Myelodysplastic Syndromes

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1 June 01, 2016 By Guillermo Montalban-Bravo, MD [1], Guillermo Garcia-Manero, MD [2], Alan List, MD [3], Hagop M. Kantarjian, MD [4], and Jorge E. Cortes, MD [5] Myelodysplastic syndromes (MDS) are a group of hematologic malignancies of the pluripotent hematopoietic stem cells. These disorders are characterized by ineffective hematopoiesis, including abnormalities in proliferation, differentiation, and apoptosis. Overview Myelodysplastic syndromes (MDS) are a group of hematologic malignancies of the pluripotent hematopoietic stem cells. These disorders are characterized by ineffective hematopoiesis, including abnormalities in proliferation, differentiation, and apoptosis. The overall clinical phenotype is peripheral cytopenias in the setting of a normocellular or hypercellular bone marrow and an increased risk for transformation to acute leukemia. The incidence of MDS approximates 3 to 4 cases per 100,000 population per year, with 30 cases per 100,000 population per year in patients > 70 years old. It is estimated that approximately 10,000 to 15,000 new cases are diagnosed annually in the United States. Data on the epidemiology of MDS are now starting to emerge. Epidemiology Gender The overall incidence of MDS is slightly higher in males than in females (1.5 to 2:1). Age The incidence of MDS increases with age, with a median age at diagnosis of about 70 years. MDS is rare in children; childhood cases are more frequently associated with monosomy of chromosome 7. Etiology and Risk Factors MDS is a clonal disorder of bone marrow stem cells. The vast majority of cases (80% to 90%) occur de novo, whereas 10% to 20% of cases are secondary. The etiology of de novo MDS is unclear. Exposure to radiation and/or cytotoxic agents is a recognized etiologic factor in secondary disease forms. Cumulative exposure to environmental toxins and chronic inflammation, genetic differences in leukemogen susceptibility and metabolism, and hematopoietic stem-cell genomic senescence may contribute to disease pathogenesis in de novo cases. Genetic Factors It has been suggested that a genetic insult causes an irreversible alteration in the structure and function of the stem cell, with disruption of a multistep process involving control of cell proliferation, maturation, and interactions with growth factors; mutations of tumor-suppressor genes and proto-oncogenes; and deregulation of apoptosis. Constitutional childhood disorders, such as Fanconi s anemia, Shwachman-Diamond syndrome, Down syndrome, neurofibromatosis, and mitochondrial cytopathies, have been associated with MDS and monosomy of chromosome 7. Recently, heritable mutations of the RUNX1, GATA2, CEBPA, DDX41, ETV6, ANKRD26, SRP72, TERT, and TERC genes have been linked to familial cases of adult MDS. Environmental Factors Exposure to benzene and its derivatives may result in karyotypic abnormalities often seen in MDS Page 1 of 14

2 and acute myelogenous leukemia (AML). Persons chronically exposed to insecticides and pesticides may have a higher incidence of MDS than the general population. An increased incidence of MDS has been reported among smokers and ex-smokers, possibly linked to associated exposures to polycyclic hydrocarbons and radioactive polonium present in tobacco smoke. An association of MDS with magnetic fields, alcohol, or occupational exposure to other chemicals has not been demonstrated. Antineoplastic Drugs Therapy-related myelodysplasia and therapy-related AML are recognized long-term complications of chemotherapy and radiotherapy. Therapy-related MDS usually develops in 0.8% to 6.3% at 20 years after conventional chemotherapy, with a median time to development of 3 to 7 years post treatment. It is most frequently related to complete or partial loss of chromosomes 5 or 7 in patients previously treated with alkylating agents. Approximately 80% of cases of AML occurring after exposure to antineoplastic drugs, particularly alkylating agents, are preceded by MDS. More than 85% of patients who develop chemotherapy-related leukemia or MDS have been exposed to alkylating agents. Patients exposed to nitrosoureas have a relative risk of developing MDS or AML of 14.4 and a 6-year actuarial risk of 4%. The mean cumulative risk of leukemia in patients exposed to epipodophyllotoxins (eg, etoposide and teniposide [Vumon]) is about 5% at 5 years. Most of these therapy-related leukemias are not preceded by a dysplastic phase and are associated with abnormalities in chromosome 11q23. Autologous Bone Marrow Transplantation Autologous Bone Marrow Transplantation (BMT) has also been associated with a 5-year actuarial risk of MDS of 15% (95% CI = 3.4% 16.6%), with a median time to development of 12 to 24 months. Fluorescence in situ hybridization analyses of pretreatment bone marrow specimens for informative cytogenetic markers indicate that these secondary myeloid malignancies derive from clones demonstrable before the transplant procedure. Prior therapy with fludarabine, older age, low CD34+ dose, and prolonged platelet reconstitution have been associated with the development of MDS or AML in patients with lymphoid malignancies after autologous stem cell transplantation (SCT). Classification TABLE 1: Main features of MDS according to the FAB classification In 1982, the French-American-British (FAB) group proposed a classification system for MDS that consists of five subgroups, based on the percentage of blast cells in the peripheral blood and bone marrow, the presence of ringed sideroblasts in the bone marrow, and the monocyte count in the peripheral blood (Table 1). The five subgroups are: - refractory anemia (RA) - refractory anemia with ringed sideroblasts (RARS) - refractory anemia with excess blasts (RAEB) - refractory anemia with excess blasts in transformation (RAEB-t) - chronic myelomonocytic leukemia (CMML). Page 2 of 14

