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BACKGROUND Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

Background Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS). Methods A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Results A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients. Conclusions The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2018;124:1251-9. © 2017 American Cancer Society.

The primary objective of this study was to evaluate the health-related quality of life (HRQOL) in lower-risk, transfusion-dependent patients with myelodysplastic syndromes (MDS) treated with deferasirox. A secondary objective was to investigate the relationship between HRQOL, serum ferritin levels and transfusion dependency.This was a prospective multicentre study enrolling 159 patients, of whom 152 received at least one dose of deferasirox. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) at baseline and then at 3, 6, 9 and 12 months. Primary analysis was performed estimating mean HRQOL scores over time by a linear mixed model on selected scales.The median age of treated patients was 72 years (range 24-87 years). No statistically significant changes over time were found in mean scores for global health status/quality of life (p=0.564), physical functioning (p=0.409) and fatigue (p=0.471) scales. Also, no significant changes were found for constipation (p=0.292), diarrhoea (p=0.815) and nausea and vomiting (p=0.643). Serum ferritin levels were not associated with HRQOL outcomes. A higher patient-reported baseline pain severity was an independent predictive factor of an earlier achievement of transfusion independence with a HR of 1.032 (99% CI 1.004 to 1.060; p=0.003).HRQOL of transfusion-dependent patients with MDS receiving deferasirox therapy remains stable over time. HRQOL assessment might also provide important predictive information on treatment outcomes.NCT00469560.

Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 ( p = 1.16 × 10 −12 ), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10 −6 and 3.34 × 10 −6 , are situated in the methylene tetrahydrofolate reductase ( MTHFR ) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.

Until the beginning of the current millennium, few concrete therapeutic possibilities were available for myelodysplastic syndrome (MDS) patients. This situation has dramatically changed in the last decade when new knowledge, new drugs and new opportunities have become available for physicians and their MDS patients. A correct diagnostic and prognostic assessment of all MDS patients wherever they are first seen in a hematology or internal medicine department is mandatory to identify the best therapeutic option and the most appropriate resources allocation. This article will review modern diagnostic criteria and classification together with correlated new therapeutic opportunities.

Purpose: Epigenetic changes play a role and cooperate with genetic alterations in the pathogenesis of myelodysplastic syndromes (MDS). We conducted a phase II multicenter study on the combination of the DNA-methyltransferase inhibitor 5-azacytidine (5-AZA) and the histone deacetylase inhibitor valproic acid (VPA) in patients with higher risk MDS. Experimental Design: We enrolled 62 patients with MDS (refractory anemia with excess blasts, 39 patients; refractory anemia with excess blasts in transformation, 19 patients; and chronic myelomanocytic leukemia (CMML), 4 patients) and an International Prognostic Scoring System (IPSS) rating of Intermediate-2 (42 patients) or high (20 patients). VPA was given to reach a plasma concentration of >50 μg/mL, then 5-AZA was added s.c. at 75 mg/m2 for 7 days in eight monthly cycles. Results: The median overall survival was 14.4 months. At a median follow-up of 12 months (range, 0.7-21.0), the disease progressed in 20 patients, with 21% cumulative incidence of progression. Of 26 patients who completed eight cycles, 30.7% obtained complete or partial remission, 15.4% had a major hematologic improvement, whereas 38.5% showed stable disease. Drug-related toxicity was mild. Favorable prognostic factors for survival were IPSS Intermediate-2 and plasma VPA of ≥50 μg/mL (log rank = 0.013 and 0.007, respectively). Analysis of polymorphisms important for the metabolism of the drugs used in the trial showed that carriers of the CYP2C19*2 variant of cytochrome P450 required higher VPA doses to achieve the target VPA plasma concentration of 50 μg/mL on day 1 of 5-AZA treatment (P = 0.0021). Conclusion: Our data show that the 5-AZA/VPA combination is active and safe in patients with MDS with a poor prognosis. Achievement of VPA therapeutic levels may indeed increase 5-AZA efficacy.

Background In the absence of randomized, controlled trial data to support iron chelation therapy in transfusion-dependent patients with myelodysplastic syndromes (MDS), continued evidence from large prospective clinical trials evaluating the efficacy and safety of iron chelation therapy in this patient population is warranted. Methods The safety and efficacy of deferasirox was examined in a prospective, open-label, single-arm, multicenter trial of transfusion-dependent patients with International Prognostic Scoring System low- or intermediate-1-risk MDS and evidence of transfusion-related iron overload. The effects of deferasirox therapy on hematological response and disease progression were also examined. Results Of 159 participants enrolled from 37 Italian centers, 152 received ≥1 dose of deferasirox (initiated at 10–20 mg/kg/day and titrated as appropriate), and 68 completed the study. Of 84 patients who discontinued deferasirox therapy, 22 died during the trial, and 28 withdrew due to an adverse event (AE). Fourteen treatment-related grade 3 AEs occurred in 11 patients, whereas no grade 4 or 5 drug-related AEs were reported. Significant risks for dropout were a higher serum ferritin level at baseline, a higher MDS-Specific Comorbidity Index, and a shorter diagnosis–enrollment interval. Median serum ferritin level fell from 1966 ng/mL to 1475 ng/mL (P

