ALBERT

Description: Patients with Philadelphia-negative myeloproliferative neoplasm (MPN) are prone to the development of second cancers, but the factors associated with these events have been poorly explored. In an international nested case-control study, we recruited 647 patients with carcinoma, nonmelanoma skin cancer, hematological second cancer, and melanoma diagnosed concurrently or after MPN diagnosis. Up to 3 control patients without a history of cancer and matched with each case for center, sex, age at MPN diagnosis, date of diagnosis, and MPN disease duration were included (n = 1234). Cases were comparable to controls for MPN type, driver mutations and cardiovascular risk factors. The frequency of thrombosis preceding MPN was similar for cases and controls (P = .462). Thrombotic events after MPN and before second cancer were higher in cases than in controls (11.6% vs 8.1%; P = .013), because of a higher proportion of arterial thromboses (6.2% vs 3.7%; P = .015). After adjustment for confounders, the occurrence of arterial thrombosis remained independently associated with the risk of carcinoma (odds ratio, 1.97; 95% confidence interval, 1.14-3.41), suggesting that MPN patients experiencing arterial events after MPN diagnosis deserve careful clinical surveillance for early detection of carcinoma. This study was registered at www.clinicaltrials.gov as NCT03745378.

Description: The absolute content of CD34+ cells in the peripheral blood of 84 patients with myelofibrosis with myeloid metaplasia (MMM) and 23 patients with other Philadelphia-negative (Ph−) chronic myeloproliferative disorders (CMDs) was investigated. In MMM, the median absolute number of circulating CD34+cells was consistently high (91.6 × 106/L; range, 0-2460 × 106/L). Receiver operating characteristic curve analysis showed that 15 × 106/L as a decision criterion for CD34+cells produced an almost complete discrimination between MMM patients out of therapy and other Ph− CMDs (positive predictive value, 98.4%; negative predictive value, 85.0%). MMM patients with higher numbers of CD34+ cells had a significantly longer disease duration (P = .019) and higher spleen volume index (P = .014), liver volume (P = .000), percentage of circulating immature myeloid cells (P = .020), and percentage of myeloid blasts (P = .000). When CD34+ cells were correlated with the use of Dupriez risk stratification, CD34+ cells increased significantly from low-risk (median, 68.1 × 106/L) to intermediate-risk (median, 112.8 × 106/L) and high-risk patients (median 666.1 × 106/L) (F = 4.95;P = .009). When CD34+ cells were correlated with a severity score on the basis of both myeloproliferative and myelodepletive characteristics of the disease, only the myeloproliferation index was significantly associated with CD34+ cell level (F = 5.7;P = .000). Overall survival and interval to blast transformation from the time of CD34+ cell analysis were significantly shorter in patients with more than 300 × 106/L CD34+ cells (P = .005 and .0005, respectively). In conclusion, the absolute number of CD34+ circulating cells allows MMM to be distinguished from other Ph− CMDs; it is strongly associated with the extent of myeloproliferation and predicts evolution toward blast transformation.

