Myelodysplastic syndrome treatment

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. 

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... 

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... 

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... 

Cys i replaced by Ser) mahgnant skin tumours and in the treatment of aplastic anaemia and myelodysplastic syndrome... 

The inhibitors available for human use, azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome (MDS) [98, 99[. MDS summarizes a set of different conditions that affect the maturation of blood cells. It is a group of bone marrow stem cell malignancies that have a pathogenetic overlap with acute myeloid leukemia, show peripheral blood cytopenias and, in more advanced subtypes, varied degrees of maturation arrest [100]. Both drugs are approved for all subtypes of MDS. Response rates are usually around 30%. The question whether the clinical benefit results more from epigenetic effects and re-activation of silenced maturation factors or more from cytotoxic effects on the immature hyperproliferative cells remains open. 

Griffiths, E.A. and Gore, S.D. (2008) DNA methyltransferase and histone deacetylase inhibitors in the treatment of myelodysplastic syndromes. Seminars in Hematology, 45, 23-30. 

Kuendgen, A. and Lubbert, M. (2008) Current status of epigenetic treatment in myelodysplastic syndromes. Annals of Hematology (in press). 

H. Other considerations Epoetin alfa has been designated an orphan product for use in the treatment of anemia of end-stage renal disease, HIV infection, or prematurity in preterm infants, or treatment of myelodysplastic syndrome. 

CC-4047 (Actimid) is another IMiD that is being investigated for the treatment of myelodysplastic syndrome, myeloma, and prostate cancer. 

Deferasirox is a tridentate chelator with a high affinity for iron and low affinity for other metals, eg, zinc and copper. It is orally active and well absorbed. In the circulation, it binds iron, and the complex is excreted in the bile. Deferasirox was recently approved for the oral treatment of iron overload caused by blood transfusions, a problem in the treatment of thalassemia and myelodysplastic syndrome. 

Negrin RS, Haeuber DH, Nagler A, Kobayashi Y, et al. 1990. Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte-colony stimulating factor. Blood. 76 36—43. 

Bennett JM, Kaminski MS, Leonard JP, Vase JM, et al. 2005. Assessment of treatment-related myelodysplastic syndromes and acute myeloid leukemia in patients with non-Hodgkin lymphoma treated with tositumomab and Iodine I 131 tositumomab. Blood. 1052 4576-4582. 

Anabolic steroids are also still used in refractory anemias, although with recombinant human erythropoietin now widely available they appear to be seen mainly as a means of increasing the response to erythropoietin in highly resistant cases combination treatment with erythropoietin, a glucocorticoid, and nandrolone has also been recommended for treating myelodysplastic syndromes (13). Again, in such exceptional situations the risks of anabolic steroids have to be accepted. 

Owing to thalidomide s serious toxicity profile, considerable effort has been expended in the development of analogs. Immunomodulatory derivatives of thalidomide are termed IMiDs. Some IMiDs are much more potent than thalidomide in regulating cytokines and affecting T cell proliferation. CC-5013 (Revimid) is an IMiD that in in vitro and animal studies has been shown to be similar to thalidomide in action but without the sedative effects or teratogenicity. CC-5013 is currently in phase I and II clinical trials for the treatment of myeloma, some myelodysplastic syndromes, and melanoma. Preliminary results show efficacy with decreased toxicity compared with thalidomide. 

Risks in patients with Hodgkin s disease The actuarial risks of developing secondary malignancies and/or myelodysplastic syndrome at 5, 10, and 15 years after treatment for Hodgkin s disease have been calculated (76). 

Hoppe RT. Secondary leukemia and myelodysplastic syndrome after treatment for Hodgkin s disease. Leukemia 1992 6(Suppl 4) 155-7. 

Su YW, Chang MC, Chiang MF, Hsieh RK. Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade ghoma. J Neurooncol 2005 71(3) 315-18. 

An 82-year-old woman with a myelodysplastic syndrome died of Escherichia coli septicemia after 5 months of treatment with deferiprone (17). There was no granulocytopenia. 

In a prospective, multicenter, cohort study of 113 patients with aplastic anemia under 18 years of age, 12 developed myelodysplastic syndrome after a median of 37 months after the diagnosis of aplastic anemia and four others developed other cytogenetic clonal changes, of which the most common abnormality was monosomy 7 (80). From a multivariate analysis, G-CSF treatment duration and non-response to immunosuppressive therapy at 6 months were statistically significant risk factors for the development of myelodysplastic syndrome. The... 

The risk of secondary cancer has been assessed in 412 children treated with etoposide and anthracyclines for acute lymphoblastic leukemia, 99 of whom also received G-CSF and 58 of whom received cranial irradiation (91). Overall, 20 children developed myeloid leukemia and myelodysplastic syndrome at a median of 2.3 years after treatment. The 6-year cumulative incidence of these secondary cancers was 11% among patients who received G-CSF, close to that observed in those who received cranial irradiation (12%), but significantly higher than in those who received neither irradiation nor G-CSF (2.7%). 

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