3 TABLE 2: Criteria for myelodysplastic syndromes (MDS) according to the WHO classification The presence of Auer rods in granulocyte precursors classifies a patient as having RAEB-t, even if blasts comprise < 20% of bone marrow cells. The presence of > 30% blast cells in the bone marrow or peripheral blood establishes the diagnosis of AML rather than MDS. In 2008, the World Health Organization (WHO) proposed a modified classification of hematologic malignancies (Table 2). The following changes were proposed, based on the effect of cytogenetics and the number of dysplastic lineages on clinical behavior: - Elimination of the FAB classification of RAEB-t. - Changing the blast percentage that defines AML to 20%. - Defining RA and RARS by dysplasia restricted to the erythroid lineage either with or without ringed sideroblasts, respectively. - Including RA and single lineage dysplasias limited to the myeloid or megakaryocyte lineage in the category of refractory cytopenia with unit lineage dysplasia (RCUD). - Regarding the presence of dysplasia in erythroid and nonerythroid lineages (multilineage dysplasia with or without ringed sideroblasts) and MDS with isolated deletion 5q as separate entities of MDS. - Division of RAEB into two categories distinguished by marrow blast percentage (ie, RAEB-1: 5% 9%; RAEB-2: 10% 19%) or the presence of Auer rods (RAEB-2). In addition, two new provisional categories were introduced in the 2008 proposal: (a) RARS with thrombocytosis (RARS-T), ie, 450,000 μl platelet count (b) MDS with minimal cytogenetic criteria, ie, absence of dysplasia in the presence of a clonal cytogenetic abnormality characteristic of MDS. - CMML is included in a separate category of myelodysplastic/myeloproliferative neoplasms that also includes atypical CML and juvenile myelomonocytic leukemia. CMML is further classified into CMML-1 ( 9% blasts), CMML-2 (10% 19% blasts), and CMML-Eos (eosinophils 1,500 μl). This proposal represents a step ahead, but there are some aspects that still need to be addressed. For example, some biologic features that have been associated with MDS, such as the presence of spontaneous apoptosis, increased angiogenesis, and presence of specific mutations such as TET2, SF3B1, SRSF2, JAK2, or NRAS may define better specific subsets, and the WHO classification does not incorporate unfavorable cytogenetic patterns. In fact, as will be addressed later in this chapter (see the section, Cytogenetic and Molecular Findings ), since this last WHO proposal in 2008 noticeable progress has been made in characterization of mutational patterns, as well as certain disease phenotypes and their biology. Signs and Symptoms Nearly 50% of patients with MDS are asymptomatic at the time of initial diagnosis. Signs and symptoms relate to hematopoietic failure, leading to anemia, thrombocytopenia, or leukopenia. Symptoms Related to Anemia These may range from fatigue to exertional dyspnea that may exacerbate angina or cause congestive heart failure. Infection Page 3 of 14

4 Approximately one-third of patients report recurrent localized or systemic infections as a result of granulocytopenia or dysfunctional granulocytes and monocytes. Bleeding Manifestations Bleeding manifestations such as petechiae or gross hemorrhage, can occur with thrombocytopenia or platelet dysfunction. However, < 10% of patients present with serious bleeding. Organomegaly and Lymphadenopathy Splenomegaly and/or hepatomegaly may be found in 5% to 25% of patients. A large spleen is more frequently seen in CMML. Acute Neutrophilic Dermatosis and Pyoderma Gangrenosum Acute neutrophilic dermatosis (Sweet s syndrome) and pyoderma gangrenosum may be observed, particularly in patients with CMML or advanced MDS. Sweet s syndrome can present both as an acute nonrelapsing condition after administration of granulocyte colony-stimulating factor (G-CSF, filgrastim), or as a chronic relapsing-remitting form that tends to respond to MDS therapy with disease-modifying agents such as 5-azacitidine. Paraneoplastic Syndromes Diabetes insipidus, vasculitis, and other rare paraneoplastic syndromes have been described in patients with MDS. Laboratory Features Peripheral blood Anemia. Anemia is the most frequent abnormality in MDS, with > 80% of patients presenting with hemoglobin concentrations < 10 g/dl. The anemia is usually normocytic or macrocytic, but the mean corpuscular volume rarely exceeds 120 μm³. Other red blood cell (RBC) abnormalities. Hypochromic changes and red-shape abnormalities are frequent, including poikilocytosis, anisocytosis, elliptocytosis, macro-ovalocytosis, and sometimes stomatocytes. Stippled and nucleated RBCs can be observed in 10% of cases. Reticulocyte counts are usually reduced. White blood cell (WBC) abnormalities. The peripheral WBC count may be normal or low in MDS but is frequently elevated in CMML. The proportion of monocytes may be increased, and a circulating monocyte count of 1 109/L defines CMML. Neutropenia is seen in about 50% of patients with MDS at diagnosis, often associated with pseudo Pelger-Huët anomaly (neutrophils have condensed chromatin and unilobed or bilobed nuclei with a pince-nez shape), ring-shaped nuclei, hypogranulation, and hypolobulation or other signs of dysgranulopoiesis. Granulocytes frequently disclose reduced myeloperoxidase activity, increased α-naphthyl acetate esterase activity, and other functional abnormalities. Chemotactic and bactericidal capability is impaired, which can potentiate the risk of infection, even in the presence of normal WBC counts. Patients frequently have a decreased number of natural killer cells and helper T lymphocytes. Platelet abnormalities. Thrombocytopenia is present at diagnosis in approximately 30% of patients. Platelets may be abnormally large; have poor granulation; or have large, fused central granules. Decreased platelet aggregation is observed when platelets of patients with MDS are challenged with collagen or epinephrine. Thrombocytosis may be seen in association with the 5q syndrome and in those with RARS-t. Bone marrow Bone marrow aspiration and biopsy should be performed in every patient suspected of having MDS or unexplained persistent cytopenias. The finding of a total of 500 nucleated cells with at least 30 megakaryocytes should be evaluated if possible. The bone marrow is normocellular or hypercellular in 85% to 90% of patients with MDS but may be hypocellular for the patients age in as many as 10% to 15% of cases. Trilineage dyspoiesis. The main morphologic feature of MDS is hematopoietic dyspoiesis, although myelodysplastic features do not always involve all three lineages. Cytologic dysplasia must be Page 4 of 14

