ALBERT

Description: Background: Severe thrombocytopenia is an uncommon event in lower risk MDS patients, but it may significantly influence the prognosis. In fact, when it occurs, major bleeding may be a life-threatening complication. No licensed pharmacologic approach is nowadays available yet for these patients. Eltrombopag seems to be a very interesting product, but its efficacy and safeness are still to be better demonstrated. Romiplostim could be suitable too, but, at present, its safety is uncertain in MDS patients. Also danazol, an attenuated androgen, seems to have some ability to increase the platelet count in this context. Patients and methods: We retrospectively reviewed 17 thrombocytopenic patients affected by MDS, treated with danazol and observed for at least 6 months. Three patients of these had a therapy-related MDS. At the starting time of danazol therapy, the IPSS was “low” or “intermediate-1” in 16 cases; “intermediate-2” in 1 case. The IPSS-R was “very low”, “low” or “intermediate” in 16 cases; “very high” in 1 case. In 14 patients the platelet count was lower than 25x109/L, in the other 3 lower than 40x109/L, but with spontaneous bleeding. The initial dose was 600 mg/day for all the patients. The IWG criteria of response (Cheson 2006) were adopted. The outcomes were observed after 3 and 6 months from the beginning of therapy. Only descriptive statistical analysis was used. Results: At the beginning of therapy, the average platelet count of the 17 patients was 22.6 x109/L (S.D. 8.8, range 6-38). After 3 months, the therapy with danazol was ongoing in 16 patients (in 1 case the drug was discontinued due to renal failure). Platelet improvement, according to IWG criteria, was observed in 8 cases (47%). The average platelet count was 45.3x109/L (S.D. 32.9, range 4-133). The only one “high risk” patient did not show response. After 6 months danazol was still ongoing in 11 patients (in 5 cases the drug was stopped for inefficacy). The response according to IWG criteria was evident in 9 patients (52% of the initial 17 patients). The average platelet count was 66x109/L (S.D. 63.9, range 11-218). Adverse events recorded were as follows: increase in transaminases in 3 cases (in 2 of these the dose was reduced to 400 mg/day); severe but reversible renal failure in 1 case (the drug was stopped); moderate increasing of serum creatinine in 1 case (the drug was reduced to 400 mg/day); reversible cutaneous rush (the drug was reduced to 400mg/day); amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusions This series confirms the efficacy of danazol to improve platelet count in approximately half of patients with severe thrombocytopenia due to “low-risk” MDS. In all patients with increased platelet count, the response was clinically significant. The response may not be immediate. Actually, there was an improvement of platelet count even after three months of therapy. The toxicity profile of this drug is low. The mechanism of action of danazol in MDS patients remains unclear. Waiting for more information on the efficacy and safety of eltrombopag from the clinical trials in progress, danazol may be a good therapeutic option for these patients. Disclosures Off Label Use: Danazol in MDS patients with severe trhombocytopenia.

Description: Introduction: Although blast-rich specimens immunophenotype studies in myelodysplastc syndromes (MDS) could associate bone marrow (BM) blast expression of CD7 and/or CD117 antigens with poor outcome (Ogata et al., Blood 2002), the prognostic role of markers of myeloid cell immaturity and committment in not enriched BM samples is largely unexplored. Patients and Methods: The expression of CD33, CD34 and CD117 antigens in not enriched BM samples of 50 newly diagnosed MDS was compared with both BM blast WHO category and IPSS score. Immunophenotyping was carried out by using the panel of quadruple monoclonal antibodies CD34/CD117/CD45/CD33, conjugated with the fluorochromes FITC, PE, PerCP, APC, respectively. Acquisition of information on 1x105 stained cells corresponding to the whole BM cellularity was assessed on a dual-laser FACSCalibur flow cytometer using the CellQUEST software (Becton Dickinson, San José CA USA). Multiple group comparisons were made using non parametric ANOVA for BM blasts; general linear model with Wald’s test and Kruskal-Wallis (KW) test to confirm significance was used for IPSS. Results: According to IPSS, 5 (10%) low risk, 27 (54%) intermediate risk-1, 14 (28%) intermediate risk −2 and 4 (8%) high risk pts were identified, respectively. The expression of CD33, CD34 and CD117 significantly correlated with both blast WHO category and IPSS, as shown in the Table 1. Interestingly, by analyzing the subset of 30 pts with BM blasts

