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226 EFFICACY OF DECITABINE IN 10-DAY REGIMEN IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE CHEMOTHERAPY
Poster Presentations – 13th International Symposium on Myelodyspastic Syndromes / Leukemia Research 39 S1 (2015) S1–S166
Bax and p53 were upregulated in both resistant cell variants when compared with their sensitive counterparts. Moreover, at least five times the elevation in overall glutathione S-transferase activity was measured with 1-chloro-2,5-dinitrobenzene as a substrate in the resistant variant of both cell lines. Conclusion: Together, these data indicate that the application of Aza could lead to a drug-resistant phenotype with the integration of different mechanisms that could cause a lack in cell sensitivity to a large group of drugs including substrates of P-gp and GST in addition to Aza. Acknowledgements: This research was supported by APVV grant agency (APVV-02-90-10; APVV-0282-11) and VEGA grant agency (Vega 2/0182/13; Vega 2/0028/15).
226 EFFICACY OF DECITABINE IN 10-DAY REGIMEN IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE CHEMOTHERAPY B. Moreno de Gusmão1, I. Esteves1, F.P.S. Santos1, M. Petrolli1, F. Ferreira1, C. Galvão Jr1, G. Perini1, J. Hyppolito1, R. Helman1, N. Hamersclak1 1 Hematology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil Introduction: Currently the hypomethylating agents (azacitidine, decitabine) are safe and effective alternative treatment for patients with acute myeloid leukemia (AML) that do not fit for intensive chemotherapy treatments. Several studies have been described the modification of the treatment regimen with hypomethylating agentes. We analyzed the effectiveness of decitabine in patients with acute leukemia not eligible for intensive therapy. Materials and methods: We reviewed 11 patients with AML treated with DEC between June 2010 and January 2015. The schedule was DEC 20 mg/m2 x 10 days in induction therapy. Patients who achieved remission cytological (defined as <5% blasts in the bone marrow aspirate) received consolidation therapy with DEC 20 mg/m2 x 5 days until progression and the remaining patients received a re-induction before start consolidation therapy. Results: 36.4% were de novo AML 63.6% were secondary AML (2 myelofibrosis, 4 MDS and CMML 1). All patients were male with a median age of 82 years old (range 69-86) and 36.4% patients had cytogenetic abnormalities in diagnosis according to European Leukemia Net (ELN): 6 patients were favorable risk, intermediate risk 1 and 3 high-risk. 54.5% patients had >30% blasts and 45.4% received treatment previously. 91% of patients had some comorbidities. A median of 6 cycles (range 1-10) were administered in total 57 cycles of decitabine. All patients had adverse effects during treatment, the most frequent febrile neutropenia (63%) and there was an early death (<8 weeks) associated with liver failure in a patient previously diagnosed. According to ELN, with induction in 10 days, we had a global response rate of 72.7% (2 CR with cytogenetic remission; 2 CR, 4 CR with incomplete hematologic recovery, 1 PR and 3 patients with refractory disease. Secondary AML, transfusion dependence and number of blasts >30% at diagnosis, had no effect on treatment response induction. In our study 6 patients died because disease progression infection. Median follow-up of 340 days (range 148-1506 days) with OS of 63% in 1-year and 45.5% during the follow up with a DFS of 45.5%. Conclusions: In our experience , decitabine in 10-day regimen in elderly patients is safe and very effective, even in poor prognosis patients.