BACKGROUND: Patients with higher risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) have poor life expectancy making accurate prediction of overall survival (OS) a critical issue for optimal and personalized patients' management. PURPOSE: The primary objective of this study was to develop a patient-based prognostic index for higher risk-disease, that would include self-reported fatigue into the widely used IPSS classification. A secondary objective was to examine whether this patient-based index would provide more accurate OS prediction than the standard IPSS classification. PATIENTS AND METHODS: Analysis is based on 280 newly diagnosed patients with MDS classified with an intermediate-2 or high-risk score (i.e., higher-risk) according to the IPSS. Patients were recruited in an international prospective cohort observational study involving 37 centers. OS was defined as the date of diagnosis of IPSS intermediate-2 or high risk MDS up to death for any cause. Patients were censored at the date of last follow up if not dead at the time of analysis. Before treatment start, all patients completed the EORTC QLQ-C30 questionnaire and the fatigue scale was a priori selected for possible inclusion into the IPSS. Among all observed values of the fatigue score (range: 0-100) we looked for a threshold defining four risk groups, formed by patients reporting either low or high fatigue respectively in intermediate-2 and high risk IPSS groups. The final prognostic index was developed based on univariate and multivariate Cox models. Differences among Kaplan-Meier OS estimation of new risk categories were assessed by log-rank test. Sensitivity analyses were performed, 1) assessing differences in patients' baseline characteristics among risk groups, by Kruskal-Wallis and Fisher's exact tests 2) accounting for several potential confounding factors (baseline and time-dependent) in a multivariate extended Cox model, including treatment received after baseline assessment and further evolution into acute myeloid leukemia, 3) performing a bootstrap resampling procedure to internally validate the final prognostic index. Discrimination and calibration of the new index were evaluated. For all analyses, α=0.05. RESULTS: With a median follow- up of 15 months (IQR 8-27) we observed 113 deaths. The median OS of the overall population was 17 months (95% CI, 15-19). The majority of patients (N=165, 59%) received treatment with hypomethylating agents. The final cut-off value selected for the EORTC QLQ-C30 fatigue scale was 45 points discriminating between patients with low ( CONCLUSION: The FA-IPSS(h) is a new prognostic index that integrates patient's self-reported fatigue into the well established IPSS index. Its use might enhance physicians' ability to more accurately predict OS in higher-risk MDS. Also, implementation of this index into standard practice might have important implications to elicit a more active patient participation during initial consultations. Disclosures Efficace: Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Bonnetain:Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgène: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Integragen: Consultancy, Honoraria; Nestle: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Merck Serono: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Fianchi:Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Breccia:Novartis: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Platzbecker:Celgene Corporation: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding.

Introduction Azacytidine(AZA) is the current standard of care for patients with high-risk myelodysplastic syndrome (MDS) in Europe. AZA has shown a survival advantage when compared with conventional therapies and has also shown activity in IPSS lower-risk patients. However, about 40% of patients do not respond and most patients show a loss of response within 2 years. Treatment options for MDS patients who progressed while on, failed to respond to, or became intolerant tohypomethylatingagents are scarce and it has been shown that overall survival (OS) is extremely short. Objectives of this study were to describe in a cohort of real life MDS patients treated with AZA, the reasons to discontinue treatment, and to evaluate their clinical outcomes. Methods We present here the results of a real life study from a large group ofnon selectedpatients recorded in the MDS registry of FondazioneItalianaSindromiMielodisplastiche(FISM). Only patients treated with AZA from January 2009 to June 2014 were considered for the analysis. All types of conventional published schedules of AZA were allowed. The primary end point was the evaluation of OS from start of AZA treatment to the date of death from any cause. Secondary end points were clinical response, cause of discontinuation, salvage treatments and OS from discontinuation of the drug. Results Between January 2009 to June 2014 1799 newly diagnosed MDS patients were enrolled , and 420 received AZA; 271 patients received AZA as 1st line treatment, 115 patients as 2nd line treatment, 34 as a line ≥3rd. Median age was 73 years (IQR: 67-77); 261 patients (62%) were male. WHO diagnosis was RA or RARS (n=27, 6%), RCMD with or without RS (n=62, 15%) AREB-1 (n=126, 30%), AREB 2 (n=190, 45%), other subtypes (n=15, 4%). At start of AZA therapy IPSS score was low in 11 (3%), int-1 in 80 (19%), int-2 in 143 (34%), high in 54 patients (13%), and not available in 132 patients (31%). Forty-three (47%) low and int-1 risk MDS patients had a transfusion-dependent anemia. Patients received a median of 7 courses of treatment (range 3-12). Twenty-four patients (6%) received concomitant erythropoietin therapy. OS at 1 year from beginning of AZA therapy was 73% for the whole cohort (420 pts)(95%CI: 0.69-0.78), and median OS was 23 months, 25 months for patients with IPSS lower-risk MDS and 21 months for those with IPSS higher risk MDS (log-rank test: 0.72). OS after discontinuation of AZA was 8 months. Clinical response was reported according to IWG criteria only in 288/420 patients (69%); 94 patients (33%) achieved a hematological response, that was complete in 35 patients (12%) and partial in 59 (20%), 78 patients (27%) had stable disease while 116 (40%) patients did not respond. Response was achieved after a median of 6 cycles (IQR: 4-11), in both lower and higher risk MDS patients. After a median follow up of 16 months (IQR:7-35) in 97 patients (23%) AZA therapy was still ongoing and in 323 has been discontinued (77%). Interruption of treatment was due to loss of response/worsening of hematological parameters in 24 patients who achieved complete or partial response (7%) and in 20 patients with stable disease (6%). AML evolution was the cause for interruption in 105 cases (32%), death in 28 (9%), toxicity or poor compliance in only 26 (8%), while clinical decision of the treating hematologist determined interruption in 22 cases (7%). In additional 98 patients AZA was discontinued early for reasons not reported by the treating physician (30%). Of the 323 patients who discontinued AZA 10 (3%) were managed with intensive AML-like chemotherapy, 17 (5%) underwent an allogeneic HSCT, 18 (6%) received low-dose chemotherapy, 42 (14%) other treatments and 236 patients (73%) received only transfusions and other supportive therapy. Conclusions Our data confirm that AZA therapy is effective for MDS patients, both with higher and lower IPSS risk disease. Response rate is consistent with what previously reported and median OS is 23 months. The interesting observation is that at 16 months, 77% of patients had discontinued treatment, either for progression or loss of response (45% of cases) and only in 8% of cases for reported toxicity. As there are few treatment options after AZA interruption, it is important to establish the reasons other than progression yielding to a stop in therapy, in order to avoid too early discontinuation and loss of survival advantage. Disclosures Finelli: Celgene: Research Funding; Celgene: Other: Speaker fees; Novartis: Other: Speaker fees. Angelucci:Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Astex: Consultancy; Amgen: Consultancy; Onconova: Consultancy.

