogeneous. The development of clinical systems that allow accurate prognostication of individual patients into low- and high-risk categories has proven essential to guide rational management decisions and allow the introduction of investigational drug protocols. The IPSS (²) is the most widely used system for assessment of prognosis and treatment planning. It provides an assessment of the prognosis of patients with primary MDS at the time of initial diagnosis. It was designed by the retrospective analysis of a large pool of 816 patients with MDS and followed the natural history of the disease to determine important factors related to patient outcome. Overall survival and the risk of transformation to acute leukemia were related to the number of blood cytopenias, the percentage of myeloblasts in the bone marrow, and the presence of specific cytogenetic abnormalities. The risk associated with cytogenetic abnormalities was determined to be good if a normal diploid karyotype, isolated del(5q), isolated del(20q), or isolated -Y were present. Poor risk abnormalities were defined as abnormalities involving chromosome 7 or complex karyotypes with the presence of three or more karyotypic abnormalities. All other cytogenetic abnormalities were considered intermediate risk. The IPSS weighed these variables to produce a score that stratifies patients into four separate risk groups: low, intermediate-1, intermediate-2, and high risk (Table 5-3). Survival and risk of transformation to acute leukemia are then predicted from cohorts of different ages as illustrated in Table 5-3B. Patients classified as IPSS low and intermediate-1 risks are generally considered to have low-risk MDS, and patients classified as having IPSS intermediate-2 and high are grouped into those with high-risk MDS.

Low-risk MDS are typically treated more conservatively than higher risk MDS. Prognostication in this low-risk group may be particularly important as it is unclear at this time whether some low-risk patients may benefit from early therapeutic intervention. To determine which low-risk patients should be considered for treatment protocols investigating early intervention, patients with low-risk MDS at MD Anderson were analyzed to further stratify prognosis in low and intermediate-1 IPSS groupings (⁴). Factors associated with worse prognosis in this low-risk group included thrombocytopenia (platelets <50 × 10⁹/L), anemia (hemoglobin concentration <10 g/dL), age (>60 years), blast count >4%, and a karyotype that was not diploid or del(5q). This model stratified low-risk patients into three subgroups with a median survival of 80, 27, and 14 months, respectively. Increased ferritin and β₂-microglobulin were also associated with worse survival, but these factors were not included in the prognostic model. As patient survival was significantly different between these low-risk categories, investigation of early intervention protocols in low-risk patients with relatively poor survival may be warranted (Table 5-4). We described the cause of death of patients with lower risk MDS (⁵⁹). Approximately 80% of patients died from a complication intrinsic to MDS and not due to disease progression, which only occurred in 10% to 20% of patients. The most frequent cause of death was infection, followed by bleeding. Patients with increased percentage of blasts and a monosomy 7 had an increased risk of transformation to AML (⁵⁹).

The IPSS determines risk at the time of initial diagnosis, but it does not provide information regarding changes in risk as patients progress through the course of their disease. A dynamic prognostication system has been developed to address this deficiency and provides a score that is predictive of survival and leukemic transformation over time. The WHO classification-based Prognostic Scoring System (WPSS) weights three variables: WHO diagnostic classification, karyotype abnormalities categorized according to the IPSS criteria, and transfusion requirement (³). This stratifies patients into five disease groups that demonstrate different survival and risk of evolution to acute leukemia over time. Very low-risk patients in this classification have an overall mortality rate that was not different from the general population. This model incorporates changes in the disease risk profile over time, allowing further refinement in prediction of survival and leukemic progression as the disease progresses. A model has been developed by the MD Anderson group that accounts for both de novo and secondary disease and includes CMML. It also allows prognostication at diagnosis or any time during the course of MDS (⁶⁰). The characteristics of this model are shown in Tables 5-5, 5-6, and 5-7.

The presence of fibrosis on the bone marrow biopsy occurs in a minority of patients with MDS, but this pathological feature is not incorporated into routine diagnostic classifications or prognostic systems. Fibrosis is more frequently observed in patients with multilineage dysplasia or with karyotype abnormalities and, when present, is associated with a more rapid progression to severe bone marrow failure and shortened survival (⁶¹). In younger patients, it may warrant early consideration of alloSCT.