Description: Chronic myeloproliferative diseases are clonal disorders of the hematopoietic stem cell. Among these conditions myelofibrosis with myeloid metaplasia (MMM) is characterized by increased numbers of circulating CD34+ cells compared to other Ph-negative myeloproliferative disorders and normal controls. Increased numbers of circulating CD34+ cells are likely due to mobilization of primitive hematopoietic stem cells/progenitor cells (HSC/HPC) from the bone marrow of patients with MMM following activation of proteases and disruption of adhesion interactions, which normally result in the retention of HSC/HPC within the marrow. A more detailed characterization of circulating CD34+ cells in MMM suggested that a cell fraction which included VEGFR-2+, CD34+VEGFR-2+, CD133+, and CD34+CD133+ cells contained endothelial progenitor cells. In the present work we cultured peripheral blood mononuclear cells (PBMNC) from three patients with MMM (one male and two females), from one female patient with essential thrombocythemia (ET) and from three normal females in the presence of fibronectin and vascular endothelial growth factor (VEGF) for 7 days, in order to obtain endothelial cell colonies. The endothelial origin of colonies was assessed by VE-cadherin and CD31 staining. Clonality of endothelial cell colonies was evaluated in female subjects by X-chromosome inactivation studies based on determination of differential DNA methylation at the two alleles of X-linked polymorphic loci (Humara or PGK). Such evaluation was performed on at least 8 single colonies and on a pool of 7–8 colonies from each subject. The male patient with MMM had a 7q34 deletion in 50 % of metaphases. The deletion resulted in loss of heterozygosity at the polymorphic marker D7S684 which was therefore evaluated on both endothelial and hematopoietic colonies grown from PBMNC. Normal subjects showed a polyclonal pattern of X-chromosome inactivation in endothelial colonies, whereas MMM and the ET female patients showed selective inactivation of the same chromosome X which was inactivated in clonal peripheral blood polymorphonuclear cells. Loss of heterozygosity at the polymorphic marker D7S684 was observed in 6/10 and 4/9 endothelial and hematopoietic colonies, respectively, from the male patient with the 7q34 deletion. Our results suggest that in MMM, and possibly in other chronic myeloproliferative diseases, circulating endothelial progenitor cells are clonal and the disease is due to transformation of a hematopoietic stem cell which also retains endothelial differentiation potential.

Description: BACKGROUND: Treatment of patients with fludarabine-resistant chronic lymphocytic leukemia (CLL) is an unmet clinical need. Fludarabine resistance in CLL can be ascribed to intrinsic genetic features of the tumor cells, mainly consisting in TP53 disruption, and to the interactions of CLL cells with stromal cells (SC) of the tumor microenvironment. One of the main players of SC-induced fludarabine resistance is the CXCL12/CXCR4 axis, which activates in CLL cells the Ras/ERK1-2 and RhoA-dependent signaling pathways. To be active transducers Ras and RhoA need to undergo isoprenylation by means of small molecules produced by the mevalonate (Mev) pathway. We reported that the Mev pathway-regulated Ras and RhoA signaling cascades and the downstream hypoxia inducible factor (HIF)-1α/P-glycoprotein axis are more active in IGHV unmutated than in mutated CLL cells, leading to a constitutive protection from doxorubicin-induced cytotoxicity. HIF-1α is a transcription factor constitutively expressed in CLL cells and controls the expression of several genes implicated in survival and cell metabolism. The Mev pathway manipulation with simvastatin (Sim), as well as the targeted inhibition of ERK1-2, RhoA kinase and HIF-1α, restore the sensitivity of CLL cells to doxorubicin. The role of the Mev pathway, the Ras and RhoA signaling, and the transcription factor HIF-1α in regulating the SC-induced fludarabine resistance of TP53 disrupted (TP53dis) CLL cells is currently unknown. AIM: The aim of this study was to evaluate the activity of the Mev pathway-regulated Ras and RhoA signaling cascades and the