Myelodysplastic syndromes

GM-CSF, G-CSF, M-CSF, multi-CSF cytotoxic injury bone marrow transplantation myelodysplastic syndromes AIDS neutropenia rodent and human... 

Azacitidine is used for treating patients with some myelodysplastic syndrome subtypes and chronic mye-lomonocytic leukemia. The most commonly occurring adverse reactions include nausea, anemia, thrombocytopenia, vomiting, pyrexia, leucopenia, diarrhea, fatigue, neutropenia, and ecchymosis. 

Decitabine is specifically indicated for the treatment of multiple types of myelodysplastic syndromes and chronic myelomonocytic leukemia. As anticipated, use of decitabine is associated with bone marrow suppression including neutropenia and thrombocytopenia which are the most frequently observed serious adverse effects. 

Patients in the more aggressive categories are less likely to exhibit involvement of the skin and have a less favorable prognosis [10]. Those patients may have a definable hematological disorder such as a myelodysplastic syndrome, myeloproliferative disorder, acute leukemia, or a malignant lymphoma. In aggressive mastocytosis and mast cell leukemia, the clinical course is determined by the rapidity of the increase in mast cell numbers. 

Azacitidine, a cytidine analog, causes hypomethylation of DNA, which normalizes the function of genes that control cell differentiation to promote normal cell maturation. The suspension is administered as a subcutaneous injection daily for 7 days for the treatment of myelodysplastic syndrome, a preleukemia disease. The pharmacokinetics of azacitidine are best described by a two-compartment model, with a terminal half life of 3.4 to 6.2 hours, whereas peak concentrations are achieved 30 minutes after a subcutaneous injection.7 Azacitidine has been shown to be clinically active in the treatment of myelodysplastic syndromes. The side effects include myelosuppression, renal tubular acidosis, renal dysfunction, and injection-site reactions. 

Topotecan inhibits topoisomerase I to cause single-strand breaks in DNA. The pharmacokinetics of topotecan can be described by a two-compartment model, with a terminal half-life of 80 to 180 minutes, with renal clearance accounting for approximately 70% of the clearance.19 Topotecan has shown clinical activity in the treatment of ovarian and lung cancer, myelodysplastic syndromes, and acute myelogenous leukemia. The intravenous infusion may be daily for 5 days or once weekly. Side effects include myelosuppression, mucositis, and diarrhea. 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

Lenalidomide was approved recently for the indication of myelodysplastic syndrome where the 5q deletion is present. Since lenalidomide is an analog of thalidomide, all the same precautions must be taken to prevent phocomelia. The time to maximum lenalidomide concentrations occurs 0.5 to 4 hours after the dose. The terminal half-life ranges from 3 to 9 hours. Approximately 65% of lenalidomide is eliminated unchanged in the urine, with clearance exceeding the glomerular filtration rate. To date, no pharmacokinetic studies have been done in patients with renal dysfunction. Lenalidomide is used in the treatment of myelodysplastic syndrome and multiple myeloma. Other side effects are neutropenia, thrombocytopenia, deep vein thrombosis, and pulmonary embolus. 

Risk factors for the development of AML include exposure to environmental toxins, Hispanic ethnicity, and genetics.6 Of greater concern is the increased prevalence of AML as a secondary malignancy, resulting from chemotherapy and radiation treatment for other cancers. Alkylating agents, such as ifosfamide and cyclophosphamide, and topoisomerase inhibitors, such as etoposide, are linked to an increased risk of myelodysplastic syndrome (MDS) and AML.8... 

For patients with myelodysplastic syndrome or AML as a secondary neoplasm, there are a number of key features characteristic of the leukemia. Alkylator-related secondary leukemias after Hodgkin s disease usually have a myelodysplastic prodrome and a monosomy 5 or monosomy 7. Secondary ANLL with the use of epipodophyllotoxin (etoposide) demonstrates mainly M4 or M5 morphology and exhibits translocations within the MLL gene with 1 lq23 chromosomal alterations.8... 