Description: Background The p53 protein is an onco-suppressor protein encoded by the TP53 gene, which is mutated in 5-10% of cases of de novo myelodysplastic syndromes (MDS). In 75% of cases TP53 mutations lead to store the p53 protein within the nucleus of the neoplastic cells. TP53 mutations were shown to have an unfavorable prognostic impact in patients with MDS. The immunohistochemical (IHC) expression of p53 in bone marrow (BM) biopsy has in itself negative impact on prognosis in low risk MDS, especially in MDS with isolated del(5q) category. However, the p53 cut-off value related to prognosis has not been established with accuracy, ranging between 1 and 5% in different reports. Moreover, no data are available on the possible prognostic impact of p53 BM expression and cut-off levels in patients with higher risk MDS. Aim To evaluate the prognostic value of IHC expression of p53in BM biopsies from patients with intermediate, high and very high R-IPSS risk MDS Methods BM biopsies performed at diagnosis in patients with intermediate, high and very high R-IPSS risk MDS with a follow up of at least three years were revised and screened for IHC p53 expression. Percentage of p53 expression was evaluated by two independent pathologists (L.B.; M.T.), and related to patient survival. Only cells with strong p53 staining were counted as positive. The statistical evaluations were carried out with the logistic analysis and the influence of p53 expression on survival was analyzed by Cox regression. A ROC analysis was carried out using theYouden method to analyze the optimal cut-off value influencing the survival. The verification was performed with the positive and negative predictive values (respectively PPV and NPV), the sensibility and the specificity with their respective 95% confidence intervals (95%CI). Survivorships were estimated with the Kaplan-Meier product limit method, followed by the logrank test, and by the Cox proportional-hazard regression. The association among categorical variables was evaluated by Fisher exact test. Results A total of 60 BM biopsies performed at MDS diagnosis were screened for p53 expression. Themedian age of these 60 patients was 67 years (range 19 - 82). Diagnoses, according to WHO, were RCMD in 26/60 (43.3%) cases; RAEB1 in 21/60 (35%) cases; RAEB2 in 13/60 (21.7%) cases. The IPSS-R was intermediate in 43 (71.7%) cases; high in 9 (15%) cases and very high in 8 (13.3%) cases. Cytogenetic risk according to the IPSS-R stratification was: very low in 1(1.6%) case; low in 30 (50%) cases; intermediate in 10 (16.7%) cases; high in 12 (20%) cases; very high in 7 (11.7%) cases. Median overall survival was 41 months. The p53 expression was: 〈 1% in 39 cases (65.0%), 1% in 5 cases (8.3%), 2% in 6 cases (10.0%), 3% in 2 cases (3.3%), 5% in 3 cases (5.0%),at least 10% in 5 cases (8.3%). Upon analysis, a significant association between percentage of p53 expression and patient survival was found (p=0.013; Hazard Ratio 1.067; 95%CI: 1.014 - 1.124). A cut-off value of 10% p53 expression was associated with outcome (specificity 100%; sensibility 13.5%;PPV 100%; NPV 41.8%). Specifically, as shown in figure 1, a significantly better overall survival was observed in the 55 (91.7%) patients whose BM p53 expression was 〈 10% compared to the 5 (8.3 %) patients with a BM p53 expression at least 10% (p=0.0038). No association was found between either BM blast countor BM grade of fibrosis and p53 expression.A significant association between the cytogenetic risk according to R-IPSS stratification and the expression of p53was instead found: any single unitary arbitrary increase in the cytogenetic risk score rises by 1600% the odds of a BM p53 expression at least 10% (p=0.015). Conclusion In our study population we confirm the unfavorable prognostic significance of BM p53 expression in higher risk MDS patients. Contrary to the reported cut-off values of p53 expression in low risk MDS, in our cohort of higher risk MDS the levels related to prognosis were greater (10% compared with 1 to 5% according to different reports). A tentative explanation for this difference may be that factors other than p53 expression strongly impact on survival in patients with higher risk MDS. Thus the negative prognostic value of p53 only emerges at higher levels of expression. The association between p53 expression and the IPSS-R cytogenetic risk score, if confirmed on a larger cohort, should be evaluated in specific biologic investigations. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: Severe thrombocytopenia is an uncommon event in patients (pts) with lower-risk MDS, but it may significantly affect the prognosis. No specific pharmacological approaches other than hypometilating agents (not licensed in Europe in lower-risk MDS), able to improve platelet count in this setting, are currently available. Trials testing efficacy and safety of Eltrombopag are ongoing (Oliva 2017). Few data were reported about danazol, an attenuated androgen, that seems to have also some effectiveness in this still unmet need (Wattel 1994; Chan 2002). Aims: To assess the efficacy and safety of danazol in improving the platelet count in low risk MDS pts with severe thrombocytopenia. Methods: We retrospectively reviewed 35 thrombocytopenic MDS pts treated with danazol. The initial and maximal dose was 600 mg/day for all pts, modulated according to response and toxicity. The response was evaluated according to IWG response criteria (Cheson 2006). The outcome was strictly observed every 3 months (mo) up to the 12th mo, and the platelets average number in each observation moment was described. The time to response, the response rate and the enduring of response were also recorded. Results: Of the 35 pts, according to 2016 WHO classification, 4 pts were MDS-ULD; 19 were MDS-MLD (3 of them with medullar hypocellularity), 7 were MDS-EB1 and 5 were affected by MDS/MPN. At baseline the platelet count was lower than 20x10^3/mL in 11 pts, the median was 23x10^3/mL . At starting time of danazol therapy the IPSS-R cytogenetic class of risk was very low in 2 cases, low in 28 cases, intermediate in 3 cases and very high in 1 case. Cytogenetic was not available in one patient. In the 30 MDS pts, the IPSS-R was "very low" in 1 patient, "low" in 16, "intermediate" in 7, "high" in 4 and "very high" in 1. In 1 case it was not evaluable due to the lack of cytogenetics. Two pts were not included in the analysis because they were treated for less than 3 mo (in 1 case danazol was withdraw to permit the beginning of another therapy and in 1 case due to death for other neoplastic disease). The response rate was 63,6% (21 responders on 33 evaluable). Median time to response was 3.5 mo (range 0.3 - 12.4 mo); the average response time was 5.09 mo. In the first year of treatment, the platelet count (evaluated at baseline, 3, 6, 9 and 12 mo) changed in a significant way (F test after repeated measures ANOVA: p 〈 0.001 as shown in Figure 1). Pairwise comparisons of platelet count according to Bonferroni showed a significant difference for baseline vs. 3 mo (p = 0.0013), baseline vs 6 mo (p = 0.0255), baseline vs 9 mo (p = 0.0047) and baseline vs 12 mo (p = 0.0014); however, no significant differences (p ≥ 0.05) in counts were seen for all the further pairwise comparisons at 3, 6, 9 and 12 mo. The median and average duration of the response for the entire population were respectively 12,5 and 32,5 mo. Only 6 of the 21 responders (28%) lost the response (the median and average duration of response were respectively 5.8 and 12.9 mo). Within the 21 responders, the median progression free survival was not reached after 24 mo. The probability to maintain the response after 50 mo was assessed at 58.2% (C.I. 24.1% to 81.4% - Figure 2). The overall survival showed a significant difference (logrank test: p = 0.0064) between responders and non-responders (Figure 3). Adverse events recorded were as follows: moderate (grade 1 and 2) increase in transaminases in 4 cases (with reduction of danazol to 400 mg/day); 1 case of severe but reversible liver toxicity (grade 3) (with subsequently drug suspension); severe (grade 3) but reversible renal failure in 1 case (the drug was stopped); moderate (grade 1 and 2) increasing of serum creatinine in 6 case (with reduction of danazol to 400 mg/day in 2 of these); reversible cutaneous rash in 3 cases; amenorrhea in 1 case (the only fertile woman in the series); weight loss and loss of appetite in 1 case, weight gain in 1 case. Conclusion: Even if the mechanism of action of danazol in pts with MDS is unclear, this series confirms its efficacy to improve platelet count in the most of MDS pts with severe thrombocytopenia. The response was often clinically significant. It may not be immediate but seems to be reachable after 3-6 mo of treatment. A responsive patient has a good probability to maintain a long-lasting response. The toxicity profile of this drug is acceptable. Waiting for more effective options, danazol may be a good therapeutic option for these pts. Disclosures Riva: Jannsen and Cilag: Consultancy; Novartis: Consultancy; Celgene: Consultancy. Reda:Celgene: Consultancy; Janssen and Cilag: Consultancy; Gilead: Consultancy; ABBVIE: Consultancy. Molteni:AMGEN: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Celgene: Consultancy; Janssen and Cilag: Consultancy.

