ALBERT

Description: Introduction With standard intensive induction regimens, up to 80% of Acute Myeloid leukemia (AML) patients can achieve complete remission (CR). Several evidences demonstrated that the persistence of detectable disease (MRD) assessed with highly sensitive techniques such as Multicolor-Flow-Cytometry (MFC) and PCR based molecular analysis, retains a prognostic value among patients achieving morphological remission (Walter RB, 2015; Araki D et al, 2016, Zhou Y et al, 2016). The aim of the present study was to retrospectively evaluate the prognostic impact of MRD in a cohort of uniformly treated AML patients. One hundred and ten consecutive AML patients who had been treated in our center between January 2004 and December 2014 were retrospectively analyzed. All patients had received a fludarabine-containing induction (FLAI-5) and received second cycle and further consolidation therapy according to our published strategy (Guolo F, 2016). Median age was 47 years (range 17-61). Median follow up was 59 months. Patients features are summarized in Table I. MRD assessment was performed through 4-colour MFC analysis (MFC-MRD)and through WT1-gene expression analysis, as previously described (Guolo F, 2016). Three different MRD time-points (TP)were considered: TP1, after induction I; TP2, after induction II; TP3, after consolidation therapy for patients who did not undergo HSCT and at HSCT for patients who underwent HSCT. Relapse-free survival (RFS) was calculated from the time of diagnosis until last follow-up or documented leukemic relapse. CR rate after 1st and 2ndinduction was 82.7 and 85.5%, respectively, whereas 30 and 60 days mortality was 6.4% and 8.2%, respectively. Overall, patients showed MRD reduction from TP1 to TP2. Detailed MRD negativity rates are provided in table II. MRD clearance probability was significantly influenced only by ELN risk group and Karyotype (p

Description: Abstract 4848 Objectives: the prognosis of patients with cytogenetically normal acute myeloid leukemia (CN-AML) is highly variable and can be influenced by several clinical and biological variables. Nevertheless, some biological data may be conflicting and difficult to combine with the clinical ones. Methods: in order to propose a simple scoring system, we retrospectively analysed the clinical data of 337 patients newly diagnosed with CN-AMLs, aged less than 65 years, consecutively treated in eleven hematological Italian Centres from 1990 to 2005. Two hundred nineteen patients (65%) received a fludarabine-based induction regimen. All the other patients received a conventional induction regimen, including cytarabine, one anthracycline with or without etoposide. Univariate and multivariate analysis on event free survival and overall survival (EFS and OS) were performed. Patients addressed to allogeneic stem cell transplantation were censored at the time of transplant. Factors found to be significant in univariate analysis were tested in multivariate analysis. A numerical score was derived from the regression coefficients of each independent prognostic variable. The Prognostic Index Score (PIS) for each patient was then calculated by totalling up the score of each independent variable. Patients could thus be stratified into low-risk (score = 0–1), intermediate-risk (score = 2) and high-risk group (score grater than 3). The score obtained in this group of patients (training set) was then tested on 193 patients with newly diagnosed with CN-AMLs, aged less than 65 years, enrolled in the GIMEMA LAM99p clinical trial (validation set). Results: the clinical variables that were independent prognostic factors on EFS in the training set of patients were: age 〉 50 yrs (regression coefficient: 0.39, HR 1.5, score = 1), secondary AML (regression coefficient: 0.90, HR 2.5, score = 2) and WBC 〉 20 × 10^9/L (regression coefficient: 0.83, HR 2.3, score = 2). For what concerns the OS, the same variables showed the followings statistical data: age 〉 50 yrs (regression coefficient: 0.48, HR 1.6, score = 1), secondary AML (regression coefficient: 0.99, HR 2.7, score = 2) and WBC 〉 20 × 10^ 9/L (regression coefficient: 0.87, HR 2.4, score = 2). In the training set of patients, the median EFS was 22, 12 and 8 months in the low, intermediate and high-risk group (p

