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Introduction: The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP. Results: Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers. As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment. With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p < 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT. Conclusions: Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. Figure 1 Figure 1. Disclosures Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment. We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p= 2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80% Disclosures Motta: Roche: Honoraria; Janssen: Honoraria. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi:Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni:Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin:Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini:Roche: Research Funding. Pulsoni:Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background: Therapy-related acute myeloid leukemia (t-AML) or AML evolving from a myelodisplastic syndrome are characterized by a low response rate to conventional chemotherapy and high relapse rate with poor overall survival (OS) despite intensive treatment and allogeneic stem cell transplantation consolidation (HSCT). CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin, in a fixed synergistic 1:5 molar ratio. CPX-351 has been approved by FDA for the treatment of patients affected by t-AML or AML with myelodisplasia-related changes (MRC-AML) based on the results of a randomized phase III trial where the drug was compared with conventional 3+7 induction (Lancet et al, JCO 2018). Notably, CPX-351 proved to increase survival probabilities in comparison with standard chemotherapy even among patient achieving complete remission (CR) and proceeding to HSCT, suggesting that CPX-351 may allow deeper responses. However, few information is available on minimal residual disease (MRD) assessment after CPX-351 treatment, or on the impact of molecular alterations on response probability. Aims: The aim of this study was to evaluate the clinical activity of CPX-351 in a real life setting, with particular focus on molecular characterization at diagnosis and MRD evaluation in responding patients. Methods: Seventy five patients were enrolled in a compassionate use program (CUP) in 37 Italian Hematology Centers. CUP started on December 2018 and closed on June 2019. Data collection began on July 2019 and was completed, at the time of writing, for 25/75 patients, enrolled in 9 Centers. Median age was 69 years (56-73), 10 patients were female. Molecular and MRD analysis were performed in each Center as per internal standard. MRD was assessed in most Centers with multicolor flow cytometry. NPM1 mutation was found in 2/22 assessed patients, FLT3-ITD in 3/22, with low allelic burden in 2/3 patients. TP53 mutations have been found in 4/12 patients.Four patients had complex Karyotype, one had isolated del(7q) whereas the remaining 19 had normal karyotype. Six patients had t-AML; 15 patients were previously diagnosed with MDS and 5 of them had already received hypomethilating agents for a median of 5 cycles (2-49). European Leukemia net risk score was low in 2 (8%), intermediate in 12 (48%) and high in 11 (44%) patients. Most patients (20/25) had relevant comorbidities upon enrollment, mostly COPD, diabetes and/or hypertension. As per CUP inclusion criteria, all patients had normal left ventricular function at the time of enrollment (defined by a normal ejection fraction). Results: Induction-related mortality was 2/25 (8%). Fourteen patients experienced grade >1 extra hematological adverse event during induction (mainly infections). Alopecia was observed in 4/25 patients (16%).Response was assessed in 20 patients:2 patients died during induction and 3 patients were not yet evaluated for response at the time of analysis. CR or CRi was observed in 19/22 (86.3%). MRD was performed in 11 patients, with 4 of them achieving flow MRD negativity after first cycle (defined as Conclusions: Our preliminary data confirm the high clinical activity and good tolerability of CPX-351 in a challenging AML cohort. The high median age and the high incidence of severe comorbidities did not result in unacceptable risk of death during induction. With the limitation of very small numbers, CPX-351 showed good antileukemic activity among TP53 mutated patients. Disclosures No relevant conflicts of interest to declare.

Background: Understanding health-related quality of life (HRQOL) profile, including functional aspects and symptom burden, of yet untreated patients with myelodysplastic syndromes (MDS) is important to help clinicians to better identify subgroup of patients in need of special attention from the very beginning of therapy. Aims: The primary objective of this study was to investigate baseline (i.e., pretreatment) HRQOL profile of untreated patients with lower-risk MDS, examining differences by age, gender, risk score category and comorbidity. A secondary objective was to provide age and sex baseline reference HRQOL values, according to the EORTC QLQ-C30 questionnaire, to be used as benchmark comparisons in future MDS studies. Methods: This analysis is based on 443 newly diagnosed adult MDS patients with International Prognostic Scoring System (IPSS) risk score of low (46 %) or intermediate-1 (54%), enrolled in an international prospective cohort observational study. Median age was 75 years (range 32-94), with 261 men (59%) and 182 (41%) women. HRQOL was assessed by the EORTC QLQ-C30 questionnaire at study entry, before any treatment (except for transfusions). This well validated questionnaire consists of five functioning scales: physical, role, emotional, cognitive and social; three symptom scales: fatigue, nausea/ vomiting and pain; six single item scales: dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact; and the global health status/HRQOL scale. The items were scaled and scored using the recommended EORTC procedures. At the time of baseline HRQOL assessment, 111 (25%) patients had received at least one red blood cell transfusion. We used Wilcoxon-Mann-Whitney and Kruskal-Wallis tests for all comparisons. We used the false discovery rate approach to account for multiple testing, with a nominal α-level=0.05. In addition to statistical significance, clinically relevant HRQOL differences were also evaluated based on previously published criteria (Cocks K, et al, J Clin Oncol 29:89-96, 2011). Results: There were not statistically significant differences in any of the HRQOL scales measured by the EORTC QLQ-C30, by the specific IPSS risk category (i.e., low risk vs intermediate-1 risk score). Overall, women reported worse HRQOL scores than men, with clinically relevant differences for physical (Δ=-7.1, P=0.002), role (Δ=-9.9, P=0.002) and emotional functioning, (Δ=-10, P Conclusion: Pretreatment HRQOL profile in lower-risk MDS patients vary substantially by age group categories, sex and number of comorbidities, and these differences should be highly considered at the time of treatment start. As in MDS research, the EORTC QLQ-C30 is currently one of the most frequently used HRQOL measure, our baseline reference values provide benchmark data against which other MDS studies using this questionnaire may be compared. Disclosures Efficace: Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Orsenix: Consultancy; Incyte: Consultancy; TEVA: Research Funding; TEVA: Consultancy; Lundbeck: Research Funding; Amgen: Consultancy; AMGEN: Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Voso:Celgene: Research Funding, Speakers Bureau. Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Novartis: Honoraria. Lubbert:Teva: Other: Study drug; Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau.

