Search

Background In combination with dexamethasone, lenalidomide is prescribed in the oral treatment of Multiple Myeloma for patients who have received at least one previous therapy. Objective The objective of this study is to evaluate medication adherence to lenalidomide of Multiple Myeloma patients, as well as Progression Free Survival and Overall Survival one year from the beginning of the treatment. Setting The study was carried out in Pescara Hospital, in Italy. All Multiple Myeloma patients who began lenalidomide therapy between January 1, 2012 and June 30, 2016 were included in our study. Methods Adherence to treatment was calculated by using the ratio between the Received Daily Dose and the Prescribed Daily Dose. Effectiveness in real world has been evaluated as Progression Free Survival and Overall Survival one year from the beginning of the treatment. Main outcomes measure: We assessed medication adherence and effectiveness of lenalidomide in the treatment of Multiple Myeloma. Results Adherence to the overall mean treatment was 0.73 ± 0.15, relative to 81 patients evaluated in our study. 32% of patients achieved an adherence equal to or greater than 80%. Real-life effectiveness in terms of Progression Free Survival and Overall Survival showed values of ​​53.75% and 88%, respectively, one year from the beginning of treatment. Conclusion The analysis of adherence in Multiple Myeloma patients treated with lenalidomide one year from the beginning of therapy reveal a concerning lack of adherence. Moreover, the lack of correlation of the levels of adherence with patient-related variables shows that, in the case of Multiple Myeloma, adherence is not related to personal, social and environmental characteristics that may determine each patient’s correct treatment implementation, but is directly influenced by disease evolution.

Background. Infections represent a major cause of toxicity in newly diagnosed multiple myeloma (NDMM) patients, and their incidence is higher during the first 4 months of therapy (Dumontet, Leukemia 2018). The use of prophylactic levofloxacin for the first 3 months of therapy demonstrated to reduce rates of infections (Dryson, Lancet Hematol 2019). However, factors predicting the risk of infections in patients treated with novel agents and the need for antimicrobial prophylaxis for all vs selected patients remain under debate. We investigated the incidence of severe infections and associated baseline risk-factors in NDMM patients. Methods. Data from Italian patients enrolled in clinical trials and receiving carfilzomib-based (IST-CAR-506, IST-CAR-561), bortezomib-based (EMN02) and lenalidomide-based (EMN01, RV-MM-PI-0752, RV-MM-EMN-441) treatment were pooled together and analyzed. The primary aim of the analysis was to evaluate the incidence of severe infections, defined as any grade (G) 3-5 event or G2 if involving the lung/lower respiratory tract (CTCAE version 4.0). The rate of early severe infections (i.e. infections occurring during the first 4 months of treatment) was also analyzed. Secondary goals were to identify baseline factors associated with an increased risk of early severe infections and to evaluate the impact of early severe infections on treatment outcome. Results. A total of 1892 patients were included in the analysis. Median age was 65 years, 970 (51%) patients were transplant eligible (TE) and 922 (49%) transplant ineligible (NTE). Overall, 1059 (56%) patients received IMiD-based induction therapy and 833 (44%) a PI-based induction therapy. Median follow-up was 68 months. We recorded 898 infections of any grade, of which 436 (49%) were considered severe. Most frequent severe infections included lung/lower respiratory tract infection (50%), febrile neutropenia (23%) and sepsis/septic shock (10%). Overall, severe infections occurred when myeloma response to treatment was ≤PR in 62% of cases, VGPR in 29% and sCR/CR in 9%. 654 (35%) patients reported at least 1 infection of any grade and 377 (20%) patients at least one severe infection. Early infections (first 4 months) occurred in 243 patients (13%) and early severe infections in 129 patients (6.8%). Overall, 21 patients (1.1%) died due to infection, of whom 6 during the first 4 months. In a multivariate analysis (Table), main factors associated with increased risk of early severe infections were ISS stage 3 (OR 2.14, 95% CI 1.32-3.48), presence of del17p by FISH (OR 1.80, 95% CI 1.1-2.96), intermediate fit status (OR 1.88 95% CI 1.1-3.21) and frail status (OR 2.12, 95% CI 1.08-4.18) according to IMWG frailty score (Palumbo, Blood 2015). No difference in risk of early severe infections was observed according to induction treatment with PI vs IMiD (OR 1.10, 95%CI 0.68-1.78). In a time-dependent Cox regression analysis adjusted for potential confounders (age, RISS stage and performance status), the risk of disease progression/death was significantly higher in patients who had an early severe infection compared to patients without early severe infection (median PFS 21.3 months vs 31.3 months, HR 1.32, 95% CI 1.07-1.63, p Conclusions. We found that 34% of patients experiencing severe infections had the event during the first 4 months of therapy. Patients with aggressive disease and elderly frail patients are at higher risk of early severe infections, hampering treatment adherence and efficacy, and eventually affecting PFS and OS. Identifying patients more susceptible to severe infections through easily available parameters could pave the way for the evaluation of risk-adapted antimicrobial prophylaxis in clinical trials. Table 1 Disclosures D'Agostino: GSK: Membership on an entity's Board of Directors or advisory committees. Offidani:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Petrucci:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Liberati:JANSSEN: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding; BMS: Honoraria; BEIGENE: Honoraria; ARCHIGEN: Honoraria; BIOPHARMA: Honoraria; FIBROGEN: Honoraria; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Gaidano:Sunesys: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Galli:Takeda: Honoraria; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria. Corradini:Janssen: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Sanofi: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; KiowaKirin: Consultancy, Honoraria; Kite: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Conticello:Amgen, Takeda, Janssen: Honoraria. Cavo:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Honoraria, Speakers Bureau; Karyopharm: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel accomodations, Speakers Bureau. Sonneveld:Skyline Dx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Boccadoro:Mundipharma: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Bringhen:Bristol-Myers Squibb: Honoraria; Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, 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. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma (including carfilzomib, cyclophosphamide, dexamethasone, bortezomib, melphalan, prednisone and lenalidomide).

Panobinostat represents the first oral pan-histone deacetylase (HDAC) inhibitor approved in combination with bortezomib and dexamethasone for the treatment of relapsed/refractory multiple myeloma (...

Chronic myelomonocytic leukaemia (CMML) is a myelodysplastic/myeloproliferative disorder characterized by monocytosis and single- or multi-lineage dysplasia. Skin infiltration is rare and predicts disease progression or transformation to acute leukaemia [1]. Nearly 60% of CMML patients bear TET2 gene mutations, which are associated with good response to hypomethylating agents (HMA) in myelodysplastic syndromes (MDS) [2]. At present, although HMA are the standard of care for CMML, the overall response [...]

Background Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic antimyeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma. Methods PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1.3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308. Findings 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6.47 months (IQR 1.81-13.47) in the panobinostat group and 5.59 months (2.14-11.30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11.99 months [95% CI 10.33-12.94] vs 8.08 months [7.56-9.23]; hazard ratio [HR] 0.63, 95% CI 0.52-0.76; p

