ALBERT

Description: 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

Description: Introduction. Discontinuation (D/C) of Imatinib or other TKIs in Chronic Myeloid Leukemia (CML) represents an important issue in the management of this disease. It is generally accepted that relapse develops (and treatment must be resumed) when patients (pts) lose Major Molecular Remission (MMR), i.e. when the amount of the BCR-ABL1 transcript, measured in peripheral blood by RT-PCR, exceeds 0.1 %. The Imatinib Suspension And Validation (ISAV) study, which started in 2011, enrolled pts with CML treated with Imatinib who showed no evidence of BCR-ABL1 transcript for at least 18 months before enrollment. Methods. A digital PCR (dPCR) for BCR-ABL1 was performed at the time of Imatinib D/C while a second dPCR was performed when non relapsed patients exited the study, 36 months later. dPCR experiments were performed by the QX200 system (BioRad) in the same lab and using the same methodology. The BCR-ABL1 fusion and ABL1 transcripts were quantified using DigiDrop P210 MasterMix and DigiDrop P210 Positive Control (Bioclarma), according to manufacturer's protocol. The target concentration in each sample was expressed as percentage of BCR-ABL1/ABL1. Results. A total of 107 pts were enrolled in the ISAV study. Relapses occurred in 54 pts (52%); among the 53 non relapsed pts, 41 (77%) presented at least one positive RT-PCR result following Imatinib D/C, and only 12 (23%) maintained PCR negativity throughout the duration of the study. Among the non-relapsed pts dPCR performed at treatment D/C showed positivity in 20.6% of cases (95% confidence interval [C.I.] 9-36%), while 91.1% of pts (95%, C.I. 80-97%) evaluated 36 months later showed a positive dPCR value, although no patient resumed treatment. The evaluation of non relapsed pts by dPCR showed that mean values at D/C were 0.00143% +/- 0.0006 (SE); when tested at study exit, the same pts showed average dPCR values of 0.0115 % +/- 0.002. This difference is statistically highly significant and corresponds to a change of approximately 1 log in the residual tumor burden: from 2x107 to 2x108 cells. There was no correlation between the results of RT-PCR performed during the study and the dPCR status at study exit: pts who tested negative by RT-PCR during the study were uniformly negative in dPCR at D/C but tested positive at study exit in 83.3% of cases; pts who showed at least on positive RT-PCR during the study showed positivity by dPCR in 25% at D/C and in 89.3% at study exit. Finally, half of the pts who tested negative by dPCR at study exit showed dPCR positivity when tested at the time of Imatinib D/C. Conclusions. These results show that during a three year period, the D/C of Imatinib led to the increase of approximately 1 log in the tumour burden of non-relapsed pts, although none of them lost MMR and resumed treatment. These data strongly indicate the need for a long-term monitoring of pts who D/C Imatinib; they also suggest that the functional status of residual CML cells rather than their number could represent the critical factor to predict the tumour load present after 3 years of Imatinib D/C. Disclosures Le Coutre: Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau. Elena:Novartis: Consultancy; Pfizer: Consultancy. Assouline:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria. Stagno:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Il-Yang co.: Research Funding. Fava:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Gambacorti-Passerini:Bristol-Meyers Squibb: Consultancy; Pfizer: Honoraria, Research Funding.

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: 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 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: Introduction: Myelodysplastic syndromes (MDS) are a highly heterogeneous group of clonal disorders, with very different prognosis in given individuals, overall survival (OS) ranging from more than 10 years (y) for the more indolent conditions to only few months (m) for the forms approaching AML; beside of the well-established disease-related prognostic systems (classical IPSS or its revised form [IPSS-R], the prognostic implication of comorbidities is emerging as a relevant patient-related factor influencing clinical outcome. Aim of our study was to evaluate the clinical impact of comorbidities in a series of MDS patients whatever treated in a “real-life” setting. Methods: this retrospective cohort study involved the MDS patients consecutively registered between Jan 2011 and Dec 2013 into the Registro Ligure delle Mielodisplasie database, a regional registry established within the framework of the Italian Network of regional MDS registries. Data of 318 patients (pts) with available complete assessment of comorbidities at diagnosis were included into the study. The clinical characteristics and comorbidities were all considered into the analysis. Comorbidities were evaluated according to both hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and MDS-specific comorbidity index (MDS-CI). All survival analyses were made from the date of diagnosis to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions. Results: Our cohort mainly consisted of older (median age 75y (range 40-98) “lower-risk” MDS pts: according to IPSS stratification, 151 (54.7%) pts were classified as low-risk, 86 (31.2%) as intermediate-1, 32 (11.6%) as intermediate-2 and 7 (2.5%) were in the high-risk group. One or more comorbidity of any grade of severity was seen in 177 (55.7%) pts at diagnosis. The more common comorbidity was cardiac (26.5%). At least a single comorbidity was present in 61.2% of pts older than 75y and in 50.6% of younger pts (p=0.07). Cardiovascular disorders were more frequent among older (32.9% for 〉75y vs 15.1% for ≤ 75y, p75 y (48% vs. 28.9% for 〈 75 y (p=0.001). A lower comorbidity score impacted on the clinical choice for active forms of therapy, while pts with an higher burden of comorbidities were preferentially treated with supportive care, even if difference did not reach significance (p=0.07). Overall survival and risk of non-leukemic death (NLD) were analyzed (median f.u. 26.9 m (range 1-220). HCT-CI did not significantly correlated with OS nor NLD (p= 0.1 and p= 0.07, respectively), while MDS-CI was found to be of prognostic significance both for OS (mean 136.6 (95%CI 116-157) m for the low-risk group, 81.3 (95%CI 61-102) m for the intermediate group and 48.1 (95%CI 30-66) m for the high-risk group, p=0.001) and for NLD (mean 159.6 (95%CI 139-180) m for the low-risk group, 96.5 (95%CI 72-121) m for the intermediate group and 49 (95%CI 31-67) m for the high-risk group (p