Recently, an international consortium developed a new MDS classification known as IPSS-R, or Revised IPSS (⁵). The basis for this effort was to improve on known limitations of the initial IPSS. IPSS-R includes a refined cytogenetic annotation and newer thresholds of cytopenias and blast percentages. Tables 5-8 and 5-9 show the characteristics of this new classification. The IPSS-R divides patients into five categories (very low, low, intermediate, high, and very high). Algorithms have been developed to calculate expected survival and time to progression based age and IPSS-R score. Although IPSS-R is the classification that the MDS expert community wishes it used when reporting on patients with MDS, practically and clinically it has not been adopted by MD Anderson. The main issues are the complexity of the score and the fact that it is unclear how to approach patients with intermediate risk disease. Furthermore, all drugs currently used in MDS were approved under IPSS or FAB criteria. Finally, it is likely that all these classifications will soon be modified to incorporate newer molecular data.

Patients with MDS are older and may suffer from other comorbidities. We have calculated the impact of comorbidities using the ACE-27 (Adult Comorbidity Evaluation-27) comorbidity score on the outcome of patients with MDS (⁶²). This analysis indicated synergism between the presence of comorbidity and disease score. The same was observed when ACE-27 was calculated with IPSS-R (⁶³).

The number of effective drug treatments available to treat MDS has expanded in recent years, providing a range of management alternatives. Some treatments improve hematopoietic function and alleviate symptoms related to blood cytopenia; other therapies alter the natural history of the disease and improve survival. Both approaches may be appropriate in different clinical contexts, and many patients receive different combinations of treatments throughout their disease course.

The goals of therapy in MDS vary in different patient populations. A management plan should consider the patient's age, comorbidities, and disease risk. Patients with low-risk MDS most commonly experience problems related to chronic anemia, and the disease may remain stable for prolonged periods. If these patients are elderly, they may best be managed with relatively nontoxic therapies that aim to maintain quality of life. Treatment options include transfusions of blood products, growth factor therapies (erythropoietin with or without colony-stimulating factors), and non–growth factor therapies with immune modulators (lenalidomide) and epigenetic drug treatment (azacitidine and decitabine). High-risk MDS has a poor prognosis and forms a continuum with acute myeloid leukemia. Aggressive therapies may be warranted in these high-risk patients to eradicate the malignant clone and improve survival. Intensive therapies may include high-dose chemotherapy and consideration of alloSCT in younger patients. Intensive treatment protocols are not suitable for all patients because they expose the patient to significant risks of treatment-related morbidity and mortality. An algorithm for treatment approaches at MD Anderson Cancer Center is shown in Fig. 5-7.

Assessing response to treatment in MDS can be complex as treatment goals in low- and high-risk disease may be different. Clinical response criteria in low-risk disease usually measure improvements in peripheral blood cell counts and quality-of-life factors. Response in high-risk disease is typically more stringent, with measures of resolution of bone marrow changes by morphological and cytogenetic criteria. Standardized criteria are available to assess response to treatment in MDS and are particularly useful to allow comparisons between drug trials (⁶⁴).

Supportive Care

Chronic blood cytopenia is a principal characteristic of MDS. Therapies aimed at alleviating problems related to anemia, neutropenia, and thrombocytopenia are an essential component of management. Bacterial infections require aggressive treatment with antibiotics. Platelet transfusions are administered for episodes of bleeding or for prophylaxis in patients with severe thrombocytopenia. Transfusion thresholds at MD Anderson include a hemoglobin level of 8 g/dL (unless the patient is otherwise symptomatic) and a platelet count of less than 10 K/UL (unless there is evidence of bleeding). Additional hemostatic support with the use of antifibrinolytic agents may be considered for problematic mucosal bleeding or for surgical procedures. The role of prophylactic antibiotics is less established in neutropenic patients. It is our practice at MD Anderson to use triple therapy (antibacterial with a quinolone, antiviral, and antifungal) in all patients with severe neutropenia who are receiving therapy.

Symptomatic anemia is often the major clinical problem in patients with low-risk MDS. In this group, red cell transfusion is effective symptomatic therapy, but a prolonged transfusion program may cause problems with transfusion-related hemosiderosis, alloantibody formation, and volume overload in patients with impaired cardiac function. Deposition of iron in body tissues is treated with iron chelation. The efficacy of iron chelation therapy is best demonstrated in thalassemia major, where regular deferoxamine therapy reduces iron deposition in organs and improves survival (⁶⁵). In MDS, it is hypothesized to have similar advantages (⁶⁶), but this needs to be confirmed in ongoing randomized clinical trials. The parenteral administration of deferoxamine is inconvenient. The development of effective oral iron-chelating drugs, such as deferasirox, has allowed iron chelation to be performed more easily (⁶⁷). Iron chelation should start with parenteral deferoxamine or oral deferasirox after 20 to 40 units of red cells have been administered, particularly if there is an expectation of prolonged survival and continued transfusion therapy. Serum ferritin may be used as a guide to chelation therapy, with a ferritin concentration greater than 1,000 μg/L typically attained after transfusion of 20 red cell units (⁵⁸). Iron chelation therapy should also be considered in a younger patient who may be a candidate for allogeneic transplantation. An elevated pretransplant ferritin has been associated with a lower overall survival after allogeneic transplantation and an increase in the hepatic transplant complication of veno-occlusive disease (⁶⁸).