INTRODUCTION: Elderly patients with newly diagnosed multiple myeloma (NDMM) are highly heterogeneous and their outcome is influenced by many factors: beside age, also comorbidities, general physical fitness, and cognitive function play a crucial role. The IMWG frailty score combines age, functional status, and comorbidities, and it identifies fit, intermediate-fit and frail patients, with different risk of toxicity, treatment discontinuation, and mortality (Palumbo A et al. Blood 2015). Until now, evidence-based tailored treatments according to patients' frailty are still lacking. Therefore, this phase III study investigated the efficacy and feasibility of dose/schedule-adjusted lenalidomide-dexamethasone therapy followed by lenalidomide maintenance (Rd-R) versus continuous lenalidomide-dexamethasone (Rd) in elderly, intermediate-fit NDMM patients. METHODS: Intermediate-fit NDMM patients, with a total frailty score (age, Charlson Index, ADL and IADL) of 1 (http://www.myelomafrailtyscorecalculator.net/), were enrolled and randomized to receive Rd-R or continuous Rd. To better approximate a real-world older population, patients usually excluded from clinical trials or with abnormal laboratory values could be included in the trial. Rd-R treatment consisted of nine 28-day cycles of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, followed by lenalidomide maintenance 10 mg/day for 21 days, until disease progression. Continuous Rd consisted of lenalidomide 25 mg/day for 21 days and dexamethasone 20 mg on days 1,8,15,22, until disease progression. The dose and schedule of continuous Rd was the one adopted in patients >75 years in the FIRST trial (Hulin C et al. JCO 2016). The primary endpoint was event-free survival (EFS), defined as progression or death for any cause or discontinuation of lenalidomide or occurrence of any hematological grade 4 or non-hematological grade 3-4 adverse events (AEs), including Secondary Primary Malignancies (SPMs), whichever came first. RESULTS: 199 patients (98 in Rd-R arm and 101 in continuous Rd arm) could be evaluated. Patients characteristics were well balanced between the 2 arms. Median age was 75 and 76 years (p=0.06); 47% in Rd-R vs 57% in continuous Rd were defined intermediate-fit for age (≥76 years), 53% vs 43% due to an impairment in Charlson Index, ADL or IADL (p=ns). In intention-to-treat analysis, after a median follow-up of 25 months, EFS was 9.3 vs 6.6 months (HR 0.72, 95% CI 0.52-0.99, p=0.04), in Rd-R versus continuous Rd, respectively (Figure 1). Best response rates were not significantly different between the 2 groups: ≥PR rates were 73% vs 63%, and ≥VGPR rates were 43% vs 35% in the Rd-R vs Rd continuous group, respectively (p=ns). No difference in progression-free survival (PFS) and overall survival (OS) was observed. Median PFS was 18.3 vs 15.5 months (HR 0.93, 95% CI 0.64-1.34, p=ns) (Figure 1), 18 month-OS was 85% versus 81% (HR 0.73, 95% CI 0.40-1.33, p=ns). Adverse events accounting for EFS (any hematologic grade 4, non-hematologic grade 3-4) were less frequent in the Rd-R group (30% vs 39%) than in the continuous Rd group (p=ns). The most frequent adverse events were neutropenia, infection and skin reactions (less than 10% in each arm). After 9 treatment cycles, these adverse events were less frequent in Rd-R vs continuous Rd group (3% vs 7%, p=ns). Lenalidomide dose reduction after 9 treatment cycles was required in 1% of Rd-R patients and 21% of continuous Rd patients (p =0.06). Dexamethasone dose reduction was required in 17% vs 29% of patients, respectively (p=0.06). CONCLUSION: This is the first prospective randomized phase III trial specifically designed for real-life intermediate-fit NDMM patients. A dose/schedule-adjusted Rd-R treatment was more feasible compared to full dose continuous Rd treatment in elderly intermediate-fit NDMM patients, with no negative impact but rather a comparable outcome. These results confirm the need for an appropriate definition of patient frailty, and pave the way to a frailty-adjusted treatment approach to better balance efficacy and safety in elderly NDMM patients. Figure 1. Figure 1. Disclosures Larocca: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Amgen: Honoraria. De Paoli:Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; Celgene: Other: Advisory Board; Gilead: Other: Advisory Board. Galli:Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Sigma-Tau: Honoraria. Montefusco:Janssen: Other: Advisory Board; Amgen: Other: Advisory Board; Celgene: Other: Advisory Board. Caravita di Toritto:Johnson & Johnson: Other: Advisory Board, Travel and Accomodation EHA; Amgen: Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Travel and Accomodation EMN; Takeda: Other: Advisory Board; Celgene: Other: Advisory Board, Travel and Accomodation ASH, Research Funding. Giuliani:Celgene Italy: Other: Avisory Board, Research Funding; Takeda Pharmaceutical Co: Research Funding; Janssen Pharmaceutica: Other: Avisory Board, Research Funding. Patriarca:Jazz: Other: Travel, accommodations, expenses; Janssen: Other: Advisory role; Celgene: Other: Advisory Role; Travel, accommodations, expenses; Medac: Other: Travel, accommodations, expenses; MSD Italy: Other: Advisory Role. Offidani:Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Bristol-Myers Squibb: Honoraria, Other: Advisory Board. Cavo:GlaxoSmithKline: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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. Palumbo:Takeda: Employment. Boccadoro:Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding. Bringhen:Janssen: Honoraria, Other: Advisory Board; Celgene: Honoraria; Amgen: Honoraria, Other: Advisory Board; Takeda: Consultancy; Bristol-Myers Squibb: Honoraria.

Introduction Multiple Myeloma (MM) is a hematologic malignancy characterized by proliferation of clonal plasmacells in the bone marrow and sometimes extramedullary sites which inevitably tend to relapse. Patients with relapsed/refractory MM (R/R MM) who are treated with conventional drugs as immunomodulating agents (IMiDs) and proteasoma inhibitors (PIs) have a poor survival. Based on the results of MM 003 phase III randomised trial, pomalidomide in association with dexamethasone has shown to improve R/R MM outcome. We conducted a single-center real life-based observational and pharmacological analysis to investigate the efficacy and tolerability of pomalidomide in a group of patients with R/R MM previously exposed to IMiDs and PIs. Method and Materials We included 34 patients (females 21) treated with pomalidomide (POMA) from January 2015 to May 2018 at the Hematology Department of "Santo Spirito" Hospital in Pescara, Italy. All patients were diagnosed by R/R MM according to IMWG guidelines and were classificated using ISS criteria. Prognostic cytogenetic value was identified by FISH analysis. POMA was administred at the oral daily dose of 3-4 mg (days 1-21) in combination with oral dexamethasone (days 1,8,15,22) at the dosage of 20 mg/day. Adverse events were evaluated according to the common terminology criteria for adverse reactions (CTCAE version 4.0). Overall survival (OS) and progression free survival (PFS) were designed according to Kaplan-Myer method. The adherence to therapy was determined using 'received daily dose/prescribed daily dose' method (RDD/PDD). Statistic analysis were conducted with GraphPad Prism 7.0; p values ≤ 0.05 were considered statistically significant. Results The clinical and biological characteristics of 34 patients are described in Tab.1. The median follow up after POMA therapy was 5 months (range, 1-32); at the end of this period 12 patients had completed at least 6 cycles of therapy (range, 1-21). Overall response rate (ORR) was 24%: 4 complete remission (CR), 3 very good partial response (VGPR), 1 partial response (PR); moreover 6 patients (18%) achieved a minimal response (MR). Clinical benefit rate (CBR) was 74%: ORR plus 6 MR and 11 stable disease (SD). At time of this report 12 patients (35%) are living. Among living patients, 4 are now receiving other treatments and 8 are still under POMA treatment: 4 are in CR, 1 is in PR, 1 in MR and 2 in SD. Median OS of all patients was 10 months, whereas median PFS was 6 months (Fig.1,A-B). Median PFS was notably lower in high cytogenetic risk patients (4 months) as compared to the PFS of standard cytogenetic risk patients (16 months) (p= 0.02) (Fig.1,D). Patients treated with at least 4 previous lines of therapy had a median PFS of 5 months, while those receiving until 3 previous lines of therapy had a median PFS of 24 months (p= 0.01) (Fig.1,C). Patients receiving a drug regimen lenalidomide-based as last treatment before starting POMA didn't show significant difference in PFS from those receiving other treatments (4 months vs 6 months) (p=NS). During treatment with POMA, 22 patients (65%) showed adverse drug reactions (ADRs) for a total of 77. Seventy-four ADRs were ≥ 2 grade. Forty nine ADRs (63%) were hematological and 43 ADRs (56%) occurred in the first 3 months of therapy. In particular Twenty-two of them occurred within the first month of therapy. Thirty two cases of ADRs (41%) were successfully managed with simple delay of treatment. As consequence, the adherence to therapy was not optimal (78%). However only 9 (12%) of the total ADRs were cause of end of treatment. Conclusions Despite the low sample size and short follow-up, our real life analysis contributes to show that pomalidomide therapy is a favorable option for patients with R/R MM, leading to good responses in terms of OS and PFS. The best results were obtained when POMA treatment was utilized at first relapses and in particular in patients with favorable genetic profile. About the safety, despite the frequent hematological toxicity, ADRs can be quite easily managed to allow few interruptions of the treatment and improve the adherence. Disclosures No relevant conflicts of interest to declare.