Description: Anemia is one of the most prevalent clinic condition leading to a specialist medical consult. In 2014 our Internal Medicine unit started a Multidisciplinary Anemia Ambulatory (Internist, Immune-Hematologist, Hematologist) with the purpose to rapidly manage, diagnosis and treatment of anemic patients, giving a direct connection between general practitioners and hospital services. We treated and collected data on patients come to our attention in a tertiary care hospital in Genoa (Liguria), an area characterized by elderly population, which often carries more than one comorbidity with the purpose of better define the epidemiology of such a prevalent but underestimated issue. From January 1st 2014 a total of 212 patients came to our attention for internist consult due to anemia: 165 female and 47 male, medium age 63,23 years (F 58,86, M 78,57, range 19-100). A precise classification of anemia was determined for 187 patients: 130 had iron deficiency anemia (IDA, 61,32%), 17 multifactorial anemia (inflammatory disorders, chronic kidney disease and combined deficiency, 8,02%), 16 combined deficiency anemia (iron and vitamins, 7,55%), 9 chronic kidney disease related anemia (4,25%), 7 anemia secondary to inflammatory chronic disorder (3,30%), 5 B12 deficiency (2,36%), 2 both folate and B12 deficiency (0,94%), 1 folate deficiency (0,47%). Twenty-five patients were not classified due to lack of data. Severity of anemia was defined according to WHO criteria: 53 patients (25%) presented mild anemia (Hb 129 - 110 g/L), 123 (58%) moderate anemia (Hb 109 - 80 g/L), 33 (15,6%) severe anemia (Hb 〈 80 g/L). Three patients were not anemic at the baseline evaluation. We considered comorbidities of internistic relevance, which could be worsened by anemia: cardiovascular (coronary heart disease, arrhythmias, heart failure), 30 patients; neurologic (ischemic and degenerative diseases), 19 patients; respiratory disease (COPD and asthma), 11 patients. Eleven patients had 2 comorbidities (cardiovascular and respiratory or neurological) and 3 patients had all three comorbidities. Patients were treated according to clinical practice in relation to type, severity and clinical manifestation of anemia. One hundred and thirty patients needed more than one access to ambulatory to correct anemia; data from the second access were: patient responders (normalization of Hb levels or improvement of at least 20 g/L): 78 patients; partial responders (improvement of Hb levels from 5 to 20 g/L): 34 patients; non responders: 18 patients. Fourteen patients needed at least 1 blood red cells transfusion, 12 with severe anemia and 2 with moderate anemia. A total of 93 patients needed deep diagnostic insight through specialist pathways, such as hematologic (4 patients), gastroenterologic (39 patients), gynecologic (37 patients), both gastroenterologic and gynecologic (13 patients). All patients were managed as outpatients, except for 8 patients which required hospitalization due to severity of clinical findings: 4 patients were hospitalized in Internal Medicine ward, 1 patients in Gynecology and 3 patients needed access through Emergency Care Unit. Among IDA patients, 92 were treated with intravenous iron supplement: 32 with sodium ferric gluconate (SFG) (medium 16,68 vials, range 8-43) and 50 with ferric carboxymaltose (FC) (medium 1,04 vials). Nine patients treated with SFG experienced allergic reaction, so they were switched to FC. Patients treated with SFG were successfully treated for 69,56% and 26,08% responded partially. One patient treated with FC experienced allergic reaction, so he was switched to oral therapy. FC patients fully responded in 76% and 22% were partial responders. These preliminary data shows that Multidisciplinary Anemia Ambulatory and its diagnostic-therapeutic path, with the involvement of different Specialists and Operative Unit, resulted in an improvement of the coordination and continuity of care, reducing sanitary cost in terms of hospitalization, drugs rationalization and quality of life for patients. More data will derive from the newborn Anemia Regional Register, which will lead to a better comprehension of the real size of anemia in our local epidemiology, in which health derived costs are rising together with ageing of the comorbid population which often needs longitudinal assistance, coordination and continuity of care. Disclosures No relevant conflicts of interest to declare.