Introduction: Erythropoietic stimulating agents (ESAs) have not yet received FDA nor EMA approval to treat anemia of myelodysplastic syndromes (MDS), but ESAs are in use in this clinical setting since more than 25 years. Early studies, using various but usually "standard" doses of recombinant EPO (rEPO) (30-40.000 IU weekly), showed a disappointing overall response-rate of no more than 15-25%. In recent years most studies reported a response rate of more than 50%, provided MDS patients were selected according to favorable clinical variables determined during the years ( ie low transfusion requirement, absence of blasts, endogenous EPO levels < 500). Higher response rates with respect to early studies are probably due to higher, not weight-adjusted doses of rEPO (60-80.000 UI weekly). Nevertheless, a direct comparison between the two different schedules of rEPO treatment is still lacking, and the superiority of the so called higher doses of rEPO to standards regimens is inferred only by results of meta-analysis comparing studies performed at different times with various schedules and heterogenous cohorts of MDS patients. Objectives: We aimed at clarifying whether the erythroid response rate differed in patients exposed to higher doses versus standard doses of rEPO. Methods: Within the framework of the Italian Network of regional MDS registries established by Fondazione Italiana Sindromi Mielodisplastiche (FISM) a cohort of 103 MDS patients (pts) with anemia treated with higher doses of rEPO (40.000 IU twice a week, H) for at least 3 months within 6 months from diagnosis were identified; a second cohort of 206 pts, similar for clinical parameters known to influence response to rEPO (i.e. Hb concentrations at the time of starting treatment, IPSS score, transfusion-dependency, endogenous Epo levels at diagnosis and time of treatment from diagnosis) and treated with standard doses (40.000 IU weekly, S) were compared to the first cohort. Univariate and multivariate analysis were performed as appropriate in order to identify factors influencing clinical response to treatment. 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, transfusion-dependency in 25% of H cohort and 26% of S cohort, median EPO at diagnosis 79 IU in H cohort and 69 IU in S cohort. According to IWG 2006 criteria, after 3 months of rEPO treatment the overall erythroid response-rate among all the pts in the two cohorts was 53% (163 out of 309 pts). No difference in erythroid response-rate was found between MDS pts treated with higher doses (49 (48%) responders out of 103 cases) when compared to cases treated with standard doses (114 (55%) responders out of 206 pts, p= 0.23). As expected, IPSS score, transfusion-dependency and EPO serum levels at diagnosis were statistically associated with response. In particular, at multivariate analysis, significantly lower response-rates to rEPO were associated with transfusion-dependency (yes vs no, OR= 0.59 (95%CI: 0.44-0.79, p500 vs Conclusions : Our data, although derived by a retrospective analysis, seem to indicate that standard doses of rEPO are at least as effective as higher-doses for correcting anemia in MDS patients; in this clinical scenario, a standard-doses rEPO treatment allows for a consistent reduction of costs without precluding to achieve a durable erythroid response to rEPO. Prospective, randomized studies addressing this point are necessary to definitely address this topic. Disclosures Angelucci: Novartis oncology, celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Finelli:Celgene: Research Funding; Celgene: Other: Speaker fees; Novartis: Other: Speaker fees. Oliva:Celgene: Consultancy, Honoraria, Speakers Bureau. Santini:Janssen: Consultancy, Honoraria; Onconova: Other: advisory board; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Other: advisory board; Astex: Other: advisory board; Novartis: Consultancy, Honoraria.