Introduction. The gradient echo multiecho T2* MRI technique is the most robust method for the non invasive, sensitive, and fast quantification of organ-specific iron overload. A crucial aspect is the transferability of the T2* technique among different MRI scanners, in order to expand the availability of high-quality monitoring of iron accumulation to a large population. The intra- and inter-operator reproducibility, inter-study reproducibility, and inter-scanner reproducibility of the T2* MRI method for measuring iron concentrations in the heart and liver have already been demonstrated. However, the transferability of the MRI multislice multiecho T2* technique for pancreatic iron overload assessment has not been evaluated. Thus, the aim of our study was to assess the transferability of this approach among ten MRI sites. Methods. All subjects underwent MRI using conventional clinical 1.5T scanners of three main vendors. Fifty healthy subjects, five for each site, including the reference centre, were scanned. Five patients with thalassemia were scanned locally at each site and were rescanned at the reference site in Pisa within 1 month. T2* image analysis was performed using custom-written, previously validated software (HIPPO MIOT®). T2* values over pancreatic head, body and tail were calculated and the global pancreatic T2* value was obtained as the mean. The lowest threshold of normal T2* value was 26 ms6. Results. On healthy subjects the global pancreas T2* values ranged from 28.93 to 48.89 ms (mean 37.88 ms, SD 5.08 ms). No significant difference was detected among the sites (P=0.334). Table 1 shows the global pancreas T2* values measured at the different MRI sites. The global pancreas T2* values ranged from 2.08 to 38.39 ms. There was not a significant difference between the T2* values measured in the MRI sites and the correspondent values observed in Pisa (12.02±10.20 ms vs 11.98±10.47 ms; P=0.808). All patients categorized as having pancreatic iron overload in the MRI sites, fell in the same category after the MRI executed in Pisa. There was a strong correlation between the global pancreas T2* values calculated from images obtained in Pisa and at the other MRI sites (R=0.978, P Figure 1 shows the global pancreas T2* values calculated from images obtained at the 9 MRI sites as a function of global pancreas T2* calculated from images obtained in Pisa. The line of best fit had a slope of 0.965 ± 0.021 and an intercept of 0.459 ± 0.328 ms. The R-squared value for the fit was 0.981. Neither constant bias (intercept did not significantly differs from zero) nor proportional bias (angular coefficient did not significantly differ from 1) affected the measurements. CoVs for all MRI sites are provided in Table 2; they ranged from 4.22 to 9.77%. The CoV for all the T2* values independently from the sites was 8.55%. The ICC considering all the T2* values, independently from the sites, was 0.995. The ICC for each MRI site is provided in Table 2 and it was always excellent. The comparison between Pisa and the other MRI sites by Bland-Altman analysis showed a mean absolute difference of -0.04 ± 1.47 ms for the global pancreas T2* values (Figure 2). No bias was present and no greater differences for higher T2* values were detected. The mean absolute difference in patients with pancreatic iron (N=39) was -0.15 ± 1.38 ms. Conclusion. The gradient-echo T2* MRI technique is an accurate and reproducible means for the calculation of pancreatic iron and may be transferred between MRI scanners in different centers from different manufacturers. Figure. Figure. Disclosures Pepe: Chiesi Farmaceutici S.p.A., ApoPharma Inc., and Bayer: Other: No profit support.

Lenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma patients. We randomly assigned 662 patients who were age ≥65 years or transplantation-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd). The primary end point was progression-free survival (PFS) in triplet (MPR and CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the median PFS was 22 months for the triplet combinations and 21 months for the doublet (P = .284). The median overall survival (OS) was not reached in either arms, and the 4-year OS was 67% for the triplet and 58% for the doublet arms (P = .709). By considering the 3 treatment arms separately, no difference in outcome was detected among MPR, CPR, and Rd. The most common grade ≥3 toxicity was neutropenia: 64% in MPR, 29% in CPR, and 25% in Rd patients (P < .0001). Grade ≥3 nonhematologic toxicities were similar among arms and were mainly infections (6.5% to 11%), constitutional (3.5% to 9.5%), and cardiac (4.5% to 6%), with no difference among the arms. In conclusion, in the overall population, the alkylator-containing triplets MPR and CPR were not superior to the alkylator-free doublet Rd, which was associated with lower toxicity. This study was registered at www.clinicaltrials.gov as #NCT01093196.

Purpose In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens. Patients and Methods A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment. Results Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, −3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, −1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded. Conclusion In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

High-dose melphalan plus autologous stem-cell transplantation (ASCT) is the standard approach in transplant-eligible patients with newly diagnosed myeloma. Our aims were to compare consolidation with high-dose melphalan plus ASCT versus chemotherapy (cyclophosphamide and dexamethasone) plus lenalidomide, and maintenance with lenalidomide plus prednisone versus lenalidomide alone.We did an open-label, randomised, multicentre, phase 3 study at 59 centres in Australia, Czech Republic, and Italy. We enrolled transplant-eligible patients with newly diagnosed myeloma aged 65 years or younger. Patients received a common induction with four 28-day cycles of lenalidomide (25 mg, days 1-21) and dexamethasone (40 mg, days 1, 8, 15, and 22) and subsequent chemotherapy with cyclophosphamide (3 g/m(2)) followed by granulocyte colony-stimulating factor for stem-cell mobilisation and collection. Using a 2 × 2 partial factorial design, we randomised patients to consolidation with either chemotherapy plus lenalidomide (six cycles of cyclophosphamide [300 mg/m(2), days 1, 8, and 15], dexamethasone [40 mg, days 1, 8, 15, and 22], and lenalidomide [25 mg, days 1-21]) or two courses of high-dose melphalan (200 mg/m(2)) and ASCT. We also randomised patients to maintenance with lenalidomide (10 mg, days 1-21) plus prednisone (50 mg, every other day) or lenalidomide alone. A simple randomisation sequence was used to assign patients at enrolment into one of the four groups (1:1:1:1 ratio), but the treatment allocation was disclosed only when the patient reached the end of the induction and confirmed their eligibility for consolidation. Both the patient and the treating clinician did not know the consolidation and maintenance arm until that time. The primary endpoint was progression-free survival assessed by intention-to-treat. The trial is ongoing and some patients are still receiving maintenance. This study is registered at ClinicalTrials.gov, number NCT01091831.389 patients were enrolled between July 6, 2009, and May 6, 2011, with 256 eligible for consolidation (127 high-dose melphalan and ASCT and 129 chemotherapy plus lenalidomide) and 223 eligible for maintenance (117 lenalidomide plus prednisone and 106 lenalidomide alone). Median follow-up was 52·0 months (IQR 30·4-57·6). Progression-free survival during consolidation was significantly shorter with chemotherapy plus lenalidomide compared with high-dose melphalan and ASCT (median 28·6 months [95% CI 20·6-36·7] vs 43·3 months [33·2-52·2]; hazard ratio [HR] for the first 24 months 2·51, 95% CI 1·60-3·94; p0·0001). Progression-free survival did not differ between maintenance treatments (median 37·5 months [95% CI 27·8-not evaluable] with lenalidomide plus prednisone vs 28·5 months [22·5-46·5] with lenalidomide alone; HR 0·84, 95% CI 0·59-1·20; p=0·34). Fewer grade 3 or 4 adverse events were recorded with chemotherapy plus lenalidomide than with high-dose melphalan and ASCT; the most frequent were haematological (34 [26%] of 129 patients vs 107 [84%] of 127 patients), gastrointestinal (six [5%] vs 25 [20%]), and infection (seven [5%] vs 24 [19%]). Haematological serious adverse events were reported in two (2%) patients assigned chemotherapy plus lenalidomide and no patients allocated high-dose melphalan and ASCT. Non-haematological serious adverse events were reported in 13 (10%) patients assigned chemotherapy plus lenalidomide and nine (7%) allocated high-dose melphalan and ASCT. During maintenance, adverse events did not differ between groups. The most frequent grade 3 or 4 adverse events were neutropenia (nine [8%] of 117 patients assigned lenalidomide plus prednisone vs 14 [13%] of 106 allocated lenalidomide alone), infection (eight [8%] vs five [5%]), and systemic toxicities (seven [6%] vs two [2%]). Non-haematological serious adverse events were reported in 13 (11%) patients assigned lenalidomide plus prednisone versus ten (9%) allocated lenalidomide alone. Four patients died because of adverse events, three from infections (two during induction and one during consolidation) and one because of cardiac toxic effects.Consolidation with high-dose melphalan and ASCT remains the preferred option in transplant-eligible patients with multiple myeloma, despite a better toxicity profile with chemotherapy plus lenalidomide.Celgene.

Background Cisplatin-containing regimens represent the gold standard in the treatment of advanced non-small cell lung cancer, but carboplatin is often preferred for its better toxic profile when palliation is the aim of the treatment. The synergistic effect and tolerability of carboplatin-gemcitabine combination are well known. In this phase II trial, we evaluated the activity and safety of a schedule with carboplatin and gemcitabine, defined in our previous phase I trial. Methods Thirty-seven patients with measurable stage IV non-small cell lung cancer were treated with carboplatin, AUC 4.5 mg/ml/min on day 1, and gemcitabine, 800 mg/m2 on days 1 and 8, every 21 days. All patients were treated until disease progression or intractable toxicity and were evaluated before each course of chemotherapy for toxicity and after every 3 courses for response. Results After a median follow-up of over 10 months, complete response, partial response, and stabilization of the disease were observed in 3 (8.1%), 9 (24.3%), and 15 patients (40.5%), respectively. Median time to progression was 7 months. At this writing, 27 patients have died, with a median survival of 10 months, and 29 (78.3%), 16 (43.2%), and 11 (29.7%) patients are alive after 6, 12, and 15 months of follow-up, respectively. Toxicity was mild, and mainly hematological, with a significant correlation with the number of courses of chemotherapy (P = 0.0003). Conclusions Our results are comparable with those reported in the literature and confirm the good activity and tolerability of the carboplatin-gemcitabine combination. Up to 4 courses of chemotherapy with carboplatin and gemcitabine may represent an interesting option in the palliative treatment of non-small cell lung cancer.

