- Email: [email protected]
Cytogenetic Clonal Evolution in Myelodysplastic Syndromes (MDS) with Isolated Del(5Q)
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Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
BCORL1 (66%), CDKN2A (80%, n = 5), and EZH2 (75%, n = 4). On the contrary, mutations with increasing abundance on AZA were observed in genes encoding IDH2 (75%, n = 4) and RUNX1 (62%, n = 8), the latter often related to the progression. There were also de novo mutations that developed on AZA involving seven genes: TP53, BCORL1, STAG2, DNMT3A, ASXL1, SMC3, PTPN11; again, last three related to progression. We conclude that dynamic changes observed in the mutational pattern often reflect the disease course with a decrease/elimination of allelic burden during remission. Mutation reappearance was observable upon progression or relapse while stable pattern was seen in cases of stable disease. Furthermore, in 5 patients (13%) we noted the progression-preceding mutations in ASXL1, RUNX1, SRSF2, STAG2, SF3B1 with markedly increasing allele frequency at morphological remission which was within 2–6 months exchanged into progression. We conclude that tracking of somatic mutations helps to monitor the genetic development of the mutant clone/s and to predict forthcoming disease progression. Acknowledgement: Grant support: AZV16-27790A, GAČ R1605649S, UNCE204021, LH15170, Progres Q26/Q28, NPU2 LQ1604 & RVO-VFN64165.
Results: 152 MDS pts were diagnosed in 2009 or later. Lactate dehydrogenase (LDH), bilirubin (BILI) and reticulocyte count (RETICS) were measured (elevated) in 96 (23), 109 (10) and 142 (14) pts, respectively, and haptoglobin (HAPTO) decreased in 2 of 7 measured. The direct antiglobulin test (DAT) was negative in 9 of 13 pts and serum ferritin level <100 ng/mL in 14 of 116. No pts had hemoglobinuria. 79 (52%) pts were RBC TD, with a median TR of 4 (1–8) units/8 weeks. PNH testing was positive in 1 of 11 pts tested. Reasons for PNH testing were: anemia, n = 3 (with abdominal symptoms in 1); new MDS dx, n = 2; hypoplastic MDS, n = 2; decreased HAPTO; increased TR; and iron deficiency, n = 1 each; see Figure. At a median follow up of 21.1 (0.7–69.9) months for all patients, 113 were alive and the median OS was not reached. Conclusions: PNH was tested for infrequently in MDS patients in clinical practice. Only 11 (7%) of MDS pts since 2009 had PNH testing done despite potential indicators of hemolysis in 27%. Clinical rather than laboratory indicators prompted PNH testing in 6 of 11 pts. Complement mediated hemolysis could exacerbate anemia in MDS. As there is now an effective treatment available, screening for PNH in MDS should be considered.