Description: Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX. Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts. Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first. Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2). Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI 2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001). Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb

Description: Background Bosutinib is a 2nd generation tyrosine-kinase inhibitor (TKI) active in Chronic Myeloid Leukemia (CML) patients resistant or intolerant to frontline imatinib, dasatinib or nilotinib; the favourable toxicity profile makes bosutinib potentially useful in elderly patients, but at present there are no data in unselected cohorts of these subjects. Aim To highlight this issue, a real-life cohort of 91 patients followed in 21 Italian Centers and treated with bosutinib when aged 〉 65 years was retrospectively evaluated. Patients The main clinical features of the whole cohort at diagnosis and at baseline of bosutinib treatment are reported in the Table; all patients were in CP when bosutinib was started. Median interval from diagnosis to bosutinib treatment was 49.7 months [interquartile range (IQR) 14.2 - 117.5]. Results Starting dose of bosutinib was 500 mg/day in 20 patients (22.0%), 400 mg/day in 7 patients (7.7%), 300 mg/day in 28 patients (30.8%), 200 mg/day in 34 patients (37.3%) and 100 mg/day in 2 patients (2.2%), respectively. After a median period of treatment of 18.1 months (IQR 9.4 - 27.7) all patients were evaluable for toxicity; on the whole, all grade hematological and extra-hematological toxicities were reported in 12/91 (13.1%) and 45/91 (49.4%) patients, respectively. A grade 3 - 4 hematological toxicity occurred in 5/91 patients (5.4%); a grade 3 - 4 extra-hematological toxicity occurred in 16/91 patients (17.5%). Overall, 46 patients (50.5%) never discontinued bosutinib: a temporary discontinuation 〈 6 weeks was needed in 19 patients (20.9%) and a temporary discontinuation 〉 6 weeks in 2 patients (2.2%). A permanent bosutinib discontinuation was needed in the remaining 24 patients (26.4%): in particular, 11 patients (12.1%) permanently discontinued bosutinib due to toxicity (skin rash in 3 cases, gastro-intestinal toxicity in 3 cases, pleural effusion in 2 cases, transaminitis, QTc prolongation and myalgia in 1 case each), 6 patients (6.6%) due to resistance and 7 patients (7.7%) due to other reasons (unrelated death in 6 cases and patient decision in 1 case). As to response, 5 patients (5.5%) were considered too early for assessment (〈 3 months of treatment); among the 86 patients evaluable for response, 11 patients (12.7%) did not have any response (including 6 patients who discontinued bosutinib for early toxicity), 4 (4.6%) achieved hematological response only, and 71 (82.5%) achieved Cytogenetic Response (CyR) (Major CyR in 4, Complete CyR in 67). Among the 67 patients in Complete CyR, 58 (67.4% of all 86 evaluable patients) also achieved Molecular Response (MR) [Major MR (MR 3.0) in 19 (22.1%), Deep MR (MR 4.0/4.5) in 39 (45.3%)]. The 3-year Overall Survival and Event-Free Survival of the whole cohort of patients from bosutinib start were 83.0% (CI95% 71.6 - 94.4) (Figure 1) and 59.5% (CI95% 39.9 - 72.1), respectively. Conclusions Our real-life data show that bosutinib is effective, even if initial doses in many cases were lower than recommended, with a favourable safety profile also in elderly patients with important comorbidities resistant/intolerant to previous TKI treatments,: as a consequence, it could play a significant role in the current clinical practise for these frail patients. Disclosures Latagliata: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Annunziata:Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Elena:Novartis: Consultancy; Pfizer: Consultancy. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Sgherza:Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Iurlo:Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria. Breccia:Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria.