Hematopoietic Growth Factors

Hematopoietic growth factors are the primary regulators of blood progenitor cell proliferation and are used therapeutically to promote effective hematopoiesis. Erythropoietin therapy has been explored as an alternative to red cell transfusion in patients with low-risk MDS. Recombinant erythropoietin (rEPO) in various forms, including epoetin α, epoetin β, and the long-acting darbepoetin, has been studied in different cohorts of patients. Overall, erythroid responses in unselected patients were modest, in the range of 10% to 20% (⁶⁹). The best responses were identified in patients with low-risk MDS, a low serum EPO level (<200 IU/L), and no red cell transfusion requirement (⁷⁰). In this favorable subgroup of patients with MDS, an erythroid response to rEPO therapy was observed in 40% to 60% of patients (⁷⁰). The median duration of response was 2 years, and therapy was associated with improved quality of life (⁷¹). Data suggest that patients who respond to growth factor therapy have better survival than historical control cohorts who received supportive care alone (⁷⁰).

Erythropoietin in combination with G-CSF is also effective, with response rates of 40% to 50% in selected cohorts (^71,72). The combination of these two hematopoietic cytokines appears to offer a synergistic clinical benefit and allows improvements in hemoglobin levels in some patients who fail to respond to EPO monotherapy. The benefit of this combination may be most marked in RARS and RCMD, but this has not been confirmed (⁷⁰). Disease transformation is a theoretical risk in patients receiving chronic hematopoietic growth factors, but long-term observations of these patients suggested that these cytokines do not promote leukemic transformation (^70,72). Hematopoietic growth factor therapy should be considered to treat anemia in patients with low-risk MDS associated with a low serum EPO. Erythropoietin can be initiated as monotherapy with the addition of G-CSF if there is no objective response in 2 to 3 months.

Thrombopoietin has been used to promote platelet production and minimize the bleeding complications related to severe thrombocytopenia. Initial trials with recombinant thrombopoietin were disappointing. New second-generation thrombomimetic agents are now being tested (⁷³). These drugs should not be used outside the context of clinical trials due to potential concerns of increased blasts and fibrosis.

Lenalidomide

Lenalidomide is a chemical analogue of thalidomide with diverse biological actions that encompass immune modulation and antiangiogenic effects. Selective activity of lenalidomide against MDS associated with an interstitial deletion on the long arm of chromosome 5 was first suggested in a study examining the effects of this drug on anemia in patients with low-risk MDS (⁷⁴). Erythroid responses were noted in 56% of the cohort, with the most significant response found in the subgroup with a del(5q) abnormality. This observation was confirmed in a larger multicenter phase II study of lenalidomide (⁶). This second trial demonstrated an overall erythroid response in 76% of patients with the del(5q) abnormality. Responses were prolonged and occurred rapidly, with a median time to a hematologic response of 4 to 5 weeks. A cytogenetic response was documented in 73% of patients, with 44% developing complete cytogenetic remission. Cytogenetic responses were observed in patients with the del(5q) abnormality alone and in patients with the del(5q) abnormality associated with additional cytogenetic defects. This clearly demonstrated that the activity of lenalidomide was not limited to patients with the 5q- syndrome but was also observed in patients with low-risk MDS, with a variety of WHO classifications associated with a del(5q) abnormality on cytogenetic studies. A randomized trial comparing different doses of lenalidomide versus observation further confirmed the activity of the drug at a dose of 10 mg daily (⁷⁵). Although none of these studies was powered to document improvement in survival, a recent analysis indicated that achieving a cytogenetic response with lenalidomide was associated with prolonged survival (⁷⁶).