89 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) SCREENING IN PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS) IN CLINICAL PRACTICE: FREQUENCY AND INDICATIONS S. Wong1, B. Dalal2, H.A. Leitch3 1 Medicine, The Royal College of Surgeons in Ireland, Dublin, Ireland; 2 Division of Laboratory Hematology, Vancouver General Hospital, Vancouver- British Columbia, Canada; 3Hematology, St. Paul’s Hospital and the University of British Columbia, Vancouver, Canada
90 CYTOGENETIC CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES (MDS) WITH ISOLATED DEL(5Q) Z. Zemanova1, K. Michalova1, J. Brezinova2, K. Svobodova1, H. Lhotska1, I. Sarova2, L. Lizcova1, S. Izakova1, S. Ransdorfova2, L. Pavlistova1, A. Berkova1, K. Skipalova1, M. Belickova3, M. Siskova4, R. Neuwirtova4, J. Cermak5, T. Stopka4, A. Jonasova4 1 General University Hospital and First Faculty of Medicine- Charles University in Prague, Center of Oncocytogenetics- Institute of Medical Biochemistry and Laboratory Diagnostics, Prague 2, Czech Republic; 2 Cytogenetic Department, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic; 3Department of Genomics, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic; 4General University Hospital and First Faculty of MedicineCharles University in Prague, 1st Medical Department, Prague 2, Czech Republic; 5Clinical Department, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic
Background: MDS is characterized by ineffective hematopoiesis and peripheral blood cytopenias including anemia which may lead to red blood cell (RBC) transfusion dependence (TD). In paroxysmal nocturnal hemoglobinuria (PNH), complement-mediated lysis occurs. PNH clones are detected in up to 50% of MDS pts might confound the reason for RBC TD. The first specific treatment for PNH was approved in Canada in 2009. Eculizumab reduces hemolysis and RBC transfusion requirements (TR) and has other benefits. We wanted to determine whether PNH as a contributor to anemia is considered in MDS pts in the Eculizumab era. Methods: Pts with a bone marrow biopsy confirmed MDS diagnosis (dx) since 2009 were reviewed. Data extracted included baseline clinical and laboratory features, clinical course, treatment, outcome and indicators of hemolysis. High resolution PNH testing was done by flow cytometry for expression of FLAER, CD24, CD14, and CD59 on neutrophils, monocytes and RBC.
The interstitial deletion of the long arm of chromosome 5 – del (5q) – is the most common cytogenetic finding in patients with MDS (∼30% of abnormal karyotypes). According to IPSS-R, MDS with isolated del(5q) are associated with a favorable clinical course. However in some cases, acquisition of additional genetic aberrations may occur during the course of the disease. The aim of the study was: to evaluate the frequency of cytogenetic clonal evolution (CCE) in MDS patients with isolated del(5q); to analyze the pattern of acquired cytogenetic abnormalities; and to assess the impact of CCE on transformation to AML and/or overall survival. A detailed genome-wide analysis of fixed bone-marrow cells of 184 adults with del(5q), identified with G-banding at the diagnosis of MDS, was performed during the follow-up using FISH (Vysis DNA probes, Abbott), mFISH/mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, BlueGnome or SurePrint G3 Cancer CGH+SNP 4 × 180K, Agilent). Amplicon deep sequencing of TP53 mutations (exons 4–11) was performed on a 454 GS Junior system (Roche). CCE was observed in 25/184 patients with isolated del(5q). The clinical progression occurred in 24 of them. One woman lives 56 months after CCE with no signs of disease progression. CCE was detected between 2 and 145 months after first cytogenetic evaluation (median 26 months). Median survival from the first emergence of CCE was 11 months (range 1–56 months; 22 patients died, 3 patients live). In 20/25 cases (80%), clones with del(5q)
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
acquired two or more additional aberrations and developed complex karyotypes (≥3 changes). Their median survival from the emergence of CCE was 7 months (range 1–30 months). In 17/25 patients (68%), CCE was associated with mutations of TP53 and/or unbalanced aberrations of 17p. Changes acquired during CCE involved most frequently unbalanced aberrations of the chromosomes: 1 (8×), 7 (8×), 8 (8×), 12 (10×) and 17 (11×). In six patients, deleted 5q was involved in complex rearrangements. CCE was detected in 13.6% patients with MDS and isolated del(5q). This finding was strongly associated with higher frequency of TP53 gene alterations (deletions, aUPD, mutations), short survival, disease progression and/or transformation to AML. Inactivation of TP53 gene may be a critical early event during CCE of 5q- clones, triggering genetic instability and acquisition of secondary aberrations. Our results substantiate a need for regular molecularcytogenetic monitoring of MDS patients with isolated del(5q) to help with treatment decision. Acknowledgement: Supported by RVO-VFN64165, GACR P302/12/ G157, ProgresQ28, MHCR 00023736.