Description: Introduction the natural history of Chronic Myeloid Leukemia (CML) has changed after the introduction of first generation tyrosine kinase inhibitors (TKIs). Data from clinical trials suggest that about 30% of patients fails imatinib treatment and 18% never achieves complete cytogenetic remission (CCyR). However, CCyR and major molecular response (MMR) can be achieved with second generation TKIs in many patients. Aim We have analized 119 CML patients that have received at least one course of TKI and their outcomes. We have calculated how many patient are alive and continuing to receive first TKI therapy or patients who are alive but had to switch to alternative TKI therapy. Patients and methods From May 1987 and May 2013 among chronic phase CML patients diagnosed, we have analized 119 patients who received at least one course of first, second or third generation TKIs. At diagnosis patients characteristic were: mean age 52 years (range 17-80); comorbidities unrelated to CML were found in 55 patients (i.e. arterial hypertension, ischemic heart disease, atrial fibrillation and chronic obstructive pulmonary disease (grading 1-2). Nine patients had a past history of epythelial cancer. Additional karyotype abnormalities were present in 7 patients (5%). Subjects were stratified according to Sokal score: 32 high risk, 39 intermediate risk and 48 low risk. Thirty five patients were diagnosed in pre-TKI era. Thus, they received second line imatinib, after conventional chemotherapy. Sixty-nine patients were treated with frontline imatinib, 14 subjects received frontline nilotinib and 1 frontline ponatinib in. The median follow up is 102,5 months (range 3-312). Results Response to treatment was defined in according to 2009 European LeukemiaNet guidelines In our series 20 patient died (17%) because of: disease progression in imatinib (= 2; 1.7%), acute myocardial ischemia during imatinib therapy (= 2), respiratory failure in 1 case and second tumor in 9 subjects. Of nine additional patients, three were lost at follow up and 6 subjects died. Overall 96/119 patients are alive (80,7%). Patients receiving frontline TKI are 55 ( 42in imatinib; 12 in nilotinib and 1 in ponatinib). Patients treated with second-line TKI are 30 (19in imatinib post chemoterapy, 6 in Nilotinib and 5 in dasatinib). Subjects receiving third-line TKI are 10 (9 in dasatinib and 1 in imatinib post allograft transplant). Only 1 patient receives ponatinib as fourth-line TKI. Responses are: CCyR in 96% of alive patients of whom 81% have a molecular response (MMR or better). Switch to TKI other than imatinib (24 patients) was due to failure to achieve optimal response or loss of response according to LeukemiaNet guidelines. Moreover, three patients did not tolerate first line TKI. Nilotinib was generally well tolerated: we did not observe any cardiovascular adverse event. However we found that previous failure to imatinib predicted subsequent failure to nilotinib (=11). As previously reported, dasatinib induced three pleural effusions, resolved with medical therapy without requiring switch of therapy, except for one patient. Conclusion We noticed that Sokal score does not correlate with response to TKI therapy. Imatinib is well tolerated, only few patients discontinued because of side effects.However 24% of patients switched to second-line TKI due to loss of response especially among those patients previously treated with chemotherapy. Frontline nilotinib induced a sustained optimal response in 85,7%(=12) without adverse event. Our results about percentage of patient who switched therapy are slightly lower than those of clinical trials. This result support the notion that CML patients enrolled in clinical trials are not always fully representative of a general population referred to outpatient clinic. Disclosures: No relevant conflicts of interest to declare.