transcription factor HIF-1α in TP53dis CLL cells, in order to identify biochemical and molecular targets potentially amenable to therapeutic intervention. METHODS: Purified CLL cells were cultured alone or with the M2-10B4 SC line. Cell cultures were exposed to fludarabine (10 μM), Sim (1 μM) or the HIF-1α inhibitor YC-1 (10 μM). The activity of the Mev pathway was measured by quantification of [3H]acetate-labeled cholesterol and farnesyl pyrophosphate produced by CLL cells. Ras and RhoA activities were evaluated by pull-down assay and ELISA, respectively. ERK1-2 phosphorylation was evaluated by Western Blot. RhoA kinase, Akt and HIF-1α activities were measured with specific immunoassay. The glucose flux through glycolysis and tricarboxylic acid cycle was measured by radiolabeling cells with [6-14C]-glucose and quantifying the amount of glucose transformed into CO2. Cell viability was analysed by Annexin-V/propidium Iodide immunostaining and flow cytometry. Patients with TP53 mutation or 17p deletion were considered TP53dis. RESULTS: Co-culture with SC upregulated the Mev pathway activity of CLL cells, activated the downstream Ras/ERK1-2 and RhoA/RhoA kinase signalling, and increased the transcriptional activity of HIF-1α. Blocking the Mev pathway by Sim significantly reduced the SC-induced upregulation of Ras and RhoA signalling pathways, and counteracted the SC-mediated protection of CLL cells from fludarabine-induced cytotoxicity. Based on these results we evaluated the activity of the Mev pathway, and the Ras and RhoA signalling in TP53dis and TP53 wild-type (TP53wt) CLL cells. There was no difference between the two groups in terms of Mev pathway activity, Ras/ERK1-2 and RhoA/RhoA kinase signal transduction, and Akt activity. By contrast, we found that TP53dis CLL cells had a significantly higher transcriptional activity of HIF-1α than TP53wt CLL cells (p=0.02). CLL patients carrying a percentage of 17p deletion 〉60% in the tumor clone had the higher values of HIF-1α activity. As a result, TP53dis CLL cells overexpressed the glycolytic HIF-1α target gene α-enolase and had a more active glycolytic activity than TP53wt CLL cells (p=0.003). In TP53dis CLL cells, Sim significantly inhibited the Mev pathway, and the Ras and RhoA signalling, but had no effect on the upregulated transcriptional activity of HIF-1α and on the protective effect exerted by SC toward fludarabine-induced cytotoxicity. Conversely, the HIF-1α inhibitor YC-1 partially restored the fludarabine sensitivity of TP53dis CLL cells, as shown by its ability to counteract the protective effect exerted by SC toward fludarabine-induced cell death. CONCLUSIONS: Our data demonstrate that the targeted inhibition of HIF-1α is a promising strategy to circumvent the SC-induced fludarabine resistance of TP53dis CLL cells. Disclosures Marchetti: GILEAD: Consultancy, Research Funding; JANSSEN: Other: tavel, accomodation, expenses; SANOFI: Membership on an entity's Board of Directors or advisory committees; GILEAD: Other: teaching, Research Funding; NOVARTIS: Research Funding. Gaidano:MorphoSys; Roche; Novartis; GlaxoSmithKline; Amgen; Janssen; Karyopharm: Honoraria, Other: Advisory boards; Celgene: Research Funding. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Massaia:Gilead: Research Funding; Janssen: Honoraria; Roche: Honoraria. Coscia:Roche: Honoraria, Other: Advisory board; Mundipharma: Honoraria.

Description: Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal disorder of hematopoietic stem cells causing complement-mediated intravascular haemolysis, bone marrow aplasia and thromboembolic events. Allogeneic stem cell transplantation (SCT) has the potential to cure the disease but it is burdened by transplant-related mortality (TRM), which is lower in younger patients and with reduced-intensity conditioning regimens. Eculizumab is a monoclonal antibody suited to stop the abnormal complement cascade and capable of reducing thromboembolic events and related fatalities. Which of the two therapeutic options achieves the best health-care benefit to patients is uncertain as well as the economic burden of the two options onto health-care budget. Methods: We built a decision tree