Description: Background Deferasirox (DFX) is widely employed as iron chelation therapy (ICT) in the current clinical practice in patients with myelodysplastic syndromes (MDS) and chronic transfusion need. The efficacy of DFX in reducing median ferritin levels in different cohorts of these patients has been reported in many trials, but the lack of worldwide accepted criteria of individual response to ICT makes it difficult to appreciate its clinical relevance for any single patient. Aim To highlight the clinical impact of ICT with DFX in a large real-life cohort of MDS patients, based on different individual ferritin variation during treatment. Methods A retrospective cohort of 301 consecutive MDS patients [M/F 187/114 (62.1%/37.9%)] of any age followed in 20 hematological Centers in Italy was analyzed: the main features at diagnosis are reported in the Table 1. Individual response to ICT was categorized as complete response (CR) (ferritin levels 〈 500 ng/ml), partial response (PR) (ferritin levels 〈 1,000 ng/ml), ferritin improvement (FI) (ferritin reduction 〉 50% of baseline value but with levels 〉 1,000 ng/ml), ferritin stability (FS) (ferritin levels without changes from baseline during ICT) or no ferritin response (NR) (ferritin levels increasing during ICT). Results ICT was started after a median period from diagnosis and from transfusion start of 21.0 months [interquartile range (IQR) 8.9 - 44.3] and 11.3 months (IQR 7.1 - 21.7), respectively, with a median burden of red cell transfusions at baseline of 22 units (IQR 14 - 35). The main features of patients at baseline of ICT are reported in the Table 1. Starting DFX dose was 〈 10 mg/Kg in 38 patients (12.7%), 10 - 14 mg/Kg in 110 patients (36.6%), 15 - 19 mg/Kg in 57 patients (18.9%) and ≥ 20 mg/Kg in 96 patients (31.9%). As to individual response, 4 patients (1.3%) were too early for evaluation (〈 6 months of DFX treatment): in addition, 16 patients (5.4%) discontinued ICT behind 6 months from start, due to early toxicity (10 patients, 7 for gastro-intestinal toxicity and 3 for skin toxicity) or other reasons (unrelated death, AML evolution, transplant procedure). Among the remaining 281 patients, 37 (12.3%) achieved a CR, 65 (21.6%) a PR, 23 (7.6%) a FI, 112 (37.2%) a FS and 44 (14.6%) a NR. Five-year overall survival (OS) of the whole cohort from ICT start was 43.9% (95%CI 37.1 - 50.7). Five-year OS according to ICT response was 74.8% (95%CI 57.9 - 91.7) in patients with CR, 51.7% (95%CI 37.6 - 65.8) in patients with PR, 50.6% (95%CI 28.2 - 73.0) in patients with FI, 38.6% (95%CI 27.0 - 50.2) in patients with FS and 21.1% (95%CI 5.2 - 37.0) in patients with NR (p=0.002) (Figure 1). Five-year cumulative incidence of AML evolution (CIE) of the whole cohort from ICT start was 27.1% (95%CI 20.3 - 33.9). Five-year CIE according to ICT response was 7.6% (95%CI 0 - 18.0) in patients with CR, 27.0% (95%CI 13.0 - 40.5) in patients with PR, 38.3% (95%CI 15.5 - 61.7) in patients with FI, 20.8% (95%CI 10.4 - 31.2) in patients with FS and 57.7% (95%CI 31.9 - 83.5) in patients with NR (p=0.003) (Figure 2). Notably, no statistical difference was observed for both OS and CIE among patients achieving PR, FI or FS. Conclusions Present data highlight the clinical relevance of individual response in MDS patients receiving ICT with DFX. In particular, achievement of CR seemed related to a better OS and a lower CIE, while patients with NR had a significant worst OS and CIE: furthermore, the achievement of stable ferritin levels was associated with similar OS and CIE than PR and FI and thus should be considered as a response. Disclosures Latagliata: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Oliva:Novartis: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy. Pilo:Novartis: Other: Advisory board. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Celgene: Honoraria. Foà:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Finelli:Novartis: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding, Speakers Bureau.