5 detected in 10% of the affected lineages. Dyserythropoiesis Erythroblasts usually have a megaloblastoid appearance. Iron may be abnormally deposited in mitochondria and is easily stained with Prussian blue, producing a ring-shaped staining pattern around the nucleus. Pathologic sideroblasts have five or more granules/cell. Additional dysplastic changes include nuclear and internuclear budding, karyorrhexis, multinuclearity, and incomplete hemoglobinization. Dysgranulopoiesis The characteristic findings in dysgranulopoiesis are hypogranulation and hyposegmentation with nuclear morphologic abnormalities. Additionally, the presence of pseudo Chediak-Higashi granules or Auer rods can also be observed. Excess bone marrow blasts Bone marrow blasts > 5% but < 30% are seen in 30% to 50% of patients with MDS; in the context of myelodysplasia, this finding is a feature of MDS. The FAB group distinguishes three types of blasts on the basis of the maturation as assessed by morphology. Type I blasts have an uncondensed nuclear chromatin, one to three nucleoli, and basophilic cytoplasm without a Golgi zone. Cytoplasmic granules and Auer rods are absent. In type II blasts, the nuclear/cytoplasm ratio is lower than in type I blasts, and few primary granules are seen. Type III blasts have 20 or more azurophilic granules without a Golgi zone. Dysmegakaryocytopoiesis At least 10 megakaryocytes should be evaluated. Micromegakaryocytes are small cells with a diameter two times smaller than the normal megakaryocyte (< 80 μm). Multiple, dispersed, small nuclei or mononucleated forms, as well as hypogranulated megakaryocytes, also can be found. Other abnormalities. An increase in reticulin and collagen fibers in the bone marrow may be seen in some patients. Angiogenesis. Increased marrow vascularity and increased levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor have been described in patients with MDS. Other laboratory findings Serum iron, transferrin, and ferritin levels may be elevated. As a result of ineffective hematopoiesis, lactate dehydrogenase (LDH) and uric acid concentrations are frequently increased. Monoclonal gammopathy, polyclonal hypergammaglobulinemia, and hypogammaglobulinemia are found occasionally but may be detected in up to 15% of patients with CMML. Cytogenetic and Molecular Findings Chromosomal abnormalities Clonal cytogenetic abnormalities are found at diagnosis in 50% to 60% of patients with de novo MDS and 75% to 85% of those with secondary MDS or AML. An interesting feature that distinguishes MDS from AML is the high incidence of complete or partial chromosomal loss or, less frequently, chromosomal gain and the relative rarity of translocations. Among the translocations, unbalanced translocations leading to a loss of chromosomal material are most frequent. Common cytogenetic abnormalities. Common cytogenetic abnormalities are listed in Table 1. None of them is specific for MDS, since all can be found in other myeloid disorders. Some of the most frequent abnormalities are interstitial deletion of the long arm of chromosome 5 (5q ), monosomy of chromosome 7, trisomy of chromosome 8, 20q, and loss of the Y chromosome. Complex cytogenetic abnormalities involving three or more chromosomes occur in approximately 15% of de novo MDS cases and 50% of secondary MDS cases. Therapy-related MDS. Loss of chromosome 7 and/or 7q has been reported in as many as 50% of patients previously exposed to chemotherapy for other malignancies, most frequently in association with prolonged use of alkylating agents. Other abnormalities commonly associated with prior exposure to alkylating agents include 5 and/or del(5q) in 25% of cases and involvement of chromosomes 17p and 21 in 10% to 15%. Complex chromosomal abnormalities may be found in nearly 50% of patients. Cytogenetics and FAB classification RA and RARS. Approximately 15% to 30% of patients with RA and RARS have abnormal karyotypes. The most frequent abnormality in patients with RA is 5q, whereas the most common abnormalities in patients with RARS are 5q, +8, and 20q (each occurring in 20% of patients). RAEB and RAEB-t. Nearly 60% of patients with RAEB and RAEB-t have cytogenetic abnormalities, with 5q, 7, 7q, and +8 being the most frequent. CMML. Chromosomal abnormalities are found in 25% to 30% of patients with CMML; the Page 5 of 14

6 predominant abnormalities include 7, 7q, +8, 12q, and t(5;12). Interestingly, 5q is seen in < 1% of cases of CMML. Monosomy of chromosome 7. Monosomy of chromosome 7 is found in up to 25% of children with MDS, most frequently as an isolated abnormality. In contrast, older patients most often have monosomy of chromosome 7 associated with other chromosomal abnormalities. 