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227 CD71+ ERYTHROPROGENITOR CELLS FROM PATIENTS WITH MYELODYSPLASTIC SYNDROMES DISPLAY DISTURBED REGULATION OF ERYTHROPOIESIS STIMULATING ERYTHROFERRONE (ERFE) IN ASSOCIATION WITH DIFFERENTIAL PROGNOSTIC SIGNIFICANCE M. Mossner1, A. Stöhr1, F. Nolte1, J.C. Jann1, S. Fey1, V. Nowak1, J. Obländer1, J. Pressler1, C.D. Baldus2, T.J. Schulze3, M. Neumann2, D. Nowak1, W.K. Hofmann1 1 Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; 2 Department of Hematology and Oncology, Charite Campus Benjamin Franklin, Berlin, Germany; 3Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany Introduction: Severe anemia is one of the most critical hallmarks in the clinical manifestation of myelodysplastic syndromes (MDS) and is often accompanied by deregulated iron homeostasis. While some patients respond to erythropoiesis stimulating agents such as erythropoietin (EPO), most of them become refractory to therapy with time. This likely indicates a deregulated erythropoietic regulation downstream of EPO signaling. Recently, a previously unknown regulator of iron metabolism called Erythroferrone (ERFE) was shown to be selectively produced by erythroprogenitor cells as a response to EPO treatment (Kautz et al., Nature Genetics 2014). As deregulated ERFE expression in animal models has been shown to cause strongly disturbed erythropoiesis we sought to investigate levels of ERFE transcription in CD71+ erythroprogenitors from patients with MDS and secondary acute myeloid leukemia (sAML). Methods: Bone marrow (BM) mononuclear cells were obtained from patients with MDS (n=86), sAML (n=18) and age-adjusted healthy volunteers (n=17) and subsequent isolation of CD71+ erythroprogenitor cells was carried out via immunomagnetic selection. Moreover, for three MDS patients as well as three healthy subjects we additionally isolated CD34+, CD61+, CD15+ BM and CD3+ peripheral blood (PB) cells. ERFE mRNA transcript levels were assessed via quantitative PCR and normalized to GPI as a housekeeping gene. Follow up data was available for 55 MDS and 14 sAML patients. Results: Our investigation of ERFE expression in various different cellular lineages, including CD34+, CD15+, CD61+ BM as well as CD3+ and unselected PB cells, demonstrated almost exclusive ERFE expression in CD71+ erythroprogenitor cells from MDS patients and healthy subjects. Notably, ERFE mRNA transcript levels were significantly elevated in CD71+ cells from MDS IPSSlow/int-1-risk (fold change (FC)=4.1, p<0.0001), IPSS-int-2/highrisk (FC=4.6, p<0.0001) and sAML (FC=6.5, p<0.0001) as compared to age-adjusted healthy controls. Intriguingly, low ERFE levels were associated with significantly inferior overall survival in MDS (median 1.7 years vs. not reached, p=0.0073) and sAML patients (median 0.1 vs. 0.8 years, p=0.044). Conclusions: We observed almost exclusive expression of the newly identified key regulatory gene ERFE in human healthy and MDS erythroprogenitors, which underlines its important role in human erythropoiesis regulation. Moreover, distinctive upregulation of erythropoiesis stimulating ERFE in patients usually suffering from anemia emphasizes the disturbed feedback signaling mechanisms in MDS erythropoiesis. Our detection of significantly inferior survival probability for MDS and sAML patients with low ERFE levels reveals potentially important prognostic implications. Deregulated ERFE might provide a mechanistic rationale for impaired MDS erythropoiesis and represent a promising therapeutic target.
Bax and p53 were upregulated in both resistant cell variants when compared with their sensitive counterparts. Moreover, at least five times the elevation in overall glutathione S-transferase activity was measured with 1-chloro-2,5-dinitrobenzene as a substrate in the resistant variant of both cell lines. Conclusion: Together, these data indicate that the application of Aza could lead to a drug-resistant phenotype with the integration of different mechanisms that could cause a lack in cell sensitivity to a large group of drugs including substrates of P-gp and GST in addition to Aza. Acknowledgements: This research was supported by APVV grant agency (APVV-02-90-10; APVV-0282-11) and VEGA grant agency (Vega 2/0182/13; Vega 2/0028/15).
226 EFFICACY OF DECITABINE IN 10-DAY REGIMEN IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA INELIGIBLE FOR INTENSIVE CHEMOTHERAPY B. Moreno de Gusmão1, I. Esteves1, F.P.S. Santos1, M. Petrolli1, F. Ferreira1, C. Galvão Jr1, G. Perini1, J. Hyppolito1, R. Helman1, N. Hamersclak1 1 Hematology, Hospital Israelita Albert Einstein, Sao Paulo, Brazil Introduction: Currently the hypomethylating agents (azacitidine, decitabine) are safe and effective alternative treatment for patients with acute myeloid leukemia (AML) that do not fit for intensive chemotherapy treatments. Several studies have been described the modification of the treatment regimen with hypomethylating agentes. We analyzed the effectiveness of decitabine in patients with acute leukemia not eligible for intensive therapy. Materials and methods: We reviewed 11 patients with AML treated with DEC between June 2010 and January 2015. The schedule was DEC 20 mg/m2 x 10 days in induction therapy. Patients who achieved remission cytological (defined as <5% blasts in the bone marrow aspirate) received consolidation therapy with DEC 20 mg/m2 x 5 days until progression and the remaining patients received a re-induction before start consolidation therapy. Results: 36.4% were de novo AML 63.6% were secondary AML (2 myelofibrosis, 4 MDS and CMML 1). All patients were male with a median age of 82 years old (range 69-86) and 36.4% patients had cytogenetic abnormalities in diagnosis according to European Leukemia Net (ELN): 6 patients were favorable risk, intermediate risk 1 and 3 high-risk. 54.5% patients had >30% blasts and 45.4% received treatment previously. 91% of patients had some comorbidities. A median of 6 cycles (range 1-10) were administered in total 57 cycles of decitabine. All patients had adverse effects during treatment, the most frequent febrile neutropenia (63%) and there was an early death (<8 weeks) associated with liver failure in a patient previously diagnosed. According to ELN, with induction in 10 days, we had a global response rate of 72.7% (2 CR with cytogenetic remission; 2 CR, 4 CR with incomplete hematologic recovery, 1 PR and 3 patients with refractory disease. Secondary AML, transfusion dependence and number of blasts >30% at diagnosis, had no effect on treatment response induction. In our study 6 patients died because disease progression infection. Median follow-up of 340 days (range 148-1506 days) with OS of 63% in 1-year and 45.5% during the follow up with a DFS of 45.5%. Conclusions: In our experience , decitabine in 10-day regimen in elderly patients is safe and very effective, even in poor prognosis patients.