Description: Introduction: Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by excessive red cell production and release of pro-inflammatory cytokines resulting in increased thrombotic risk, presence of systemic symptoms and reduced overall survival (OS). Abnormal body mass index (BMI) and comorbidities, as categorized by the Charlson Comorbidity Index (CCI), were found to influence treatment success and survival in several hematological malignancies, including myelofibrosis (MF). We evaluated the impact of CCI and BMI on the outcome of PV pts on the basis of real-world data. Methods: A network called "PV-NET" started in January 2019 including clinical/laboratory data of 2016 WHO-defined PV pts diagnosed and followed in 16 European Hematology Centers. Data cut-off was June 2019. OS was calculated from PV diagnosis to last contact or death (log-rank p). Cumulative incidences of events (thromboses, hemorrhages, infections, second neoplasia, and evolution into blast phase [BP] or MF) were conducted with Fine & Gray model with death as competing risk. Therapies were treated as time-to-event variables. Results: A total of 530 PV pts were collected. Median follow-up was 5.4 yrs (0.5-34) (total observation: 3633 pt-yrs). Main characteristics at diagnosis were: median age: 62.4 yrs (18.3-89.5); males: 53.4%; median (range) leukocyte/platelet count, x109/l: 9.8 (1.1-33)/448 (143-1386); median hemoglobin (g/dl)/hematocrit (%): 18.6/56 (males); 17.6/54.4 (females). Sixty-four (12.1%) and 34 (6.4%) pts had a thrombosis prior to or at diagnosis, respectively. At least one cardiovascular risk factor (CVRF) among smoke, diabetes, and hypertension was present in 343 pts (64.7%). Age-adjusted CCI was 0 (15.9%), 1 (18.9%), 2 (23.8%), and ≥3 (41.5%). Median BMI was 24 (17.4-37.3); 3.3%, 51.2%, 35.9% and 9.6% were underweight (BMI

Description: Introduction: Bosutinib is a Src/Abl tyrosine kinase inhibitor (TKI) currently licensed for patients with Ph+ chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) Chronic Myeloid Leukemia after failure or intolerance to at least 2 other TKIs. It can also be prescribed, in accordance with label if, after failure of the first TKI therapy, another option does not seem feasible. Previous studies demonstrated a potent activity of second-line bosutinib across a spectrum of BCR-ABL1 mutations and a distinct toxicity profile compared to other TKIs. Aim: We retrospectively assessed the efficacy and safety of real life Bosutinib administration in 85 patients resistant/refractory or intolerant to other TKIs, referred to 22 Italian Hematological Institutions. The main features at Bosutinib start are reported in the Table. Results: At Bosutinib start, all patients were in CP. 60 patients (71%) were resistant/refractory, 25 (29%) were intolerant to previous TKIs. BCR-ABL1 kinase mutations were reported in 5/35 evaluable patients (14%); no T315I was reported. The number of previous TKIs was less than 3 in 24/85 patients (28%) and 3 or more in 61 (72%). Comorbidities were present in 63 patients (74%), the most common being arterial hypertension (40), diabetes (14), cardiac disease (10) and chronic obstructive pulmonary disease (6). The most frequent concomitant medications were: antihypertensive in 55% patients, antiplatelets in 26%, antidiabetic in 19%. The initial dose was 100 mg in 4/85 patients (5%), 200 mg in 24 (28%), 300 mg in 18 (22%), 400 in 8 (9%); 31 patients (36%) started at the full standard dose of 500 mg. Major Molecular Response (MMR)/Deep Molecular Response (DMR) were achieved by 37/80 (46%) evaluable patients; 43/80 patients (54%) never reached a MMR/DMR at any time. Best responses in these cases were: Complete Hematologic Response (CHR) in 4 patients (9%), Partial Cytogenetic Response (PCyR) in 6 (14%), Complete Cytogenetic Response (CCyR) in 10 (23%). Dose reductions were necessary in 4 patients (5%) due to adverse events (2 cases of diarrhea, 1 transaminase elevation, 1 skin rash). After a median follow-up of 26 months (range 3-49), 75/85 patients (88%) are alive and 54/75 patients (72%) are still in treatment. Discontinuations were due to: intolerance in 8/75 patients (11%), loss of response in 3/75 (4%), resistance to therapy in 10/75 (13%). Hematological toxicity was observed in 14 patients (16%), any grade, and grade 3-4 in 3 (3%). Extra-hematological toxicity was reported in 41/85 patients (48%), any grade, and grade 3-4 in 14 patients (16%). Causes of death were: acute myocardial infarction (3), cardiac failure (2), acute respiratory distress (2), allogeneic transplant complications (1), cerebral hemorrhage (2). Conclusions: In our "real life experience" with Bosutinib, we confirm a stable long-term efficacy in heavily pre-treated, mainly elderly patients with intolerance/resistance to other TKIs, who show an initial response to treatment, as reported in clinical trials. Patients show a fast response to the drug (mainly at three months). Hematological and extrahematological toxicities are manageable. Disclosures Breccia: BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:Novartis: Consultancy; Ariad: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Castagnetti:Bristol Meyers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Bonifacio:Novartis: Research Funding; Amgen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Bristol Myers Squibb: Consultancy.