Abstract 2078 Background: Health-related quality of life profile (HRQOL) of patients diagnosed with high-risk myelodysplastic syndromes (MDS) can be compromised already at the time of diagnosis before receiving any kind of treatment. Clinical decision-making is challenging due to the poor prognosis and no data exist on the possible relationships between patient's HRQOL and the request of prognostic information on survival during consultation. Aim: The main objectives were to assess preferences for prognostic information of patients with high-risk MDS and the relationship between such preferences and patient characteristics including HRQOL. To date no such evidence exists in this population. Patients and Methods: Data were gathered through an ongoing international prospective observational study that recruits newly diagnosed patients with MDS. These patients typically have a limited life expectancy. At the time of diagnosis, and during one of the first clinical consultations in which treatment options were discussed, patients completed the European Organization for Research and treatment of Cancer, Quality of life Questionnaire (EORTC QLQ-C30). The EORTC QLQ-C30 is a psychometrically robust generic HRQOL cancer measure assessing both symptoms and functional aspects. Physicians also completed an extensive survey about their patient's preference for involvement in treatment decisions and whether the patient explicitly requested prognostic information for survival. Associations between request for prognostic information, HRQOL socio-demographic characteristics (i.e., living arrangements, age, gender, education) and clinical data including: performance status, comorbidity and disease severity (i.e. IPSS risk category intermediate 2 vs. high risk) were investigated using Fisher's exact test and Wilcoxon-Mann-Whitney test as appropriate. Results: Overall, 184 patients (36% female and 64% male) were analyzed. Mean age of patients was 70 years (range: 31–88). 65% explicitly requested information about expected survival at the time of diagnosis. The symptom profile of patients requesting prognostic information was better than those who did not in 7 out of the 8 symptoms evaluated. The largest clinically meaningful difference was found for fatigue with a mean score of 39 (SD:26) and 52 (SD:28) respectively for those requesting prognostic information versus those who did not. Request for prognostic information was significantly associated with younger age (P=.01) and fewer comorbidities (P=.04). In addition, better physical functioning (P=.009), better role functioning (P=.002) and a lower level of fatigue (P=.002) were also associated with a request for prognostic information during consultation. Additional supportive analysis revealed that patients with a higher overall mean symptom score did not request information about survival (P=.02). Conclusion: These data suggest that the majority of patients with high-risk MDS request prognostic information on survival from their physicians at the time of diagnosis. There is also an indication that patients who are more likely to request such information are those who are in better health condition reporting higher functional abilities and lower symptoms. Disclosures: No relevant conflicts of interest to declare.

Only limited data are available regarding myocardial iron overload in adult patients with transfusion dependent acquired anemias. To address this topic using MRI T2* we studied 27 consecutive chronic transfusion dependent patients with acquired anemias: (22 myelodysplastic syndrome, 5 primary myelofibrosis). Cardiac MRI T2* values obtained ranged from 5.6 to 58.7 (median value 39.8) milliseconds. Of the 24 analyzable patients, cardiac T2* correlated with transfusion burden (p=0.0002). No patient who had received less than 290 mL/kg of packed red blood cells (101 units=20 grams of iron) had a pathological cardiac T2* value (< 20 ms). All patients who had received at least 24 PRBC units showed MRI T2* detectable hepatic iron (liver T2* value

Background. Autologous stem cell transplant is a consolidation treatment for standard risk acute myeloid leukemia (AML). Traditional preparative regimens, most of all Busulphan (Bu) based, have been widely used, but the relapse risk is high and extra hematologic toxicity is a concern. Even if the combination of Busulphan intravenous formulation in association with cyclophosphamide has shown lower toxicity and suggests favorable safety and efficacy, new drugs associations are continuously explored. Methods. Since April 2004 to January 2013, 39 consecutive patients (20 males, 19 females ) entered this study. Median age at transplant was 51 years (range 21-79). Cytogenetic risk classification at diagnosis was good in 4, intermediate in 29 and poor in 6. At transplant time thirty-six patients were in first complete remission, one in partial remission and two in second complete remissions. Mean number of induction chemotherapy courses received was 2.2. Conditioning consisted of oral Busulfan/Cyclophosphamide in 13, intravenous once-daily infusion Busulphan/Cyclophosphamide in 11, intravenous Busulfan/Fludarabine in 8, intravenous Busulphan /Melphalan in 3, Treosulfan/Cyclophosphamide in 3 and Treosulfan /Melphalan in 1. In all patients aged less than 70 years an extended patient and family HLA typing was performed at diagnosis to eventually plane a salvage allogeneic transplant since the beginning of the therapy course. Cytogenetic risk, status of disease, age, number of chemotherapy courses, conditioning regimens have been analyzed. Primary objective was evaluation of overall survival, disease free survival, transplant related mortality and relapse. Comparison analyses were performed with chi square test. All analyses were intention to treat. Results: Of the 39 patients studied one patient (2.5%) died for intracranial haemorrhage during the period of aplasia. All the other engrafted. Of the latter all but one had sustained long-term engraftment. Fourteen patients (36%) did not relapse; all but one are alive and well in continuous complete remission. The only patient who died in remission had lethal infection after salvage allogeneic transplant performed for persistent cytopenias. Twenty-four patients (61%) relapsed Of the 24 relapsed patients eleven (46%) received a second allogeneic transplant after re-induction chemotherapy (all but one from alternative donors: 8 from a matched unrelated donor, 1 from an aplo-identical family member and one from an unrelated cord blood donor). Of them six have died by transplant related mortality and 5 are alive (4 in complete remission). Overall nineteen over 39 patients (49%) are alive after a median follow up of 60 months (range 18-120); seventeen (44% of the entire cohort) in complete remission and two with persistent disease. As regard the 13 patients who didn’t relapse all were transplanted in first complete remission; cytogenetic risk was good in 2, intermediate in 10 and poor in 1; leukemia chemotherapy induction was standard Daunoblastina- Cytarabine (3+7 schedule) in all; transplant conditioning regimens were oral Busulphan/Cyclophosphamide in 6 and intravenous once-daily dose Busulphan in association with cyclophosphamide or Fludarabine in 7. In our analyses the only risk factor impacting on patients’ outcome was patient age at transplant time. Age impacted overall survival and disease free survival. Median age was 61years (range 21-79 ) in patients who died versus 36 years (range21-68) in patients alive (P = 0.03 ) and 64 years ( 21-79) in patients with relapse versus 36 years (21-60) in patients who didn’t relapse (P = 0.04). No other factor had impact on outcome. Conclusion. This limited, single centre experience, confirms that autologous hematopoietic stem cell transplant is an efficient consolidation treatment for AML in remission. Relapse still remains the major problem even if some selective patients may be rescued by allogeneic transplant after a re-induction strategy. A complete HLA family study and preliminary unrelated research should be early performed in all patients for optimal treatment plan and decision. Disclosures No relevant conflicts of interest to declare.

