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42 MicroRNA changes in patients with IPSS lower-risk myelodysplastic syndromes and del5q undergoing treatment with lenalidomide
Oral Presentations / Leukemia Research 35 (2011) S14–S26
S15
3. We developed a novel epigenetic profiling-based flow cytometry to measure expressions of nuclear factors at the single cell level. Conclusion: Epigenetic regulatory mechanisms including DNA and histone methylations are important for regulating expression of RUNX1 and PU.1. Identification of epigenetic alterations on these factor encoding genes indicates the importance of epigenetic disregulation in the pathogenesis of MDS.
of MiR-155 is lower than normal controls. Lenalidomide treatment is associated with erythroid responses concurrent with significant increases in miRNA expression.
42 MicroRNA changes in patients with IPSS lower-risk myelodysplastic syndromes and del5q undergoing treatment with lenalidomide M. Cuzzola1 , R. Latagliata2 , M.A. Aloe Spiriti3 , F. Nobile4 , A. Cortelezzi5 , C. Finelli6 , G. Sanpaolo7 , G. Palumbo8 , M. Breccia2 , F. Di Raimondo8 , G. Alimena2 , E.N. Oliva4 . 1 CTMO ‘Alberto Neri’, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, 2 Department of Cellular Biotechnologies and Hematology, University of Rome ‘La Sapienza’, 3 Hematology Unit, Azienda Ospedaliera Sant’Andrea, Rome, 4 Hematology Division, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, 5 Dipartimento Scienze Mediche, Ematologia 1 CTMO, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a di Milano, Milan, 6 Institute of Haematology and Medical Oncology “L.& A. Seragnoli”, University of Bologna, Bologna, 7 Hematology Unit, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, 8 Hematology Division, Ferrarotto Hospital, Catania, Italy
A.J. Davidoff1,2 , M.R. Baer2,3 , S.R. Weiss Smith1 , X. Ke1 , J. Bierenbaum2 , F. Hendrick1 , D. McNally1 , S.D. Gore4 . 1 Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, 2 Greenebaum Cancer Center, University of Maryland Baltimore, 3 Department of Medicine, University of Maryland School of Medicine, 4 Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
MicroRNAs (miRNAs) regulate gene and protein expression and hematopoietic lineage commitment, B lymphopoiesis, granulopoiesis, erythropoiesis and monocytopoiesis. MiRNAs have been implicated in the NF-úB pathway, a mediator of inflammation which plays a role in myeloid cell development. Expression of miR145 (5q33.1) and miR-146a (5q33.3) in CD34+ bone marrow (BM) cells of individuals with myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 (del5q) is lower compared to normal controls (Starczynowski et al, Nature Medicine, 2010). Concurrent loss of both miR-145 and miR-146a results in activation of innate immune signalling through elevated expression of their respective targets, TIRAP and TNF receptor-associated factor-6. Knockdown of miR-145 and miR-146a recapitulated features of 5q− syndrome. Expression of miR-146a is inducible by TNF-a and IL-1b by NFúB-pathway. MiR-155 regulates the susceptibility of CD4+ Th cells to nTreg cell-mediated suppression. We present preliminary results of changes in miRNA expression in IPSS lower-risk MDS with del5q receiving lenalidomide. Methods: In a prospective single-arm trial investigating the efficacy of lenalidomide in 46 patients with MDS with del5q and Hb <10 g/dL, lenalidomide was administered at a starting dose of 10 mg/day for up to 12 months. Purified BM samples were obtained at baseline and every 3 months; 300 ng/ml of miRNAs were isolated by mirVana™ miRNA Isolation Kit-Ambion. TaqMan miRNA Array Analysis was performed to determine the expression of miRNAs (7900HT Sequence Detection System Applied Biosystems). Patient miRNAs were calibrated with miRNAs from BM of healthy volunteer donors. It was assumed that BM expression value of each calibrator miRNA was 1 unit. Results: Seven patients have complete miRNA expression data up to 52 weeks. Four cases were transfusion-dependent. All patients obtained an erythroid response during the study with mean Hb values significantly increasing by from 4.9 (IQ range 2.5–5.7, p < 0.0001) g/dL by the end of the study. MiR-145 progressively increased from baseline median 0.93 (0.06–10.0) to 3.68 (2.06– 5.47, p = 0.57). There was a trend in increased MiR-146a expression from median 0.09 (0.03–10.00) to 1.69 (1.69–3.12, p = 0.06) and a significant increase in miR-155 from median 0.48 (0.07–10.00) to 3.65 (2.78–3.69, p = 0.004) by 52 weeks. Conclusions: Preliminary results confirm low miR-145 and miRNA146a expression in IPSS lower-risk MDS with del(5q). Expression
43 The broad use of erythropoietic stimulating agents (ESA) for myelodysplastic syndromes (MDS) in the U.S. is not consistent with guidelines
