Universitätsklinik für Innere Medizin III mit Hämatologie, internistischer Onkologie, Hämostaseologie, Infektiologie, Rheumatologie und Onkologisches Zentrum, Landeskrankenhaus Salzburg, Universitätsklinikum der Paracelsus Medizinischen Privatuniversität.
A 77-year-old patient with a known autoimmune hemolysis for years was treated with steroids, rituximab, cyclophosphamid, cyclosporin A. Because of accompanying thrombopenia he received eltrombopag and underwent splenectomy but without lasting effect. After 3 years he presented with decreased leukocytes and worsening of thrombopenia.
A peripheral blood count showed moderate pancytopenia without blasts or left shift. Bone marrow biopsy revealed myelodysplasia with excessive blasts, cytogenetics showed partial trisomy 18q.
Treatment and course:
Because of the high risk of transformation to acute myeloid leukemia treatment with 5-azacytidine was started. Thrombopenia rapidly improved, but after an infectious complication treatment was paused for several months due to patient wish. Treatment was started again after 11 months because of progressive thrombopenia and resulted in a rapid hematological improvement.
The new diagnosis of a myelodysplastic syndrome should be considered in the case of new cytopenia even in the presence of an already established hematological disease.
[Show abstract][Hide abstract] ABSTRACT: Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens.
In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799.
Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments.
Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.
The Lancet Oncology 03/2009; 10(3):223-32. DOI:10.1016/S1470-2045(09)70003-8 · 24.69 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Thrombopoietin-receptor agonists (TPO-RAs) have been approved for use in immune thrombocytopenia (ITP) after showing safety and efficacy. There is increasing interest to expand the role of TPO-RAs, both in ITP as well as in other thrombocytopenic disorders.
In ITP, more studies are providing evidence of TPO-RA efficacy and safety, as well as their applicability to various patient groups, including children. Use of TPO-RAs in hepatitis C has shown early success in allowing treatments in patients who would otherwise be excluded due to thrombocytopenia. Use in congenital thrombocytopenias has also shown early success. The use of TPO-RAs in myelodysplastic syndrome (MDS) is questionable after reports of increasing blasts and leukemic transformation, whereas in other chemotherapy-induced thrombocytopenias (C-ITs) reports are few. Bone marrow fibrosis remains an area of active study, although the data to date suggest this is seen in a small minority of patients, and is reversible and of questionable clinical relevance. Thrombotic complications are also an area of concern and need further close follow-up.
The use of TPO-RAs continues to grow as more evidence of safety and efficacy is found. More studies are needed to determine their utility in other diseases as well as to better characterize adverse events observed to date.
Current opinion in hematology 08/2012; 19(5):392-8. DOI:10.1097/MOH.0b013e328356e909 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The impact of ten-eleven-translocation 2 (TET2) mutations on response to azacitidine (AZA) in MDS has not been reported. We sequenced the TET2 gene in 86 MDS and acute myeloid leukemia (AML) with 20-30% blasts treated by AZA, that is disease categories wherein this drug is approved by Food and Drug Administration (FDA). Thirteen patients (15%) carried TET2 mutations. Patients with mutated and wild-type (WT) TET2 had mostly comparable pretreatment characteristics, except for lower hemoglobin, better cytogenetic risk and longer MDS duration before AZA in TET2 mutated patients (P=0.03, P=0.047 and P=0.048, respectively). The response rate (including hematological improvement) was 82% in MUT versus 45% in WT patients (P=0.007). Mutated TET2 (P=0.04) and favorable cytogenetic risk (intermediate risk: P=0.04, poor risk: P=0.048 compared with good risk) independently predicted a higher response rate. Response duration and overall survival were, however, comparable in the MUT and WT groups. In higher risk MDS and AML with low blast count, TET2 status may be a genetic predictor of response to AZA, independently of karyotype.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 04/2011; 25(7):1147-52. DOI:10.1038/leu.2011.71 · 10.43 Impact Factor
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