Even though chromosomal abnormalities correlate with prognosis in adult AML, they appear to have less influence on outcome. Among children, the male gender, platelet count of less than 20 x 1 03/jllL (20 x 109/L), hepatomegaly, more than 15% bone marrow blasts on day 14 of induction, myelodysplastic syndrome (MDS), and FAB sub-type M5 all were associated with lower CR rates. The absence of these features and abnormal chromosome 16 were associated with more favorable outcomes.6... 

Lenalidomide is an immunomodulating agent related to thalidomide that was recently approved for the treatment of patients with multiple myeloma and myelodysplastic syndrome (MDS). Lenalidomide lacks the common side effects of thalidomide, such as constipation and peripheral neuropathy. Interim analyses of two phase III trials show that lenalidomide in combination with dexamethasone produces higher response rates than dexamethasone alone in relapsed and refractory myeloma. Adverse effects of lenalidomide include diarrhea, nausea, muscle cramps, hematologic side effects and deep vein thrombosis.42... 

Cancers Multiple myeloma Non-Hodgkin s lymphoma Hodgkin s disease Acute myeloid leukemia Neuroblastoma Germ cell tumors Acute myeloid leukemia Acute lymphoblastic leukemia Chronic myeloid leukemia Myelodysplastic syndrome Myeloproliferative disorders Non-Hodgkin s lymphoma Hodgkin s disease Chronic lymphocytic leukemia Multiple myeloma... 

Myelodysplastic syndrome A diverse collection of hematologic conditions united by ineffective production of some or all of the blood cells. 

Radioimmunotherapy is generally well tolerated. Toxicities include infusion-related reactions, myelosuppression, and possibly myelodysplastic syndrome or AML. 131I-tositumomab can cause thyroid dysfunction. 

Miyazato, A., et al., "Identification of Myelodysplastic Syndrome-Specific Genes by DNA Microarray Analysis with Purified Hematopoietic Stem Cell Fraction," Blood, 98, 422-427 (2001). 

G-CSF increases the number of progenitor cells in the bloodstream tenfold. It has been used in the treatment of patients with myelodysplastic syndromes (MDS 8.8) where it can increase neutrophil counts and sometimes improve neutrophil function in these patients. Because some leukaemic cells are able to proliferate rather than differentiate in response to G-CSF, this CSF may potentially induce a leukaemic transformation in these patients however, its combined use with cytotoxic agents such as cytosine arabinoside appears to decrease this possibility. No doubt clinical trials already underway will establish the optimal treatment regimen for G-CSF, so that the beneficial effects of this cytokine for the treatment and management of haematological disorders can be realised. 

Neutropenias may also arise as a side effect or deliberate consequence of therapy. For example, some drugs used in the treatment of inflammatory disorders are immunosuppressive, and if these decrease the number of circulating neutrophils to below the critical threshold level, then susceptibility to infection may result. During chemotherapy for the treatment of solid tumours, an inevitable consequence of cytotoxic therapy is that the bone marrow will be destroyed by the drugs thus, patients will have a considerable risk of infection during this induction period. Similarly, during the treatment of haematological disorders (e.g. leukemias and myelodysplastic syndromes), the aim of therapy is to attack the bone marrow so as to destroy... 

The myelodysplastic syndromes are a group of heterogeneous, haemato-logical disorders characterised by a defect in the production of one or more haematopoietic cell lineages. MDS is often associated with the elderly (age >60 yr), and many patients progress into acute leukaemia. The French-American-British (FAB) group characterise MDS into five subgroups ... 

Yuo, A., Kitagawa, S., Okabe, T., Urabe, A., Komatsu, Y., Itoh, S., Takaku, F. (1987). Recombinant human granulocyte colony-stimulating factor repairs the abnormalities of neutrophils in patients with myelodysplastic syndromes and chronic myelogenous leukemia. Blood 70,404-11. 

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