Deletion of the chromosome 20 long arm (del20q) has been reported in 3-7% of patients with Myelodysplastic Syndromes (MDS). In particular, isolated del20q seems to be associated with good prognosis, low risk of progression to AML and prolonged survival: however, very few reports addressed this subset of MDS patients up to now. To highlight this issue, we collected data from all patients with MDS and isolated del20q diagnosed and followed by Centers of the Gruppo Romano-Laziale Sindromi Mielodisplastiche (GROM-L). On the whole, 53 patients were analysed: the main features at diagnosis of these patients are reported in the Table. Platelet (PLT) count was < 100 x 109/l in 28 patients (52.8%), Hb level was < 10.0 g/dl in 23 patients (43.3%) and neutrophil count was < 1.0 x 109/l in 12 patients (22.6%). As to risk prognostication, according to IPSS score 51 patients (96.2%) had low/intermediate-1 risk and 2 (3.8%) had intermediate-2/high risk: according to r-IPSS, 8 patients (15.1%) had very low risk, 20 (37.7%) low risk, 19 (35.9%) intermediate risk and 6 (11.3%) high risk. During follow-up, 14 patients (26.4%) did not need any therapy and were only observed, 36 (67.9%) were treated with Erythropoietin (EPO), 1 (1.9%) with hypomethylating agents, 2 (3.8%) with other treatments (TNF-α inhibitor, interferon). Among the 36 patients treated with ESA after a median interval from diagnosis of 5.0 months [interquartile range (IR) 1.2 - 27.6], 24 (66.6%) received α-EPO, 11 (30.5%) β-EPO and 1 (2.9%) darbopoietin. Two patients were too early (< 3 months of treatment) for response evaluation: among the 34 evaluable patients, 21 (61.7%) achieved stable erythroid response according IWG criteria (Hb increase > 1.5 g/dl in 18 patients and reduction > 50% of basal transfusion requirement in 3 patients) while 13 (38.2%) were resistant to EPO. Nine patients (17%) progressed to Acute Myeloid Leukemia (AML) after a median time from diagnosis of 16.8 months (IR 4.1 - 51.7). At the last follow-up, 21 patients (39.6%) died (13 from MDS/AML related causes and 8 from unrelated causes), 12 (22.6%) were lost to follow-up and 20(37.8%) were alive. Median Overall Survival (OS) of the entire cohort was 61.6 months (95%CI 42.2 - 81.0): the 10-year cumulative OS was 38.6% (95%CI 18.6 - 58.6) (Figure 1). In conclusion, as MDS represent a heterogeneous group of pathologies, many efforts are ongoing to identify patients with similar biological, clinical and prognostic features (eg 5q- syndrome, MDS with ring sideroblasts). From the scarce data in the literature and from our results, it is reasonable that also patients with isolated del20q may represent a distinct clinical and biological entity, with specific clinical and prognostic features (low PLT count, low number of marrow blasts, low IPSS and r-IPSS risk score, good response to EPO, long OS). The mechanisms underlying del20q are still unclear and warrant future molecular analysis. Disclosures Breccia: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

Introduction. The development of novel therapeutic agents in the treatment of lymphoid malignancies seemed to decrease the rate of complications, including infections, in spite of standard immuno-chemotherapy regimens. Patients receiving Ibrutinib experienced serious infections and other recent studies found that these patients are at risk for serious or opportunistic infections. Aim. The aim of our study was to evaluate incidence and type of infections in CLL patients treated with BCR inhibitors: Ibrutinib and Idelalisib plus Rituximab. Results. Our retrospective study included 46 CLL patients treated at our Institution since 2015: 37 patients were treated with Ibrutinib and 9 patients were treated with Idelalisib plus Rituximab. The median number of prior treatment regimens was 2 (range 0-5); only 1 patient started Ibrutinib as first-line therapy because of TP53 mutation. We recorded 32 episodes of infections, of which 23 occurred in 11 patients (out of 37, 30%) treated with Ibrutinib and 9 episodes in 5 patients (out of 9, 55%) treated with Idelalisib plus Rituximab. Daily Ibrutinib dose was 420 mg, Idelalisib was used at the dose of 150 mg twice a day. The median duration of treatment was 12 and 13 months in Ibrutinib and Idelalisib, respectively. We confirmed the higher prevalence of infections occurred during the first year of Ibrutinib treatment (84% in Varughese et al vs. 83% in our case series) and we found a high prevalence (78%) of infective episodes with Idelalisib plus Rituximab. The rate of infections was 0.6 episodes/patient for Ibrutinib and 1.0 episodes/patient for Idelalisib; each patient with infection showed a median of 2.1 and 1.8 episodes for Ibrutinib and Idelalisib, respectively. In the group of Ibrutinib the most common infections involved the upper respiratory tract (14 events, 61%), followed by urinary tract (6 events, 26%); in the Idelalisib group we found 6 infections (66%) of upper respiratory tract. Differences were found also in the pathogens implicated in the infections (Table I). All the infections, except one bacterial sepsis, were grade I or II; the patients were treated with antibacterial, antiviral or antifungal drugs in 56% of the cases. Only 3 patients treated with Ibrutinib required hospitalization and antibacterial or antifungal treatment as inpatients but no deaths were registered. In 30% of the Ibrutinib cases and in 53% of the Idelalisib cases the treatment was temporarily stopped. None of the patients received antifungal prophylaxis and nobody had invasive fungal infections. All patients received prophylaxis for Pneumocystis jirovecii and flu shot but no antiviral prophylaxis. Moreover, we detected 10 blood viral (EBV, CMV, HBV, BK) reactivations, without active disease, of which 60% with Idelalisib and 40% with Ibrutinib. Discussion. In conclusion when we treat as second or following line CLL patients with Ibrutinib we should take in account that about 30% of patients will develop one or more episodes of infective complications; in more than 60% the type of infection is bacterial. When we use Idelalisib plus Rituximab the rate of infections will be higher, around 55%, only 1/3 will be bacterial, but viral complications will be common. Disclosures Pagano: Gilead: Speakers Bureau; Merck: Speakers Bureau; Pfizer: Speakers Bureau; Basilea: Speakers Bureau; Janssen: Speakers Bureau.

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.