comparing upfront allogeneic SCT with lifelong eculizumab. Only patients with no prior thrombosis were analysed. A Markov model tracked PNH patients lifelong and accounted for persisting health-care modifications (states, such as transfusion-dependence, long-term disability related to severe thromboembolic events or GVHD, as well as for transitory modifications (events), such as acute phase of thromboembolic events and the first 3 months after SCT. TRM for sibling and unrelated fully matched donors was considered to be 15%, as reported by EBMT for patients transplanted for aplastic anemia after the year 2002 and by other institutions after reduced-intensity conditioning (de Latour 2012; Pantin 2014). However, patients 30-40 years of age were assigned a TRM of 20% and those older than 40 a TRM of 30%. The probability of thrombotic events was estimated based onthe reported cumulative rate of 40% in 15 years (de Latour 2008), but the risk was 4 times as higher for recurrent events. The fatality rate of thrombotic events was assumed to be 10%. The probability of death not related to thrombotic events was calculated based on the rate (8% in 10 years) reported by the French retrospective study (de Latour 2008) for individuals diagnosed after 1996. Patients being treated with eculizumab, however, were assigned thrice as higher the mortality probability of age-matched general population according to the 2008 Italian life tables (Hillmen 2011). Quality of life for PNH patients was calculated from EORTC scores reported by the International PNH Registry (conversion algorithm reported by Kontodimopoulos 2009): it was 0.81 in non-transfused patients, but decreased to 0.71 after thrombotic events, and to 0.51 in transfusion-dependent patients and in those with severe GVHD. Allogeneic SCT was assigned a cost of €80,000 upfront and €100 per month subsequently. Eculizumab was assigned a monthly cost of €20,000 assuming standard scheduling (600 mg weekly for 4 weeks followed by 900 mg biweekly). Future life years and costs were discounted by 3.5% per year, according to international guidelines. The model was built and analyzed with TreeAgePro2014. Results: At baseline analysis, patients aged 35 years would expect 41.32 life years after allogeneic SCT versus 35.0 on lifelong eculizumab. At two-way sensitivity analysis, we analyzed the role of TRM and relative survival of patients treated with eculizumab, as compared with healthy individuals. Allogeneic SCT is expected to provide better life expectancy so far as mortality in patients treated with eculizumab is 〉38% higher than general population. At TRM rates of 30%, allogeneic SCT keeps more effective than eculizumab only provided that PNH-related mortality is 〉 100% higher than general population. Similar results were obtained for discounted quality-adjusted life expectancy, which was 37.1 QALYs after allogeneic SCT versus 26.8 QALYs with lifelong eculizumab. In patients aged more than 52 years, eculizumab provided a better life expectancy than SCT. Lifelong discounted costs were estimated to be €113,341 after allogeneic SCT versus €8,362,079 with eculizumab. Conclusions: In an era of improved transplant yield and of budget constraints, allogeneic SCT should still be considered a therapeutic option for younger PNH patients with an aplastic phenotype. Disclosures No relevant conflicts of interest to declare.

Description: To get a clinical classification of MMM, we enquired the database of the Italian Registry of Myelofibrosis (RIMM), a population-based prospective cohort started in 1999, and data of 871 patients at diagnosis were extracted. This population of patients was used as the learning set. The EM-algorithm (WEKA software) conducted a non-supervised data-mining based on 11 variables: age, spleen size, constitutional symptoms, hemoglobin, platelet count, white blood cell count, erythroblasts, immature myeloid cells, myeloid blasts, basophils, and plasma LDH. Differences among clusters were first tested with ANOVA or n-way Chi-square and subsequently investigated with t-test (independent samples) or 2x2 Chi-square. Cluster 1 identified a category of patients whose disease phenotype at diagnosis was of