Lenalidomide therapy in MDS is usually started at 10 mg daily. A favorable response is typically characterized by normalization of anemia and cytogenetic response (⁶). The most important side effect of therapy with lenalidomide is myelosuppression, which may necessitate dose reduction in patients with persistent thrombocytopenia and neutropenia. Interestingly, the degree of myelosuppression has been associated with response. Thrombocytopenia at diagnosis (platelet count <100 × 10⁹/L) has been associated with a worse response to lenalidomide treatment. This may reflect repeated or prolonged treatment interruptions secondary to myelosuppression.

Lenalidomide and thalidomide also demonstrated activity in low-risk MDS without the del(5q) abnormality. Lenalidomide has been studied in 214 patients with low-risk MDS (IPSS low and intermediate-1) and predominantly a normal karyotype (⁷). In this cohort, 26% of patients achieved transfusion independence, and 17% developed a reduction in transfusion requirement. The median duration of transfusion independence was 41 weeks, and cytogenetic responses were documented in 19% of patients with karyotypic abnormalities. These results were confirmed in a randomized trial (⁷⁷).

Hypomethylating Agents

5-Azacitidine and 5-aza-2′-deoxycytidine (decitabine) are chemically related drugs with a spectrum of activity that includes both low- and high-risk MDS. The mechanism of action of these drugs is uncertain, although both agents reverse abnormal promoter DNA methylation that surrounds the promoter of some tumor-suppressor genes in cancer cells. Aberrant promoter methylation is associated with transcriptional repression, or silencing, and may contribute to the loss of tumor-suppressor gene function in MDS. Decitabine and 5-azacitidine are both cytidine analogues that incorporate into DNA and form covalent bonds with DNA methyltransferase enzymes. Depletion of methyltransferase activity within the cell then causes newly synthesized DNA to be hypomethylated compared to the parent strand. After at least two cycles of cell division, DNA becomes globally hypomethylated with alteration in gene expression within the leukemic cell. Both agents display cytotoxicity at high doses, while hypomethylating activity remains prominent at lower doses. These biochemical changes are an attractive target for drug therapy as normal tissues have little gene promoter methylation, so hypomethylating therapy may have some degree of specificity for the malignant clone.

5-Azacitidine first demonstrated broad-spectrum activity in MDS. Comparison of azacitidine (75 mg/m² subcutaneously for 7 days every 28 days) to best supportive care in a randomized control trial demonstrated an overall response rate of 48% with azacitidine compared to 5% with supportive care (^78,79). Azacitidine therapy was associated with a prolongation in the time to leukemic transformation and better quality of life. The median time to response was three cycles, and response rates were independent of MDS classification. Complete responses were observed in relatively few patients (10%), with most patients experiencing hematologic improvement. A report of a multicenter phase III study of azacitidine in patients with high-risk MDS demonstrated an increase in overall survival of approximately 9 months for patients receiving azacitidine compared to other standard therapies (⁸⁰). This was the first drug trial that demonstrated a survival advantage in MDS. A subset analysis of the trial data suggested that azacitidine may have significant activity in MDS associated with abnormalities in chromosome 7, a cytogenetic abnormality associated with a poor outcome.

Decitabine has similar clinical activity to azacitidine and has been studied in various dose regimes in predominantly high-risk MDS and AML. Comparison of decitabine (45 mg/m² in three divided doses administered for 3 consecutive days every 6 weeks) to best supportive care in a randomized trial demonstrated an overall response rate of 17%, with complete remissions in 9% of patients with predominantly high-risk MDS (⁸¹). Subgroup analysis revealed that patients who received decitabine had a longer median time to transformation to AML or death if they were treatment naïve or had high-risk MDS. Myelosuppression was the major drug toxicity. Data from this trial may underestimate the efficacy of the drug as a significant proportion of patients on decitabine received a small number of treatment cycles, which may have been insufficient to demonstrate a response. This is supported by previous phase II trial data that suggested decitabine had an overall response rate similar to azacitidine (⁸²). Subsequent clinical trial development with decitabine has focused on improving response rates by lowering the daily dose and lengthening administration schedules. One such schedule of intravenous administration of decitabine for 5 days every 4 weeks demonstrated a complete response rate of 39% in a high-risk MDS cohort (^83,84). Improvements in hematopoietic function are often delayed after the initiation of azacitidine or decitabine therapy, and drug treatment should continue for four to six cycles before cessation because of poor response.

Chemical modification of histone proteins by acetylation contributes to the regulation of gene expression and probably interacts with abnormal DNA methylation to cause transcriptional suppression of tumor-suppressor genes. Histone deacetylase inhibitors alter chromatin structure to promote gene transcription, and their combination with hypomethylating agents demonstrates significant in vitro synergy (⁸⁵). Initial clinical drug trials in MDS and AML at MD Anderson indicated increased clinical activity with this type of combination (^86,87) azacitidine. None of the randomized trials (hypomethylating agent with or without HDAC inhibitor) showed a survival improvement (⁸⁸).