Poster: "ESCR 2014 / 415 / Prognostic CMR parameters for heart failure and arrhythmias in large cohort of well treated thalassemia major patients" by: "C. Tudisca1, A. Meloni2, E. Chiodi3, R. Rosso4, A. Carollo5, M. Midiri1, A. Pepe2; 1Palermo/IT, 2Pisa/IT, 3Ferrara/IT, 4Catania/IT, 5Trapani/IT"

Newly significant advances have been made in diagnosis and treatment of multiple-myeloma (MM).Until recently,MM was defined by presence of end-organ-damage,specifically hypercalcemia, renal-failure, anemia and bone-lesions(CRAB-features). International-Myeloma-Working-Group(IMWG)revised diagnostic-criteria adding three specific-markers:clonal-bone-marrow-plasma-cells greater than 60%, serum-free-light-chain-ratio (FLC)more than 100 and at least two focal-lesions on magnetic-resonance-imaging(MRI). After this update,it's now time to change therapeutic-paradigm: new-IMWG-guidelines allow earlier intervention without waiting end-organ-damage to treat . Nevertheless there is much to learn and share about these new standards that change treatment. When is the right-time to start therapy?We have tried to answer to this dilemma in our work comparing traditional-CRAB-features with recent-myeloma-diagnostic-criteria in a group of 220 newly-diagnosed-MM followed in our Department from 1999 to 2015. The aim of our retrospective-study was to analyze development of new-IMWG-biomarkers during disease-course before CRAB-events and beginning-treatment,discussing their strengths and weaknesses as well as lights and shadows. We evaluated 110 young-patients elegible for high-dose-chemotherapy and autologous-stem-cell-transplant(ASCT)and 110 old(more than 65-year-old)treated with different-kind of therapies. We highlighted presence of IMWG-new-criteria as myeloma-defining-events(MDEs) before CRAB-markers in 44 MM-patients (20% of all): 33 of them are old (median-age of 72 years,range 53-91)and 11 are young (median-age 57,range 41-65) and treated with transplant-procedure. In details most of them presented FLC ratio >100 (30 patients as 68% of this subgroup), following by MRI-lesions(10 patients as 23%) and lastly plasma-cells-bone-marrow-involvement greater of 60%(4 patients as 9%). The majority of these patients (39 as 89%) developed CRAB-characteristics after six months (median value, range 3-15) and have evolved in myeloma-requesting-treatment in less than a year. 27 of them have IgG, 12 IgA and 5 micromolecular-MM. The largest-part (40 patients)has an antecedent MGUS and smouldering-MM.Moreover five young-patients of the whole-population analysed with MDEs and good-clinical-status weren't treated based-on our clinical-judgement and continued close-observation,saving them from both early-therapeutic-toxicity and clonal-selection. Only two patients of 220 started treatment based-on new-IMWG-biomarkers,presenting with clinical-deterioration and increase in monoclonal-component. In conclusion our paper proved that movement from symptoms to biomarkers is a huge-step-forward expecially for elderly-patients,considering both clinical-signs and biological-features. However we need more pratical-implementation of new markers that are changing philosophy of treatment: these patients should be offered appropriate clinical-trial. More caution is needed in high-risk-group expecially young to avoid an overtreating-policy,considering also counter-arguments. Physicians should continue monitoring patients using tools- now-available,while waiting for results from future-prospective-studies. Increase of monoclonal-componenent was analysed not as CRAB-classic-criterion but like disease-marker. The time-difference between new -IMWG-criteria and CRAB-events is less than one year (mean-value 6 months). Figure 1 New-IMWG-criteria-versus-traditional-CRAB. We have studied in our 44-patients with new-diagnostic-markers,time-course of hemoglobin, monoclonal-protein and creatinine-values. Figure 1. New-IMWG-criteria-versus-traditional-CRAB. We have studied in our 44-patients with new-diagnostic-markers,time-course of hemoglobin, monoclonal-protein and creatinine-values. Disclosures No relevant conflicts of interest to declare.

Bendamustine, a bi-functional alkylating agent comprising a purine-like benzimidazole ring an a nitrogen mustard group, exerts a peculiar mechanism of action if compared to most conventional alkylators and this may partially explain its effectiveness in alkylator-resistant cells. In patients with MM several studies demonstrated the efficacy and tolerability of bendamustine as monotherapy or in combination with new drugs, particularly bortezomib that was found to enhance the in vitro sensitivity of MM cells to bendamustine. These observations represented the rationale for our protocol design namely to evaluate the combination bendamustine (70 mg/m2 days 1, 8), bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD). Cycles were administered every 4 weeks up to four cycles. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Patients with relapsed/refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy were enrolled in this prospective, single-arm, open-label, phase II study conducted in 21 Italian centres. The primary endpoint was achievement of a response at least PR after four cycles of BVD and response was assessed according to to IMWG criteria. From March 2011 to June 2012, 75 patients were included. Median age was 68 years (range 41-85), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. In total, 8 of 36 evaluable patients (22%) had adverse cytogenetics. All patients had received prior treatment with new drugs, including targeted agents such as thalidomide (57%), lenalidomide (54.5%) or bortezomib (46.5%). Patients had received a median of one prior line of therapy (range 1-4), including alkylators (69%), anthracyclines (29%) and ASCT (44%). Twenty-four patients (32%) were refractory to IMIDs. The response rate ≥ PR after four cycles of BVD was 71.5%, including 11 patients with CR (16%), 13 VGPRs (18.5%) and 26 PRs (37%). Also, 14 patients (20%) had disease stabilization while 6 (8.5%) had progressive disease. Median time to response was 1.2 months (range 0.9-1.4 months). Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (54.5% vs 86.5%; P = 0.003). At a median follow-up of 12 months (range 6-24), 30 patients had progressed and 18 had died. Median TTP and PFS were 16.5 months and 15.5 months, respectively while median OS had not been reached and 78% of patients were alive at 1 year. The Cox regression analysis identified prior therapy with bortezomib plus lenalidomide as the only factor that significantly reduced TTP (9 vs 17 months; HR = 4.5; 95% CI = 1.7-12.3; P = 0.005) Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 20% and to protocol discontinuation in 10.5% of patients. The most frequent severe adverse events were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), peripheral neuropathy (8%), gastrointestinal and cardiovascular events (both 6.5%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 thrombocytopenia (22% vs 37%; p=0.042) and severe infections (7 vs 19%; p=0.047) and consequently a higher rate of therapy reduction (9% vs 34.5%; p=0.007) and therapy discontinuation (7% vs 15.5%; p=0.043). Moreover, 4/5 early deaths occurred in patients aged more than 70 years. BVD combination is an effective regimen in relapsed-refractory MM patients since it elicits rapid, high (> 70%) and good quality of response (more than a third of patients achieved CR + VGPR). Moreover, BVD combination is a feasible and well tolerated regimen provided that adapted therapy and adequate antibiotic prophylaxis are employed in patients older than 70 years. Disclosures: Offidani: Mundipharma: Honoraria, Research Funding. Off Label Use: Bendamustine.

The combination of melphalan, prednisone and thalidomide (MPT) has demonstrated efficacy and acceptable toxicity in newly diagnosed and relapsed/refractory patients with multiple myeloma (MM). Panobinostat is a potent oral pan-deacetylase inhibitor (pan-DACi). In preclinical and clinical studies, panobinostat showed good anti-myeloma activity in combination with several agents. This phase II study evaluated the combination of a fixed dose of MPT with escalating doses of panobinostat (three times weekly for 3 weeks, followed by a 9-day rest period) in relapsed/refractory MM. We used a two-stage design to determine whether the combination was safe and effective. At least a partial response was observed in 38.5% of patients. The maximum tolerated dose of panobinostat in combination with MPT could not be determined due to the high rate of dose-limiting toxicities experienced with panobinostat at doses of 10 and 15 mg. The most common grade 3/4 adverse events were neutropenia (71%) and thrombocytopenia (35.5%). In conclusion, MPT in combination with panobinostat three times weekly for 3 weeks followed by a 9-day rest period is not well tolerated in patients with relapsed/refractory MM. Future studies should evaluate alternative dose schedules of panobinostat.