Background Allogeneic SCT remains the only curative option in myelodysplastic syndromes (MDS). We prospectively evaluated in a multicenter phase 2 GITMO (Italian Bone Marrow Transplantation Group) trial, the feasibility of allogeneic stem cell transplantation (ASCT, primary protocol end-point) after induction treatment with azacitidine (Vidaza, Celgene). According to the protocol, patients had to perform at least 4 and up to 12 cycles of azacitidine as induction treatment before ASCT. Patients not eligible for ASCT could continue treatment until disease progression. Methods Between November 2010 and September 2014, 102 patients were enrolled by 20 Italian hematology centers. Nine patients never started treatment due to progressive disease (PD, n=2), refusal (n=3), or unknown causes (n=4). Of remaining 93 patients, 70 had with IPSS Int-2/High-risk MDS, 15 WHO-defined acute myeloid leukemia (AML) and 8 chronic myelomonocytic leukemia (CMML). There were 32 females and 61 males with median age 59 yrs (range 21-66.5 yrs). At treatment start, ECOG performance status was: 0 in 66 patients, 1 in 17 and 2 in 10 patients, while MDS HCT-index was: low (0) in 43 patients, intermediate (1-2) in 31 and high (>2) in 18 patients. All 93 patients started azacitidine s.c. at the standard dose of 75 mg/sqm/day, 7 days/month, at a median of 0.8 months (range 0-105 months) from initial MDS diagnosis. Results At response assessment after a median of 4.5 cycles (range 1-11), 25% of patients (n=19) achieved complete remission (CR), 3% marrow-CR (n=2), 14% partial remission (PR, n=11), 9% hematologic improvement (HI, n=7), 35% had stable disease (SD, n=27) and 14% PD (n=11). ASCT was performed in 48 patients (52%), after a median of 4.5 azacitidine cycles (range: 1-11). Data on ASCT are presently available for 45 patients, transplanted with bone marrow (n=10 pts) or peripheral blood stem cells (n=35 pts) from an HLA-identical donor (sibling in 11, and MUD in 34 cases). Forty-five patients did not receive ASCT due to: disease relapse or progression (n=16, 35%), adverse events (n=12, 27%), refusal (n=5, 11%), or other causes (n=12, 27%). At a median follow-up of 18.5 months (range 0.2-31.5), 43 patients are alive (25 received ASCT), and 50 patients died. Causes of death are reported in Table 1. Median overall survival (OS) for the whole patient cohort was 13.4 months (95% CI: 10.9-18.6, Figure 1). Disease status after azacitidine was predictive of significantly improved survival for patients in CR/PR/HI, compared to SD or PD (n=77 patients who completed at least 4 cycles, Figure 2). ASCT considered as time-dependent covariate was associated to a significantly longer survival (p=0.008, HR 0.4, 95% CI: 0.2-0.8). Stratification of MDS according to IPSS and karyotype was not associated to survival. Conclusions Our study shows that allogeneic transplantation following azacitidine is feasible in HR-MDS/CMML and AML, with about 50% of patients being able to undergo HSCT. These data favourably compare with previous studies in MDS on ASCT preceded by conventional chemotherapy. Disease status at the time of HSCT confirms its significant prognostic role for survival, also in the context of hypomethylating treatment, where stabilization of disease also represents a therapeutic target. Disease relapse or progression remain the major causes of death indicating the need for other strategies aimed at improving disease control in MDS. Figure 1. Overall survival (n=93 pts) Figure 1. Overall survival (n=93 pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Figure 2. Survival according to disease status at response assessment after a median of 4.5 azacitidine cycles (n=77 evaluable pts) Disclosures Voso: Celgene: Honoraria, Research Funding. Off Label Use: Azacitidine used as induction treatment before allogeneic stem cell transplantation in MDS. Finelli:Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding.

INTRODUCTION. Resistance to carbapenems by Klebsiella pneumoniae (KP) isolates has become a significant problem in recent years in several countries, and has been recently highlighted as one of the major emerging causes of severe and fatal infections in patients suffering from hematological malignancies (HM). The aim of the present study was to identify risk factors for mortality in HM patients with concurrent bloodstream infections (BSIs) caused by KP. Particular attention was focused on defining the impact of carbapenem resistance by the bacterial isolates on mortality. METHODS. We conducted a prospective cohort study including all consecutive cases of BSIs caused by KP diagnosed in 13 Italian hematological units participating to HEMABIS registry-SEIFEM group. The outcome measured was death within 30 days of the first positive blood culture. Survivor and non-survivor subgroups were compared, and logistic regression analysis was conducted to identify independent predictors of mortality. RESULTS. A total of 278 episodes of KP BSI were included in the study between January 2010 and June 2014. One hundred-sixty-one (57.9%) KP isolates were carbapenem resistant (CRKP). The rate of carbapenem resistance among KP isolates significantly increased from 21.4% in 2010 to 75.9% in 2013 (P In multivariate analysis, significant predictors of mortality were septic shock (OR 17.34, 95% CI 6.65-45.23; P CONCLUSIONS. Carbapenem resistance has dramatically emerged during the last years as the most frequent and fatal cause of BSI among KP isolates in HM patients in Italy. Although further studies to better define epidemiology and clinical impact of these infections are needed, the efficacy of therapeutic treatment protocols for HM patients could be probably improved through the sound knowledge of the local distribution of KP isolates and their susceptibility patterns and judicious use of antibiotics and control measures to prevent the development and spread of CRKP. Disclosures No relevant conflicts of interest to declare.