Cytotoxic Chemotherapy

The relatively poor prognosis associated with high-risk MDS has initiated intensive treatment strategies incorporating high-dose chemotherapy in the same protocols used to treat acute myeloid leukemia. In high-risk MDS, AML-type treatments produce a complete response rate of about 40% to 60%, but remissions are brief (^89,90). This poor response to high-dose chemotherapy is due, at least in part, to the relatively greater proportion of patients diagnosed with RAEB having poor prognosis cytogenetics involving complex changes of chromosomes 5 and 7. Elderly patients with significant comorbidities tolerate high-dose chemotherapy poorly.

Patients with high-risk MDS have been treated with a variety of intensive chemotherapy regimens at MD Anderson Cancer Center (^91,92). Studies have examined using intermediate- to high-dose cytosine arabinoside (ara-C) (A) in various combinations with idarubicin (I), cyclophosphamide (C), fludarabine (F), and topotecan (T), as regimens: IA, FA, FAI, TA, and CAT. The overall complete response rate for these regimens was 55% to 58%. A short antecedent history of hematological disorder, a normal karyotype, performance status, age, and treatment in a laminar airflow environment were all predictive of attaining a complete response. This intensive approach was beneficial in some patients as those who developed a complete response within 6 weeks of chemotherapy obtained a survival advantage. However, these regimens were toxic, with significant treatment-related mortality in the first 6 weeks, ranging from 5% with TA to 21% with FAI. Consolidation chemotherapy was used in most cases where a remission was achieved with a regimen containing the drugs used in induction but at a reduced intensity of 50% to 66% of the initial dose. Survival of patients treated with IA and TA therapies were comparable and superior to those patients treated with FA, FAI, and CAT regimens, but prognosis remained poor. Nevertheless, this approach does benefit some younger individuals (<65 years) with a normal karyotype, achieving an encouraging 5-year survival rate of 27% with intensive treatment. For older patients, the TA combination can be considered as it has a relatively low treatment-related mortality and it does not contain anthracycline drugs (relatively contraindicated in the presence of heart disease).

Immunosuppressive Therapy

Immune dysfunction contributes to blood cytopenia in some patients with MDS, producing a clinical overlap with aplastic anemia. Immunosuppressive therapy with antithymocyte globulin (ATG) with or without the addition of cyclosporine has been explored in small numbers of patients with MDS. Response rates of 30% to 50% have been observed in selected cohorts of patients with low-risk MDS administered a course of ATG, with a minority of patients experiencing prolonged remission (^93,94,95). Features that may predict a good response to immunosuppressive therapy include younger age, HLA-DR status, shorter duration of red cell transfusion, low-risk IPSS, and bone marrow hypocellularity (^95,96,97). Selection of appropriate patients for immunosuppression is important as ATG therapy is poorly tolerated in an older population with low-risk MDS (⁹⁸). The PD-1 axis is expressed in patients with MDS. This may allow the development of new forms of therapy and combinations using inhibitors of this pathway (⁹⁹).

Hematopoietic Stem Cell Transplantation

In MDS, alloSCT is potentially, but the therapy carries significant risk associated with treatment toxicity, prolonged cytopenia, infection, and graft-versus-host disease. In young patients with suitable donors, the transplant procedure offers the best chance of cure, with a long-term disease-free survival of 30% to 50% (^{100,101,102,103,104}). Given the risks associated with this procedure, patient suitability and timing of the transplant are important issues.

Allogeneic transplantation with myeloablative conditioning has been examined exclusively in younger patients (median age in the mid-30s) in most studies. Patients with low-risk disease (RA/RARS) have experienced the best survival rate. However, this is also the subgroup of patients predicted to experience prolonged survival without aggressive therapies. This procedure is associated with a significant treatment-related mortality of up to 30% to 50% in some studies (^102, 103). Relapse after transplantation occurs in approximately 20%, and the relapsed disease has a relatively poor response to donor lymph ocyte infusion (^102,103,105). Increased risk of allogeneic transplantation mortality in MDS is associated with older age, poor risk cytogenetics (particularly abnormalities of chromosome 7 or a complex karyotype), the presence of excess blasts in the bone marrow, and longer duration of disease (^106, 107). Patients with treatment-related MDS also have a poor transplant outcome, but this is related to the frequency of high-risk cytogenetic changes (^107, 108).