Background. Allogeneic hemopoietic stem cell transplantation is the treatment of choice for high and intermediate risk acute myeloid leukemia (AML) and for higher risk myelodysplastic syndrome (MDS). Standards preparative regimens TBI-CY and BU-CY have been widely used and extra hematologic toxicity remains a concern. Even if the combination of intravenous formulation Busulphan-CY has shown lower toxicity and suggested favorable safety and efficacy profile new drugs associations are continuously explored. Recently the association Busulphan-Fludarabine has replaced the Bu-Cy regimen with the aim to further reduce toxicity. In our Institution we started to use this regimen as preparation for allogeneic transplantation in patients with AML and MDS in October 2008 using Busulphan in a single daily infusion with the primary objective of evaluating safety and efficacy. Methods. Since October 2008 to May 2014, 23 consecutive patients (19 males, 4 females) entered this study. Median age was 56 years (range 35-63). Thirteen patients presented with first remission AML, five with first or more advanced relapse or resistant disease and five with intermediate II or high risk MDS. Conditioning consisted of intravenous Busulphan (Busilvex® 9,6 -12,8 mg/kg) given once daily in a 4 hours infusion in association with Fludarabine 160 mg /m2 for 4 consecutive days. Fifteen patients received HSCs from HLA identical siblings, 1 from a family mismatched donor, 7 from matched unrelated donors. Source of stem cells was bone marrow in 13 patients, peripheral blood stem cells in 9 patients, and both in 1 patient. CSA + short MTX was used as GVHD prophylaxis and anti-Lymphocyte globulins (Thymoglobulin® or ATG Fresenius®) was added in case of unrelated donor transplants Toxicity was evaluated by WHO toxicity scale Common Terminology Criteria for Adverse Events (CTCAE) version 3. Acute Graft versus Host Disease was evaluated in patients with engraftment and graded according to the revised Glucksberg scale. Internal review board approved study. All patients gave written informed consent to procedure. Results. All patients regularly engrafted (mean time to neutrophils >500/microliter was 13 days (range 11-15). Seven patients experienced gastro-intestinal toxicity (1 grade III mucositis, 2 grade II mucositis, 4 grade I mucositis); 3 patients had grade II cystitis. Overall grade >II toxicity occurred in a single patient (4%). Acute grade IV gastro-intestinal- GvHD occurred in 1 patient, while 12 patients presented grade I skin GvHD. Cr. GVHD occurred in 4/18 evaluable patients (moderate in 1). CMV reactivation occurred in 15/23 patients (65%), no patient developed life-threatening bacterial or fungal infection. Eight out of 23 patients have died (35%) all but one by recurrent disease and 1 by grade IV acute GvHD. Fifteen patients are alive (65%), 14 in complete remission, with a median follow-up of 8 months (range 2-37 months). Conclusion. This single Centre report, even if with limited number of patients, underlines that the association of intravenous single dose infusion Busulphan plus Fludarabine is a safe and effective conditioning regimen in AML/MDS patients. Intravenous Busulphan administered once daily is convenient, well tolerated and effective. Further prospective studies are warranted. Disclosures No relevant conflicts of interest to declare.

