UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) are a heterogeneous and common group of clonal hematological disorders characterized by cytopenias, dysplastic changes of hematopoietic cells, and a high rate of transformation into acute myeloblastic leukemia (AML). MDS provide a clinical model for studying the emergency and progression of malignancy. The initiating events leading to MDS remain almost unknown. Imbalance of proliferative and differentiating capabilities of progenitor hematopoietic cells along with abnormalities in the normal process of apoptosis are involved in both the pathogenesis of MDS and transformation into AML. Multiple genomic lesions, comprising oncogene activation and tumor-suppressor gene inactivation, are probably required. Alkylating agents, cytotoxic drugs targeting topoisomerase II and benzene are the only clear etiological factors identified. Advanced age and great prognostic variability, not explained by the FAB subtype, complicates the design and analysis of clinical trials and therapy-planning. The use of recently developed prognostic scores for selecting the best treatment according to the expected risk is encouraged. In most patients therapy is unsatisfactory. At present, bone marrow transplantation is considered as the only curative approach. A better knowledge of the pathobiology of MDS should be valuable to develop new, more rationale and effective therapies.
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PMID:Etiopathogeny, prognosis and therapy of myelodysplastic syndromes. 949 87

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.
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PMID:RAS mutations in pediatric leukemias with MLL gene rearrangements. 952 5

We report 4 unusual cases of myelodysplastic syndrome with distinct persistent nodular lesions noted on serial bone marrow examinations, even during remission. The lesions were predominantly composed of immature monocytes that stained positively for CD68. Trisomy 9 and 11 were demonstrated in the cells of the nodular lesions and surrounding marrow of 1 patient, indicating the same clonal origin. Evaluation of p53 glycoprotein, retinoblastoma protein (pRb), proliferation-related protein (Ki-67), multiple drug-resistant enzyme glutathione-S-transferase pi, and topoisomerase IIalpha (Topo IIalpha) revealed decreased topoisomerase expression within the nodular lesions compared with the surrounding marrow and absence of Ki-67 antigen within nodular lesions. Most cells in the lesion were not in a proliferative cycle, with very low expression of Topo IIalpha, which may explain the apparent drug resistance of these nodular lesions.
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PMID:Nodular lesions of monocytic component in myelodysplastic syndrome. 1019 82

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders with an invariably fatal outcome. Other than bone marrow transplantation, no treatment has been able to alter the natural history of MDS. As a result, there has been an interest in identifying new and more effective chemotherapeutic agents. Many of the drugs that have been evaluated in an attempt to increase remissions and prolong survival were selected because of their activity in acute myeloid leukemia. Thus cytarabine has been the most widely studied drug. Although numerous studies suggested activity for low-dose cytarabine (LoDAC), a careful analysis of the data identified a complete remission (CR) rate of less than 20%, without meaningful clinical benefit. The issue of LoDAC was finally put to rest by a randomized trial in which survival was no better than with supportive care. 5-Azacytidine induces cellular differentiation by hypomethylation of DNA. Phase II trials noted CRs in fewer than 10% of patients, with response rates under 30%, although additional patients appeared to experience hematologic and clinical benefit. A randomized trial of 5-azacytidine versus supportive care failed to demonstrate a survival benefit. One of the most promising new agents is the topoisomerase inhibitor topotecan, which achieves CRs in more than 30% of patients. Combinations of this drug with other active agents are in development. Obviously, new treatment strategies are needed to improve the outcome of MDS patients. Combination approaches incorporating new, active agents should have sound scientific rationale, targeting biological differences among the various MDS subtypes.
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PMID:Standard and low-dose chemotherapy for the treatment of myelodysplastic syndromes. 973 95