91 DIFFERENT REPO DOSES (HIGH VS STANDARD) FOR TREATMENT OF ANEMIA IN MDS PATIENTS: A SURVEY FROM THE ITALIAN MDS REGISTRY E. Balleari1, C. Salvetti2, R. Filiberti3, B. Allione2, E. Angelucci4, M. Cavalieri5, M. Cavalleri6, D. Cilloni7, M. Clavio4, E. Crisa’2, A. Da Col1, P. Danise8, A. Di Tucci9, C. Finelli10, R. Lemoli4, M. Miglino4, E. Oliva11, M. Pellegrino12, A. Poloni13, V. Santini14 1 Internal Medicine, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 2AOU città della salute, hematology – University of Turin, Turin, Italy; 3Epidemiology, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 4 Hematology-Oncology, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 5Medicine, UO Internal Medicine, Savona, Italy; 6Medicine, UO Internal Medicine, Sestri Levante, Italy; 7AOU Città della Salute, Internal Medicine – University of Turin, Turin, Italy; 8Hematology, Nocera Hospital, Nocera Inferiore, Italy; 9Hematology, AOU Cagliari, Cagliari, Italy; 10Istituto Seragnoli, Hematology- Bologna University, Bologna, Italy; 11Hematology, Ospedali Riuniti, Reggio Calabria, Italy; 12Hematology, IRCCS CROB, Rionero sul Vulture, Italy; 13UO Hematology, Hematology-University delle Marche, Ancona, Italy; 14Hematology, AOU Careggi, Florence, Italy Introduction: REPO has been used to treat anemia in MDS anemic pts since more than 25 years. In early Ninety this treatment, using different but usually “standard” doses (inferior or equal to 30– 40.000 IU weekly), showed a disappointing overall response-rate of 15–25%. In recent years most studies reported a response rate of more than 50%, either because of a better selection of patients of MDS and possibly because higher doses (60–80.000 UI weekly) of rEPO is increasingly used. Nevertheless, a direct comparison between the two different schedules of rEPO treatment is still lacking. Methods: Within the framework of the Italian Network of regional MDS registries of FISM a cohort of 106 anemic MDS pts treated with higher doses of rEPO (40.000 IU twice a week, H) for at least 3 months were identified; a second cohort of 212 pts similar for clinical parameters known to influence response to rEPO and treated with standard doses (40.000 IU weekly, S) were compared in a 1:2 fashion. Univariate and multivariate analysis were performed as appropriate in order to identify factors influencing clinical response. Results: Characteristics of subjects were: median Hb pre-treatment 8.9 g/dL in H cohort and 9.1 g/dL in S cohort, IPSS score Intermediate-2/high in 5% of H cohort and 8% of S cohort,
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transfusion-dependency in 25% of H cohort and 26% of S cohort, median EPO 79 IU in H cohort and 69 IU in S cohort. After 3 months of rEPO treatment, the overall erythroid response-rate (IWG 2006 criteria) in the two cohorts was 53% (163 out of 309 pts). No difference in erythroid response-rate was found between MDS pts in H cohort when compared to pts in S cohort (48% responders in the H cohort vs 55% responders in the S cohort ( p = 0.23). IPSS score, transfusion-dependency and EPO serum levels at diagnosis were statistically associated with response in both cohorts. At multivariate analysis, significantly lower response-rates to rEPO were related with transfusion-dependency (yes vs no, OR = 0.59 (95%CI: 0.44–0.79, p < 0.001), higher endogenous serum EPO levels at diagnosis (>500 vs <=500, OR = 0.36 (95%CI: 0.19–0.68, p = 0.002) and higher IPSS score (intermediate 2/ high vs, intermediate 1/ low, OR = 0.42 (95%CI: 0.24–0.74, p = 0.003). Conclusions: Our data, although derived by a retrospective analysis, indicate that standard doses of rEPO are at least as effective as higher-doses for correcting anemia in lower-risk MDS patients. Prospective, randomized studies addressing this point are necessary.