Abstract 3163 Background: Fatigue can potentially compromise activities of daily living and functional abilities in patients with myelodysplastic syndromes (MDS). These patients typically also have a limited life expectancy, thus making the improvement of health-related quality of life an important goal of therapy. However, there is paucity of evidence-based data in this area. Aims: To investigate the relationships between fatigue and physical, social and emotional functions in high-risk MDS patients and to evaluate socio-demographic and clinical characteristics associated with fatigue. Methods: Newly diagnosed patients with intermediate-2 or high-risk IPSS score are recruited in an international prospective observational study. Current analysis is based on patients recruited in 37 centers. A number of socio-demographic, clinical and laboratory variables were collected prior to treatment. Also, fatigue and functional abilities were measured before treatment start. Fatigue was evaluated with the FACIT-Fatigue scale. This is a simple 13-item psychometrically robust questionnaire that assesses self-reported tiredness, weakness and difficulty conducting usual activities due to fatigue. Functional abilities and quality of life (QoL) were assessed with the EORTC QLQ-C30. Both questionnaires have undergone rigorous linguistic cross-cultural validation and were available for all patients in the appropriate language. Functional aspects investigated included: physical (PF), role (RF), emotional (EF), cognitive (CF) and social functioning (SF). These scales range from 0 to 100, with higher scores representing better outcomes. Based on previous research, 10-points were considered to be a minimally important difference (MID) for the functional and QoL scales investigated. A score difference at least equal to MID was considered as a clinically meaningful difference. The cohort was divided into four groups based on the FACIT-Fatigue scores quartiles and patients were defined as having low, low/medium, medium/high and high fatigue levels. All variables investigated were summarized according to fatigue levels. Associations between fatigue levels and functional aspects, socio-demographic characteristics (i.e., age, gender, living arrangements, education) and clinical data (i.e., performance status and IPSS risk) were investigated using Chi-square and Kruskall-Wallis tests as appropriate. Multivariate stepwise regression analysis was also performed to investigate the impact of self-reported fatigue on functional scales. Results: Analysis is based on 240 patients, of whom 77% and 23% respectively classified with intermediate-2 and high-risk IPSS score. Median age of patients was 71 years (36% female and 64% male) and 49% had at least one comorbidity. Seventy-three percent of patients had an ECOG performance status ≥1. Patients with higher levels of fatigue reported worse scores in all functional aspects investigated. PF, RF and SF scales were found to be the most compromised aspects by fatigue severity. Mean score differences, between patients reporting low versus high fatigue levels were not only statistically significant (P Conclusion: This study suggests that fatigue is the major factor greatly compromising functional abilities and QoL in high-risk MDS patients before treatment. Successfully treating fatigue is crucial to improve functional abilities in these patients and to maximize treatment outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract 425 Introduction. FDA and EMA have approved Deferasirox for iron chelation therapy for transfusion dependent MDS patients after a limited experience in selected MDS patients. Therefore we felt the need of a large, prospective, trial to verify Deferasirox safety, compliance, efficacy and effect on erythroid function in a large, “real world,” MDS population. Patients and Methods. One hundred fifty-two consecutive MDS IPSS lower risks (62 low and 90 intermediate1) transfusion dependent (minimum transfusion history 20 units received) patients were enrolled in 37 Italian centres. Patients received Deferasirox at the starting dose of 20 mg/kg. Characteristics of patients have been summarized by means of cross-tabulations for categorical variables and by means of median and range for continuous data. Adverse events (AEs) were defined according to CTCAE.3 (2003) definition. Disease progression was defined as advance to higher IPPS score group, development of acute leukemia or death. Efficacy of the treatment was measured by monitoring monthly serum ferritin levels. Transfusion independence was defined as three consecutive months without PRBC requirement with a minimum stable Hb level of 9 g/dl. The probability of drop out and transfusion independence were estimated using the appropriate non-parametric method, considering death and progression disease as a competing risk. Differences in univariate analysis were evaluated by Gray test. Fine and Gray model was used to evaluated prognostic factors in multivariate analysis. FriedmanÕs test was performed to evaluate differences in serum ferritin levels, hemoglobin level and transfusions input over time. Results. Ninety-six males and 56 females were enrolled. Median age was 72 years (66–77). Median interval diagnosis-enrolment was 32 months (17–54). Patients have been receiving regular blood transfusions for a median of 21 months (10–36) with a median number of units received of 37 (22–63). At baseline median CIRS co-morbidity score was 0 (0–1), CIRS severity score 0 (0–1), and Charlson co-morbidity score 0(0–1). Eighty-four patients (55%) prematurely interrupted the study while 68 (45%) completed the planned year of treatment. Risk of drop out was 18.8% and 28% at 6 and 12 months, respectively. Risk of disease progression or death was 12.7% and 25% at 6 and 12 months, respectively. In multivariate analyses significant risk factors for treatment interruption were shorter diagnosis-enrolment interval (P=0.0008), lower Deferasirox dose (p=0.008) and higher serum ferritin level (P=0.004). During the study 304 AEs were reported in 107 distinct patients. Of these events 93 (66 patients = 43%) were defined as possible-probably-certain drug related. Of these 93 related events fourteen in 11 distinct patients (7%) were superior to grade 2. Features of AEs were similar to those already reported. Serum ferritin significantly decreased during the study from a median starting value of 1966 ng/ml (1416–2998) to a median final value of 1475 ng/ml (915–2010), (P Conclusion. Less than 50% of the enrolled population was able to complete the planned year of treatment because of drop out (risk 28%) and progression (risk 25%) despite a limited number of >2 grade AEs. Noteworthy >69% of the AEs was not drug related indicating a basic vulnerability of this population. Deferasirox was effective in reducing serum ferritin levels. Clinical benefit was also related to erythroid improvement that was clinically significant reducing transfusion need in a relevant percentage of patients. ClinicalTrials.gov Identifier: NCT00469560 Disclosures: Angelucci: Novartis : Chair of Steering Committee of the Telesto trial Other. Vallisa:CELGENE CORPORATION: Research Funding.