younger age, normal values of hemoglobin, thrombocytosis, and small spleen. We now propose to call this cluster indolent myelofibrosis. Cluster 2 identified patients with mild anemia, no sign of myeloproliferation (neither thrombocytosis nor leukocytosis), and larger splenomegaly. Cluster 3 selected patients which featured severe anemia, large splenomegaly and high number of immature myeloid cells in peripheral blood with the presence of a significant number of blasts, that we propose to call MMM in accelerated phase. Finally, cluster 4 selected patients presenting with trilinear or bilinear cytopenia (mostly thrombocytopenia). By using a decision tree, we tested the best discriminatory parameters to be used for including a new patient in the cluster of indolent myelofibrosis. They resulted: age lower than 55 years, platelet count over 335 x109/L, Hb greater than 12 g/dL, and spleen size smaller than 5 cm from the costal margin. We applied this algorithm to a validation set of 264 patients with idiopathic myelofibrosis who had the follow-up studied (mean follow-up, 67 months, range 1 -315 months). They were 103 females (38.8%), and the mean age was 51.3 years (range 6 to 82 years). Forty-seven (17.8%) of the validation set of patients met the criteria for indolent myelofibrosis. They had a mean age of 39.1 years. The number of WBC was not significantly different in indolent myelofibrosis with respect to that of the remaining patients (9.5 x109/L vs. 9.7 x 109/L). However, the number of circulating immature myeloid cells and erythroblasts, serum LDH, and circulating CD34+ cells were significantly lower in indolent myelofibrosis with respect the remaining patients. Forty-four percent of patients with indolent myelofibrosis had a bone marrow biopsy with a grade 0 fibrosis. Only 1 patient died in the group of indolent myelofibrosis vs. 31 in the group of other patients. The 10-year severe anemia-free survival was 90% (severe anemia = Hb 〈 10g/dL), in contrast with 30% for other patients; leukopenia-free survival (leukopenia =

Description: Myelofibrosis with Myeloid Metaplasia (MMM) is characterized by an abnormal constitutive mobilization of CD34+ stem/progenitor cells. The SDF-1alpha axis chemoactracts hematopoietic stem and progenitor cells and is thought to play a crucial role in the homing/mobilization of these cells from the bone marrow, interacting with its unique receptor CXCR4. CD26 (dipeptidylpeptidase IV/DPPIV) is an extracellular peptidase, present both as membrane-bound and as a catalitically active soluble form in plasma. It has the ability to cleave SDF-1alpha at its position-2 proline inducing significant changes in its receptor binding and/or functional activation, thus inhibiting normal SDF-1alpha induced migration. In this study we evaluated the expression of CD26/DPPIV in patients with MMM (N=63) and its functional activity (N=8). CD26/DPPIV cell surface expression was measured by flow cytometry on peripheral blood mononuclear cells (PBMNC) or on immunoselected circulating CD34 + cells. The CD26/DPPIV activity was measured in 96-well microplates using the chromogenic substrate gly-pro-p-nitoanilide. The proteolytic activity was determined by measurements of the amount of nitoanilide (pNA) formed in the supernatant at 405 nm. Absorbance was measured at 405 nm and the picomoles of pNA formed were calculated by comparison with a pNA standard curve. The CD26 expression on the membrane of PBMNC of patients with MMM was comparable to that found on PBMNC of normal controls (median 29.5 %, range 0.72–61.1; median 33.1 %, range 20.3–39.2, respectively). However, the percentage of circulating CD34+CD26+ cells was significantly reduced (P