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

Description: Background: Acute Myeloid Leukemia (AML) is an incurable disease characterized by a highly unstable genome, resulting in large-scale changes at diagnosis, as well as further evolution contributing to disease progression. However, the mechanisms whereby tumor cells adapt to genomic instability are largely unknown, but recent observations have correlated these abnormalities with dysfunctional DNA damage repair (DDR) machinery. SIRT6 is an important regulator of cellular stress response and genomic integrity. Here we investigated the role of this NAD+ -dependent deacetylase in regulating ongoing DNA damage observed in AML patients. Methods: SIRT6 mRNA level was determined by RT-qPCR in AML patients (n=100) diagnosed at the Hematology Department of University of Genoa (Italy), compared with normal bone marrow derived CD34+ cells (n=5). Correlation studies with clinical and molecular characteristics of these patients were also performed. A panel of different AML cell lines and primary cells, both sensitive and resistant to conventional and novel anti-AML therapies, was used in the study. The anti-leukemic effect of DNA-damaging agents (DDAs) including idarubicin, Ara-C and fludarabine was evaluated in presence of SIRT6 depletion/inhibition by CTG assay and Annexin-V/propidium iodide staining. Mechanistic studies were performed with Western-blotting, lentivirus-mediated shRNAs and immunofluorescence assay. Analysis of DNA DSB repair was done using chromosomally integrated reporter constructs, followed by cytometer analysis. Results: AML patients were grouped into lower and higher SIRT6 expressers according to its median mRNA level. Patients with lower expression had a higher incidence of FLT3-ITD (p=0.034, Wilcoxon signed rank test). No significant association was observed with respect to mutations of NPM1, nor with WT1 and BAALC expression. SIRT6 expression correlated also with adverse clinical outcome in term of event free and overall survival (p=0.035 and p=0.025, respectively; unpaired t test). Based on these data, we evaluated SIRT6 role in biology of AML. We found higher SIRT6 protein level in AML cell lines carrying FLT3-ITD mutation (MOLM-14 and MV 4-11) compared to cell lines harboring other mutations (OCI-AML3, THP-1, KG, NB4, HL60, Nomo1 and U937). Targeting SIRT6 by specific shRNAs weakly reduced AML cell survival compared with control-scrambled cells, by impairing DNA repair efficiency. Indeed, a restricted effect of SIRT6 impairment on DNA damage proteins (H2AX, RAD51, 53BP1, RPA32) was measured. We next examined the therapeutic relevance of SIRT6 inhibition in AML by testing effects of its depletion in combination with genotoxic agents. Remarkably, SIRT6 depletion conferred increased sensitivity of AML cells to idarubicin, Ara-C and Fludarabine. Overall, enhancing genotoxic stress while concomitantly blocking DNA double-strand breaks (DSBs) repair response, may represents an innovative strategy to increase chemosensitivity of AML cells. Further mechanistic studies revealed that SIRT6 acts as a genome guardian in leukemia cells by binding DNA damage sites and activating DNA-PKcs and CtIP by deacetylation, which in turn promotes DNA repair. Conclusion: Genomic instability is present in all hematologic malignancies including AML. Strategies aimed to shift the balance towards high DNA damage and reduced DNA repair by SIRT6 inhibition can decrease AML growth and may benefit patients with otherwise unfavorable outcomes. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND AND AIMS Allogeneic bone marrow transplantation (BMT) offers the greatest chance of cure for patients with high-risk acute myeloid leukemia (AML). Persistence of disease or high levels of pre BMT minimal residual disease (MRD) have been reported to predict relapse risk after BMT. WT1 expression levels and multicolor flow cytometry (MFC) are the most common tools to evaluate MRD. We recently reported that combining WT1 expression and MFC for MRD detection after induction therapy strongly impacts on relapse risk in AML. The aim of this study was to analyze the role of pre-BMT MRD assessment as predictor for the post-transplant relapse risk. MATERIALS AND METHODS We retrospectively analyzed the outcome of 253 consecutive AML patients receiving allo-BMT. Pre-BMT marrow samples were analysed for WT1 expression and MFC as MRD evaluation . Median age at transplant