S113
227 CD71+ ERYTHROPROGENITOR CELLS FROM PATIENTS WITH MYELODYSPLASTIC SYNDROMES DISPLAY DISTURBED REGULATION OF ERYTHROPOIESIS STIMULATING ERYTHROFERRONE (ERFE) IN ASSOCIATION WITH DIFFERENTIAL PROGNOSTIC SIGNIFICANCE M. Mossner1, A. Stöhr1, F. Nolte1, J.C. Jann1, S. Fey1, V. Nowak1, J. Obländer1, J. Pressler1, C.D. Baldus2, T.J. Schulze3, M. Neumann2, D. Nowak1, W.K. Hofmann1 1 Department of Hematology and Oncology, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany; 2 Department of Hematology and Oncology, Charite Campus Benjamin Franklin, Berlin, Germany; 3Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim of the University of Heidelberg, Mannheim, Germany Introduction: Severe anemia is one of the most critical hallmarks in the clinical manifestation of myelodysplastic syndromes (MDS) and is often accompanied by deregulated iron homeostasis. While some patients respond to erythropoiesis stimulating agents such as erythropoietin (EPO), most of them become refractory to therapy with time. This likely indicates a deregulated erythropoietic regulation downstream of EPO signaling. Recently, a previously unknown regulator of iron metabolism called Erythroferrone (ERFE) was shown to be selectively produced by erythroprogenitor cells as a response to EPO treatment (Kautz et al., Nature Genetics 2014). As deregulated ERFE expression in animal models has been shown to cause strongly disturbed erythropoiesis we sought to investigate levels of ERFE transcription in CD71+ erythroprogenitors from patients with MDS and secondary acute myeloid leukemia (sAML). Methods: Bone marrow (BM) mononuclear cells were obtained from patients with MDS (n=86), sAML (n=18) and age-adjusted healthy volunteers (n=17) and subsequent isolation of CD71+ erythroprogenitor cells was carried out via immunomagnetic selection. Moreover, for three MDS patients as well as three healthy subjects we additionally isolated CD34+, CD61+, CD15+ BM and CD3+ peripheral blood (PB) cells. ERFE mRNA transcript levels were assessed via quantitative PCR and normalized to GPI as a housekeeping gene. Follow up data was available for 55 MDS and 14 sAML patients. Results: Our investigation of ERFE expression in various different cellular lineages, including CD34+, CD15+, CD61+ BM as well as CD3+ and unselected PB cells, demonstrated almost exclusive ERFE expression in CD71+ erythroprogenitor cells from MDS patients and healthy subjects. Notably, ERFE mRNA transcript levels were significantly elevated in CD71+ cells from MDS IPSSlow/int-1-risk (fold change (FC)=4.1, p<0.0001), IPSS-int-2/highrisk (FC=4.6, p<0.0001) and sAML (FC=6.5, p<0.0001) as compared to age-adjusted healthy controls. Intriguingly, low ERFE levels were associated with significantly inferior overall survival in MDS (median 1.7 years vs. not reached, p=0.0073) and sAML patients (median 0.1 vs. 0.8 years, p=0.044). Conclusions: We observed almost exclusive expression of the newly identified key regulatory gene ERFE in human healthy and MDS erythroprogenitors, which underlines its important role in human erythropoiesis regulation. Moreover, distinctive upregulation of erythropoiesis stimulating ERFE in patients usually suffering from anemia emphasizes the disturbed feedback signaling mechanisms in MDS erythropoiesis. Our detection of significantly inferior survival probability for MDS and sAML patients with low ERFE levels reveals potentially important prognostic implications. Deregulated ERFE might provide a mechanistic rationale for impaired MDS erythropoiesis and represent a promising therapeutic target.