The development of nonmyeloablative allogeneic transplantation with reduced-intensity conditioning has allowed allogeneic transplantation to be considered in older patients with MDS and in patients whose comorbidities or organ dysfunction would exclude them from myeloablative treatment (¹⁰⁹). This procedure has reduced the transplant-related mortality, the major problem limiting the availability of this potentially curative therapy to older patients. This therapy aims to minimize organ toxicity related to initial chemo- or radiotherapy and allow stable engraftment of donor cells that provide the curative potential associated with the graft-versus-leukemia effect. Comparison of reduced-intensity conditioning transplantation with standard myeloablative conditioning showed reduced transplant-related mortality but increased relapse rate, resulting in comparable rates of overall survival between the two transplantation strategies (^106,110,111).

Statistical modeling based on historical allogeneic transplantation outcomes for matched sibling transplantation suggested that the maximal overall survival is achieved by different transplant strategies in different MDS risk groups (¹¹²). Patients with low-risk disease (IPSS low and intermediate-1 groups) maximize overall survival by delaying transplantation after diagnosis until evidence of disease progression but before the development of overt acute leukemia. This delayed transplant approach provided the greatest survival benefit to younger patients (<40 years).

Specific features of disease progression have not been defined, but evidence of new cytogenetic abnormalities, progressive cytopenia, and increasing blast percentage in the bone marrow are suggested as potential triggers for transplantation. Patients with high-risk disease (IPSS intermediate-2 and high) should ideally receive the transplant as soon as possible after diagnosis. The presence of bone marrow fibrosis delays engraftment in allogeneic transplantation and its presence is an additional risk factor in transplant outcome in high-risk MDS. In this group, fibrosis considerably increases transplantation risk.

Early consideration of transplantation is suggested in a younger patient with significant MDS-associated fibrosis (¹⁰⁸). The IBMTR studied the outcomes of patients older than 60 years of age with MDS treated with either reduced-intensity transplantation or hypomethylating agents (⁸). The results of this analysis indicated that transplant should not be considered as first-line therapy in lower risk MDS. Of interest, in higher risk MDS it appears that there is a benefit toward transplant compared to hypomethylating-based therapy, but survival curves cross significantly later than after 24 months of therapy. This indicated that there is probably a specific group of patients, not yet defined, that derive the maximal benefit from transplantation.

Despite the clinical activity of several agents described earlier, most patients with MDS will eventually succumb to their disease. This emphasizes the need to develop better strategies both up-front and in patients who have failed prior therapies.

Treating Patients With Lower-Risk Disease and Poor Prognosis

It is now demonstrated that the prognosis of patients with lower-risk MDS is very heterogeneous, with a significant subset of patients having poor prognosis (⁴). Because most of these patients die as a consequence of MDS, introducing therapy early in this selected group of patients may help. This has significant implications not only for the role of alloSCT in MDS but also for the incorporation of disease-modifying strategies. We have studied the role of very low-dose or oral schedules of hypomethylating agents in this setting (^113, 114). Randomized phase III trials are being conducted to investigate the impact of these interventions on survival.

Hypermethylator Failure MDS

One of the major problems is the treatment of patients who have failed therapy with a hypomethylating agent. Data from MD Anderson indicated that prognosis is very poor for patients with higher risk disease and hypomethylating failure with a median survival of less than 5 months (¹¹). The survival of patients with lower risk disease and hypomethylating failure is less than 17 months (¹¹). In general, this group of patients is refractory to most conventional antileukemia agents available, such as cytarabine. These patients should be treated with investigational new agents or be considered for alloSCT as soon as possible. Agents currently being studied include nucleoside analogues (clofarabine and sapacitabine) and the multikinase inhibitor ON1910. Following encouraging pilot data, a phase II randomized trial of ON01910 versus best standard of care (2:1) in patients with MDS and failure of hypomethylation therapy showed a trend for survival benefit with ON01910 (median survival 8.5 vs 5.5 months; P = .08), which was significant in the subsets of patients with primary resistance to hypomethylating agent therapy or with higher risk MDS (¹¹⁵). Additional studies of ON01910 in MDS are under consideration. Other investigational agents of interest include vosaroxin (topoisomerase inhibitor), volasertib (polo-like kinase inhibitor), omacetaxine, checkpoint inhibitors (eg, PD-1 and PDL1 inhibitors), ACE11, and others.