Multiple Myeloma (MM) is still considered an incurable disease despite a substantial global outcome improvement observed during the past decade. Despite better understanding of biological pathways, availability of sophisticated diagnostic tools and increasing number of therapeutic options almost all patients experience disease relapse. The aim of our retrospective study was to analyze global outcome in newly diagnosed MM patients eligible for high dose chemotherapy and autologous stem cell transplant (ASCT) treated in our Institution in the last 15 years. We evaluated 177 MM patients transplanted in our Institution from November 1999 to February 2015. Median age at start therapy was 58 years (range 36-71) and median follow up time (from start therapy to last follow up) was 52 months (range 7-185). Patients received different induction therapies before transplant reflecting the availability of new drugs and consequently more therapeutic choices. 65 patients received conventional chemotherapy-based induction (VAD 27, 15%, Total Therapy 2-like 37, 22%, EDAP 1 patient); 15 patients thalidomide-based (TD, 8%); 88 patients bortezomib-based (VTD 74, 43%; VCD 8, 5%; PAD 3, 1%; VD 3, 1%) and 9 patients lenalidomide-based (RD, 5%). After induction regimen 23 patients (13%) received additional therapy before transplant: 14 for Progressive Disease (PD), 9 were considered in suboptimal/unsatisfactory response (5 in Partial Response, PR and 4 in Stable Disease, SD). 71 patients received a single ASCT, 106 patients double ASCT; 11 tandem autologous and allogeneic SCT. All patients had a PR/VGPR/CR after ASCT. Treatment related mortality was 1% (3 patients: 2 of them after Allogenic ASCT, 1 for acute Graft versus Host Disease, 1 for Veno Occlusive Disease). After first line therapy 7 patients died: 3 for progressive disease, 4 for other causes (2 myocardial infarction, 1 intestinal ischemia and 1 breast cancer). 90 patients (51%) experienced MM relapse (median time from ASCT 24 months) and were treated according to different chemotherapy schedules. At last follow-up 115 patients were alive (65%), 61 of them in Complete Response, 31 in Very Good Partial Response, 8 in Partial Response, 4 in SD, 11 in PD. Median global overall survival (OS) was 109 months, median global Progression Free Survival1 (PFS1) 51 months and median global PFS2 (time from start therapy to second disease progression or death from any cause) 80 months. According to different induction therapy (chemotherapy vs bortezomib vs thalidomide vs lenalidomide-based) median OS was 117 months vs not reached (more than 96) vs 68 vs not reached (more than 60); median PFS1 was 47 months vs 60 vs 35 vs not reached (more than 60); median PFS2 was 76 months vs 92 vs 57 vs not reached (more than 60), respectively. As reported in literature the improvement of biological, diagnostic and clinical knowledge and the availability of new therapeutic tools translates in improved outcome in MM patients treated in our Center. The introduction of the proteasome inhibitor bortezomib in the induction therapy gave the best results in terms of OS, control of the disease (PFS) and response to second line therapy after relapse (PFS2). Considering the remarkable progress done in the past decade the dream of a cure is a challenge for the future. Disclosures No relevant conflicts of interest to declare.

The clinical and biological spectrum of paroxysmal nocturnal hemoglobinuria (PNH) is variable, ranging from classical hemolytic forms to PNH associated with aplastic anemia or other bone marrow (BM) failure syndromes. We report a previously undescribed case of PNH occurring after autologous stem cell transplantation (ASCT) in a patient affected by relapsing non-Hodgkin’s lymphoma. The intensive chemotherapy and the ASCT resulted in a contraction of the effective hematopoietic stem cell (HSC) pool and a derangement of the immune system. The delayed engraftment and the BM hypoplasia represented a favorable environment for the expansion of the pathological clone. This case is paradigmatic even for the unexpected trend of the PNH clone during treatment with the terminal complement inhibitor eculizumab; in fact, the clone reduced until undergoing unexpected extinction, i.e. the recovery of normal hematopoiesis. Eculizumab seems not to play a direct role in HSC kinetics; the clinical remission probably occurred because the environmental conditions that led to the expansion of the PNH clone were transient and disappeared.

The introduction of new drugs such as thalidomide, lenalidomide, and bortezomib has led to novel treatment strategies and significantly improved the outcome of patients with multiple myeloma (MM). The enhanced knowledge of myeloma pathogenesis has allowed the identification of new therapeutic targets and many clinical trials are either planned or in progress to evaluate these more selective drugs in the near future. The results of these studies, however, will have to be compared with the results of existing novel therapies for the treatment of MM in order to define whether new protocols do not duplicate current new standards and constitute a real improvement. We reviewed the results of a series of phase I, II, III studies with thalidomide, lenalidomide, and bortezomib combinations for newly diagnosed MM in order to define a reasonable standard in terms of activity, efficacy, and toxicity and to have a potentially useful starting point for comparisons with future investigational trials. Three-drug regimens appear to double the complete remission (CR) rate (20%), though regimens containing 4 drugs triple the CR rate (30%), compared with those containing only 2 agents (10%). These improvements in the depth and quality of response translate into a progressive increase in the progression-free survival rate at 2 years (from approximately 54%-62% to 75%, respectively). Conversely, by using additional agents, a marked increase in hematologic toxicity has been described (8%, 28%, and 28% respectively), whereas nonhematologic toxicity appears to be similar (26%, 24%, and 27%, respectively). These results suggest that new trials in the future will constitute significant progress if they can improve on the current relatively favorable efficacy/toxicity ratio. Nonetheless, exciting new combinations in development do hold promise and results from these studies are eagerly awaited.

Recruitment of neoplastic T cells to skin is a critical step in the pathogenesis of mycosis fungoides (MF) lesions. Cutaneous T-cell attracting chemokine (CTACK)/CCL27 attracts memory T cells to skin, resulting in increased cutaneous expression. The interactions between neoplastic cells and skin immune system require further elucidation. CTACK/CCL27 expression and density of dendritic cells (DC), CD8+ and CD4+ lymphocytes were investigated in skin lesions of 52 early-stage MF patients treated by interferon (IFN)-alpha in combination with photochemotherapy (psoralen plus ultraviolet A, PUVA). Skin lesion biopsies obtained at diagnosis and after treatment were studied by immunohistochemistry. Initial CTACK/CCL27 expression was abnormal/suprabasal in 36 patients. Normal/basal CTACK/CCL27 expression tended to correlate with a high DC density and low CD4+ cell density in the neoplastic infiltrate. Treatment induced a significant increase in CTACK/CCL27 expression (chi(2) test: P=0.004). Overall, 33 patients relapsed [median event-free survival (EFS), 46 months] during follow-up (median, 92.5 months, range, 43-165). Normal/basal CTACK/CCL27 expression at the end of treatment correlated with lower rates of recurrence and a longer median EFS (111 months vs. 39 months with suprabasal expression; log rank test: P=0.031). CTACK/CCL27 overexpression in early-stage MF might thus be related to a balance between neoplastic cells and immunomodulant DC. Normal CTACK/CCL27 expression after treatment designates a subset of patients with favorable disease behavior. The mechanisms underpinning CTACK/CCL27 overexpression after therapy in the remaining patients, who are at greater risk of recurrence, warrant further investigation.

Objectives: The therapy of advanced, relapsed or refractory primary cutaneous lymphomas is often unsatisfactory. Recent data indicate a favourable pharmacokynetic, pharmacodynamic and toxicity profile of pegylated liposomal doxorubicin (Peg-Doxo) in primary cutaneous T-cell lymphomas, while in primary cutaneous B-cell lymphomas (PCBCLs), the drug efficacy has never been assessed so far. Methods: We performed a prospective phase II pilot clinical trial of Peg-Doxo monotherapy (20 mg/m2) in PCBCLs. One patient had a marginal zone B-cell lymphoma and four were affected by diffuse large B-cell lymphoma-leg type, all with widespread nodular lesions. Results: All the patients achieved a complete response (CR = 100%) in a short period of time (median 3 months), even when pretreated with radio-chemotherapy. Two experienced a relapse. At follow-up, one patient died for progressive disease; four are in CR after 5, 52, 63 and 69 months. As concerning the toxicity profile, the treatment was well-tolerated, no one decreased or delayed the dose. The haematological toxicity was mild with only one case of grade III neutropenia; a patient showed a grade I neurotoxicity. Dermatological toxicity, in particular the palmar–plantar erythrodysesthesia, did not occurred, probably because of both the low dosages of Peg-Doxo monotherapy and the oral prophylaxis with pyridoxine. Conclusions: In spite of the small number of patients, it emerges that monochemotherapy with Peg-Doxo has a significantly high clinical activity and a good safety profile in PCBCLs, even in aggressive forms, compared with other therapeutic regimens, which are completely reviewed. It suggests the need of further investigations in this field.

Pegylated liposomal doxorubicin (Peg-Doxo) is a promising drug for advanced/recalcitrant primary cutaneous T-cell lymphomas (CTCLs). This prospective phase II trial enrolled 19 patients. We observed overall and complete response rates of 84.2% and 42.1% (with no significant differences between stage I-IIA and IIB-IV patients), and 11% grade III/IV toxicity. After a maximum 46 month-follow-up, median overall (OS), event-free (EFS) and progression-free (PFS) survival were 34, 18 and 19 months. OS, EFS and PFS rates at 46 months were 44%, 30% and 37% respectively. Peg-Doxo seems to be an active and safe principle that should be used in plurirelapsed, early stage-MF and in combination with other chemotherapeutic agents in advanced and aggressive CTCLs.

