Abstract: Introduction - Aims: Several prognostic scoring systems have been developed for patients with myelodysplastic syndromes (MDS), including the International Prognostic System (IPSS), the WHO Prognostic Scoring System (WPSS) and the Revised IPSS (IPSS-R). We evaluated the prognostic value of the IPSS-R on an independent group of 2,582 Greek patients with MDS, registered in the Hellenic National MDS Registry. The aim of this multicenter study was to validate the IPSS-R as a predictor for leukemia-free survival (LFS) and overall survival (OS), in newly-diagnosed MDS patients and to compare its prognostic significance with that of IPSS and WPSS. Moreover, to investigate the predictive value of IPSS-R in association with other recognized prognostic variables, such as patient's age, baseline serum lactate dehydrogenase (LDH), and ferritin concentrations, IPSS, WPSS, Eastern Cooperative Oncology Group (ECOG) performance status, transfusion dependency, and response to first-line treatment. Methods: Clinicopathological data from 2,582 MDS patients, diagnosed between 1/2000 - 1/2015 and registered in the Hellenic National MDS Registry were analyzed. Patients with MDS/MPN were excluded. Data included age, gender, date of diagnosis, clinical characteristics, WHO-2008 classification, laboratory parameters, transfusion dependency, bone marrow aspirate and biopsy morphology, cytogenetic findings, and type of treatment. LFS was calculated from the date of initial diagnosis of MDS until bone marrow blast increased to ≥20% [transformation to acute myeloid leukemia (AML), according to the WHO classification], or last contact. OS was defined as the time from MDS diagnosis to death, or last contact. Patients alive and not having developed AML until last follow-up were censored for OS and LFS, respectively. Kaplan-Meier survival analysis and Cox regression analysis were performed with regard to LFS and OS. Differences between Kaplan-Meier curves were evaluated using the Mantel-Cox (log-rank) test. All significant variables identified by univariate Cox regression analysis and clinical factors important for MDS were used to build the multivariate Cox regression models. Multivariate Cox regression analysis included only those patients for whom the status of all variables was known, and comprised age, serum LDH, and ferritin levels, transfusion dependency, response to first-line treatment, IPSS, WPSS, and IPSS-R. Confidence intervals (CI) were estimated at the 95% level; all tests were two-sided, accepting p 〈 0.05 as indicative of a statistically significant difference. All statistical analyses were performed with the statistical software SPSS (version 21). Results: 1,623 male (62.9%) and 959 female MDS patients with a median age of 74 years at diagnosis were included in the current study. Complete follow-up information was available for 2,376 patients. The estimated median OS was 58 months (95% CI = 52.9 - 63.1 months). For 1,974 patients, data used in the calculation of all three scoring systems were complete, thus allowing risk score calculation and comparison of the three risk assessment systems. Median OS was significantly different in patient subgroups classified according to IPSS, WPSS, and IPSS-R, as shown by the Kaplan-Meier survival analysis (p 〈 0.001). Fig. 1 shows Kaplan-Meier OS curves of MDS patients stratified according to IPSS-R (p 〈 0.001). Moreover, the comparison of the prognostic value of the IPSS, WPSS, and IPSS-R revealed that the IPSS-R was significantly superior to both, WPSS and IPSS (p 〈 0.001 in all cases). Multivariate Cox regression analysis demonstrated that the high prognostic value of IPSS-R, in terms of LFS and OS, was independent of patient's age, serum LDH, and ferritin concentration, ECOG performance status, and transfusion dependency (p 〈 0.001). Interestingly, besides IPSS-R, patient age and transfusion dependency retain their small - yet significant - prognostic impact in the multiparametric models, thus implying that these two parameters could add prognostic value to the IPSS-R. Conclusions: Our data support the notion that all three prognostic scores are very useful predictors for both, LFS and OS in MDS, yet IPSS-R is superior to IPSS and WPSS as a prognostic tool, with regard to OS. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: The currently used prognostic systems for myelodysplastic syndromes (MDS) do not consider the prognostic role of monocytopenia, although monocytes may participate in the prognosis of the disease as part of the host immunity. Aim: We studied the prognostic significance of monocytopenia in patients with MDS registered in the Hellenic National MDS registry. Methods: We analyzed clinicopathological data from patients with MDS recorded in a large retrospective national registry. Patients with MDS/MPN were excluded, while patients treated with allogeneic hematopoietic cell transplantation were censored for overall survival (OS) and leukemia-free survival (LFS). IBM SPSS statistics, version 23.0 (IBM Corporation, North Castle, NY, USA) was used for the analysis of the results. Kaplan-Meier survival analysis and Cox regression analysis were performed for LFS and OS. Results: The study comprised 1719 patients with MDS per the 2008 WHO classification