Abstract 4953 Background: Shared decision-making between patients and physicians is broadly advocated in medicine, however little research is available to understand whether this approach would be desirable to all patients regardless of disease type and severity or individual patient characteristics. While clinical decision-making in high-risk myelodysplastic syndromes (MDS) is critical for a number of reasons including: associated comorbidity, symptom burden, and limited life expectancy, no evidence-base data currently exist on patients' preferences. Aim: The objective of this study is twofold: 1) to investigate to what extent high-risk MDS patients prefer to be involved in treatment decision making during consultation just after diagnosis; 2) to identify possible clinical, socio-demographic and patient-reported health status factors associated with patients' preferences for involvement in treatment decisions. Patients and Methods: Data were gathered through an ongoing international prospective observational study involving 15 countries that recruits newly diagnosed patients with intermediate-2 or high-risk IPSS score. All patients were classified according to the WHO histology classification. During the first encounter with their treating physicians, discussing treatment options just after diagnosis, patients were administered a previously internationally validated “control preference scale”. This scale broadly categorizes patients into one of three roles depending on the extent of their preferred involvement in treatment decision-making: “active” (where the patient themselves prefer to decide on which would be the most appropriate treatment option for themselves); “collaborative/shared” (where the patient and the doctor jointly decided on the most appropriate treatment option); “passive” (where the patient prefer to leave decision on the most appropriate treatment option to the doctor). Associations with the following variables were investigated: performance status, comorbidity (“Hematopoietic Cell Transplantation”-“Comorbidity index”), living arrangements, age, gender, education, cultural group, IPSS risk category, evolution from lower IPSS risk scores and patient-reported symptoms (using symptom scales of the EORTC QLQ-C30). Descriptive statistics were used and Mann-Whitney U-test, Kruskall-Wallis test and Fisher's exact test were used as appropriate to test statistical significance of performed comparisons. Results: Study population included overall 121 patients (38% female and 62% male). Mean age of patients was 69 years (min:31.3 max: 87.9) and 80% were diagnosed with IPSS int-2 risk score and 20% with IPSS high risk score. Twenty-six percent evolved from lower IPSS risk scores, while 74% were newly diagnosed with higher-risk. Forty-nine percent favored a passive while only 13% preferred an active role in treatment decision-making; the remaining 38% favored a collaborative/shared decision-making approach. Investigation of factors possibly related to preferred roles, found that passive role was significantly associated with lower education levels (P=.04). Among lower educated patients, 62.5% preferred a passive role compared with only 5% preferring an active role. When investigating relationships with patient-reported symptoms, a general trend for patients preferring a passive role, showing worse outcomes, was also evident. Higher symptom mean scores were found for passive vs. active role groups, being respectively: 46 (sd.26.6) vs. 37 (sd.29.9) for fatigue; 20 (sd.31.8) vs. 2 (sd.8.6) for constipation; 34 (sd.33) vs. 24 (sd.29.5) for dyspnea. Exploratory analysis showed that overall mean symptom score was statistically significant worse in patients preferring a passive role vs. those preferring an active role (P=.01). While other trends of associations were noted, these were not statistically significant. Conclusion: This is the first evidence suggesting that a consistent percentage of high-risk MDS patients prefer a passive role when discussing treatment options with their treating physicians at the time of diagnosis. There is also an indication that these patients are those with lower education levels and presenting with a higher symptom burden. Results need to be confirmed in a larger sample size. Disclosures: No relevant conflicts of interest to declare.

Abstract 2928 Introduction. The recent development of a safe and efficient once daily oral iron chelator (Deferasirox, ExjadeÒ) made possible regular chelation therapy in transfusion dependent MDS patients. However in this category of patients the reported clinical experience is limited to selected populations. For this reason the GIMEMA group developed a phase IIIb prospective trial to test safety and efficacy of Deferasirox in a large population of patients comparable to general MDS population. Methods. One hundred and fifty-nine transfusion dependent IPSS low-intermediate1 risk MDS patients were enrolled. Analysis has been performed on 123 patients who had completed the planned year of treatment. Baseline characteristics were the following (data are expressed as median with upper and lower quartile unless specifically indicated): median age was 72 years (range 24 – 87); 48 were IPSS low risk and 75 Intermediate1; duration of transfusion dependency before treatment was 20 months (12-36) corresponding to 38 (22-70) packed red blood cells transfusions received. Baseline serum ferritin was 2000 ng/ml (1471-3000). Baseline Charlson and CIRS comorbity scores were 1 (0-1) and 0.2 (0.1-0.4), respectively. Patients started treatment with the standard 20 mg/kg Deferasirox dose but dose adjustments on clinical indications were allowed. Results. 61 patients (49%) prematurely interrupted the study (drop out), 62 (51%) patients completed the planned year of treatment. In logistic model for drop out rate high Charlson co-morbidity score showed a trend as significant risk factors (p=0.06). Drops out were related to: ten patients (8%) had progression to acute leukemia during the study; twenty patients (16%) experienced MDS related clinical problem (three had cardiac failure, seven had severe infectious diseases, four had severe bleeding, three died at home, three presented others MDS related problems); five patients underwent hemopoietic stem cell transplantation and thirteen discontinued treatment for unrelated problems. Drug related toxicity was drop out cause in 13 patients (11% of the entire population). Main causes of toxicity related drops out were increase of creatinine and gastro-intestinal disturbance. Out of 123 patients analyzed for adverse events only 4 (3%) presented grade 3–4 drug related adverse events. Severe adverse events with suspected relationship with study drug were diarrhea and increase of liver enzymes. Serum ferritin was monthly recorded in the 62 patients who completed the protocol with a statistically significant decrement during the 12 months follow up: median baseline value 2000 ng/ml (interquartile range 1471–3000), median final value 1550 ng/ml (interquartile range 775–2200) P < 0.001, Friedman test analyzing the entire study period. Analysis of quality of life is ongoing. One patient showed a complete erythroid response to Deferasirox treatment acquiring transfusion independence that is still ongoing after 18 months. Discussion. Preliminary results from the GIMEMA MDS0306 study confirmed feasibility of Deferasirox therapy in transfusion dependent MDS patients. Drop out rate, toxicity related drop out and severe side effects were similar to those reported in other trials even if the present population presented clinical characteristics of more advanced disease and age. The rate of progression is coherent with prolonged disease story. Serum ferritin behavior confirms Deferasirox efficacy. The serum ferritin reduction was more evident in the more heavily overloaded population indicating successful iron depletion in this group of patients as clinically requested. ClinicalTrial.gov identifier NCT00469560. Disclosures: Angelucci: Novartis: Honoraria. Saglio:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria.