Description: Background: International guidelines recommend erythropoiesis stimulating agents (ESA) to improve chemotherapy-related anemia (CRA), however, two meta-analyses proved that intravenous iron (II) improves the chance of obtaining a response to ESA by 28% (Gafter-Gvili 2013, Petrelli 2012). Recently, biosimilar ESAs have been approved for CRA, we therefore aimed at comparing the cost-effectiveness of different therapeutic strategies for CRA eventually including II and/or biosimilar ESAs. Methods: A decision model was built comparing 5 strategies: no ESA, brand ESA, brand ESA plus II, biosimilar ESA, biosimilar ESA plus II. Ferric gluconate was assumed to be administered 125 mg per week for 6 weeks overall: 4 infusions were planned in days different from chemotherapy administration. ESA was started at hemoglobin values lower than 11 g/dl. The model included a Markov tree of 13 health states representing hemoglobin level during 26 therapy weeks. Weekly probability of hemoglobin improvement by 1 g/dL was estimated to be 10% with ESA and 15% with ESA plus II but null without ESA. The efficacy of biosimilar ESA was assumed to be the same as ESA. Weekly probability of death was assumed to be 0.4% (Pedrazzoli 2008). The rate of severe events during II infusion was assumed to be 0.2% per week without fatal events. Quality of life at different hemoglobin levels was driven from literature. The economic analysis was run in the perspective of the Health Care System and of the society. II administration was charged €50 and blood transfusion €400. Indirect costs for iron infusions and transfusions planned in days not devoted to chemotherapy was estimated to be €100 for transportation and care-giver time. Based on local data, the per-unit cost of biosimilar ESA versus brand ESA was considered to be 1 in 5.All the analyses were run TreeAgePro2014. Microsimulations and first-order MonteCarlo analysis were run. Results: ESA improve quality-adjusted survival of patients from 14.51 to 14.82 quality-adjusted weeks but II adjunct increased the gain to 15.20 weeks. In the perspective of the health-care system, the management of cancer-related anemia without ESA costs €1,550, while ESA therapy increased the costs by €618 (biosimilars) and €2,933 (brand); ESA plus II increased the costs by €359 and €2,437, respectively. Therefore, the adjunct of II reduced overall health-care costs by €259 in the biosimilar strategy and €496 in the brand ESA strategy. Societal costs similarly increased with ESA use, but the increment was lower: €584 with biosimilar ESA and €2,866 with brand ESA. II allowed to achieve minimal savings in the biosimilar strategy, while savings were €288 in the brand ESA strategy. Savings to the health-care system and to the society were even higher (further €300 to the healthcare-system and €90 to the society) in the hypothesis that liposomial oral iron (30 mg per day for 60 days) achieved similar results as II, at €1 per day charged to the patient (in Italy liposomal iron it is not refunded). Ferric carboxymaltose 750 mg single administration at a cost of €280 might compete with multiple ferric gluconate administrations. Finally, we explored the efffect of threshold hemoglobin: starting ESA at hemoglobin levels lower than 10 g/dl instead of 11 g/dl allowed to reduce health-care costs of ESA therapy by €172, but quality of life was increased by only 0.14 and 0.59 weeks, without and with II, respectively. Conclusions: Rational allocation of health-care resources imposes to choose the most convenient therapeutic strategy among those recommended by practice guidelines. Intravenous iron allows to save health-care and society resources and to improve quality of life by a more rapid hematopoietic response to ESA. Different iron formulations need to be tested in association with ESA in this setting in order to improve the efficiency of avilable therapeutic strategies. Cost-effectiveness analyses should be shared by clinicians and hospital pharmacy to adopt the most effective and efficient therapeutic strategies. Disclosures No relevant conflicts of interest to declare.