for MDS. The main characteristics of the patients are shown in Table 1. At the time of data cut-off, 818 patients were deceased and the median follow-up for the remaining 901 patients was 23.0 months. The median absolute monocyte count (AMC) was 0.30 x 109/L (0.00 - 0.99 x 109/L). Patients with excess blasts (RAEB1/2) tended to have lower AMCs (median 0.19 versus 0.32 for patients without excess blasts, p 〈 0.0001) and lower AMCs were found in higher IPSS-R categories (very low, 0.37 x 109/L; low, 0.30 x 109/L; intermediate, 0.25 x 109/L; high, 0.16 x 109/L; very high, 0.20 x 109/L) while there was a highly significant difference between lower risk (very low and low) and higher risk (intermediate, high, very high) MDS (0.33 x 109/L vs 0.21 x 109/L, p 〈 0.0001). In univariate analysis, patients with AMCs below 0.2 x 109/L had a median OS of 34.0 months vs 63.0 months for patients with higher AMCs (p 〈 0.0001) with a hazard ratio (HR) for death of 1.57 (95% CI 1.37 - 1.81, p 〈 0.0001). In a multivariate Cox regression model including hemoglobin below 10 g/dL, absolute neutrophil count (ANC) below 1.0 x 109/L, and platelet count below 100 x 109/L (all of them being prognostic for OS in univariate analysis), monocytopenia retained its prognostic significance (HR, 1.16; 95% CI, 1.00 - 1.36, p=0.049). There was a positive correlation between the AMC and the ANC (Pearson Correlation 0.393, p 〈 0.0001). Nevertheless, in a model comprising of AMC and ANC, both variables were independently correlated to OS. Moreover, in a model including AMC below 0.2 x 109/L, the cytogenetic risk score per the IPSS-R, the number of cytopenias, and bone marrow blasts (categorized per the IPSS-R), no additional prognostic impact was found for AMC (HR, 1.01; 95% CI, 0.86 - 1.17; p=0.957). After stratification per the IPSS-R categories, low AMC was prognostic for low OS only in patients with low IPSS-R (median OS, 57 months for patients with low AMC vs 75 months for those with high AMC, p=0.039), but there was no additional prognostic impact after multivariate analysis. Moreover, AMC was prognostic for LFS, since patients with low AMCs ( 〈 0.2 x109/L) had a median LFS of 57.0 months, while the median LFS for patients with higher AMCs was not reached (HR, 2.47, 95% CI, 2.01 - 2.47, p 〈 0.0001). In a Cox regression model including the above stated factors (cytopenias, bone marrow blasts, cytogenetic risk, and AMC), AMC retained its prognostic significance for LFS (HR, 1.27; 95% CI, 1.02 - 1.58; p=0.031). In a subgroup of 162 patients treated with hypomethylating agents (HMAs), monocytopenia was not predictive or response to treatment, but low AMC was correlated to a shorter median progression free survival (27.0 months vs not reached for patients with higher AMC, p=0.001). This correlation was not translated into a survival benefit (survival after HMA initiation, 27.0 vs 28.0 months respectively, log rank p=0.213). Conclusions: Based on a large patient cohort, we found that patients with MDS with excess blasts as well as higher risk patients per the IPSS-R have low AMCs. Moreover, we showed that low AMCs are prognostic of lower OS in univariate analysis and of lower LFS in both univariate and multivariate analysis, highlighting a possible pathogenetic role for AMCs in MDS. Further analysis is needed to define the exact prognostic role of AMC in MDS. Disclosures Pappa: Amgen: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kotsianidis:Celgene: Research Funding. Symeonidis:MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Vassilakopoulos:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; WinMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Front-line bevacizumab (BEV) in combination with taxanes offers benefit in progression-free survival (PFS) in metastatic breast cancer (mBC). The medical records of mBC patients, treated with front-line BEV-based chemotherapy, were retrospectively reviewed in order to generate real life safety and efficacy data. Patients with human epidermal growth factor receptor 2 (HER2)-negative mBC treated with front-line BEV in combination with chemotherapy were eligible. Maintenance therapy with BEV and/or hormonal agents was at the physicians’ discretion. Among the 387 included patients, the most common adverse events were anemia (61.9%, mainly grade 1), grade 3/4 neutropenia (16.5%), grade 1/2 fatigue (22.3%), and grade 1/2 neuropathy (19.6%). Dose reductions were required in 164 cycles (7.1%) and toxicity led to treatment discontinuation in 21 patients (5.4%). The median PFS and the median overall survival (OS) were 13.3 (95% CI: 11.7–14.8) and 32.3 months (95% CI: 27.7–36.9), respectively. Maintenance therapy, with hormonal agents (ET) and/or BEV, was associated with longer OS versus no maintenance therapy (47.2 versus 23.6 months; p 〈 0.001) in patients with hormone receptor (HR)-positive disease and BEV maintenance offered longer OS versus no maintenance in patients with HR-negative disease (52.8 versus 23.3; p = 0.023). These real-life data show that front-line BEV-based chemotherapy in HER2-negative mBC patients is an effective treatment with an acceptable toxicity profile. The potential benefit of maintenance treatment, especially ET, is important and warrants further research.

