Myelodysplastic syndrome (MDS) in many patients is characterized by peripheral blood cytopenias in the presence of cellular or hypocellular marrow. While a proportion of patients will eventually develop acute leukemia, 40 percent-50 percent of patients die with hemorrhagic or infectious complications. Satisfactory therapy, in the form of hemopoietic stem cell transplantation, is available only to a small proportion of patients. New treatment modalities are needed. Recent studies show increased expression of negative regulators of hemopoiesis such as tumor necrosis factor (TNF)-alpha and a high rate of apoptosis (programmed cell death) in MDS marrow. Preliminary investigations suggest that hemopoiesis can be improved by blocking negative regulatory signals or by eliminating the cellular source of those signals. The applicants propose to 1) conduct a series of clinical trials to determine the efficacy of TNFR:Fc (a soluble TNF receptor), antithymocyte globulin (ATG, an anti-T-cell agent), and flt3-ligand (an early activating cytokine) alone and in combination, in improving peripheral cytopenias and stabilizing hemopoiesis in patients with MDS; 2) to carry out in vitro/ex vivo studies on marrow from patients enrolled in those trials to characterize morphology, immunophenotype, expression of TNF-alpha, Fas and Fas-ligand, as well as cytogenetic abnormalities, before and after therapy and to correlate in vitro/ex vivo parameters with in vivo treatment responses and """"""""quality"""""""" of response; 3) to develop additional treatment approaches utilizing new probes and reagents. These studies are expected to generate data that will guide the selection of patients for future specific protocols. Optimization of therapy, in turn, should reduce morbidity and mortality associated with MDS and improve the quality of life of patients with MDS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA087948-04
Application #
6633823
Study Section
Special Emphasis Panel (ZRG1-CONC (01))
Program Officer
Wu, Roy S
Project Start
2000-07-01
Project End
2006-06-30
Budget Start
2003-07-18
Budget End
2006-06-30
Support Year
4
Fiscal Year
2003
Total Cost
$389,250
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Deeg, H Joachim; Bredeson, Christopher; Farnia, Stephanie et al. (2015) Hematopoietic Cell Transplantation as Curative Therapy for Patients with Myelofibrosis: Long-Term Success in all Age Groups. Biol Blood Marrow Transplant 21:1883-7
Salit, Rachel B; Deeg, H Joachim (2014) Role of hematopoietic stem cell transplantation in patients with myeloproliferative disease. Hematol Oncol Clin North Am 28:1023-35
Marcondes, Mario; Deeg, H Joachim (2008) Hematopoietic cell transplantation for patients with myelodysplastic syndromes (MDS): when, how and for whom? Best Pract Res Clin Haematol 21:67-77
Iwata, Mineo; Pillai, Manoj; Ramakrishnan, Aravind et al. (2007) Reduced expression of inducible gelatinase B/matrix metalloproteinase-9 in monocytes from patients with myelodysplastic syndrome: Correlation of inducible levels with the percentage of cytogenetically marked cells and with marrow cellularity. Blood 109:85-92
Lesnikov, V A; Abbasi, N; Lesnikova, M P et al. (2006) Protection of human and murine hepatocytes against Fas-induced death by transferrin and iron. Apoptosis 11:79-87
Deeg, H Joachim (2006) Transplant strategies for patients with myelodysplastic syndromes. Curr Opin Hematol 13:61-6
Scott, Bart L; Sandmaier, Brenda M (2006) Outcomes with myeloid malignancies. Hematology Am Soc Hematol Educ Program :381-9
Scott, Bart; Deeg, H Joachim (2006) Hemopoietic cell transplantation as curative therapy of myelodysplastic syndromes and myeloproliferative disorders. Best Pract Res Clin Haematol 19:519-33
Deeg, H Joachim (2005) Optimization of transplant regimens for patients with myelodysplastic syndrome (MDS). Hematology Am Soc Hematol Educ Program :167-73
Wilson, H M P; Lesnikov, V; Plymate, S R et al. (2005) High IGFBP-3 levels in marrow plasma in early-stage MDS: effects on apoptosis and hemopoiesis. Leukemia 19:580-5

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