5q- syndrome The isolated interstitial deletion characteristic of the 5q syndrome involves a variable segment length that includes a 1.5-megabase segment critical deleted region extending between bands 5q32 and 5q33, a region known to contain genes coding for numerous growth factors, micrornas (mir-145 and mir-146a), tumor suppressor genes (EGR1, APC, SAPRC), and receptors. However, the critical gene deletion involved in this syndrome may be a ribosomal protein processing gene, RPS14, haploinsufficiency of which limits erythroid differentiation and survival in laboratory models by free ribosome accumulation, MDM2 inhibition and subsequent increased free p53 and erythroid progenitor apoptosis. Clinical features. The 5q syndrome represents a subset of MDS with isolated chromosome 5q deletion that has characteristic clinical features, including older age, female predominance, diagnosis of RA without excess (< 5%) blasts in 75% of cases, macrocytosis with severe anemia, erythroblastopenia, normal leukocyte counts, normal or increased platelet counts, and hypolobulated megakaryocytes in the bone marrow. Progression to AML is infrequent (< 20%), and the prognosis is usually good. However, not every patient with del(5q) has this syndrome and its associated good prognosis. Additional cytogenetic abnormalities or the presence of 5% blasts in the peripheral blood or bone marrow is inconsistent with this diagnosis. Molecular findings and disease phenotype Overall, up to 90% patients with MDS harbor at least one gene mutation, with more than 50% of patients with a normal karyotyype having one or more mutations. Due to high-throughput DNA sequencing with next-generation sequencing, more data related to the mutational landscape of MDS have become available. The most common mutations occurring in patients with MDS are listed in Table 3. TABLE 3: Recurrent mutations in MDS A difference in the surface expression of phosphatidylserine (a marker of apoptosis) on cell membranes among de novo AML, MDS, and secondary AML and normal bone marrow cells has been found (increased in MDS and secondary AML). Epigenetic silencing of the CDKN2B tumor-suppressor gene by promoter hypermethylation occurs particularly among patients with high-risk MDS and is associated with a poor prognosis. RARS. Approximately 80% patients with RARS harbor mutations in the splicing gene SF3B1, with recent data suggesting that this mutation induces hemoglobin synthesis and terminal erythroid differentiation. RARS-T. Similar to RARS, up to 80% patients present with mutations in SF3B1. Additionally, 60% to 80% patients have co-occuring mutations in JAK2 or MPL, which are probably responsible for the observed thrombocytopenia. CMML. Characterized by a high incidence of TET2, SRSF2, and ASXL1 mutations and defined by co-occurrence of TET2 and SRSF2 mutations. Page 6 of 14

7 Atypical CML. This entity is characterized by MDS/MPN features, including anemia, thrombocytopenia, neutrophilic leukocytosis with granulocytic dysplasia. Patients harbor mutations of SETBP1 in 25% of cases and mutations of CSF3R in 40% of cases. Staging and Prognosis Prognostic Factors FAB and WHO classifications The FAB classification has a long history of use to evaluate survival and risk for AML transformation (Table 1). The WHO classification has similar prognostic implications, based primarily upon the prognostic impact of blast percentage and the number of dysplastic lineages. Cytogenetics Patients with complex karyotypes and abnormalities in chromosome 7 have a poor prognosis, whereas those with a normal karyotype, Y, 5q, or 20q have a favorable prognosis. TABLE 4: International Prognostic Scoring System (IPSS) for MDS Peripheral cytopenias Peripheral cytopenias (hemoglobin level < 10 g/dl, absolute neutrophil count [ANC] < /L, and platelet count < /L) have a cumulative adverse effect on prognosis. Other prognostic factors Other parameters associated with a poor outcome include CD34 cell expression, high serum LDH, abnormal localized immature myeloid precursors, severe thrombocytopenia, CDKN2B inactivation, certain mutations (Table 3), and extent of genomic methylation. However, it is unclear whether these factors have independent prognostic value. International Prognostic Scoring System An International MDS Risk Analysis Workshop has proposed a system International Prognostic Scoring System (IPSS) that combines clinical, morphologic, and cytogenetic data to generate a consensus prognostic system. By multivariate analysis, the most significant independent variables were percentage of bone marrow blasts, cytogenetics, and number of cytopenias (Table 4). It is important to keep in mind, however, that other variables (eg, age and prior therapy) not included in this system may alter the prognosis and influence the results of therapy among patients in similar IPSS groups. Still, this may be the most valuable risk classification for treatment planning. TABLE 5: Revised International Prognostic Scoring System (IPSS-R) for myelodysplastic syndromes TABLE 6: Revised International Prognostic Scoring System (IPSS-R) The IPSS described above has served as the basis of clinical care and clinical trial development for patients with MDS since Recently, an international effort was conducted to improve on IPSS. This has resulted in the development of a revised IPSS scoring system. This new system included data on more than 7,000 patients from centers worldwide. In contrast to the original IPSS Page 7 of 14

8 classification, it divides patients into five prognostic subsets (Table 5) and uses a more complex cytogenetic classification (Table 6). This new prognostic system has been consistently validated in multiple retrospective studies, with improved discrimination capacity compared with the initial WHO classification-based Prognostic Scoring System (WPSS) or the IPSS system. Although this classification should now be considered the standard prognostic score for patients with MDS, it should be noted that it has not been tested prospectively and that its value in the context of therapy is not known at this point. Several studies are evaluating this as well as the impact of new molecular alterations. Other Scoring Systems The IPSS and WHO classifications have the following limitations in assessing the risk of patients with MDS: excess weight toward percentage of blasts, lack of discrimination of patients with lower-risk disease, and other clinical characteristics. In addition, both the IPSS and IPSS-R were developed for newly diagnosed patients, and therefore should not be used dynamically to reassess disease risk in treated patients throughout the course of the disease. TABLE 7: Multivariate analysis parameters and assigned score for patients with low/int-1 disease