Abstract: Introduction: The three main choices for the primary treatment of WM are alkylating agents, nucleoside analogues and rituximab. There is evidence that combinations of nucleoside analogues and rituximab are highly effective. However, when such regimens are administered, there are concerns regarding myelosuppresion, immunosuppression and impact on stem cell collection. We designed a phase II study which included previously untreated WM patients (with clearly defined criteria for initiation of treatment) who were treated with a combination of dexamethasone, rituximab and cyclophosphamide (DRC). Patients and methods: Patients with WM received primary treatment with dexamethasone 20mg i.v. followed by rituximab 375mg/m2 i.v. on day 1 and cyclophosphamide 100mg/m2 p.o. bid days 1–5 (total dose 1000mg/m2). This regimen was repeated every 21 days for 6 courses. Results: Since July 2002, 70 patients have been enrolled in this multicenter study. As of July 2006, 60 patients have completed the scheduled courses of treatment. Patients characteristics include: median age of 71 years (range 33 to 89 years), 63% male, 28% B symptoms, 32% splenomegaly, 40% lymphadenopathy, 25% hyperviscosity syndrome, 62% hemoglobin & lt;10g/dL, 43% serum monoclonal protein ≥4gr/dL, 36% serum albumin & lt;3,5g/dL, 40% serum β2 microglobulin & gt;4mg/dL. On an intent to treat basis, 70% of patients achieved at least 50% reduction of serum monoclonal protein concentration, including 7% of patients who achieved immunofixation-negative complete response. Furthermore in 20% of patients & lt;50% reduction of monoclonal protein or disease stability was observed, whereas progressive disease during treatment was documented in only 10% of patients. The median time to response was 4 months (range 0,7 months to 14 months). With a median follow-up of 24 months, 60% of patients are progression-free. With the exception of one patient who died of interstitial pneumonia, the DRC regimen was well tolerated. 20% of patients developed grade 3–4 neutropenia. Severe opportunistic infections were not observed. Mild or moderate effects related to rituximab infusion such as fever, rigors and headache were seen in 20% of patients. In patients where stem cell collection was attempted, this procedure was successful in all Conclusion: Our large, multicenter trial showed that the non-stem cell toxic DRC regimen is an active and well tolerated treatment for symptomatic patients with WM. With this treatment, disease control can occur in the majority of patients without the risks of myelosuppression and immunosuppression which may occur when nucleoside analogues are used. This regimen may be particularly useful when high-dose therapy is an option for patients with WM.