J Med, 2014). Rd continuous also resulted in overall survival (OS) benefits vs MPT (HR 1⁄4 0.78). This prespecified analysis examined the impact of age ( 75 vs > 75 y) on outcomes in the FIRST trial. Methods: Transplant-ineligible NDMM pts were treated with Rd continuous until disease progression (n1⁄4 535); Rd for 18 cycles (72 w; n 1⁄4 541); or MPT for 12 cycles (72 w; n 1⁄4 547). Starting doses of dexamethasone, melphalan, and thalidomide were reduced in pts aged > 75 y. The primary endpoint was PFS with Rd continuous vs MPT (primary comparators). Key secondary endpoints included OS, overall response rate (ORR, partial response), duration of response (DOR), and safety. Response was investigator-assessed. Results: Median follow-up was 45.5 mo, using a data cutoff of March 3, 2014. 1056 pts (65%) were aged 75 y and 567 (35%) were aged > 75 y. Baseline characteristics were well balanced across arms. ISS stage III disease and severe renal impairment were more common in pts > 75 y vs 75 y. PFS and OS outcomes favored Rd continuous over MPT in both age groups. Rd continuous led to a 36% reduced risk of progression or death vs MPT for pts aged 75 y (hazard ratio [HR] 1⁄4 0.64; 95% CI, 0.53-0.77; P 75 y (HR 1⁄4 0.80; 95% CI, 0.62-1.03; P 1⁄4 .084). OS was improved with Rd continuous vs MPT in both age groups ( 75 y: HR 1⁄4 0.76; 95% CI, 0.60-0.96; > 75 y: HR 1⁄4 0.72; 95% CI, 0.54-0.96). ORR was consistently higher with Rd continuous vs MPT in pts aged 75 y (82.2% vs 70.8%) and > 75 y (78.0% vs 60.6%). Median DOR with Rd continuous was longer vs MPT in pts aged 75 y (36.8 vs 22.1 mo) and pts > 75 y (27.4 vs 21.6 mo). Safety profiles did not differ notably by age. Conclusion: Rd continuous provided PFS and OS benefits vs MPT in pts aged 75 and > 75 y. The safety profile of Rd continuous was comparable across age groups. Rd continuous represents a new standard of care for pts with NDMM who are SCT-ineligible regardless of age.

Introduction: Bendamustine, a bifunctional alkylating agent, exerts a mechanism of action different from that of other conventional alkylators despite it remains mostly unknown. In patients with newly diagnosed or relapsed-refractory MM bendamustine has proven to be active either as monotherapy or in combination with new drugs, particularly bortezomib and immunomodulatory agents. Methods: The preliminary results of this prospective, phase II study conducted in 22 Italian centres are recently published (Blood Cancer J. 2013, 3: e162). Here we present the conclusive results of the combination Bendamustine (70 mg/m2 days 1, 8), Bortezomib (1.3 mg/ m2 days 1, 4, 8, 11) and Dexamethasone (20 mg days 1-2, 4-5, 8-9, 11-12) (BVD) administered every 4 weeks in patients with relapsed-refractory MM of any age, with adequate cardiac, liver and hematological function, not refractory to bortezomib and treated with no more than four previous lines of therapy. The primary endpoint of this study was achievement of a response at least PR, as to IMWG criteria, after four cycles of BVD. Patients achieving a response less than a PR were taken off-study. Patients obtaining at least a PR received two additional treatment cycles followed by a 12-months consolidation phase with cycles repeated every 2 months. Therefore, patients with a PR after the induction phase could receive up to 18 months of treatment and up to 12 cycles of BVD. Results: 75 patients were included in the study. Median age was 68 years (range 41-85 years), 26.5% had ISS stage 3, 19% IgA myeloma and 9% renal failure. Eight of 36 evaluable patients (22%) had high-risk cytogenetics. Patients had received a median of one prior line of therapy (range 1-4). All patients had received prior treatment with new drugs, such as thalidomide (57%), lenalidomide (54.5%), bortezomib (46.5%) or both (20%). Twenty-four patients (32%) were refractory to IMIDs. Best response rate was 75%, including 14 CRs (20%), 22 VGPRs (24%) and 27 PRs (31%). Five patients (6.5%) died early. Only prior treatment with bortezomib significantly reduced the response rate ≥ PR (48.5% vs 80%; P = 0.004). At a median follow-up of 27 months (range 18-38), 45 patients had progressed and 43 had died. Median TTP and PFS were 17 and 12.5 months, respectively while median OS was 24 months (40% at 3 years). After longer follow-up, prior therapy with bortezomib plus lenalidomide was confirmed as the only factor that significantly reduced TTP (9 vs 19 months; HR = 2.7; 95% CI = 1.3-5.8; P = 0.009), PFS (9 vs 15 months; HR = 2.1; 95% CI = 1.2-3.8; P = 0.020) and OS (17 vs 32 months; HR = 2.1; 95% CI = 1.2-3.9; P = 0.043). Grade 3-4 adverse events occurred in 55% of patients leading to therapy reduction in 24% and to protocol discontinuation in 11% of patients. The most frequent severe adverse events were thrombocytopenia (28%), neutropenia (20%), infections (12%), peripheral neuropathy (9%), gastrointestinal (5%) and cardiovascular events (4%). Compared with younger, patients aged > 70 years had a significantly higher incidence of grade 3-4 side effects particularly thrombocytopenia and infections with, consequently, a higher rate of therapy reduction and discontinuation. Moreover, 4/5 early deaths occurred in patients aged more than 70 years. Conclusions: BVD combination is an effective and well tolerated regimen in relapsed-refractory MM. Data suggest that the optimal target of BVD maybe patients younger than 70 years who has not previously received both bortezomib and lenalidomide. Disclosures Offidani: Mundipharma, Janssen: Honoraria. Off Label Use: Bendamustine. Corvatta:Janssen: Honoraria. Ballanti:Janssen: Honoraria. Brunori:Janssen: Honoraria.

Objectives Combined high-dose Interferon-alpha and psoralen plus ultraviolet A irradiation (PUVA) have been reported to be effective in the treatment of early mycosis fungoides (MF); however, our study is the first controlled prospective study in the literature exploring the activity and tolerability of the combination with low dosages and evaluating further clinical outcome of early-MF patients. Methods We carried out a multicentric prospective Phase II clinical study on 89 patients with early-stage IA to IIA MF treated for 14 months with low-dose IFN-alpha2b (6-18 MU/wk) and PUVA. Treatment success was analysed in terms of freedom from treatment failure. Results and conclusions Complete remission (CR) was achieved in 84% and an overall response rate in 98% of cases: six-month CR was associated with a non-confluent skin infiltrate at histology (P = 0.044) and 14-month CR with high epidermal CD1a+ dendritic-cell density (P = 0.030). The combination protocol was successfully tolerated and the most common reason of 'failure' was related to relapse and not to toxicity. Sustained remissions were achieved in 20% of patients. High CD8+ lymphoid T-cell density was associated with a lower relapse rate (P = 0.002). We think that our combination therapy can be considered an alternative approach compared with other modalities. Good immunological host surveillance in the skin lesions seems to be an optimal basis for the therapeutic success.

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

Introduction In the non-thalassemic population hypothyroidism has been associated with an increased risk of cardiac disease while the link thyroid-heart disease has been little explored in thalassemia major (TM). This retrospective cohort study aimed to systematically evaluate in a large historical cohort of TM in the cardiovascular magnetic resonance (CMR) era whether hypothyroidism was associated with a higher risk of heart complications (heart failure, arrhythmias and pulmonary hypertension). Methods From a cohort of 957 TM patients who underwent CMR for myocardial iron overload (MIO) assessment, quantification of biventricular function and detection of myocardial fibrosis within the MIOT network (Myocardial Iron Overload in Thalassemia), we identified 115 (12%) hypothyroid patients. Each hypothyroid patient was matched by sex and age (at the time of the CMR) with two non-hypothyroid patients, creating 115 triples. A cardiac event was considered valid if diagnosed at an age older than the hypothyroidism’s onset age for the hypothyroid patient in the belonging triple. Results Hypothyroid and non-hypothyroid patients had comparable MIO, but hypothyroid patients showed significantly lower biventricular stroke volume index, ejection fraction and left ventricular cardiac index. Accordingly, the prevalence of overall heart dysfunction (LV, RV or both) was higher in hypothyroid patients (43.5% vs 33.5%, P=0.0314). Hypothyroid patients had a significant higher frequency of heart failure (19.1% vs 9.1%, P=0.003) and arrhythmias (11.3% vs 4.3%; P=0.003). Figure1 shows odds ratios (OR) estimating the relationship between hypothyroidism and cardiac involvement. Hypothyroid patients had a significant higher risk of heart dysfunction, heart failure and arrhythmias, also adjusting for the endocrine co-morbidity. Conclusions Hypothyroidism seems to increase the risk for heart failure, arrhythmias and heart dysfunction in TM patients. Our data confirm the link thyroid-heart disease also in TM patients and they stress the need to prevent hypothyroidism in this population. Disclosures: No relevant conflicts of interest to declare.