TABLE 8: Estimated survival outcomes within each score range and proposed risk categories Recently, several newer models have been developed to address these issues, such as the WHO classification based prognostic scoring system, the global MD Anderson Cancer Center model, and the MD Anderson low-risk model. In one study, investigators found it possible to use the MD Anderson low-risk model to identify patients with lower-risk MDS and a poor prognosis who may benefit from early intervention (Tables 7 and 8). This model has been validated by several later studies and is being used to identify patients with poor prognosis lower-risk disease who could be candidates for early therapy. The implementation of this model may have significant implications for clinical trial design and eventually treatment decisions for patients with lower-risk MDS. Treatment The treatment of MDS is dictated by the risks imposed by the disease, age, and patient preference. Suggested guidelines are outlined in Table 9 and discussed later in this chapter. Supportive care The use of transfusions affords temporary benefits and is an alternative that can be considered in patients with lower-risk MDS or that otherwise can be used in conjunction with more definitive therapy. To delay or prevent end-organ complications, chelation therapy could be considered when RBC transfusions exceed 25 U or ferritin levels are > 1,000 to 2,500 ng/ml. Recent reports suggest that the use of chelation or growth factors may be associated with improved survival. Several ongoing prospective clinical trials, including a large phase III study (ClinicalTrials.gov identifier: NCT ), are evaluating the potential benefit of oral chelation in terms of event-free survival, hematologic improvement, and overall survival. Erythropoiesis-stimulating agents (ESAs). Darbepoetin or recombinant human erythropoietin (rhuepo) has been consistently used in patients with anemia and low-risk MDS. Although no Page 8 of 14

9 prospective randomized studies are available, response rates of 30% to 60% in terms of increased Hb threshold and improved transfusion dependency have been reported. In a study by Park et al, patients treated with ESAs had a better survival. Patients with low transfusion requirements (< 2 units of RBCs/month) and serum erythropoietin levels < 500 miu/ml are more likely to benefit from this approach. Early use of ESAs increases the likelihood of response. Addition of G-CSF in patients without hematological improvement can increase response rates. G-CSF and GM-CSF. G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF) may improve neutropenia and decrease infections in up to 70% of patients with MDS, but the effect is usually transient. No increase in the probability of developing AML has been demonstrated with extended use of these cytokines. Other alternatives TABLE 9: Suggested approach to the treatment of MDS Antithymocyte globulin. Antithymocyte globulin (ATG) has been associated with response (defined as independence from transfusions) in 34% of patients, which was sustained for a median of 36 months in 81% of them. Also, 48% had sustained platelet improvement and 55% had an increase in neutrophils. Younger patients are more likely to respond than older patients. A simple method for predicting response to immunosuppressive therapy in MDS has been proposed. It is based on the age of the patient, the duration of RBC transfusion dependence, and the HLA (human lymphocyte antigen)-dr15 status. Younger patients with a shorter duration of transfusion requirements have a higher predicted probability of response (40% to 100%), particularly when their status is positive for HLA-DR15. A subsequent validation study showed that age < 60 years is the most powerful predictor for response to ATG. However, benefit of ATG in terms of survival is controversial. A randomized study comparing ATG plus cyclosporine vs best supportive care showed higher response rates in the ATG arm, but ATG failed to have an impact on survival or risk of transformation to AML. Cyclosporine. Cyclosporine significantly increases cell colony growth in laboratory studies of hypoplastic rheumatoid arthritis. Responses have been reported in a limited number of patients. Lenalidomide. Lenalidomide (Revlimid) is a thalidomide analog that belongs to the immunomodulatory family of drugs. Lenalidomide has numerous properties that make it attractive for the management of neoplastic and inflammatory conditions, including the inhibition of production of cytokines such as tumor necrosis factor-α (TNF-α), IL-1, IL-6, IL-10, and IL-12. Lenalidomide is markedly more potent than thalidomide (Thalomid) in inhibiting the secretion of TNF-α. In addition, lenalidomide may potentiate erythropoietin-induced signaling in erythroid progenitors and stimulate stem cell differentiation to erythroid cells. Lenalidomide has been approved for the treatment of patients with MDS with abnormalities in the long arm of chromosome 5 (5q abnormalities), whether they are isolated or present together with other cytogenetic abnormalities. In 5q MDS, lenalidomide seems to act by inducing degradation of CK1α, a protein kinase that regulates apoptosis, and by correcting several of the molecular hallmarks that arise from 5q haploinsufficiency including normalization of SPARC (secreted protein acidic rich in cysteine; also known as osteonectin) and levels of the micro-rnas mir-145/mir-146a, stabilization of the protein MDM2 (mouse double minute 2 homolog), and inhibition of PP2A (protein phosphatase 2A) and CDC25C (M-phase inducer phosphatase 3). In a study of patients with transfusion-dependent MDS with 5q abnormalities, 75% of patients responded, with 66% of the total population becoming transfusion-independent. The response rate was similar regardless of whether the cytogenetic abnormality was isolated or seen in conjunction with other cytogenetic abnormalities, and more than half of the responses were durable for more than 1 year. In addition, a cytogenetic response was observed in 70% of patients. Recently, early use of lenalidomide in transfusion-independent patients with del(5q) MDS has shown to increase Hb levels, induce erythroid responses, and improve quality of life raising the question of the potential benefit of therapy prior to Page 9 of 14