The major established cause of acute myeloid leukemia (AML) in the young is cancer chemotherapy. There are two forms of treatment-related AML (t-AML). Each form has a de novo counterpart. Alkylating agents cause t-AML characterized by antecedent myelodysplasia, a mean latency period of 5-7 years and complete or partial deletion of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline NF-1 and p53 gene mutations and the GSTT1 null genotype may increase the risk. Epipodophyllotoxins and other DNA topoisomerase II inhibitors cause leukemias with translocations of the MLL gene at chromosome band 11q23 or, less often, t(8;21), t(3;21), inv(16), t(8;16), t(15;17) or t(9;22). The mean latency period is about 2 years. While most cases are of French-American-British (FAB) M4 or FAB M5 morphology, other FAB AML subtypes, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) occur. Between 2 and 12% of patients who receive epipodophyllotoxin have developed t-AML. There is no relationship with higher cumulative epipodophyllotoxin dose and genetic predisposition has not been identified, but weekly or twice-weekly schedules and preceding l-asparaginase administration may potentiate the risk. The translocation breakpoints in MLL are heterogeneously distributed within a breakpoint cluster region (bcr) and the MLL gene translocations involve one of many partner genes. DNA topoisomerase II cleavage assays demonstrate a correspondence between DNA topoisomerase II cleavage sites and the translocation breakpoints. DNA topoisomerase II catalyzes transient double-stranded DNA cleavage and rejoining. Epipodophyllotoxins form a complex with the DNA and DNA topoisomerase II, decrease DNA rejoining and cause chromosomal breakage. Furthermore, epipodophyllotoxin metabolism generates reactive oxygen species and hydroxyl radicals that could create abasic sites, potent position-specific enhancers of DNA topoisomerase II cleavage. One proposed mechanism for the translocations entails chromosomal breakage by DNA topoisomerase II and recombination of DNA free ends from different chromosomes through DNA repair. With few exceptions, treatment-related leukemias respond less well to either chemotherapy or bone marrow transplantation than their de novo counterparts, necessitating more innovative treatments, a better mechanistic understanding of the pathogenesis, and strategies for prevention.
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PMID:Secondary leukemias induced by topoisomerase-targeted drugs. 974 98

The treatment of cancer with alkylating drugs or topoisomerase II inhibitors can be responsible for the development of myelodysplastic syndromes and acute myelogenous leukemia. Alkylating agents such as melphalan and cisplatinum mainly produce damages at chromosomes 5 and 7 whereas topoisomerase II inhibitors-induced lesions essentially affect chromosomes 11 and 21. Rearrangements of the MLL gene at band 11q23 are frequently observed in human de novo myeloid and lymphoid leukemia as well as in leukemia or myelodysplasia secondary to therapy with drugs targetting topoisomerase II such as the epipodophyllotoxins. A relationship between the treatment with etoposide on teniposide and the development of translocations of the MLL gene has been clearly evidenced. The potential molecular basis of the chromosomal rearrangements implicating topoisomerase II and its inhibitors are discussed. The chemical structure of the inhibitors, their mechanism of action and the genes targetted by these drugs are presented. DNA cleavages induced directly by topoisomerase II inhibitors or by the drug induced apoptotic cellular response are responsible for nonrandom chromosomal aberrations and contribute to leukemogenesis.
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PMID:[Chromosome translocations and leukemias induced by inhibitors of topoisomerase II anticarcinogenic drugs]. 975 16

CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.
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PMID:CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. 976 73