was 45 years. Disease phase was CR1 in 161, CR2 in 63, and CR3 in 29 patients. One hundred eighty-two received myeloablative conditioning, whereas 71 patients received reduced intensity conditioning. Median follow-up was 59 months (95% CI 46.2 - 71.8 months). Relapse-free survival (RFS) was calculated from the time of transplantation until last follow-up or documented leukemic relapse. Overall Survival (OS) was calculated from the time of transplantation until death by any cause or last follow-up. A positive MFC MRD was defined by the presence of no less than 25 clustered leukemic cells/105 total events (threshold of 2.5x10-4 residual leukemic cells) at four-color flow-cytometry. Real-time PCR for WT1 was performed on DNA Engine 2 (Opticon®, MJ Research®). WT1 copy number/Abl copy number 500x104 was used as cut-off value for abnormal WT1 expression. RESULTS Relapse occurred in 81 patients (32%). Three-year estimate of RFS was 63.7% (median not reached). The probability of relapse was significantly affected by disease status (first or subsequent CR, p

Description: Background and aims Myelodisplastic syndromes (MDS) are a group of hemopoietic disorder characterized by an impaired blood cell production, morphologic dysplasia and peripheral cytopenias; they are the most common hematologic neoplastic disorder and its diagnosis relays on morphologic evaluation, associated to a karyotypic assay. In order to predict the outcome of patients affected from these disorders, knowing that the order of survival can be extremely variable, several prognostic index were developed such as International Prognostic Score Sistem (IPSS) or the most usefull WHO-Prognostic Score Sistem (WPSS). On the contrary of acute leukemia, these disorders have not a biomolecular profile evalutation of intrinsic markers able to stratify patients in different prognostic risk groups. The aim of our study is to assess the risk of leukemic evolution, in MDS patients, on the basis of the levels expression of WT1 and BAALC at disease diagnosis, and to evaluate the leukemia free survival (LFS) at 6-12-24-36 months of follow up, among the different risk category according to IPSS and irrespectively of treatment. Materials and method In five years we analized 102 patients with a diagnosis of MDS divided according to the WHO classification such as follows: 38 AR, 1 AR with del(q5), 21 aREB-1, 23 AREB-2, 3 chronic myelomonocitic leukemia, 1 RARS, 1 MDS, 11 RCMD, 1 5q- syndrome, 2 suspected MDS. According to IPSS 58 belonged to the low risk category, 21 to the intermediate-1, 23 to the intermediate-2/high risk. Cytogenetic assay showed 20 people with an abnormal karyotype, 8 of them fallen into the high risk class and 12 into the intemediate risk. Low risk and intermediate-1 patients were treated only with supportive care; high risk patients were treated with hypomethylating agents. Iron chelation were used when necessary. Lenalidomide was used in the only case of 5 q- syndrome Samples of bone marrow were analized with Real-Time quantitave PCR and levels of WT1 and BAALC expression were determinated. Molecular datas were analized with X-square Test and a significant association was recorded between overexpression of the genes evaluated (WT1 higher than 100 copy numbers and BAALC higher than 1000 copy numbers) and the probability of develop acute myeloid leukemia ( AML ). Results Nine out of 102 patients showed an isolated WT1 hyperexpression (3 of them developed an AML ), in 15 cases we reported an isolated BAALC overexpression (3 of them developed an AML ), while 13 out 18 patients ( 72% ) with combined WT1 and BAALC overexpression developed AML within an average time of 6 months; instead only 5% of patients, which expressed low levels of WT1 and BAALC, developed AML within the interval of observation. In particulary a combined high expression of WT1 and BAALC were strongly associated with an high risk to develop leukemia and a short LFS, especially in INT-1 subset. After that we calculated the LFS, divided for the risk category at 6-12-24-36 months of follow up. Patients with combined overexpression of WT1 and BAALC showed a LFS of 40% at 6 months of follow up and 0% at 24 months. Conclusion MDS have a great variable survival, and the current approach to these diseases relays on morphological evaluation, karyotypic assay and need of transfusional support; gene expression could be a promising system to predict the prognosis in these patients. Analysis of gene expression, which belong to AML evaluation, allows to divide patients in several risk groups; furthermore is not the single gene evaluation that is more predictable but a combined assay. With this method, which seems to be more realiable than IPSS, we could find that a great percentage of patients with levels of WT1〉100 and BAALC 〉1000, indipendently from karyotypic status and treatment, developed AML and have a shorter LFS than the population with WT1