92 MANAGEMENT OF MYELODYSPLASTIC SYNDROMES WITH ERYTHROPOIESIS STIMULATING AGENTS (ESAS) IN REAL-LIFE EXPERIENCE: AN UPDATE FROM RECAMDS C. Cerchione1, O. Vitagliano1, R. Della Pepa1, G. Cerciello1, A.E. Pareto1, M. Di Perna1, I. Soriente1, A.M. D’Arco2, P. Danise2, F. Alfinito1, F. Pane1 1 Hematology, AOU Federico II, Napoli, Italy; 2Hematology, Ospedale Pagani, Pagani SA, Italy Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. It’s matter of debate whether the clinical response is a result of proliferation and maturation of the dysplastic clone or stimulation of residual normal erythropoiesis by ESAs. Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS: an analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non trasfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed. 183 patients, treated with standard-dose ESAs, have been retrospectively analyzed (Table 1). Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dL, mean serum EPO concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1–118). Overall response rate (ORR) was 83.6% (153/183), no difference among WHO and IPSS subgroups was found: 132/183 (72.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease (nonresponders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocyticresponders group 83.2% exhibits again macrocytosis after 3 months, while 16.8% become normocytic. In the normocyticresponders group 89.8% exhibits again normocytosis, while 10.2% become macrocytic: in these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
BCORL1 (66%), CDKN2A (80%, n = 5), and EZH2 (75%, n = 4). On the contrary, mutations with increasing abundance on AZA were observed in genes encoding IDH2 (75%, n = 4) and RUNX1 (62%, n = 8), the latter often related to the progression. There were also de novo mutations that developed on AZA involving seven genes: TP53, BCORL1, STAG2, DNMT3A, ASXL1, SMC3, PTPN11; again, last three related to progression. We conclude that dynamic changes observed in the mutational pattern often reflect the disease course with a decrease/elimination of allelic burden during remission. Mutation reappearance was observable upon progression or relapse while stable pattern was seen in cases of stable disease. Furthermore, in 5 patients (13%) we noted the progression-preceding mutations in ASXL1, RUNX1, SRSF2, STAG2, SF3B1 with markedly increasing allele frequency at morphological remission which was within 2–6 months exchanged into progression. We conclude that tracking of somatic mutations helps to monitor the genetic development of the mutant clone/s and to predict forthcoming disease progression. Acknowledgement: Grant support: AZV16-27790A, GAČ R1605649S, UNCE204021, LH15170, Progres Q26/Q28, NPU2 LQ1604 & RVO-VFN64165.
Results: 152 MDS pts were diagnosed in 2009 or later. Lactate dehydrogenase (LDH), bilirubin (BILI) and reticulocyte count (RETICS) were measured (elevated) in 96 (23), 109 (10) and 142 (14) pts, respectively, and haptoglobin (HAPTO) decreased in 2 of 7 measured. The direct antiglobulin test (DAT) was negative in 9 of 13 pts and serum ferritin level <100 ng/mL in 14 of 116. No pts had hemoglobinuria. 79 (52%) pts were RBC TD, with a median TR of 4 (1–8) units/8 weeks. PNH testing was positive in 1 of 11 pts tested. Reasons for PNH testing were: anemia, n = 3 (with abdominal symptoms in 1); new MDS dx, n = 2; hypoplastic MDS, n = 2; decreased HAPTO; increased TR; and iron deficiency, n = 1 each; see Figure. At a median follow up of 21.1 (0.7–69.9) months for all patients, 113 were alive and the median OS was not reached. Conclusions: PNH was tested for infrequently in MDS patients in clinical practice. Only 11 (7%) of MDS pts since 2009 had PNH testing done despite potential indicators of hemolysis in 27%. Clinical rather than laboratory indicators prompted PNH testing in 6 of 11 pts. Complement mediated hemolysis could exacerbate anemia in MDS. As there is now an effective treatment available, screening for PNH in MDS should be considered.