Background: Treatment guidelines recommend ESA use for MDS patients with symptomatic anemia, low serum erythropoietin (EPO) levels, and limited transfusion dependence. Clinical trial results suggest minimum 8 week exposure; patients who do not demonstrate benefit within 8–12 weeks are recommended to discontinue ESA use, undergo dose escalation, or the addition of myeloid growth factors (GFs). Purpose: We describe population based patterns of ESA use in the U.S. relative to selected treatment guidelines. Methods: Medicare beneficiaries diagnosed with MDS from 2001– 2005 were identified in Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data. We measured any ESA use, constructed episodes of continuous use, and determined timing of EPO level measurement. Risk categories were assigned based on a modified FAB classification, including lower risk (RA, RARS, RCMD, or del(5q) syndrome), high risk (RAEB), and MDS not otherwise specified. Transfusion status was evaluated each week, based on the receipt of transfusions during the current and preceding 7-week period (rolling). Transfusion dependence (TD) required transfusions during 2 of the 8 weeks, separated by at least 3 weeks. Transfusion independence (TI) required a period of 8 weeks without any transfusions after a period of transfusion use, and we defined an intermediate transfusion user (TU) category. Bivariate analyses examined sample means and proportions, overall and by risk group. Results: 4,112 or 64.6% of 6,588 MDS patients received ESAs during the observation period; rates did not differ significantly between lower and high risk (68.5% versus 67.9%, p = 0.75). Serum EPO level was determined in 33.0% of patients, (42.6% of ESA users, compared to 15.5% of non-users). Most ESA users received erythropoietin-alpha (87.7%), while 38.1% received darbepoetin; 25.8% of users received both types of ESA. At ESA initiation, 55.4% were transfusion-na¨ıve, 27.9% were TU, 10.9% were TD, and 5.8% had achieved TI. Of 17,047 episodes of ESA observed, 59.4% were <8 weeks duration. 27.3% of ESA recipients received no episodes ≤8 weeks. We also found evidence of prolonged use of ESA after transitioning to transfusion dependence. Conclusion: Utilization of ESA to treat MDS patients is widespread. The small percentage of patients beginning ESAs following a recent serum EPO determination, short duration episodes of ESA administration, and general failure to differentiate by risk status suggests that extant guidelines for ESA use in MDS patients are not generally followed.
S15
3. We developed a novel epigenetic profiling-based flow cytometry to measure expressions of nuclear factors at the single cell level. Conclusion: Epigenetic regulatory mechanisms including DNA and histone methylations are important for regulating expression of RUNX1 and PU.1. Identification of epigenetic alterations on these factor encoding genes indicates the importance of epigenetic disregulation in the pathogenesis of MDS.
of MiR-155 is lower than normal controls. Lenalidomide treatment is associated with erythroid responses concurrent with significant increases in miRNA expression.
42 MicroRNA changes in patients with IPSS lower-risk myelodysplastic syndromes and del5q undergoing treatment with lenalidomide M. Cuzzola1 , R. Latagliata2 , M.A. Aloe Spiriti3 , F. Nobile4 , A. Cortelezzi5 , C. Finelli6 , G. Sanpaolo7 , G. Palumbo8 , M. Breccia2 , F. Di Raimondo8 , G. Alimena2 , E.N. Oliva4 . 1 CTMO ‘Alberto Neri’, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, 2 Department of Cellular Biotechnologies and Hematology, University of Rome ‘La Sapienza’, 3 Hematology Unit, Azienda Ospedaliera Sant’Andrea, Rome, 4 Hematology Division, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, 5 Dipartimento Scienze Mediche, Ematologia 1 CTMO, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Universit` a di Milano, Milan, 6 Institute of Haematology and Medical Oncology “L.& A. Seragnoli”, University of Bologna, Bologna, 7 Hematology Unit, IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, 8 Hematology Division, Ferrarotto Hospital, Catania, Italy
A.J. Davidoff1,2 , M.R. Baer2,3 , S.R. Weiss Smith1 , X. Ke1 , J. Bierenbaum2 , F. Hendrick1 , D. McNally1 , S.D. Gore4 . 1 Pharmaceutical Health Services Research, University of Maryland School of Pharmacy, 2 Greenebaum Cancer Center, University of Maryland Baltimore, 3 Department of Medicine, University of Maryland School of Medicine, 4 Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA
MicroRNAs (miRNAs) regulate gene and protein expression and hematopoietic lineage commitment, B lymphopoiesis, granulopoiesis, erythropoiesis and monocytopoiesis. MiRNAs have been implicated in the NF-úB pathway, a mediator of inflammation which plays a role in myeloid cell development. Expression of miR145 (5q33.1) and miR-146a (5q33.3) in CD34+ bone marrow (BM) cells of individuals with myelodysplastic syndrome (MDS) with deletion of the long arm of chromosome 5 (del5q) is lower compared to normal controls (Starczynowski et al, Nature Medicine, 2010). Concurrent loss of both miR-145 and miR-146a results in activation of innate immune signalling through elevated expression of their respective targets, TIRAP and TNF receptor-associated factor-6. Knockdown of miR-145 and miR-146a recapitulated features of 5q− syndrome. Expression of miR-146a is inducible by TNF-a and IL-1b by NFúB-pathway. MiR-155 regulates the susceptibility of CD4+ Th cells to nTreg cell-mediated suppression. We present preliminary results of changes in miRNA expression in IPSS lower-risk MDS with del5q receiving lenalidomide. Methods: In a prospective single-arm trial investigating the efficacy of lenalidomide in 46 patients with MDS with del5q and Hb <10 g/dL, lenalidomide was administered at a starting dose of 10 mg/day for up to 12 months. Purified BM samples were obtained at baseline and every 3 months; 300 ng/ml of miRNAs were isolated by mirVana™ miRNA Isolation Kit-Ambion. TaqMan miRNA Array Analysis was performed to determine the expression of miRNAs (7900HT Sequence Detection System Applied Biosystems). Patient miRNAs were calibrated with miRNAs from BM of healthy volunteer donors. It was assumed that BM expression value of each calibrator miRNA was 1 unit. Results: Seven patients have complete miRNA expression data up to 52 weeks. Four cases were transfusion-dependent. All patients obtained an erythroid response during the study with mean Hb values significantly increasing by from 4.9 (IQ range 2.5–5.7, p < 0.0001) g/dL by the end of the study. MiR-145 progressively increased from baseline median 0.93 (0.06–10.0) to 3.68 (2.06– 5.47, p = 0.57). There was a trend in increased MiR-146a expression from median 0.09 (0.03–10.00) to 1.69 (1.69–3.12, p = 0.06) and a significant increase in miR-155 from median 0.48 (0.07–10.00) to 3.65 (2.78–3.69, p = 0.004) by 52 weeks. Conclusions: Preliminary results confirm low miR-145 and miRNA146a expression in IPSS lower-risk MDS with del(5q). Expression
43 The broad use of erythropoietic stimulating agents (ESA) for myelodysplastic syndromes (MDS) in the U.S. is not consistent with guidelines
Background: Treatment guidelines recommend ESA use for MDS patients with symptomatic anemia, low serum erythropoietin (EPO) levels, and limited transfusion dependence. Clinical trial results suggest minimum 8 week exposure; patients who do not demonstrate benefit within 8–12 weeks are recommended to discontinue ESA use, undergo dose escalation, or the addition of myeloid growth factors (GFs). Purpose: We describe population based patterns of ESA use in the U.S. relative to selected treatment guidelines. Methods: Medicare beneficiaries diagnosed with MDS from 2001– 2005 were identified in Surveillance, Epidemiology, and End Results (SEER) registries, with linked Medicare claims providing detailed treatment data. We measured any ESA use, constructed episodes of continuous use, and determined timing of EPO level measurement. Risk categories were assigned based on a modified FAB classification, including lower risk (RA, RARS, RCMD, or del(5q) syndrome), high risk (RAEB), and MDS not otherwise specified. Transfusion status was evaluated each week, based on the receipt of transfusions during the current and preceding 7-week period (rolling). Transfusion dependence (TD) required transfusions during 2 of the 8 weeks, separated by at least 3 weeks. Transfusion independence (TI) required a period of 8 weeks without any transfusions after a period of transfusion use, and we defined an intermediate transfusion user (TU) category. Bivariate analyses examined sample means and proportions, overall and by risk group. Results: 4,112 or 64.6% of 6,588 MDS patients received ESAs during the observation period; rates did not differ significantly between lower and high risk (68.5% versus 67.9%, p = 0.75). Serum EPO level was determined in 33.0% of patients, (42.6% of ESA users, compared to 15.5% of non-users). Most ESA users received erythropoietin-alpha (87.7%), while 38.1% received darbepoetin; 25.8% of users received both types of ESA. At ESA initiation, 55.4% were transfusion-na¨ıve, 27.9% were TU, 10.9% were TD, and 5.8% had achieved TI. Of 17,047 episodes of ESA observed, 59.4% were <8 weeks duration. 27.3% of ESA recipients received no episodes ≤8 weeks. We also found evidence of prolonged use of ESA after transitioning to transfusion dependence. Conclusion: Utilization of ESA to treat MDS patients is widespread. The small percentage of patients beginning ESAs following a recent serum EPO determination, short duration episodes of ESA administration, and general failure to differentiate by risk status suggests that extant guidelines for ESA use in MDS patients are not generally followed.