10 transfusion dependency in this subset of patients. Lenalidomide has also been investigated for patients with MDS without 5q abnormalities. Erythroid responses were seen in over 40% of patients, with 27% of the total population becoming transfusion-independent. Preliminary data from an ongoing phase III trial confirm these results, showing 26.7% transfusion independency within the first 16 weeks of therapy, median duration of transfusion independence of 8.2 months, and no increased incidence of AML. Resistance or loss of response to lenalidomide and disease progression has been associated in several reports both to karyotypic complexity and TP53 mutations. Azacitidine and 5-aza-2'-deoxycytidine. Azacitidine (Vidaza) and 5-aza-2'-deoxycytidine (Dacogen, DAC, decitabine) are hypomethylating agents that have shown activity in MDS. In a randomized trial, 191 patients with MDS (63% RAEB or RAEB-t) were treated with azacitidine or supportive care. Responses were observed in 60% of those treated with azacitidine (complete response [CR], 6%; partial response [PR], 10%; hematologic improvement, 47%) compared with 5% with supportive care. There was a significant improvement in probability of transformation to AML and in overall survival when the confounding effect of early crossover to azacitidine was eliminated. Of note, the survival advantage with azacitidine is independent of bone marrow blast percentage, cytogenetics, and age. Recent data even confirm activity in patients with TP53 mutations. Azacitidine is approved by the US Food and Drug Administration (FDA) for the treatment of patients with all types of MDS. The standard dosage is 75 mg/m2/d subcutaneously for 7 days every 4 weeks, for as long as the patient benefits. Responses occur after a median of 3 to 4 cycles, so it is recommended to continue therapy for at least 4 to 6 cycles, unless there is significant toxicity or progression of disease. The dose may be increased to 100 mg/m2/d after 2 cycles if no improvement has occurred. Myelosuppression may occur but is not a reason to discontinue therapy, although increase in cycle periodicity to every 5 to 6 weeks can be considered to allow count recovery and not compromise further cycles of therapy. Patients should be supported during myelosuppression and should continue therapy to give them the best opportunity of response. In a post-approval phase III trial, treatment with azacitidine significantly improved survival by a median of 9 months (median survival, 25 months vs 15 months) compared with a conventional-care arm that included supportive care, low-dose cytarabine (Ara-C), and conventional leukemia induction and consolidation therapy. Several more recent studies have confirmed its impact on survival in elderly patients with high-risk MDS and AML. Development of an oral formulation of azacitidine (CC-486) has been developed both for patients with MDS and AML. Recently published data from a phase III international trial of CC-486 in patients with low-risk MDS showed ORRs of 36% to 41%, with 31% to 38% of patients achieving transfusion independency. Decitabine is approved by the FDA for the treatment of patients with all types of MDS. In a multicenter phase II study, 66 patients (73% RAEB or RAEB-t) were treated with decitabine. The overall response rate was 49% (CR, 20%; PR, 4%; improvement, 24%). The actuarial median response duration was 31 weeks, and median survival was 22 months. In addition, 31% of patients with cytogenetic abnormalities presented before treatment achieved a cytogenetic response. Cytogenetic response conferred a survival advantage to these patients. However, in a post-approval phase III trial comparing treatment with decitabine to supportive care, decitabine yielded no survival advantage. Multiple dose schedules for decitabine have been explored; decitabine at 20 mg/m2 on a 5-day schedule has been shown to be superior to a 10-day or subcutaneous administration, and therefore should be considered the standard. There are scarce data on decitabine use in lower-risk patients. A phase II trial comparing a 3-day subcutaneous schedule with a weekly 3 months schedule showed no significant differences between study arms but reported 60% transfusion independence with minimal toxicity in patients with low-risk disease. Use of azacitidine at a lower dose schedule of 75 mg/m2 for 5 days or, conversely, decitabine at 20 mg/m2 for 3 days has been considered, due to the better response rates and lower toxicities observed in available studies. As a result of this, an ongoing phase II trial is comparing the effectiveness of these two treatment schedules in patients with lower-risk MDS. Chemotherapy The rationale for this strategy stems from the concepts that MDS is a clonal disorder and that MDS and AML are overlapping illnesses with an arbitrary frontier defined by the WHO and FAB classifications (ie, a 20% 30% blast threshold). The Cancer and Leukemia Group B (CALGB) treated 874 patients with AML and 33 patients with MDS with AML-like chemotherapy. The CR rate was 79% for patients with MDS vs 68% for patients with AML (P =.37), median CR duration was 11 vs 15 months (P =.28), and median survival was 13 vs 16 months. The authors concluded that the FAB distinction between MDS (RAEB and RAEB-t) and AML Page 10 of 14