Introduction. The granulocyte transfusions (GTXs) are used to booster antimicrobial drugs in severely neutropenic hematological patients. However, the optimal GTX dose and the actual efficacy of this practice are debated. Methods. We retrospectively evaluated the infection-attributable mortality (IAM, i.e. the mortality at 30 days after the last GTX) in 84 consecutive patients with hematological malignancies receiving GTXs (January 2009- December 2014). The indications for GTXs were i) presence of absolute neutrophil count (ANC) Results. Among 84 patients, 101 infectious episodes requiring GTXs were recorded (422 transfusions in total). Patients characteristics are summarized in Table I. Bacterial infections were documented in 94 episodes (Klebsiella pneumonia in 35 cases, Escherichia coli in 16 and Pseudomonas aeruginosa in 13), invasive fungal infections (IFI) in 34 cases (including 18 pulmonary aspergillosis and 14 candidemia); 8 cases were considered as FUO. The infection was mono-microbial in 60 cases and poly-microbial in 33. Sepsis occurred in 67 cases. The overall IAM was 26.7 % (27 deaths among 101 infective episodes). At univariate analysis we failed to detect statistical association between IAM and several evaluated variables, either patient-related (age, sex, diagnosis, status of disease, allo-HSCT, aplasia duration) or infection-related (bacterial infection or IFI, sepsis, XDR, G-SCF concurrent administration) or GTX-related (number of GTXs received, PMN /Kg/course, PMN/Kg/day of neutropenia). However, when we grouped patients according to the value of the median dose of PMN per transfusion, we found that patients receiving 1.5 - 3 x 10^8/kg (GTXs A) had a lower IAM than patients receiving less than 1.5 (GTXs B) or more than 3 x 10^8 /kg (GTXs C) (15,7%, 35,3% and 44,4%, for GTXs A, B and C, respectively, p=0,014 at chi-square test). The dose's cut off were derived from the Guide to the preparation, Use and Quality assurance of Blood Components of the European Committee on Blood Transfusion (16th Edition). If the analysis was carried out by pooling together GTXs B and C, the association between PMN dose and IAM was even more pronounced (p value =0.006 at Fisher test for GTXs A versus GTXs B+C). At Kaplan-Meier analysis, the median survival was 59 days for GTXs A-patients and 30 days for GTXs B+C-patients (p =0,010). When patients with bacterial of fungal infections were separately evaluated, the effect of PMN dose on IAM was confirmed in bacterial (n=54, p=0,008) but not in fungal (n=23, p=0,588) infections. We then introduced the PMN dose (GTXs A or GTXs B+C) in a Cox proportional-hazards regression model together with variables with p Conclusions. These findings suggest that appropriate GTX doses can improve the post-infection survival of severely neutropenic hematological patients. Transfusion-related immunomodulation, leukostasis or transfusion-associated GVHD may underlie the detrimental effect of high PMN doses and deserve to be better explored. Table 1. Clinical characteristics of 84 patients treated with GTXs. A total of 101 courses were recorded. Characteristics Age (years, median value range) 46 (20-74) Male/Female 54/30 Underlying disease (n, %)Acute myeloid leukemiaLymphomaAcute lymphoblastic leukemiaMyelodysplastic syndromeMultiple myelomaChronic lymphocytic leukemia 63 (75%)12 (14%)5 (6%)2 (3%)1 (1%)1 (1%) Disease status at PMN transfusion (n, %)OnsetRelapse/resistanceComplete remission 49 (48,5%)41 (40.5%)11 (10.8%) Duration of neutropenia (days, median value, range) 18 (3-79) Site of infection (n, %)Sepsis LungBowelOthersMultiples (≥3 involved sites) 67 (66.3%)22 (21.9%)4 (3.9%)8 (7.9%)4 (4%) Allo-HSCTYes No 21(20.7)80(79.2) Transfusions per course (median value, range) 4 (1-14) PMN x 108/kg/course (median value, range) 8.78 (0.53-53.23) PMN x 108/kg/transfusion (median value, range) 2.11 (0.46-7.34) Disclosures No relevant conflicts of interest to declare.

Introduction: Incidence of fungal infections is reducing in the last years due to wider use of effective antifungal prophylaxis. On this basis, we evaluated clinical characteristics and outcome of patients (pts) with hematological malignancies (HMs) and fungal bloodstream infections (FBSI). Patient and Methods: This retrospective/prospective study gathered consecutive documented FBSI observed among HMs diagnosed between January 2011 and June 2015 in 19 Italian Hematology Departments that refer to SEIFEM (Sorveglianza Epidemiologica Infezioni Fungine Emopatie Maligne) group. Results: We collected overall 100 patients including retrospective pts and those observed in the first six months of the prospective study with FBSI among 16 centers; further 3 centers reported no cases of FBSI. Regarding patients' characteristics male/female ratio was 1, median age was 55 yeras. (IQR 18-88). Two-third of FBSI were detected in AML (43 - 43%) and NHL (27 - 27%); the remaining pts were affected by ALL (9 - 9%), MM (6 - 6%), MDS (5 - 5%), MDS/MPN (5 - 5%), CLL (3 - 3%) and HL (2 - 2%). Thirty-five pts had FBSI at the onset of HM or after the first induction, 47 after treatment for refractory/relapsed disease, 13 when in remission, 28 pts during transplant procedures (17 from allogeneic donor, 11 from autologous cells). Fifty-nine pts were receiving antifungal prophylaxis at FBSI breakthrough: 26 posaconazole, 16 fluconazole, 6 itraconazole, 3 amphotericin B, 3 caspofungin, 1 voriconazole, and 4 combination of amphotericin B/azoles; 4 pts were treated with secondary prophylaxis after previous fungal infection. Eighty-nine pts had a central venous catheter. Eighty-four pts presented a neutrophils count < 500/mmc for a median time of 7 days before FBI onset (0-70 d); 50 pts received steroids and other 17 immunosuppressive treatment for allo-HSCT. Yeasts were the most common agent detected. Candida spp. represent the most represented yeast, counting for 77% of all infections; (21 albicans and 56 non albicans); 8% of FBI were due to 8% Geotrichum, 3% Trichosporon and 2% Rhodotorula, Molds were rare but not infrequent: 8% were caused by Fusarium and 1% by Scedosporium. Three patients died before starting any antifungal. Fifty-two received echinocandins (49 caspofungin and 3 anidulafungin), 22 liposomal amphotericin B (L-AmB), 15 azoles (7 fluconazole, 3 posaconazole, 3 voriconazole and 2 itraconazole) and 8 pts combo therapy (5 posa+L-AmB, 2 Caspo+L-AmB, 1 vori+caspo). Thirty-eight pts died within 30 days from FBSI diagnosis, 28 (74%) of whom due to infection. Among these 12 (43%) suffered from AML (1 in induction, 1 in CR, 10 had refractory/relapsed disease), 2 (7.2%) from ALL (all with refractory/relapsed disease), 7 (25%) from NHL (2 in induction, 2 in CR, 3 with refractory/relapsed disease), 4 (14%) from refractory/relapsed MM, 1 (3.6%) from MDS in remission, 2 (7.2%) from newly diagnosed MDS/MPN. In 8 pts (21%) for whom we cannot discriminate if death was subsequent to FBSI only or to uncontrolled HMs, fungal isolates were all rare yeast or molds except 2. Mortality was related only with advanced phase of underlying HM (p Conclusions: Nowadays FBSI represents a rare complication of HMs, as a consequence of wider availability of effective antifungal prophylaxis. Candidemia still represents the most important cause of FBSI, although about 25% of FBSI are due to rare yeast or molds. Regardless a lowering incidence, the observed mortality remains high even with target treatment. Disclosures No relevant conflicts of interest to declare.