Paroxysmal nocturnal hemoglobinuria (PNH) derives from a non malignant clonal expansion of hematopoietic stem cells (HSCs) harbouring somatic mutations of the X-linked PIG-A gene, leading to the complete or partial loss of glycosylphosphatidylinositol membrane-anchored proteins (GPI-APs) from the cell surface of the HSCs and of their mature progeny. The resulting intravascular hemolysis is caused by uncontrolled activation of the complement cascade and determines hemoglobinuria, anemia, fatigue, renal impairment, pulmonary hypertension, smooth muscle dystonias and thromboembolism, with a bad quality of life. Moreover PNH is usually embedded with a various degree of bone marrow (BM) failure syndromes, from mild cytopenias up to aplastic anemia.We describe 5 PNH patients: 3 males and 2 females; median age was 36 year (18-54). All developed PNH after other haematologic disorders. The first one was a rare case occurring after autologous stem cell transplantation(ASCT) for relapsing non-Hodgkin’s lymphoma; the second had experienced an aplastic anemia, successfully treated with immunosuppressive therapy; two were affected by anemia and thrombocytopenia of unspecified nature; in the fifth young patient (18 ys), hereditary spherocytosis had been diagnosed 2 years before, based on erythrocyte membrane protein analysis and splenectomy had been performed. All patients had strong intravascular hemolysis (reticulocytosis, elevated LDH, gross hemosiderinuria); the flow cytometry immunophenotyping study of GPI-APs expression on peripheral blood cells showed large cellular populations of erythrocytes, granulocytes and monocytes which had undetectable expression of GPI-APs, suggesting PNH. According to the previous hematological disorders or therapy (ASCT) in the mentioned series of patients, PNH occurred after 2, 5, 9, 1 and 2 years respectively. Three patients were transfusion dependent. After unsuccessful therapy with prednisone, folate and even cycles of steroid therapy, the terminal complement inhibitor eculizumab (EC) was started. All the patients received vaccination against Neisseria meningitides. EC was infused according to the standard schedule, 600 mg weekly for 4 weeks, followed by 900 mg every other week. EC was started respectively after 7 months, 24 months and 8 years from PNH diagnosis in the first three patients and after 4 months from PNH diagnosis in in the last 2 patients. The intravascular hemolysis was completely controlled in all patients. Only one patient continued but reduced erythrocyte transfusions; she shows significant extravascular hemolysis, building up GPI- C3d coated erythrocytes (DAT ++), and is candidate for splenectomy. Despite the different haematological response all 5 patients experienced a dramatic clinical improvement in the quality of life. In the transplant patient the cytometry showed a progressive reduction and ultimately extinction of the pathological clone; this provided the unique possibility to discontinue treatment after 12 months, then maintaining remission for some years. Probably in this case, EC did not play any direct role in the kinetics of the PNH clone, while the conditions which led to expansion of the clone were somehow unique and possibly related to the ASCT and resulted transient. Our small series, including even 2 rare cases (one pediatric PNH patient and one occurred after ASCT) shows how variable are the clinical and biological spectrum of manifestations in this strange and fascinating disease; moreover its clinical evolution in each single patient remains frequently unpredictable. Disclosures: No relevant conflicts of interest to declare.

Abstract 3953 Oral bexarotene, a novel retinoid that selectively activates retinoid × receptors, is approved for the treatment of cutaneous manifestations of refractory or relapsed cutaneous T cell lymphomas (CTCL) as monotherapy. Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of CTCL who were refractory or intolerant to the previous therapy but the recommended bexarotene dose of 300 mg/m2/day is associated with significant side-effects. Novel studies are looking for synergistic therapies combining lower bexarotene doses in order to reach the same or even better outcomes while avoiding a negative impact on the quality of life. Early studies with bexarotene and psoralen plus ultraviolet A photochemotherapy (PUVA) show promise. Synergy between bexarotene and PUVA may derive from retinoid-induced reductions in epidermal thickness, which consequently improves UVA penetrations, and/or from retinoid-specific enhancement of immune functions. The aim of this study was to assess the efficacy and safety of a 2 stage-protocol (induction and maintenance) with low dose bexarotene (Targretin) and PUVA in refractory and/or resistant patients with Mycosis Fungoides (MF) and Sézary Syndrome (SS). A prospective, phase 2 clinical study was conducted between February 2007 and May 2010 by two Italian academic hospital centers. We enrolled 15 patients with stages I through IV MF/SS; all patients had failed PUVA or several systemic regimens. Response to treatment was assessed with clinical endpoints such as remission of symptoms (pruritus, pain, sleep disturbance) and signs (erythema, scaling, thickness of plaques, presence of nodules, tumours, peripheral lymphadenopathy). Complete remission (CR) was defined as the disappearance of all clinical evidence of disease for at least 4–6 weeks, partial remission (PR) as 50% or more decrease in extent or severity of disease. Overall response (OR) rate was defined as the combination of CR/PR. Patients with MF/SS were started with bexarotene (150 mg/day) and PUVA (three times weekly). Increments of bexarotene to a maximum of 300 mg/day were scheduled. Patients who achieved CRs and PRs during the induction remained on the same dose in the maintenance period, whereas the frequency of PUVA was gradually reduced. A preventive therapy to lower triglycerides and elevated thyroid hormone levels in the blood, was administered in all cases; therapeutic dietary and lifestyle changes were often recommended. Primary endpoint were OR rate at the end of induction and maintenance; secondary endpoints were safety and event-free survival (EFS). Kaplan-Meyer method and long-rank test was used for statistical analysis. All 15 patients (8 M and 7F) were evaluable for response; ten patients had early-stage (IB) and 5 had advanced stage (2 IIB, 1 IIIA, 1 IIIB, 1 IV). The median age was 68 years (34-81). The OR rate was 93% with 33% CR after induction period and 93% with 47% CR at the end of the protocol. A response was observed even in 1 case with SS and in 2 cases with MF in large cell transformation. Significantly, patients treated previously with PUVA monotherapy achieved better and faster CR compared with those treated with more than one systemic therapy (83% and 22% respectively; χ2 test, P=0.041; median time to maximal response 4 weeks and 8 weeks respectively, P=0.007). Median EFS at 37 months, for the whole group was 27 months. All patients have been closely monitored for adverse events during treatment; 2 of 15 patients (13%) had mild grade I-II asthenia, hypercholesterolemia and central hypothyroidism, 2 patients developed elevations of CPK (grade 3). With regard to hematologic toxicity, leukopenia was mild (grade I) and occurred in 3 patients (20%). In conclusion, our study have demonstrated a greater than 90% response rate in patients with all stages of CTCL refractory or intolerant to the previous therapies; the efficacy is more pronounced in patients previously treated with PUVA monotherapy. Starting treatment at lower dose of bexarotene followed by dose escalation may improve the efficacy and safety of both bexarotene and PUVA. Moreover the additional maintenance phase seems to improve the OR and length of remissions. Disclosures: Leoni: Celgene: Honoraria.