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (p

Description: Background: About 10% of low risk patients with myelodysplastic syndromes (MDS) experience severe thrombocytopenia. Bleeding and the scarce efficacy of platelet (PLT) transfusions drive research in novel treatments. Eltrombopag is an oral agonist of the thrombopoetin-receptor (TPO-R). Its potential in increasing platelet (PLT) counts in low risk MDS has not been evaluated. We present interim results on the efficacy and safety of eltrombopag in inducing PLT responses in patients with low and intermediate-1 International Prognostic Scoring System (IPSS) risk MDS with severe thrombocytopenia in a Phase II, multicentre, prospective, placebo-controlled, single-blind study (EQoL-MDS). Methods: Primary endpoints are safety and efficacy of eltrombopag. Secondary endpoints include changes in quality of life (QoL), PLT transfusion requirement, incidence and severity of bleeding, and survival. Inclusion criteria are adult age; PLT200 Gi/L or adverse events. Study design is shown in the figure. PLT response, assessed at each visit, is defined as Response if: 1) baseline PLT〉20 Gi/L: absence of bleeding and increase by at least 30 Gi/L from baseline; 2) baseline PLT20 Gi/L and increase by at least 100%, not due to PLT transfusions; and Complete Response if PLT≥100 Gi/L and absence of bleeding. QoL scores are analysed by MDS-specific instrument, QOL-E v. 3. Results: Seventy patients (46 on eltrombopag - Arm A, 24 on placebo -Arm B) have been randomized at the time of this report. Mean age is 68.3 (SD 13.0) years, M/F 38/32. ECOG performance status was 0 in 47 cases, 1 in 16 cases, 2 in 7 cases. Ten patients had comorbidities. According to the WHO 2008 classification, 22 patients had refractory cytopenia with unilineage dysplasia, 9 had refractory anemia with ringed sideroblasts, 31 had refractory cytopenia with multilineage dysplasia (of which 15 with ringed sideroblasts), 6 had refractory anemia with excess blasts-1 and 2 were unclassified. IPSS score was low in 48 cases. Mean baseline platelet (PLT) count was 17.1 (SD 8.2) Gi/L, mean hemoglobin level 10.8 (SD 2.5) g/dL and mean white blood cell count was 5.0 (SD 3.8) Gi/L. Twenty-five (36%) patients were red blood cell transfusion-dependent. Thirty-three had a WHO bleeding scale of 1, 2 experienced mild blood loss, 4 a gross blood loss and 1 a debilitating blood loss. Fourteen patients in Arm A and 8 in Arm B had required PLT transfusions in the 8 weeks prior to randomization. Twenty-three cases (50%) in Arm A have responded versus 2 (8%) in Arm B (p=0.001). Thirty-three patients have completed at least 24 weeks of study. Median time to response was 14 days (IQR 7-46 days) at a median daily dose of 75 (IQR 50-162.5 mg). PLT count increased by mean 53.2 (SD 68.1) Gi/L (p=0.001) in Arm A versus no significant changes in Arm B by week 24. QOL-E scores at baseline and 12 weeks in 47 cases in both arms are shown in the table. There was an increase in treatment outcome index,mainly experienced in the first 3 weeks (p=0.034). Fatigue improved from baseline to 12 weeks associated with response (p=0.016). Related Grade III-IV adverse events (AE) occurred in 10 patients (22%) in Arm A and consisted in: nausea (4), hypertransaminasemia (3), hyperbilirubinemia (1), sepsis (1), pruritis (1), heart failure (1), asthenia (1), vomit (1), while in Arm B 1 patient (4 %) experienced grade 3 bone marrow fibrosis. MDS disease progression occurred in 5 (11%) in Arm A versus 2 (8%) in Arm B, p=ns. Conclusions: Preliminary data indicate that lower risk MDS patients with severe thrombocytopenia undergoing treatment with eltrombopag experience significant improvements in PLT counts accompanied by improvements in fatigue. The drug appears to be well-tolerated and not associated with MDS progression. Further follow-up is required to evaluate the impact on survival. Figure 1. Study design Figure 1. Study design Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Figure 2. QOL-E domains at baseline and 12 weeks between Arm A (eltrombopag) and Arm B (placebo) Disclosures Oliva: Novartis: Speakers Bureau; Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Palumbo:Novartis: Honoraria, Other: Advisory Board. Fenaux:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria, Research Funding.

Description: 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.

Description: Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count 2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P

Description: Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving 〉 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p