11 has minimal therapeutic implications. Estey et al used AML-type chemotherapy to treat 372 patients with AML, 52 with RAEB, and 106 with RAEB-t. CR rates were 62% for patients with RAEB, 66% for those with RAEB-t, and 66% for those with AML (P =.79). Use of chemotherapy typically used for AML to treat patients with MDS tends to be associated with lower CR rates (ranging from 40% to 60%), shorter durations of response, and increased duration of aplasia compared with oucomes observed in patients with AML. Event-free survival was significantly better for patients with AML/RAEB-t than for patients with RAEB. However, when cytogenetics and other prognostic variables were considered in a multivariate analysis, no difference in outcome could be identified among FAB subgroups. These findings suggest that the prognosis is determined more by cytogenetics and other prognostic features than by the percentage of blasts or FAB classification. In fact, presence of an unfavorable karyotype such as 7/del(7q), complex karyotype, or TP53 mutations are associated with low CR rate and short duration of responses. Use of AML-like chemotherapy should therefore be limited to younger or fit patients with favorable cytogenetics who are candidates for allogeneic stem-cell transplantation. Combination regimens. Different combination chemotherapy regimens have been investigated. The combination of cytarabine and anthracycline is the cornerstone of intensive chemotherapy, leading to CRs in 40% to 60% of patients. However, despite the fact that cytogenetic remissions frequently accompany hematologic CRs, the median duration of remission and median survival times are brief, rarely exceeding 1 year. The death rate during induction therapy is 5% to 20%. Stem cell transplantation Stem cell transplantation (SCT) is a treatment option for some patients with MDS, although its timing remains controversial. An International Bone Marrow Transplant Registry analysis used a Markov model to examine three transplantation strategies for newly diagnosed MDS: transplantation at the time of diagnosis, transplantation at the time of progression to leukemia, and transplantation at an interval from diagnosis but prior to leukemic progression. Although transplantation at diagnosis may be superior for patients with intermediate-2 and high-risk IPSS scores, delayed transplantation was associated with improved life expectancy. Allogeneic SCT. Allogeneic SCT can be of benefit in a subset of patients with MDS. However, most series have concentrated on younger patients, who constitute a minority of patients with MDS and frequently have favorable cytogenetics and therefore a better prognosis. The best results to date have been reported in patients with a better prognosis (ie, those with RA/RARS). In most series, allogeneic SCT is associated with a long-term remission rate of approximately 40%, a relapse rate of 30%, and a rate of transplant-related death of 30%. The timing of transplantation remains controversial. Runde et al reported on a group of 131 patients (median age: 33 years; range: 2 55 years) who underwent allogeneic SCT as front-line therapy without prior induction chemotherapy. The 5-year disease-free survival rate was 34%, the overall survival rate was 41%, and transplant-related mortality was 38%. The actuarial probability of relapse at 5 years was 39%, with better results observed in the RA/RARS subgroup. Patients with adverse cytogenetics have a poor outcome with other treatment modalities, and SCT can be considered for such patients during first CR. A study from the International Bone Marrow Transplant Registry suggested early transplantation in high-risk MDS is associated with improved survival. However, there seems to be a survival cross-over at 3 years of therapy when compared with patients treated with hypomethylating agents, and results with allogeneic SCT remain poor in patients with chromosome 7 alterations; complex karyotype; and, as has been recently published, DNTM3A and TP53 mutations. Long-term outcome for these patients after SCT has not proved to be superior to outcomes of any other approach, although the procedure may prove to be curative in a small percentage of patients. The need for chemotherapy with hypomethylating agents prior to SCT remains controversial. Some authors support the use of AML-type chemotherapy for patients with > 10% blasts. Others favor use of hypomethylating agents or enrollment in clinical trials, particularly in patient populations with a lower likelihood of attaining CR, such as those with adverse cytogenetics or TP53 mutations. SCT should be considered in the setting of a clinical trial. New applications for allogeneic SCT with respect both to the conditioning regimen (non-myeloablative) and donor source (haploidentical and umbilical cord blood) are being explored to make this option available to a greater number of patients and in the case of reduced-intensity conditioning, to the typical patient with MDS (who is frequently older and has other associated medical problems). In fact, recent studies show similar outcomes in patients with MDS undergoing haploidentical transplantation vs MUD allogeneic SCT, along with feasibility of umbilical cord blood Page 11 of 14

12 transplantation in older patients (> 70 years) with MDS. However, further prospective studies are required to confirm these data. Autologous SCT. In the majority of patients with MDS, lymphocytes do not appear to be part of the clone, suggesting the presence of normal nonclonal stem cells. De Witte et al described 79 patients with MDS or secondary AML who underwent autologous SCT during first CR. The 2-year survival, disease-free survival, and relapse rates were 39%, 34%, and 64%, respectively. The 2-year survival rate for the MDS group was 40%, and treatment-related mortality was 9%. The best outcome was seen among patients with RA/RARS. However, autologous SCT is not considered standard of care in patients with MDS. Treatment recommendations Treatment of patients with MDS is an evolving and controversial issue, and enrollment in a clinical trial should be encouraged. Treatment can be considered according to the IPSS. Low or intermediate-1 IPSS scores. Patients with low or intermediate-1 IPSS scores can frequently be treated with supportive measures. Agents such as ATG and cyclosporine could be used alone or in combination in patients with hypocellular MDS. Patients with 5q benefit from