Abstract: Interactions between myeloma (MM) cells and marrow microenvironment are crucial for myeloma growth and resistance to anti-myeloma therapy. Bortezomib (VELCADE®; V) and thalidomide (T) have proven anti-MM effect and exert their action partly through perturbation of the MM microenvironment. Furthermore, bortezomib enhances the cytotoxic potential of other agents, such as melphalan (M), and dexamethasone (D) in resistant cell lines. We hypothesize that combining VT (to target both MM cells and microenvironment) with M and D may help overcome resistance and increase clinical efficacy of these agents in relapsed/refractory disease. The aim of this phase II study was to determine the efficacy and safety of the VMDT regimen and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 1–4, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Responders and patients with SD continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring the serum levels of angiogenic cytokines, such as VEGF, angiogenin, angiopoietin-2, and bFGF at baseline and after cycles 4 and 8. Bone remodeling was studied by the measurement of a series of serum indices: i) osteoclast stimulating factors [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α ] , ii) bone resorption markers (CTX, TRACP-5b), and iii) bone formation markers [bALP, osteocalcin (OC), and CICP]. Thirty-one pretreated pts (median age: 66 y; range: 45–83 y) have been enrolled in this study, including 20 pts treated during refractory relapse. Median time from 1st treatment to VMDT was 40 months. Many pts had features of advanced disease including ISS stage 3 (32%), high LDH (23%), and creatinine & gt;2mg% (10%). The median number of previous treatments was 2 (range: 1–6), including M (48% of pts), T (65%), D (100%), V (3%) and ASCT (39%). Among 25 pts evaluable for response so far, 14 (56%) achieved an objective response (CR 8% and PR 48%). Furthermore, 2 pts (8%) achieved a MR and 5 (20%) SD. Median time to response was 30 days. Adverse events included fatigue (56%), thrombocytopenia (12% grade 3/4), neutropenia (8% grade 3/4), anemia (8% grade 3), neuropathy (48% grade 1/2, no grade 3/4 observed), infections (36%, including 2 HZ cases), and hyponatremia (12%). No pt experienced DVT, while 2 pts died due to sepsis. At baseline, MM pts had increased serum levels of sRANKL, sRANKL/OPG ratio, MIP-1α , VEGF, angiogenin, angiopoietin-2, and bFGF (p & lt;0.01) compared with controls, while serum levels of CTX, TRACP-5b, bALP, OC were decreased (p & lt;0.03) since all pts have been on zoledronic acid treatment. Our preliminary analysis showed that sRANKL and MIP-1α levels reduced after 4 cycles of VMDT. In conclusion the VMDT combination with intermittent T is associated with significant activity in pts with heavily pretreated MM. The toxicities are manageable; due to intermittent T administration there was no severe neurotoxicity and no DVT. Our study will also provide further data regarding post-treatment changes of cytokines involved in interactions between MM and stromal cells.

Abstract: Introduction: Renal failure (RF) is a common and severe complication of patients with multiple myeloma (MM). The purpose of our study was to assess the incidence of RF in a contemporary series of newly diagnosed patients with MM, its association with specific clinical and laboratory features and its impact on early death rate, on myeloma response and on patients survival. Patients and Methods: Between January 1995 and December 2004, 756 newly diagnosed symptomatic patients with MM were included in the database of the GMSG. Renal failure, was defined as a serum creatinine ≥2mg/dL at the time of diagnosis. The incidence of RF was correlated with multiple clinical and laboratory variables by univariate and Cox regression analysis. Results: The incidence of RF in this series of patients was 21%. This figure was similar to the incidence of RF (19%) in patients diagnosed during the preceding decade. Severe RF (serum creatinine ≥6mg/dL) occurred in 4% of patients. There was a significant association of renal failure with poor performance status (p=0.001), increased ISS stage (p & lt;0.001), elevated serum β2microglobulin (p & lt;0.001), hypercalcemia (p & lt;0.001), increased Bence Jones proteinuria (p & lt;0.001), high serum LDH (p & lt;0.002), low platelet count (p=0.004), low albumin (p=0.036) and light chain only on IgD myeloma (p & lt;0.001). Multivariate analysis showed that RF was independently associated only with ISS and Bence Jones proteinuria. Early death, within 2 months from treatment initiation, was observed in 10% of patients with RF and in 4% of patients without RF (p=0.2). At least partial response (EBMT criteria) was documented in 61% of patients without RF and in 55% of patients with RF (p=0.2). The median survival of patients with RF was 19.5 months versus 40.4 months for patients without RF (p & lt;0.001). Other variables associated with impaired survival by univariate analysis included poor performance status, thrombocytopenia, hypercalcemia, high serum LDH, advanced age and elevated serum β2 microglobulin. However, when multivariate analysis was performed the independent variables were poor performance status, thrombocytopenia, advanced age, high LDH and elevated serum β2 microglobulin but not high creatinine. The median survival of patients with ISS stage 2 and 3 without RF was 36 months and 22 months respectively compared to 19 months and 20 months for patients with RF (p=0.1 and 0.5 respectively). Conclusions: The incidence of RF remains significant and essentially unchanged in patients with MM diagnosed over the last 20 years. The presence of RF is associated with a trend for higher early death rate but with a similar response to primary therapy. Patients with RF have lower survival compared to patients without RF. The prognostic significance of RF is mainly attributed to its association with higher β2;microglobulin and Bence Jones proteinuria.