Description: Background and Aims: A number of therapeutic options proved to be effective for relapsed or refractory chronic lymphocytic leukemia (R/R CLL), but the optimal sequence of therapies as well as their economic impact is still to be ascertained. Idelalisib, a first-in-class PI3k inhibitor, has been recently approved in combination with Rituximab (IR) for R/R CLL. Therefore, we aimed at assessing the cost-effectiveness of IR as compared with fludarabine-cyclophosphamide-rituximab (FCR), bendamustine-rituximab (BR), bendamustine-ofatumomab (BO), rituximab (R) and ofatumomab (O) for CLL patients requiring a second-line treatment, in the perspective of the Italian national health-care system. Methods: A life-long Markov model simulated patients moving through 5 health states: progression-free on intravenous therapy, progression-free on oral extended therapy, progression-free off-therapy, progressed disease, death. Pairwise comparisons between 2nd -3rd line treatment sequences were conducted: each pair included a sequence adopting IR for the 2nd line therapy, followed either FCR, BR, BO, R or O for the 3rd line, versus a sequence modelling IR for the 3rd line therapy. Progression-free survival, toxicities, treatment schedules and duration of treatment were obtained from phase II-III studies (Furman et al. 2014, Byrd et al 2014, Fisher et al. 2011, Cortelezzi et al. 2014, Awan et al. 2014). The probability of progression reported by published studies was adjusted for the median number of treatment lines according to the reported hazard ratio of 1.4 (Fisher et al. 2011, Holzer-Goor et al. 2014). Progressed disease and progression-free health states were assigned a utility of 0.65 and 0.85, respectively (Beusterien et al. 2010). Quality of life decrements and costs (Capri et al. 2007) were applied to the portion of patients incurring grade 3-4 adverse events (anemia, neutropenia, pneumonia, thrombocytopenia, diarrhea). The following unit costs (average wholesale price) were considered: idelalisib 150 mg (€66.67), rituximab 100 mg (€277), ofatumumab 100 mg (€241). Bendamustine, fludarabine and cyclophosphamide were not valued because they are not refunded. Median charge for intravenous drugs administration (€288/day) was obtained from a published retrospective analysis (Pasdera et al. 2013). Future life gains and costs were discounted at a 3% annual rate. First and second-order sensitivity analysis was performed. Results: Second-line treatment with IR was expected to improve quality-adjusted life expectancy (QALE) to 4.49 quality-adjusted life years (QALYs), that is prolongation of 0.94-1.68 QALYs as compared with combination therapies and 2.09-2.62 QALYs versus single agent B or O. Cumulative discounted health-care cost for patients receiving second line treatment with IR (eventually followed by 3rd treatment with BR or BO) were expected to be €169,291-171,217 but incremental cost-utility ratio (ICUR) of IR versus BR and BO resulted to be lower than €40,000/QALY with a probability higher than 90%. Second line IR (eventually followed by 3rd line FCR) as compared with second line FCR (eventually followed by 3rd line IR) was calculated to prolong life expectancy by 0.94 QALYs at an incremental cost lower than €40,000/QALY in 81% of the simulations (Monte-Carlo analysis). Comparison between IR and single-agent immunotherapies (R and O), showed a prolonged life expectancy at an incremental cost lower than €20,000/QALY. Results were sensitive to the time horizon of the analysis and idelalisib unit cost. Conclusions: The lack of head-to-head studies in the different CLL treatment lines makes indirect comparisons among treatments possible only using simulation analyses. Hence, a decision analysis allowed us to compare IR with five treatments in the second-line setting: IR was expected to provide a reasonable value for money as compared with FCR, BR, BO, R and O and the results were quite robust at sensitivity analysis. Table 1. TREATMENT QUALITY-ADJUSTED LIFE EXPECTANCY(QALYs) INCREMENTAL QALE (QALYs) COST INCREMENTAL COST ICUR FCR 3.55 0.94 €147,836 €19,051 €20,441 BR 2.95 1.54 €128,741 €40,550 €26,445 BO 2.81 1.68 €135,672 €35,945 €21,466 R 2.40 2.09 €143,860 €29,873 €14,376 O 1.87 2.62 €182,305 €3,294 €1,263 Disclosures Marchetti: GILEAD: Other: teaching, Research Funding; SANOFI: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Other: tavel, accomodation, expenses; GILEAD: Consultancy, Research Funding; NOVARTIS: Research Funding. Cuneo:Roche: Speakers Bureau; Gilead: Speakers Bureau; Jannsen: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Montillo:GSK: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie: Research Funding; Infinity: Research Funding. Martelli:GILEAD: Employment. Pedone:GILEAD: Employment.