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are heterogeneous disorders for which there exist few active therapies and where the standard of care is still considered supportive. Identification of new effective therapies in MDS and CMML is a high priority for hematologic oncologists. We have evaluated the efficacy of single-agent topotecan, a topoisomerase I inhibitor, in patients with MDS (refractory anemia with excess blasts [RAEB] and refractory anemia with excess blasts in transformation [RAEB-T]) and CMML. Sixty patients (MDS = 30; CMML = 30) with a median age of 66 years were treated. Chromosomal abnormalities were present in half of the patients, as was thrombocytopenia. Topotecan was administered at 2 mg/m2 by continuous intravenous infusion over 24 hours daily for 5 days every 4 to 6 weeks until remission, followed by one course every 4 to 8 weeks for a maximum of 10 courses. Nineteen patients (32%) achieved a complete response (CR); seven had hematologic improvement. CRs were observed in 11 of 30 patients with MDS (37%) and eight of 30 patients with CMML (27%). Conversion to diploid karyotype was observed in eight patients with karyotypic abnormalities at diagnosis who later achieved a CR. History of prior chemotherapy and monocytosis was associated with poor prognosis. Mutation of the RAS oncogene was found in six CMML patients (20%), and none responded to topotecan therapy. The estimated 12-month survival rate was 33%, the median survival time was 9.3 months, and the median remission duration was 7 months. The most significant toxicities were gastrointestinal, including mucositis (67%; severe 23%) and diarrhea (38%; severe 17%). Febrile episodes were noted in 85% of the patients, while documented infection occurred in 47%. Topotecan has demonstrated significant single-agent activity in MDS and CMML with generally manageable side effects. Future studies will evaluate topotecan-based combination therapies with topoisomerase II reactive agents, cytarabine, alkylating agents, and hypomethylating agents.
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PMID:Topotecan in the treatment of hematologic malignancies. 977 79

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).
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PMID:Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. 992 42

Two main types of therapy-related acute myeloid leukemias (tAML) and myelodysplastic syndromes (tMDS) have been described. The first classical type typically occurs late after use of alkylating agents and presents as MDS with -7/del 7q and/or -5/del5q. The second form occurs early after the use of agents targeted at topoisomerase II, and presents as AML with 11q23 or other rearrangements of de novo AML. Recently, we and others reported, in AML and MDS, a strong correlation between cytogenetic rearrangements leading to 17p deletion, a specific type of dysgranulopoiesis and p53 mutation; several of those cases of 17p- syndrome were therapy-related. Over the last 15 years, we observed 25 cases of tAML and tMDS with 17p deletion, which represented 36% of the AML and MDS with 17p deletion diagnosed during that period. Median age was 59 years. Twenty-one patients had tMDS and four tAML. Typical dysgranulopoiesis and p53 mutation and/or overexpression were seen in 22 of 24 and 16 of 19 evaluable patients, respectively. 17p deletion resulted from unbalanced translocations involving 17p (18 cases), monosomy 17 (five cases), i(17q) (one case) or del 17p (one case). Twenty-one patients also had -5/del 5q, and/or -7/del 7q. Median interval from treatment of the first tumor of tAML and tMDS was 94 months (range 19-252). Median survival was only 7 months. Based on primary tumor and antineoplastic agents used, patients could be relatively well divided into two groups: a first group of 11 cases, occurring mainly after a lymphoid neoplasm (eight cases) treated by chemotherapy with an alkylating agent (10 cases), and a second group of 14 cases occurring after essential thrombocythemia (ET) or polycythemia vera (PV) treated mainly by hydroxyurea (10 cases), pipobroman (eight cases), 32P (six cases) but rarely by alkylating agents (two cases). -7/del 7q was found in 10 of the 11 patients in the first group, as compared to three of the 14 patients of the second group (P = 0.0001). Therefore, therapy-related cases represent a high proportion of AML and MDS with the 17p- syndrome. They have many features in common with classical tMDS and tAML, including long interval from the first tumor, a usual preleukemic phase, and frequent occurrence of -5/del 5q. About one half of them, in addition, occur after alkylating agents and generally carry -7/del 7q. The other half, however, occur mainly after ET or PV treated by hydroxyurea or other non-alkylating agents, and usually have no -7/del 7q. These findings bring further support to a possible relationship between prior drugs used and cytogenetic rearrangements in tAML and tMDS.
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PMID:Therapy-related myelodysplastic syndrome and acute myeloid leukemia with 17p deletion. A report on 25 cases. 1002 99

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