89 PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) SCREENING IN PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS) IN CLINICAL PRACTICE: FREQUENCY AND INDICATIONS S. Wong1, B. Dalal2, H.A. Leitch3 1 Medicine, The Royal College of Surgeons in Ireland, Dublin, Ireland; 2 Division of Laboratory Hematology, Vancouver General Hospital, Vancouver- British Columbia, Canada; 3Hematology, St. Paul’s Hospital and the University of British Columbia, Vancouver, Canada
90 CYTOGENETIC CLONAL EVOLUTION IN MYELODYSPLASTIC SYNDROMES (MDS) WITH ISOLATED DEL(5Q) Z. Zemanova1, K. Michalova1, J. Brezinova2, K. Svobodova1, H. Lhotska1, I. Sarova2, L. Lizcova1, S. Izakova1, S. Ransdorfova2, L. Pavlistova1, A. Berkova1, K. Skipalova1, M. Belickova3, M. Siskova4, R. Neuwirtova4, J. Cermak5, T. Stopka4, A. Jonasova4 1 General University Hospital and First Faculty of Medicine- Charles University in Prague, Center of Oncocytogenetics- Institute of Medical Biochemistry and Laboratory Diagnostics, Prague 2, Czech Republic; 2 Cytogenetic Department, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic; 3Department of Genomics, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic; 4General University Hospital and First Faculty of MedicineCharles University in Prague, 1st Medical Department, Prague 2, Czech Republic; 5Clinical Department, Institute of Hematology and Blood Transfusion, Prague 2, Czech Republic
Background: MDS is characterized by ineffective hematopoiesis and peripheral blood cytopenias including anemia which may lead to red blood cell (RBC) transfusion dependence (TD). In paroxysmal nocturnal hemoglobinuria (PNH), complement-mediated lysis occurs. PNH clones are detected in up to 50% of MDS pts might confound the reason for RBC TD. The first specific treatment for PNH was approved in Canada in 2009. Eculizumab reduces hemolysis and RBC transfusion requirements (TR) and has other benefits. We wanted to determine whether PNH as a contributor to anemia is considered in MDS pts in the Eculizumab era. Methods: Pts with a bone marrow biopsy confirmed MDS diagnosis (dx) since 2009 were reviewed. Data extracted included baseline clinical and laboratory features, clinical course, treatment, outcome and indicators of hemolysis. High resolution PNH testing was done by flow cytometry for expression of FLAER, CD24, CD14, and CD59 on neutrophils, monocytes and RBC.
The interstitial deletion of the long arm of chromosome 5 – del (5q) – is the most common cytogenetic finding in patients with MDS (∼30% of abnormal karyotypes). According to IPSS-R, MDS with isolated del(5q) are associated with a favorable clinical course. However in some cases, acquisition of additional genetic aberrations may occur during the course of the disease. The aim of the study was: to evaluate the frequency of cytogenetic clonal evolution (CCE) in MDS patients with isolated del(5q); to analyze the pattern of acquired cytogenetic abnormalities; and to assess the impact of CCE on transformation to AML and/or overall survival. A detailed genome-wide analysis of fixed bone-marrow cells of 184 adults with del(5q), identified with G-banding at the diagnosis of MDS, was performed during the follow-up using FISH (Vysis DNA probes, Abbott), mFISH/mBAND (MetaSystems) and array CGH/SNP (CytoChip Cancer SNP 180K, BlueGnome or SurePrint G3 Cancer CGH+SNP 4 × 180K, Agilent). Amplicon deep sequencing of TP53 mutations (exons 4–11) was performed on a 454 GS Junior system (Roche). CCE was observed in 25/184 patients with isolated del(5q). The clinical progression occurred in 24 of them. One woman lives 56 months after CCE with no signs of disease progression. CCE was detected between 2 and 145 months after first cytogenetic evaluation (median 26 months). Median survival from the first emergence of CCE was 11 months (range 1–56 months; 22 patients died, 3 patients live). In 20/25 cases (80%), clones with del(5q)
Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S45–S167
acquired two or more additional aberrations and developed complex karyotypes (≥3 changes). Their median survival from the emergence of CCE was 7 months (range 1–30 months). In 17/25 patients (68%), CCE was associated with mutations of TP53 and/or unbalanced aberrations of 17p. Changes acquired during CCE involved most frequently unbalanced aberrations of the chromosomes: 1 (8×), 7 (8×), 8 (8×), 12 (10×) and 17 (11×). In six patients, deleted 5q was involved in complex rearrangements. CCE was detected in 13.6% patients with MDS and isolated del(5q). This finding was strongly associated with higher frequency of TP53 gene alterations (deletions, aUPD, mutations), short survival, disease progression and/or transformation to AML. Inactivation of TP53 gene may be a critical early event during CCE of 5q- clones, triggering genetic instability and acquisition of secondary aberrations. Our results substantiate a need for regular molecularcytogenetic monitoring of MDS patients with isolated del(5q) to help with treatment decision. Acknowledgement: Supported by RVO-VFN64165, GACR P302/12/ G157, ProgresQ28, MHCR 00023736.
91 DIFFERENT REPO DOSES (HIGH VS STANDARD) FOR TREATMENT OF ANEMIA IN MDS PATIENTS: A SURVEY FROM THE ITALIAN MDS REGISTRY E. Balleari1, C. Salvetti2, R. Filiberti3, B. Allione2, E. Angelucci4, M. Cavalieri5, M. Cavalleri6, D. Cilloni7, M. Clavio4, E. Crisa’2, A. Da Col1, P. Danise8, A. Di Tucci9, C. Finelli10, R. Lemoli4, M. Miglino4, E. Oliva11, M. Pellegrino12, A. Poloni13, V. Santini14 1 Internal Medicine, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 2AOU città della salute, hematology – University of Turin, Turin, Italy; 3Epidemiology, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 4 Hematology-Oncology, IRCCS-AOU San Martino-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy; 5Medicine, UO Internal Medicine, Savona, Italy; 6Medicine, UO Internal Medicine, Sestri Levante, Italy; 7AOU Città della Salute, Internal Medicine – University of Turin, Turin, Italy; 8Hematology, Nocera Hospital, Nocera Inferiore, Italy; 9Hematology, AOU Cagliari, Cagliari, Italy; 10Istituto Seragnoli, Hematology- Bologna University, Bologna, Italy; 11Hematology, Ospedali Riuniti, Reggio Calabria, Italy; 12Hematology, IRCCS CROB, Rionero sul Vulture, Italy; 13UO Hematology, Hematology-University delle Marche, Ancona, Italy; 14Hematology, AOU Careggi, Florence, Italy Introduction: REPO has been used to treat anemia in MDS anemic pts since more than 25 years. In early Ninety this treatment, using different but usually “standard” doses (inferior or equal to 30– 40.000 IU weekly), showed a disappointing overall response-rate of 15–25%. In recent years most studies reported a response rate of more than 50%, either because of a better selection of patients of MDS and possibly because higher doses (60–80.000 UI weekly) of rEPO is increasingly used. Nevertheless, a direct comparison between the two different schedules of rEPO treatment is still lacking. Methods: Within the framework of the Italian Network of regional MDS registries of FISM a cohort of 106 anemic MDS pts treated with higher doses of rEPO (40.000 IU twice a week, H) for at least 3 months were identified; a second cohort of 212 pts similar for clinical parameters known to influence response to rEPO and treated with standard doses (40.000 IU weekly, S) were compared in a 1:2 fashion. Univariate and multivariate analysis were performed as appropriate in order to identify factors influencing clinical response. Results: Characteristics of subjects were: median Hb pre-treatment 8.9 g/dL in H cohort and 9.1 g/dL in S cohort, IPSS score Intermediate-2/high in 5% of H cohort and 8% of S cohort,