Intro:Myelodysplastic syndromes (MDS) are a heterogeneous group of hematology neoplasms ranging from indolent to very aggressive conditions. The reported incidence is of 5/100,000/year in the whole population changing up to 50/100,000/year after the age of 60 and up to 165 after 65. Due to the heterogeneity of MDS, patients are stratified into subgroups according to prognostic score systems (IPSS) to identify the best risk-adapted treatment strategy. These therapeutic strategies are not univocally agreed, creating differences among groups. Moreover data on economic aspects are partial and sometimes controversial, owing to different healthcare resources considered (transfusions, medications, procedures, hospitalization, treatment of comorbidities, first of all infectious complications). The adoption of Regional Hemato-Oncology Registries of Diagnostic Service Registries can allow for better quality in diagnostic procedures and treatment as well as improving the evaluation of healthcare costs in these patients. Methods: In the Italian Lazio Region the Rome and Lazio Group of Myelodysplasias (GROM-L) is presently active as a registry of MDS in adults, exploiting the collaboration of all Hematology Centers in the Region: diagnostic procedures and therapeutic protocols of patients included into this registry are harmonized. In the present study we report the results of the evaluation of costs of the healthcare resources supplied to 659 patients with MDS in the Lazio Region during the period 2002-2009, adopting the ‎ third party payer viewpoint (.e. the Healthy Service of the Lazio Region -SSR Lazio). In Table 1 is reported the distribution of the MDS diagnostic categories in our cohort of patients. The following healthcare resources are included: Red Blood Cell (RBC) and Platelet (Plt) transfusions, Erythropoietic Stimulating Agents, antineoplastic and immunomodulatory drugs, hospitalization and treatment of infectious (bacterial, viral and fungal) complications (Table 2). Healthcare resources are valued according to published ‎sources. Costs are expressed in Euros (€) 2013. Costs occurred after 2002 are discounted at 3% real social rate. Results:The overall cost for the 659 patients of the GROM-L Registry is €22.05 millions (US$24.21 millions), with an average cost per patient of €33.455,65 (US$ 36.727) (Table 3). The estimated annual cost for the SSR Lazio for the management of all the resident patients with adult MDS (around 183 per year) reaches €1.23millions (US$ 1.35millions). Data on costs related with MDS diagnostic subgroups are available too. In particular our data confirm that the transfusion dependency do represent one of the more valid predictor index of the healthcare costs in patients with MDS (Frytak et al., 2009, Drummond et al. 2005, Goldberg et al. 2012). The reduction of transfusion dependency in these patients do represent a new challenge for improving not simply the healthcare costs but the Health-Related Quality of Life- HRQoL) in these patients (Drummond et al. 2005; Brazier et al. 2007, Szende et al. 2009). Acknowledgments The study was supported by a grant from Regione Lazio: " Sindromi mielodisplastiche dell'adulto nell'area di Roma e del Lazio: Grant 2011-Progetti di farmacovigilanza -Area tematica 5". The authors would like to thank all the patients and investigators who took part in the study. Table 1. Distribution of the 659 patients among the WHO diagnostic categories of MDS. WHO MDS categories RARS RA RCMD RAEB-1 RAEB-2 5q- MDS-U Patients 33 246 148 96 81 27 28 Table 2. Health care resources supplied to 659 patients with adult MDS in the period 2002-2009 included in the Italian Lazio Region. 659 Patients in Total Treatment Quantity Transfusions RBC 7875 Units Plt 74 Units High cost therapies Azacytidine 126 cycles Lenalidomide 34 cycles Erythropoietin 554 cycles Hospitalizations due to infectious complications Antibacterial 345 cycles Antiviral 25 cycles Antifungal 42 cycles Table 3. Cost details of 659 patients with adult MDS included into the GROM-L Registry in the period 2002-2009 in the Italian Lazio Region. Healthcare resources Overall Costs Average cost per patient % of the overall costs RBC transfusions €3.04 millions €4.606,32 13,77% Plt transfusions €28.619,07 €43.43 0,13% High cost therapies €18.55 millions €28.146,41 84,13% Treatment for infectious complications €0.43 millions €659.50 1,97% Grand total €22.05 millions €33,455.65 100,00% Disclosures Voso: Celgene: Honoraria, Research Funding.

Background: Patients myelodysplastic syndromes (MDS) diagnosed with higher-risk disease have poor prognosis thus making improvements in health-related quality of life (HRQOL) a major goal of therapy. Understanding HRQOL profile of untreated patients is important to help clinicians to better target subpopulations in need of special attention from the very beginning of therapy. Aims: The primary objective of this study is to investigate whether HRQOL differences exist by age and gender in untreated patients with higher-risk MDS. A secondary objective is to provide age and gender pretreatment HRQOL profiles to be used as reference baseline data for comparing HRQOL of MDS patients under treatments. Methods: This analysis is based on 280 adult patients diagnosed with IPSS risk score of intermediate-2 (74%) and high-risk (26%), enrolled in an international prospective observational study. Median age of patients was 71 years (range 32-89), 176 were men (63%) and 104 (37%) women. HRQOL was assessed at study entry and before treatment for higher-risk disease (except for transfusions), with the EORTC QLQ-C30, the most widely used HRQOL outcome measure in MDS research. Thus, our data are likely to further ease interpretation of outcomes in many studies using this questionnaire. One hundred seventy-five patients had received at least one red blood cell transfusion at the time of baseline HRQOL assessment. HRQoL data of MDS patients were age-gender matched with those general population norms. Wilcoxon-Mann-Whitney and Wilcoxon signed ranks tests were used for unmatched and matched comparisons, respectively (α=0.05). Effect sizes were also computed. Results: No statistically significant differences existed in any of the HRQOL domain by IPSS category (intermediate-2 versus high-risk). However, HRQOL profiles differed by age and gender and results are reported in Table 1. Women generally reported lower HRQOL scores than men, with statistically significant impairments in the global quality of life (P=0.008), role (P=0.014), emotional (P=0.024) and social functioning (P=0.028). When compared to their peers in the general population, HRQOL was found to be impaired in all age group categories (Figure 1, A and B). However, the magnitude of impairments across HRQOL domains was markedly larger in younger patients (aged 30-59 years) compared to older age groups (≥60 years). The top three largest impairments in this younger group were found for: fatigue (ES=2.47, P Conclusion: Pretreatment HROQL of higher-risk MDS patients vary by age and gender and current reference data will help making more accurate comparisons with HRQOL of patients under treatment. Clinicians should also pay special attention to younger patients, as these are those most in need of HRQOL improvements. Figure 1. Adjusted mean differences between MDS patients and their respective control groups by age categories (30-59 years, 60-69 years, 70-79 years and over 80) in functional aspects and global quality of life. A score below 0 line means worse outcomes for MDS patients. *= Statistically significant (P Disclosures Gaidano: MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding. Santini:celgene, Janssen, Novartis, Onconova: Honoraria, Research Funding. Platzbecker:Celgene: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Novartis: Honoraria; Amgen, Inc.: Honoraria. Di Renzo:Celgene: Research Funding.

Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndromes (MDS). Cytopenias are a major problem during the first treatment cycles due to MDS itself and to the mechanism of action of the drug, which includes not only demethylation, but also cytotoxicity and apoptosis. We evaluated the incidence of infectious complication during AZA treatment in 200 “real life” patients, collected retrospectively by the italian cooperative groups Gruppo Romano MDS (GROM) and Basilicata MDS Registry. Patients gave informed consent and the study was approved by the Ethycal Committes of partecipating Centers. Patient started AZA between 3/2006 and 3/2014. Median age at treatment start was 71 years (range 33-93 yrs, 66 females, 134 males). There were 182 MDS (up to 20% BM-Blasts) and 18 AML (median BM-blasts 23%, range 21-60% BM-blasts). In MDS, IPSS stratification (n=178) was: low: 4%, Int-1: 19%, Int-2: 60%, high 17%, and according to R-IPSS (n=123 pts): low: 4%, intermediate: 20%, high: 51%, very-high: 20%. MDS-specific comorbidity index (MDS-CI) was available for 154 patients: 50 patients were classified as low-risk (0), 85 as intermediate (1-2), and 19 as high risk (>2). Azacitidine was started at a median of 1.4 months from initial diagnosis. One-hundred-sixty-six patients received AZA at the standard dose of 75 mg/sqm (7 days continuously: 22%, 5-2-2 days: 64%, 6-1-1: 4%) while 34 patients received AZA at 50 mg/sqm for 5- 7 days. Response, according to IWG 2006 criteria, was evaluable in 188 patients: 27 obtained complete remission (CR, 14%), marrow CR was achieved in 6 (3%), partial remission (PR) in 30 (16%), hematological improvement (HI) in 40 (21%), disease was reported stable (SD) in 54 (29%), whereas 31 patients presented progressive disease (16%). A median of 10 (range 1-62) cycles of AZA were delivered. Probability of response was independent from age, IPSS, IPSS-R, MDS-CI, and was associated to a shorter time from diagnosis to therapy initiation (p=0.04) and to the 75 mg/sqm through 7 days vs 50 mg/sqm through 5 -7 days schedule (60 vs 30% CR/PR/HI, p=0.007). With a median follow-up of 14.8 months (range 0-100 months), 57 patients are alive, resulting into a median overall survival of 17.2 months. IPSS and MDS-CI did not predict survival, while grouping according to IPSS-R was associated to a significantly different survival probability (p=0.0007). Across delivery of a total of 1547 AZA cycles, 213 (13%) febrile events were recorded. Fever of unknown origin was diagnosed in 20 patients (10%). Of 193 clinically documented events, a positive microbiologic test was available in 49 cases (25%, 44 for bacteria, 5 for viruses). A single episode of infection was recorded in 124 patients (62%) at a median of 3.8 months from therapy initiation (0-53 months), 53 (26.5%) patients suffered from a second infectious event and 28 (14%) patients from a third one (at 5.6 and 8.3 months from AZA start, respectively). Infections were the attributable cause of death in 30 patients (15%, 3 in CR, 17 with progressive disease and 10 SD). Most frequent infection sites were lungs (45%), cutis (9%), mouth (9%), bowel or peri-anal region (7%). The risk of infectious complications was lower in IPSS low-risk (p=0.05) or IPSS-R low/int MDS (p=0.01), and in patients with MDS-CI 0-2 (p=0.0001). Our data indicate that treatment with AZA is associated with a relatively high probability to develop infectious complications, especially pneumonia, which is however rarely the cause of death. The risk to develop infections is the highest during the first courses of AZA delivery and correlates to baseline patients’ characteristics, including disease stage and comorbidities. Once the infectious episode has occurred, the outcome depends on the disease status. Disclosures Voso: Celgene: Consultancy. Venditti:celgene: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.

Introduction In 2001, the World Health Organization (WHO) recognized therapy-related myeloid neoplasms (t-MN) as a distinct entity including acute myeloid leukemia (AML) and myelodisplastic syndromes (MDS). At present, about 10% of all AML patients have a previous history of exposure to chemotherapy and/or radiation for a primary malignancy or autoimmune disease. In 2009, we initiated a Web-based epidemiological registry, with the purpose of collecting t-MN diagnosed at Italian Hematological or Oncological Divisions. Methods Demographic and clinical information on t-MN patients were included in the database whose access was restricted to selected users and was password-protected. Between May 2009 and June 2013, 279 t-MN patients [121 males and 158 females; median age 64 years (range 23-88 years)], observed at 22 Italian Centers between 1999 and 2012, were registered in the web-database. Results The primary malignancy (PM) was a hematological neoplasm (HM) in 123 cases (44%), a solid tumor in 145 cases (52%), and an autoimmune disease in 11 patients (4%). Twenty patients (7%) had a history of two or more previous cancers. Among hematological malignancies, the most frequent PM were lymphoproliferative diseases (92/122 cases), while breast cancer (65/146 cases) was the most frequent primary solid tumor. In particular, hematological PM were: 92 lymphoprolipherative diseases (68 Non Hodgkin and 18 Hodgkin lymphoma, 6 chronic lymphocytic leukemia); 12 Multiple myeloma; 14 myeloproliferative neoplasms (7 Myelofibrosis; 3 polycitemia vera; 3 essential thrombocythemia; 1 Hypereosinophilic syndrome.); 1 Acute lymphoblastic leukemia; 4 Acute myeloid leukemia (acute promielocytic leukemia in 2 cases). Sites of primary solid tumors were: 65 Breast; 32 Uro-genital (14 prostate; 5 bladder; 8 uterus; 5 ovarium); 17 Colon-rectal; 8 Lung; 8 Thyroid; 15 others (2 stomach; 5 CNS; 2 skin, 4 oropharynx; 2 sarcoma). Eleven patients had previously received immunosuppressive therapy for an autoimmune disease (5 with mitoxantrone, 5 with methotrexate, 1 with chlorambucil). Two-hundred-thirty-six patients had previously received chemotherapy for their primary malignancy, associated to radiotherapy (RT) in 94 cases. RT represented the only primary treatment in 43 cases. Median latency between PM and t-MN was 5.6 years (range 0.5-48). There were no differences between t-MN after lymphoprolipherative diseases or after breast cancer when considering patients’ age (p=0.09) or median latency (p 0.20) between PM and t-MN. According to morphology, t-MN were classified as 164 AML, 108 MDS and 7 ALL. Karyotype was available for 204 patients and was unfavorable in 81 patients (complex in 54 patients including del(7) in 19 cases; 15 cases with isolated del(7)]. A recurrent chromosomal translocation was present in 13 patients [1 t(8;21), 8 t(15;17) and 1 inv(16); 3 t(9;22)], while 75 patients had a normal karyotype. One-hundred-thirty-five patients received chemotherapy for t-MN, while the hypomethylating drug Azacitidine was administered to 63 patients. Fifty-six patients underwent bone marrow transplantation (45 allogeneic and 11 autologous). Median OS from the t-MN diagnosis was 7.7 months (range 0.2-158+). Conclusions The incidence of t-MN is rising as a result of the increasing number of cancer survivors. Lymphoprolipherative diseases and breast cancer are the most common primary malignancies at risk of developing a therapy-related myeloid neoplasm. Disclosures: Santini: Novartis: Honoraria; Janssen : Honoraria; Celgene: Honoraria; gsk: Honoraria.