Cardiac T2* Magnetic Resonance Imaging (MRI) has been recently used to evaluate myocardial iron deposition in patients with transfusion dependent beta-thalassemia major. No comparable studies have been published for patients with myelodysplastic syndromes receiving chronic red blood cell transfusion. Therefore we measured cardiac-MRI T2* in 16 patients (10 male, 6 female) with myelodysplastic syndromes (aged 54 – 82 years, median age 67). All of them were transfusion dependent having received a median number of 60 (range 16–225) packed red blood cell transfusion equivalent to 3.2 – 45 (median 12) grams of iron. Nine have been irregularly and sporadically chelated by deferoxamine, seven were unchelated. Serum ferritin levels ranged from 1163 to 6241 mg/dl (median value 2086). None of the patients presented signs or symptoms of cardiac dysfunction at the time of the study. Cardiac-MRI T2*values obtained ranged from 5.6 to 80 (median value 46.5) milliseconds (ms). Correlation between serum ferritin and cardiac T2* value was weak ( r= 0.43, r2 =0.18). According to D. Pennel we considered as significant of myocardial iron deposition a relaxation time ≤ 20ms. Cardiac T2* was < 20ms in 3 patients who had never used iron chelators (5.6, 12.4 and 8.5 ms, respectively). They had received 39, 101 and 200 units of red blood cell transfusion, corresponding to 7.8, 20 and 40 grams of iron, respectively. Of relevance 2 of them died within few months after the end of the study and one showed early signs of left ventricular dysfunction. None of the patients with a cardiac T2* value >20 ms showed instrumental nor clinical signs of cardiac deterioration in six months follow up. No patient who had received less than 39 transfusions presented cardiac T2* value ≤20 ms. Evaluation of myocardial iron deposition by T2* cardiac MRI could be recommendable in myelodyplasia patients who had received more than 30 packed red blood cells transfusisions.

Background Anemia is a common symptom in patients with Myelodysplastic Syndromes (MDS) and although erythropoietic agents are often active, it is frequently treated with red blood cell (RBC) transfusions. A substantial proportion of patients might also eventually become transfusion-dependent and, Iron-chelating therapies might be important to minimize complications of iron overload. Objectives To investigate the impact of deferasirox therapy on health-related quality of life (HRQOL) of lower risk transfusion-dependent MDS patients over a one year period. Secondary objectives were to investigate relationships between HRQOL and ferritin levels and to explore the prognostic value of baseline HRQOL on the probability of achieving transfusion independence. Patients and Methods This was a prospective study whose clinical findings (i.e., primary endpoint was safety and tolerability) were previously reported. HRQOL was a secondary endpoint of the study and we herein report, for the first time, HRQOL prospective findings. Eligible patients included: MDS patients 18 years or older, International Prognostic Scoring System (IPSS) low or intermediate-1 risk and diagnosed with transfusional siderosis following a minimum of 20 blood transfusions. Patients received daily oral deferasirox at a dose between 10 and 30 mg/kg of body weight for a period of 1 year. HRQOL was assessed with the EORTC QLQ-C30. HRQOL at baseline and at 3, 6, 9 and 12 months after treatment start. The EORTC QLQ-C30 consists of 30 items and includes five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The mean trend of HRQOL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Such covariance structure provided the best model fit among those investigated. Results Overall, 159 patients were screened at 37 centers. The median duration of disease at enrollment was 32 months and median number of units of packed RBC received was 37. Seven patients did not start treatment at all and thus there were 152 expected HRQOL forms at baseline assessment. Out of these, 146 patients returned the questionnaire yielding a baseline compliance of 96%. No statistically significant differences over time were found for any scale of the EORTC QLQ-C30. Figure 1 depicts mean scores over time for selected scales of: fatigue, physical functioning, pain and global HRQOL. No HRQOL differences were found between patients with serum ferritin levels lower or higher than 2000 μg/L (pretreatment median value) at baseline. Also, the possible impact of ferritin level on HRQoL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Coefficients and p values are reported in table 1. The prognostic impact of baseline HRQOL on the probability of achieving transfusion independence (i.e., defined as freedom from transfusion for 3 consecutive months) was investigated. Higher severity of pain (P=0.007) was associated with a greater likelihood of achieving transfusion independence. Multivariate analysis, controlling for age, IPSS risk score, time from diagnosis, number of previous blood transfusions and baseline ferritin level confirmed the independent value of pain (P=0.003). Conclusion Current findings suggest that Deferasirox therapy does not decrease HRQOL in lower risk transfusion-dependent MDS patients. Patients with higher baseline pain severity seems more likely to achieve transfusion independence and further analysis is needed to understand underlying reasons. Disclosures: No relevant conflicts of interest to declare.