Description: Backgrounds and aims Prevention and prompt treatment of invasive fungal infections (IFI) in acute myeloid leukemia (AML) patients can improve overall survival not only by reducing infection-related mortality but also allowing to comply induction regimens on time. The aim of the study was to estimate efficacy and feasibility of primary antifungal prophylaxis with posaconazole (PSZ) in patients affected by acute myeloid leukemia receiving front-line chemotherapy and to optimize our clinical practice. Materials and methods From January 2013 to May 2014, 28 AML patients undergoing intensive chemotherapy and potentially eligible for bone marrow transplantation in our institute received PSZ prophylaxis for IFI. All patients received a fludarabine, cytarabine and idarubicin containing regimen as first line treatment. We performed a retrospective analysis to evaluate the efficacy and feasibility of PSZ prophylaxis; to detect factors affecting drug exposure we analyzed each period of hospitalization as a single independent event. PSZ was given at the standard dose of 200 mg for 3 times/day, concurrently with a fat snack or with at least 100 ml of an acidic drink. Because of unpredictable absorption rates PSZ serum levels (TDM) were assessed routinely according to a validated high-performance liquid chromato-graphic (HPLC) method as described. A comparison with an historical cohort with similar features who had received fluconazole (FLC) prophylaxis was made. The use of empirical or targeted antifungal therapies and the incidence of IFI were compared. Results and discussion PSZ showed a good tolerability profile with no serious adverse events clearly related to prophylaxis occurring. A median number of 2 TDM for each period of hospitalization was performed (range 2-5). The achievement of a plasmatic PSZ concentration 〉 0,7 mcg/mL is considered optimal for prophylaxis efficacy; in 30/47 (64%) episodes of hospitalization and treatment, with at least two TDM, the threshold PSZ serum concentration was reached, with stable plasmatic levels. Median PSZ plasmatic value at first assessment was 0.89 mcg/mL (range 0.1-3.3). Table 1 summarizes patients features and factors that might affect PSZ plasma concentrations. The strongest negative factors affecting PSZ absorption are the discontinuation of prophylaxis and the concomitant assumption of proton pump inhibitors since their negative impact is shown both in univariate and multivariate analysis. No proven IFI were observed in our cohort with only one probable IFI occurring in a patient with refractory disease who did not reach adequate serum PSZ concentration. Table 2 summarizes the comparison with our historical cohort. The risk of experiencing IFI (proven or probable) during AML treatment is significantly higher in the FLC cohort (HR: 9.488, CI: 1,404 - 64,122). Moreover, the use of targeted or empirical antifungal therapies had been significantly higher in FLC cohort (HR: 2.7, CI: 1,212 - 6,050). Our clinical experience confirms the utility and cost-effectiveness of primary prophylaxis with PSZ in AML patients receiving intensive treatment. Table 1: Factors affecting PSZ serum concentration Reached plasmatic concentration threshold (%) p(univariate) p(multivariate) All Hospitalizations 30/47 (64) - - Sex Male 17/23 (74) 0.227 - Female 13/24 (54) Disease Status Active Disease 13/27 (57) 0.014 0.156 Complete Response 17/20 (85) Mucositis None or Grade 1 25/32 (78) 0.008 0.228 Grade 〉=2 5/15 (33) Age 45 years 18/26 (69) Concomitant PPI No 28/36 (78) 0.001 0.000 Yes 2/11 (18) Concomitant Ranitidine No 26/42 (62) 0.640 - No 4/5 (80) Concomitant Levofloxacine prophylaxis Yes 27/39 (69) 0.118 0.042 No 3/8 (38) Prophylaxis Discontinuation Never 27/36 (75) 0.009 0.003 At least for 2 dd 3/11 (27) Infectious Complications None 8/11 (73) 0.722 - At least one episode 22/36 (61) PSZ Assumption with Fat snack 5/11 (46) 0.153 0.150 Acidic drink 25/35 (71) Table 2: Historical comparison FCZ PSZ p All hospitalizations 54 47 - Median age (range) 47 (17-72) 47 (19-68) 0.560 Median ANC