In the AZA001 trial, azacitidine prolonged OS in all cytogenetic IPSS risk subgroups and in particular reduced 67% risk of death for all patients with -7/del(7q). Aim of our study was to assess azacitidine efficacy according to cytogenetic risk at baseline in a large group of intermediate/high-risk MDS patients treated outside clinical trials. One hundred and sixty-six patients represented the whole cohort of patients with primary or secondary MDS (CMML were excluded) diagnosed and treated with azacitidine in 6 different hematologic units. Patients were recruited consecutively, without any criteria of exclusion. All patients received azacitidine with a schedule of 5+2+2 or of 7 consecutive days every 28 days until progression or unacceptable toxicity. Clinical parameters (age, sex, WHO classification, IPSS) and baseline cytogenetic evaluation were retrospectively collected. Of 166 patients recruited, 103 were males and 63 females; median age was 69.5 years (range 49-89). A median of 8 cycles was performed (range 1-60). According to IPSS stratification there were 29 patients with intermediate-1 risk, 118 patients with intermediate-2 and 15 high–risk (7 patients not determined). According to WHO classification, 37 patients were diagnosed as having RAEB-1, 101 patients as RAEB-2, 28 patients as RCMD. According to IPSS cytogenetic risk stratification, 88 patients were in the good risk, 22 patients were in intermediate risk and 39 in the poor risk. The most frequent cytogenetic aberration, apart from normal karyotype, was -7 or del(7q). According to cytogenetic stratification, after a median of 4 cycles for the first evaluation, we revealed the following responses according to IWG criteria: of 88 patients classified as good risk, 68 were evaluable and overall 30% achieved a complete (CR), partial remission (PR) or hematological improvement (HI), 59% maintained a stable disease, 4% progressed to acute leukemia and 7% failed to achieve any response. Of 22 patients classified as intermediate cytogenetic risk, 19 patients were evaluable after 4 cycles: overall, 52.6% achieved a CR/PR and 42% maintained a stable disease, none experienced a progression and 5% failed to achieve any response. Of 39 patients stratified as high cytogenetic risk, 30 were evaluable: 36.6% achieved a CR/PR/HI, 36% maintained a stable disease, 20% progressed to acute leukemia and 7% failed to achieve any response. Our results, based on a retrospective evaluation in a large series of patients treated outside clinical trials, shown that azacitidine was clinically effective independently from cytogenetic profile, as proved in the AZA001 trial. Disclosures: No relevant conflicts of interest to declare.

Objective: To evaluate the efficacy of Caspofungin in patients with hematological malignancies (HM) and candidemia Design: The study was prospectively conducted in 11 Hematology Divisions in a tertiary care or university hospital setting.; neutropenic hematological patients with clinical evidence of infection and a positive blood culture for Candida were enrolled. Patients and results: Between January 2005 and November 2007, 38 episodes of candidemia among patients with HM were registered. Among these, 24 eligible neutropenic patients, collected in 8/11 participating centers, were evaluated. All these patients had received chemotherapy for their underlying hematological diseases: acute myeloid leukemia (AML) in 11 patients (46%); non Hodgkin’s lymphoma (NHL) in 6 patients (25%); acute lymphoblastic leukemia (ALL) in 4 patients (16%); multiple myeloma (MM) in 2 patients (8%); chronic lymphoblastic leukemia (CLL) in 1 patient. In 11 patients (46%) the infection onset after a HSCT procedure (7 allogeneic and 4 autologous). Before the infection onset, all patients were neutropenic (ANC Conclusions: Our data confirm the efficacy of Caspofungin in the treatment of neutropenic pts with HM and concomitant candidemia as well as it was reported for non hematological subgroups. Caspofungin was well tolerated also in very compromised pts.

Backround: Gentuzumab Ozogamicin (GO) is effective as single agent in the treatment of poor risk acute myeloid leukemia (AML) patients (pts). The aim of this study was to evaluate the efficacy and safety of a chemotherapy including growth factors, cytabine and GO in the treatment of secondary AML (sAML) elderly pts. Patients and Treatments: From September 2003 to September 2006, a total of 23 pts, median age 69 years (range 58–77) with sAML were enrolled in G-AraMy protocol which was divided in two phases. In the first phase from September 2003 to December 2004 11/23 pts received G-AraMy-1 treatment: rhG-CSF (5 μg/kg, on days 1–8), Aracytin as continuous perfusion (100 mg/m2 on days 4–8), GO (6 mg/m2 iv on day 9). In the second phase from January 2005 to September 2006 12 pts was treated according G-AraMy-2 protocol: G-CSF (5 μg/kg, on days 1–8), Ara-C as continuous perfusion (100 mg/m2 on days 2–8), GO (6 mg/m2 iv on day 9). In pts reaching complete (CR) or partial remission (PR), consolidation therapy was performed. In G-AraMy-1 this consisted of: G-CSF(5 μg/kg, on days 1–6), Ara-C as continuous perfusion (100 mg/m2 on days 2–6), GO (6 mg/m2 iv on day 7). G-Ara-My-2 group was consolidated with: G-CSF(5 μg/kg, on days 1–5), Ara-C (1 g/m2 every 12 hours on days 2–5), GO (6 mg/m2 iv on day 6). Results: Among the 23 treated pts 11 (48%) presented a post-MDS AML while 12 pts (52%) had received chemotherapy for a prior malignancy (3 Hodgkin’s lymphoma, 5 breast, 2 thyroid, 1 gut, 1 bladder). Ten out 23 pts (43.5%) had previously received chemotherapy for AML being relapsed (4) or primary resistant pts (6) while 13 (56.5%) were untreated pts. Cytogenetic study was performed in all pts; karyotype was at “intermediate prognosis” in 11 cases, at “worse prognosis” in 7 cases, at “good prognosis” in 2 cases. In 3 pts no metaphases were observed. After induction and consolidation therapy 14 pts (6 group 1; 8 group 2) (61%) achieved a CR and 2 pts obtained PR. Five pts (22%) resulted refractory to treatment and 2 died during the aplasia period post induction treatment (1 due to sepsis, 1 due to cerebral haemorrhage). The most common adverse event was myelosuppression, as expected. No VOD was recorded. Seven pts (30%) developed documented infection (including pulmonary aspergillosis in 2 cases). Two pts died while in CR, 1 due to bladder cancer relapse and 1 to ischemic stroke. Nine of CR pts (39%) relapsed; at March 2007 5 pts (22%) are alive, of whom 1 are still in CR (4%). Median time to treatment failure (TTF) and median overall survival (OS) of whole population were 7.1 months (range 1–40.6+) and 8.6 months (range 1.7–40.6+) respectively. Stratifying pts according the two treatment groups median TTF was 4.4 months (range 3–10.5) in the first group and 7.2 months (range 1–40.6+) in the second; median OS was 6 months (range 1–13.6) in the first group and 9.1 months (range 1.7–40.6+) in the second. Conclusions: G-AraMy protocol could be considered an useful approach for elderly sAML pts considering the low reported side effects with a CR rate similar to that reported in literature. Unfortunately CR duration is brief. The modification of protocol schedule in the G-AraMy 2 group with the addition of more aggressive consolidation therapy seems to improve the duration of CR and OS.