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transfusion-dependency in 25% of H cohort and 26% of S cohort, median EPO 79 IU in H cohort and 69 IU in S cohort. After 3 months of rEPO treatment, the overall erythroid response-rate (IWG 2006 criteria) in the two cohorts was 53% (163 out of 309 pts). No difference in erythroid response-rate was found between MDS pts in H cohort when compared to pts in S cohort (48% responders in the H cohort vs 55% responders in the S cohort ( p = 0.23). IPSS score, transfusion-dependency and EPO serum levels at diagnosis were statistically associated with response in both cohorts. At multivariate analysis, significantly lower response-rates to rEPO were related with transfusion-dependency (yes vs no, OR = 0.59 (95%CI: 0.44–0.79, p < 0.001), higher endogenous serum EPO levels at diagnosis (>500 vs <=500, OR = 0.36 (95%CI: 0.19–0.68, p = 0.002) and higher IPSS score (intermediate 2/ high vs, intermediate 1/ low, OR = 0.42 (95%CI: 0.24–0.74, p = 0.003). Conclusions: Our data, although derived by a retrospective analysis, indicate that standard doses of rEPO are at least as effective as higher-doses for correcting anemia in lower-risk MDS patients. Prospective, randomized studies addressing this point are necessary.
92 MANAGEMENT OF MYELODYSPLASTIC SYNDROMES WITH ERYTHROPOIESIS STIMULATING AGENTS (ESAS) IN REAL-LIFE EXPERIENCE: AN UPDATE FROM RECAMDS C. Cerchione1, O. Vitagliano1, R. Della Pepa1, G. Cerciello1, A.E. Pareto1, M. Di Perna1, I. Soriente1, A.M. D’Arco2, P. Danise2, F. Alfinito1, F. Pane1 1 Hematology, AOU Federico II, Napoli, Italy; 2Hematology, Ospedale Pagani, Pagani SA, Italy Erythropoiesis stimulating agents (ESAs) are the frontline treatment in low-risk anemic MDS patients and an employment of this therapy in the earlier stage of the disease can delay the need for RBC transfusion, hypothetically by slowing the disease course. It’s matter of debate whether the clinical response is a result of proliferation and maturation of the dysplastic clone or stimulation of residual normal erythropoiesis by ESAs. Macrocytosis is one of the cytological hallmarks of dyserithropoiesis in MDS: an analysis of the erythropoietic response to ESAs therapy in a cohort of anemic non trasfusion-dependent MDS patients, enrolled in a retrospective register, RECAMDS, subgroup of Italian register, was performed. 183 patients, treated with standard-dose ESAs, have been retrospectively analyzed (Table 1). Data analysis was performed, according to IWG 2006 criteria, at the baseline, after 3 and 6 months of continuous treatment, with a subanalysis of the patients according to WHO and R-IPSS risk stratification. ESAs were started at mean Hb concentration of 9.31 g/dL, mean serum EPO concentration: 51 mU/L, after a mean time from diagnosis of 6 months (r.1–118). Overall response rate (ORR) was 83.6% (153/183), no difference among WHO and IPSS subgroups was found: 132/183 (72.1%) achieved response after 3 months of treatment, while other 21/183 (11.2%) after 6 months. 19 patients with stable disease (nonresponders, according to IWG criteria), in which treatment was continued, achieved response after 9 months. In the macrocyticresponders group 83.2% exhibits again macrocytosis after 3 months, while 16.8% become normocytic. In the normocyticresponders group 89.8% exhibits again normocytosis, while 10.2% become macrocytic: in these patients, after 3 months, there was a contemporary worsening in neutropenia and thrombocytopenia, with transfusion-dependence, regarded as first signs of progression of disease. Non-responders were 30/183 (16.3%): in the macrocytic