Description: BACKGROUND: Iron overload from chronic transfusion therapy can be extremely toxic and most patients (pts) do not receive adequate iron chelation therapy (ICT) despite evidence of transfusional iron overload (IOL). Deferasirox (DFX) is the principal option currently available for ICT in the management of IOL due to transfusion dependent anemia, such as in MDS pts. The most common adverse events (AEs) are gastrointestinal disorders, skin rash, elevations in liver enzymes levels and non-progressive transient increases in serum creatinine also in MDS pts, most of whom are elderly with significant comorbidities and side effects of other concomitant therapies. In order to achieve effective ICT with minimal toxicity in individual pts, regular monitoring to assess IOL and adverse effects of DFX treatment is essential. METHODS: The safety and efficacy of DFX were examined in a retrospective multicenter observational study of transfusion-dependent (TD) MDS pts with International Prognostic Scoring System (IPSS) low-or Int-1-risk. We included all pts treated with DFX up to 12 months, divided into two groups; the first one (group A) not under a multidisciplinary assessment, including pts not adequately treated, in terms of dosing and discontinuation of ICT and the second one (group B) with pts under multidisciplinary control. The DFX starting dosing was 10 mg/kg/die in all pts. The aim of our retrospective analysis was to assess the effectiveness of ICT in relation of dosing and right management of AEs. RESULT: We evaluated 45 MDS pts (12F/33M); 27 belonging to the group A and 18 to group B. The age was 74.2±8.8 and 77.3±4.8 respectively. The ECOG 0-1 was 85,1% in group A and 88,9% in group B. The transfusion episodes prior starting DFX were22.1±12.1 and 24.5±35.4 in the first and in the second group, respectively. The serum ferritin level at baseline was respectively 1285.1±489.6 ng/mL and 1452.6±748.1 ng/mL. The mean serum ferritin level increased from 1285.1+489.6 ng/mL to 1412.1+842.8 ng/mL in group A while decreased from 1452.6+748.1 ng/mL to 1166.1+ 723.4 ng/mL in group B. The rate of inadequate therapy, in terms of dosing and/or discontinuation ICT, was 85% in group A compared to 60% in group B (p= 0.086).The rate of severe SAE observed in all pts was 10%.The most common AEs were diarrhea, nausea, upper abdominal pain, serum creatinine increase. The positive hematological response rate was observed in 15% of all pts. CONCLUSIONS: The study showed that group B obtained advantage in terms of efficacy and toxicity. The difference between the two groups derived from the ability to manage comorbidities, concomitant therapies and AEs, in particular the rise in serum creatinine, the most common cause DFX discontinuation or dosing reduction. In this setting, the most important specialist was the nephrologist. In our multidisciplinary group experts in management of ICT were hematologist, internist, immune-hematologist and nephrologist. We shared how we monitored kidney function and managed a possible nephrotoxicity (table.2), in order to ensure DFX efficacy. Positive hematological responses were observed, and a subset of pts achieved transfusion independence. The timing of future multidisciplinary evaluation is set on 24 and 36 months, time in which we expect the best response to DFX therapy. Table 1. Ferritin trend group A (n27) group B (n18) Ferritin N mean±SD Median (range) N mean±SD Median (range) Baseline 27 1285.1±489.6 1134 (388-2099) 18 1452.6±748.1 1515 (160-3018) 3 months 22 1451.5±720.5 1247.5 (529-2791) 13 1312.7±909.8 1064 (521-3859) 6 months 23 1850.5±1079.1 1419 (374-4185) 11 1168.4±648.4 1300 (160-2409) 12 months 17 1412.1±842.8 1372 (111-3127) 9 1166.1±723.4 930 (277-2536) Table 2. Management of renal changes during therapy with DFX Creatinine and urine examination:1) in two successive determinations prior to initiation of therapy, then every month 2) in pts with other risk factors for kidney disease, every week for 1 month after start of DFX or dose increase and, subsequently, every month Changes in creatinine:1) increased by 33% in two successive determinations: reduce DFX dose of 5 mg/kg 2) progressive increase of creatinine: interrupt DFX and then re-challenge it at a lower dose with gradual increase if the clinical benefits outweigh the risks Disclosures No relevant conflicts of interest to declare.