Background: To evaluate the incidence and the outcome of fungal infections in patients (pts) affected by hematological malignancies (HM). Methods: A retrospective study, conducted over 1999–2003, in pts with HM, admitted in 18 Italian Hematology divisions in tertiary cares or university hospitals, who developed proven or probable fungal infections. Results: The population included 11,802 pts: 3,012 AML (25.5%), 1,173 ALL (9.9%), 596 CML (5%), 1,104 CLL (9.4%), 1,616 MM (13.7%), 3,457 NHL (29.3%), 844 HL (7.2%). Pts who underwent HSCT were included in a different analysis. A fungal infection occurred in 538 pts, with an incidence of 4.6%; in particular we registered 346 episodes sustained by moulds (incidence 2.9%) and 193 by yeasts (1.6%). The incidence rate depends upon underlying malignancy (12.3% in AML, 6.5% in ALL, 2.7% in CML, 0.6% in CLL, 0.5% in MM, 1.6% in NHL, 0.9% in HL). Among moulds, the etiological agents were Aspergillus (310 episodes, incidence 2.8%), Mucorales (13 pts, 0.1%), Fusarium (15 pts, 0.1%), and other rare fungi (7 pts, 0.1%). Among yeasts we registered septicemia due to Candida (175 pts, 1.6%). Other yeast infections were caused by Cryptococcus (8 pts, 0.1%), Tricosporon (7 pts, 0.1%) and other rare agents (2 pts). We did not observed an increase of A.terreus infections while the number of episodes sustained by A.flavus increased from 1999 to 2003 (RR 2.10; IC95% 0.8–5.49; p-value 0.117). The overall mortality rate was 1.8%. Among 538 pts with fungal infection 39% died for this complication, with differences between aspergillosis (42%), zygomycosis (63%), fusariosis (53%) and candidemia (33%). There was not variation in mortality rate during the study period; comparing these pts with those observed in our previous studies during the period 1987–1988 we observed a significant reduction of death due to aspergillosis (RR 1.90; IC 95% 1.17–3.09), but no differences in mortality rate due to Candida. Conclusions: Our study confirms the general trends already described: infections due to moulds are more frequent than those caused by yeast. Aspergillus remains the main etiologic agent, followed by Candida. The other agents (Mucorales, Fusarium, Trichosporon) remain rare. AML represents the most frequently involved category. The mortality rate due to aspergillosis is actually about 40%, with a remarkable decrease when compared to past years; as for candidemia, we observed a reduction in the incidence, but not in the mortality rate.

Gentuzumab Ozogamicin (GO) is an anti-CD33 antibody linked to the cytotoxic antibiotic calicheamycin and it is effective as single agent in the treatment of poor risk acute myeloid leukemia (AML) patients. In 3 Italian Hematology Departments from September 2003 to December 2004, we treated 26 AML patients, both untreated (12 cases) and resistant (14 cases) with the following protocol: rhG-CSF(5 μg/kg, on days 0 through 8), Aracytin as continuous perfusion (100 mg/m2 on days 4 through 8) followed by GO (6 mg/m2 iv over 2 hours on day 9) (G-GOA). Inclusion criteria were: 1) CD33+ de novo or secondary AML (except M3 AML; 2) Primary refractory AML or relapse of AML in patients between 61 and 80 years; 3) Untreated patients 〉70 years or not eligible for aggressive chemotherapy. There were 13 male and 13 female with a median age of 69 years (range 58–77). FAB classification was 5 M0, 5 M1, 7 M2, 2 M4, 1 M5, 6 AML post-MDS. Ten patients presented a secondary AML. The median duration of first complete remission (CR) of 9 patients with relapsed AML was 48 weeks (range 8–76). Cytogenetic study was performed in all patients; karyotype was intermediate in 13 cases, unfavourable in 7 cases. In 6 patients no metaphases were observed. All patients performed the CD33+ evaluation on BM, the median percentage of CD33 positive blasts was 90% (range 25%–95%). Fourteen patients (56%) achieved a CR and 1 patient had CR with delayed platelet recovery (CRp) with an overall response (OR) of 58% (7 untreated AML and 8 resistant patients). One patient obtained a partial remission with only a transient hematologic improvement, characterized by a peripheral increase of all hematological parameters and by a 50% reduction of the bone marrow blast count. Five patients (19%) resulted refractory to treatment and 5 patients died during the aplasia period post induction treatment. The most common adverse event was myelosuppression, as expected. Median durations of neutropenia and thrombocytopenia in patients reaching CR were 19 days (range 15–62) and 16 days (range 10–37) respectively. No VOD was recorded. Six patients (23%) developed documented infection (including pulmonary aspergillosis in 3 cases). Notably, in 2 cases we observed a grade III/IV bleeding consisting in CNS haemorrhage. Two patients died while in CR, 1 due to bladder cancer relapse and 1 to ischemic stroke. Seven patients (27%) relapsed; the median CR duration was 20 weeks (range 8–41+). At March 2005 10 patients (38%) were alive of whom 6 are still in CR (27%). The median overall survival was 17,5 weeks (1–60 weeks). On the basis of our results the G-GOA protocol could be considered an useful approach for poor risk elderly AML also in consideration of the low reported side effects. We did not observe any case of VOD, which characterized other trials using GO at higher dosage. Unfortunately the CR duration was brief. Probably it could be improved with the addition of more aggressive consolidation schedule (i.e. Intermediate doses of Ara-C).