lenalidomide, particularly in terms of erythroid response, and this should be considered the treatment of choice in these patients. Some patients with MDS without the 5q abnormality may also benefit from lenalidomide, but its use in this setting is still being investigated. Azacitidine should be considered for all patients in view of its effect on survival. Decitabine is another possible option for patients with MDS, although a recent study did not reveal a survival benefit. High or intermediate-2 IPSS scores. Patients with high or intermediate-2 IPSS scores have a significant risk of mortality from cytopenias or AML evolution. They should be considered for treatment options with the intention to cure, extend survival, or delay the progression of AML. In view of the survival effect of azacitidine, it should be considered as first-line therapy for patients with higher-risk disease. Preliminary results of a similar survival study with decitabine administered in the European 3-day schedule compared with best supportive care showed no survival benefit. Intensive chemotherapy did not appear to improve survival in an European Organisation for Research and Treatment of Cancer (EORTC) study. SCT. SCT is an alternative for younger patients with higher-risk MDS and an HLA-identical donor, particularly patients with adverse cytogenetic abnormalities. However, the best results to date have been reported in patients with a better prognosis (ie, younger patients and those with RA/RARS). Therefore, allogeneic transplantation and other transplant alternatives should be performed preferentially in a research setting (eg, mixed-unrelated donor, minitransplants, and haploidentical transplantation). Timing of transplant, although still controversial, should take into account factors such as donor type, cytogenetic abnormalities, and appropriate disease control to maximize outcome and decrease the risk of post-transplant relapse. For patients with lower-risk MDS, allogeneic transplantation should only be considered after the patient has failed to respond to multiple lines of therapy. Suggested Reading Bejar R, Stevenson K, Abdel-Wahab O, et al: Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med 364: , Bejar R, Stevenson KE, Caughey B, et al: Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation. J Clin Oncol 32: , Cutler CS, Lee SJ, Greenberg P, et al: A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: Delayed transplantation for low-risk myelodysplasia is associated with improved outcome. Blood 104: , Di Stasi A, Milton DR, Poon LM, et al: Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors. Biol Blood Marrow Transplant 20: , Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: A randomised, open-label, phase III study. Lancet Oncol 10: , Garcia-Manero G, Gore SD, Kambhampati S, et al: Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes. Leukemia 30: , Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al: Phase 1/2 study of the Page 12 of 14

13 combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 108: , Garcia-Manero G, Shan J, Faderl S, et al: A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia 22: , Garcia-Manero G, Yang H, Bueso-Ramos C, et al: Phase I study of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in patients with advanced leukemias and myelodysplastic syndromes. Blood 111: , Greenberg P, Cox C, LeBeau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: , Jädersten M, Saft L, Smith A, et al: TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 29: , Kantarjian H, Issa JP, Rosenfeld CS, et al: Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study. Cancer 106: , Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of 3 schedules of low-dose decitabine in higher-risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52 57, List A, Dewald G, Bennett J, et al: Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355: , Malcovati L, Germing U, Kuendgen A, et al: Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 25: , Mallo M, del Rey M, Ibañez M, et al: Response to lenalidomide in myelodysplastic syndomres with del(5q): Influence of cytogenetics and mutations. Brit J Haematol 162:74 86, Mughal TI, Cross N, Padron E, et al: An International MDS/MPN Working Group s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of mylodysplastic/myeloproliferative neoplasms. Haematologica 100: , Müller-Thomas C, Rudelius M, Rondak IC, et al: Response to azacitidine is independent of p53 expression in higher-risk myelodysplastic syndomres and secondary acute myeloid leukemia. Haematologica 99:e179 e181, Oliva EN, Lauseker M, Aloe Spiriti MA, et al: Early lenalidomide treatment for low and intermediate-1 International Prognostic Scoring System risk myelodysplastic syndromes with del(5q) before transfusion dependence. Cancer Med 4: , Papaemmanuil E, Gerstung M, Malcovati L, et al: Clinical and biological implications of driver mutation in myelodysplastic syndromes. Blood 122: , Raza A, Reeves JA, Feldman EJ, et al: Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111:86 93, Rollison DE, Howlader N, Smith MT, et al: Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, , using data from the NAACCR and SEER programs. Blood 112:45 52, Silverman LR, Demakos EP, Peterson BL, et al: Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the cancer and leukemia group B. J Clin Oncol 20: , Soriano AO, Yang H, Faderl S, et al: Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 110: , Steensma DP, Baer MR, Slack JL, et al: Preliminary results of a phase II study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndrome (MDS). Blood 110:434A 435A, Wijermans P, Suciu S, Baila L, et al: Low dose decitabine versus best supportive care in elderly patients with intermediate or high risk MDS not eligible for intensive chemotherapy: Final results of the randomized phase III study (06011) of the EORTC Leukemia and German MDS Study Groups. Blood 112:226, Source URL: Links: Page 13 of 14

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