Myelodysplastic syndromes MDS

This disease was first observed in the mid- to late-1970s when several patients presented with recurrent bacterial infections, primarily of the skin and subcutaneous tissues, middle ear and oropharyngeal mucosa. When examined in vitro, the neutrophils from these patients had defects in chemo-taxis, phagocytosis, particle-stimulated respiratory-burst activity and granulation. Some patients also had a leukocytosis, and many had a delayed umbilical cord separation. Treatment is by prophylactic antibiotic therapy and aggressive antibiotic therapy during infections, but mortality rates are very high. 

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  

Anaemia is common ( 11 g/dl, normal range 12-18 g/dl), and neutropenias, thrombocytopenias and monocytosis may be observed. 

Infection is the most common cause of morbidity and mortality in MDS patients, accounting for 40-60% of deaths in various studies. The common infections are those normally associated with neutropenias, such as Gramnegative septicaemia and bacterial bronchopneumonias. Indeed, most MDS patients are neutropenic at some stage in their disease. Even those who do not have a neutropenia may have a defect in their neutrophil function. Many patients have clearly-defined defects in T- and B-lymphocyte functions, and variable defects in monocyte numbers or function have been described. Disorders of neutrophil function are common. Many reports indicate that phagocytosis, chemotaxis, respiratory-burst activity and degranulation are defective in some MDS patients, and hypogranulation is often observed. 

There has been a great deal of interest in the use of colony-stimulating factors to treat MDS. GM-CSF and G-CSF, which have been used in clinical trials, offer a potential dual benefit. Firstly, they can affect neutrophil development in the bone marrow, and so can improve the neutropenia that is associated with these disorders. Secondly, they have the potential to increase or repair the function of circulating neutrophils. Indeed, there are some reports to indicate that these CSFs can result in enhanced function of peripheral blood neutrophils in these patients. Most patients show improvements in neutrophil counts after GM-CSF or G-CSF administration. In some cases, this has been associated with a decrease in the number of infective episodes. 

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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... 

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... 

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. 

Mechanisms by which ionizing radiation induces leukemia are of fundamental importance. Secondary myelodysplastic syndrome (MDS) is referred as one of stochastic late radiation effects and a stage for leukemia development. CD34-h cell counts were elevated both in BM and PB and significantly higher than in non-exposed. Blasts were identified as... 

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. 

In Phase II studies of agent 1 in patients with myelodysplastic syndrome (MDS), overall response rates of 42% to 54% were achieved, including complete responses in 20% to 28% of patients.14,15... 

An evaluation of occupational chemical exposure, histological subtype, and cytogenetics was conducted on case studies of newly diagnosed AML or CML, or myelodysplastic syndromes (MDS) treated in the Main Hospital of Torino, Northern Italy, between October 1, 1989 and December 31, 1990 (Ciccone et al. 1993). There was a nonstatistically significant increased relative risk for exposure to benzene. Data show 3 AML, 2 CML, and 4 MDS cases with regard to benzene exposures. No excess of clonal chromosome abnormalities was detected among occupationally exposed AML patients. 

FIGURE 16.12 Hypothetical scheme for the pathogenesis of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) following cancer chemotherapy with alkylating agents. 

Despite these promising clinical data, the toxicities, cost, and complexities of administration have limited the use of radioimmunotherapy. The murine antibodies induce an immune response. This may manifest as acute infusion reactions and human anti-murine antibodies (HAMA), which occur in approximately 2% of patients treated with Y ibritumomab tiuxetan and 9% of patients treated with I tositumomab. Myelosuppression 6-9 weeks after administration is common. Ten percent of patients treated with I tositumomab develop hypothyroidism [92]. The most feared complication of radioimmunotherapy is treatment-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Rates of these late, generally incurable toxicities range 1.5—2.5% for Y ibritumomab tiuxetan and 3.5—6.4% for tositumomab [63, 93, 94]. Because ionizing radiation is teratogenic, radioimmunotherapy is contraindicated in all stages of pregnancy. 

Elastic transformation of chronic myeloid leukemia (BT-CML) ANLL after myelodysplastic syndromes (ANLL-MDS) Myelodysplastic syndromes (MDS)... 

Cashen AF, Shah AK, Todt L, Fisher N, DiPersio J. Pharmacokinetics of decitabine administered as a 3-h infusion to patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Cancer Chemother Pharmacol 2008 61(5) 759-66. 

Cephalotaxine and its esters are of particular chemical and medical interest. Among these, 18 and harringtonine are most promising anticancer agents [89]. Homoharringtonine has been submitted to extensive phase 1/11 clinical studies in patients with different solid tumors, such as malignant melanoma, sarcoma, head and neck carcinoma, breast carcinoma, and colorectal carcinoma. Also, several clinical trials include studies efficacy in patients with acute leukemia, myelodysplastic syndrome (MDS), acute promyelocytic leukemia (APL), and chronic myeloid leukemia [90]. 

Nolte F, Hochsmann B, Giagounidis A, Lubbert M, Platzbecker U, Haase D, et al. Results from a 1-year, open-label, single arm, multi-center trial evaluating the efficacy and safety of oral deferasirox in patients diagnosed with low and int-1 risk myelodysplastic syndrome (MDS) and transfusion-dependent iron overload. Ann Hematol January 2013 92(2) 191-8. 

Expression of NOS by Leukemia Cells and Myelodysplastic Syndrome (MDS) Cells... 

A Randomized Controlled Phase 3 Study of Oral Paeritinib Versus Best Available Therapy in Patients With Primaiy Myelofibrosis, Post-Polyc5 themia Vera Myelofibrosis, or Post-Essential Thrombotythemia Myelofibrosis Phase II Study of SB1518 for Patients With Myelodysplastic Syndrome (MDS)... 

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