Description: INTRODUCTION The incidence of secondary cancer (SC) in patients with myeloproliferative neoplasms (MPN) is high and comparable to that of thrombosis. However, the identification of patient subgroups that might be at increased susceptibility of developing SC has not been systematically addressed. We report here the results of an international case-control study (MPN-K) aimed at comparing the frequency of exposure to possible causes of SC in patients with classical MPN, polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). METHODS This European Leukaemia Network (ELN) study reports MPN patients from 28 sites of 5 European countries and Israel, diagnosed in the period from 2000 to 2016. Cases were MPN patients with concomitant diagnosis of a non-myeloid SC (n=15) or its presentation during the course of the disease (n=412). Controls were MPN patients cancer-free, matched to the paired case for sex, age (±5 years), date of MPN diagnosis (±5 years), and MPN disease duration (±6 years). A multivariable conditional logistic regression model was used to estimate the effect of selected variables on total SC risk and in different types of SC. RESULTS Among 1,259 MPN patients, there were 427 cases and 832 matched controls. Cases presented melanoma (n=20; 4.7%), non-melanoma skin cancer (n=69; 16.2% - basal/squamous cell carcinoma), non-skin solid cancer (n=290; 67.9%) including breast, ovary/uterus, colorectal, upper gastrointestinal, liver/pancreas, lung, prostate/urinary, other and lymphoproliferative diseases (n=48; 11.2%) including multiple myeloma, chronic lymphocytic leukemia, low and high grade B- and T-lymphoma. At diagnosis, there were slightly more patients with PV among SC cases (n= 152; 35.6%) than controls (n=256; 30.8%), while conversely there were slightly less ET patients among cases (n=196; 45.9%) than controls (n=426; 51.2%). Cases and controls presented similar proportion of MF diagnosis (n=79 cases, 18.5% and 150 controls, 18.0%). Driver mutations (JAK2 V617, EXON-12, CALR, MPL), non-driver mutations and abnormal karyotype were equally represented in cases and controls. Other variables such as cardiovascular risk factors, exposure to cancerogens, family history of cancer and chronic inflammatory diseases were reported with similar frequency in cases and controls. After MPN diagnosis, exposure to first and other lines of treatments until the index event, with Phlebotomy (n=193; 15.3%), Hydroxyurea (n=814; 64.7%), Anagrelide (n=14; 1.1%), Interferon (n=30; 2.4%), Pipobroman (n=8; 0.6%), Busulphan (n=13; 1.0%), Ruxolitinib (n=11; 0.9%), was similar in the two groups except for aspirin that was used less frequently (p=0.043) in cases (n=320; 74.9%) compared to controls (n=664; 79.9%). In particular, the lower use of aspirin was circumscribed to non-skin solid tumors. A multivariable analysis was carried out in all patients and stratified by different type of tumors (Table). In non-skin solid cancers, the time to exposure of the MPN disease 〉 5 years (OR=2.95; 95% CI 1.54-5.66, p=0.001) and the PV phenotype (OR=2.40, 95% CI 1.15-5.01, p=0.020) were more burdened by the incidence of events than the reference ET group. No difference in SC risk was found for MF patients compared to patients with ET. Interestingly, the independent protective role of aspirin retained its statistical significance only in non-skin SC. In non-melanoma skin cancer, multivariable analysis revealed that the presence of JAK2 mutation was less associated with SC (OR=0.32, 95% CI 0.13-0.81, p=0.016) and confirmed that exposure to HU and other cytotoxic agents was associated with a significantly higher risk of SC (OR=6.00, 95% CI 1.23-29.28, p=0.027 and OR=9.80, 95% CI 1.24-77.78, p=0.031, respectively). This finding was not seen in non-skin SC and in lymphoma. CONCLUSION The considered clinical and biological features, at MPN diagnosis, were not different in cases with SC and controls. During the course of the disease, three factors significantly and independently affected the risk of SC in these MPN patients: 1) patients with PV had a 77% higher risk than those with ET, 2) patients with MPN duration of more than 5 years had a twice higher risk than those with lower duration, 3) for the first time, we documented that in non-skin solid cancers, aspirin treatment reduced SC risk of 38%. Exposure to HU and other cytoreductive drugs was confirmed as a risk factor for non-melanoma skin cancer. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Marchetti:Gilead: Consultancy; takeda: Speakers Bureau; amgen: Speakers Bureau; janssen: Speakers Bureau. Griesshammer:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.