Abstract 3019 Background: Panobinostat (LBH-589) is a pan-deacetilase inhibitor that targets histone proteins increasing tumor suppressor gene activities leading to cell-cycle and differentiation arrest besides to target non-histone proteins such as HSP90, aggressomes, p53, HIF-1a, and a-tubulin somehow promoting cell death. Panobinostat, combined with steroids and/or immunomodulatory drugs, demonstrated additive/synergistic activity in Multiple Myeloma (MM) and ability to overcome previous chemoresistance. Several combination studies with Panobinostat plus novel drugs are now ongoing in MM. Methods: This is a multicenter, open-label, phase I-II study exploring the combination of a standard therapy such as MPT (Melphalan 0.18 mg/kg per os for 4 days, Prednisone 1.5 mg/kg per os for 4 days, Thalidomide 50 mg/day continuously) with Panobinostat 15 mg p.o. thrice weekly for 3 weeks in a 28-day cycle to assess safety profile and activity of this combination in patients with relapsed/refractory MM having adequate performance status and haematological, cardiac, liver and neurological functions. The study was designed according to the Briant and Day method that plans a “dose-escalation phase” to determine both the MTD and the activity of the study drug and an “expansion-phase” in which the MTD of the study drug is used to further assess its safety and efficacy. Despite in the first phase of this study 19 patients were planned according to the study design, protocol was amended after 13 patients had been enrolled since more than 50% grade 3–4 toxicity occurred although response criteria were met. Therefore, Panobinostat was reduced to 10 mg p.o. thrice weekly for 3 weeks in a 28-day cycle whereas the dose of drugs of the MPT combination was not modified. Toxicity and response were assessed according to CTC version 4 and IMWG criteria, respectively. Results: As of February 2010, 24 patients were enrolled in this study. Median age was 71.5 years (range 40–81 years) and 12 patients (50%) had ISS 2–3 score. Patients had received a median of 2 prior therapies (range 1–6) and 5 (21%) three or more prior lines of therapy. Sixteen (73%), 13 (54%), 18 (75%), 11 (46%) and 9 (37.5%) patients had been previously treated with ASCT, thalidomide, bortezomib, lenalidomide and all 3 new-drugs, respectively. Seven patients (29%) were refractory to the last therapy. Twelve patients (50%) had a disease history longer than 5 years. In the first 13 patients treated with Panobinostat 15 mg, grade 3–4 thrombocytopenia and neutropenia occurred in 6 (46%) and 9 patients (69%), respectively. Moreover, 4 patients (31%) developed non-hematological adverse events such as fatigue, constipation, infection and arrythmia. In the group of 11 patients treated with Panobinostat 10 mg, grade 3–4 thrombocytopenia decreased to 18% (2 patients) but neutropenia was still high (8 patients: 72.5%). Three patients (27%) had grade 3–4 non-hematological toxicity (one fatigue and two constipation). No patients had QTcF prolongation or severe neuropathy. Dose adjustment was necessary in 9 patients (37.5%, all due to hematological toxicity) while 6 patients (25%) interrupted the protocol because of side effects (5 due to no resolution of grade 3–4 hematological toxicity within 4 weeks and one due to atrial fibrillation). One patient (4%) died on study due to sepsis during prolonged neutropenia. Response ≥ PR were observed in 12 patients (50%) including 4 VGPR and 8 PR. Additionally, 2 patients had MR and 8 SD. Only 2 patients progressed during treatment. There was no difference between the two cohorts of patients (Panobinostat 15 mg and Panobinostat 10 mg) in terms of response ≥ PR (54% vs 45.5%) or disease progression (7.5% vs 9%). Notably, response was obtained also in 2/7 patients (28%) who progressed during bortezomib or IMIDs. Conclusions: This study suggests that MPT-Panobinostat combination has an encouraging anti-myeloma activity since responses were still seen in patients with advanced stage or resistant to new drugs diseases. Different schedules of Panobinostat/melphalan should be explored to reduce haematological toxicity. Disclosures: Offidani: Celgene: Honoraria. Off Label Use: Panobinostat in relapsed/refractory multiple myeloma. Cavallo:Celgene: Honoraria. Polloni:Celgene: Honoraria. Ballanti:Celgene: Honoraria. Catarini:Celgene: Honoraria. Alesiani:Celgene: Honoraria. Corvatta:Celgene: Honoraria. Gentili:Celgene: Honoraria. Boccadoro:Celgene: Honoraria, Research Funding. Leoni:Celgene: Honoraria. Palumbo:Celgene: Honoraria, Research Funding.

Abstract 4959 Introduction Notwithstanding recent findings, multiple myeloma (MM) remains an incurable disease and almost all treated patients invariably relapse. The clinical presentation of recurrent MM is heterogeneous. Extramedullary relapses (EMRs) are rare, but recently an increased frequence has been reported, probably favoured by the new diagnostic imaging techniques, and maybe caused by the induction chemotherapeutic regimens. Patients We report 6 cases of EMRs, occurring after a median time of 3 years (yrs) from stem cell transplantation (SCT). Five (A,B,C,D,E) male and one (F) female patients (pts), median age 50 yrs (39-63), were affected by IgGk (5 pts) and IgAk (1 pt) MM, all in stage IIIA. At diagnosis one pt (E) had an EM sternal extrapleural plasmocytoma, which was successfully irradiated. Three pts were treated with total therapy II (B,D,E), 2 pts with VAD and autologous-SCT (ASCT) (A,F) or ASCT followed by mini allogeneic-SCT (AlloSCT) (C). The patient F showed an orbital localization after VAD, before ASCT. After SCT all 5 patients resulted in complete remission (CR). Results A systemic relapse occurred after 3 yrs in pt A, who was treated according to EDAP chemotherapy (etoposide-dexamethasone-cytarabine-carboplatin); after 2 yrs in pt B, treated with combination of bortezomib-thalidomide-dexamethasone (VTD). Both pts reached a second CR and a maintenance with thalidomide was started. However, after one yr, pt A had a lumbar paravertebral EMR, and pt B lumbosacral extradural and dorsal endocanalar EMRs, besides a tumour mass in the pelvic bone, jutting in abdominal cavity. As regarding the other 4 pts, C had a pulmonary embolism 4 yrs after first CR and an EMR was demonstrated, looking as a 6 cm long lumbar mass, infiltrating the inferior vena cava and determining thrombosis of it. In pt D the EMRs occurred 2 yrs after ASCT: one lumbar 3 cm long mass and another of 9 cm of diameter in the pelvic bone. Finally patient E and F had a dorsal 7 × 5 cm paravertebral and a femoral mass, respectively, 1 and 4 yrs after ASCT. Only in pt B elevated lactate dehydrogenase levels were present when EMR was diagnosed. Therapeutic approaches to EMRs were represented by radiotherapy; in addition pts B,C,E,F were treated with EDAP, without response; AlloSCT was performed in pt A; PAD plus lenalidomide in pt D. The latter (D) reached a third CR, so an AlloSCT was performed, but unfortunately the patient died because of hepatic acute GVHD. The other patient firstly treated with AlloSCT (pt A) was refractory and was treated with VTD chemotherapy, but he recently showed nodular lesions in the liver, showing hypercaptation at PET. Chemotherapy with lenalidomide, dexamethasone and cyclophosphamide (LDC) was started, but after 2 cycles a progressive hepatic EM disease (lesion of 7 cm) is now present. As we mentioned 4 patients (B,C,E,F) has been treated with EDAP, which resulted ineffective. Patient C, after EDAP, started bortezomib-dexamethasone therapy (VD), with initial clinical and radiological response (PET negative); however shortly after, he showed other scapular and axillary PET positive EMRs; radiotherapy, thalidomide-dexamethasone (TD) and then donor lymphocyte infusions (DLI) from the allogeneic donor were performed; as results the previous hypercaptant scapular regions resulted negative at PET, but various new lesions appeared, so a salvage therapy with LDC has been recently started. Femoral and humeral radiotherapy has been simultaneously started. Patient F died soon after EDAP because of renal failure. The other 2 pts, refractory to EDAP chemotherapy, showed successive EMRs. The patient B died after progressive cranial, orbital, encephalic EMRs, complicated by CD56 negative plasma cell leukaemic meningitis. Patient E developed maxillary, cranial, orbital, zygomatic MM masses, pelvic, humeral and radial fracture and died. Discussion From the initial diagnosis of MM one pt died after 3 and three patients died after 4.5 yrs respectively; 2 patients are still long survivors after 7 and 9 yrs. EMRs could be the consequence of a clonal selection after high dose chemotherapy, with the persistence of a plasmacellular clone after induction therapy before ASCT. In spite of the small number of patients, our experience shows that EMRs appear refractory to radiotherapy and to conventional and even high dose chemotherapy. Instead it seems that regimens including new drugs (thalidomide, bortezomib, lenalidomide) could be useful, prolonging survival, as demonstrated for patient A and C, still surviving, and for patient D, who died in CR for acute GVHD. Disclosures No relevant conflicts of interest to declare.

Idiopathic retroperitoneal fibrosis (RPF) is a rare clinical entity characterized by the progressive proliferation of connective tissue in the retroperitoneum. The chronic inflammatory process can entrap the retroperitoneal structures, mainly the ureters and the great vessels. Although the causes are unknown, immunogenetic factors and immunopathologic/autoimmune mechanisms are probably involved. The pathogenesis appears to be related to IgG4 autoimmune mechanisms (“hyper-IgG4 disease”). Surgical treatments are frequently performed such as ureterolysis and aneurysm repair; steroids and immunosuppressive agents are also used. In January 2008 a 62-year-old Caucasian man was referred to our institution for mild leucopenia and progressive thrombocytopenia. In 1999 he had a diagnosis of RPF treated surigically and complicated by chronic renal failure. He did not undergo regular follow-ups during the following years. When he came to our attention his peripheral blood count showed: Hb 14.5 g/dl, WBC 3.800/uL (N 60%, L 28%, M 8%), Plt 79.000/uL, confirmed by numerous measurements. He did not present signs or symptoms of cutaneous or mucosal bleeding and he did not report any recurrence of infectious episodes. At physical examination the spleen was palpable at 5 cm from the ribs, neither liver enlargement nor superficial lymphoadenopathies were noted. A peripheral blood (PB) smear showed only anisocytosis of red blood cells. To exclude an underlying hematologic disorder a bone marrow (BM) aspiration and a BM trephine biopsy were performed, both demonstrating a regular representation of the three hematopoietic series without any pathologic patterns. Cytogenetic examination revealed normal karyotype and molecular biology analyses resulted negative for Bcr/Abl rearrangement and for mutation V617F of JAK2 gene. Routine laboratory tests including liver function, LDH, Beta2 microglobulin serum levels, autoimmune tests, PB mononuclear cell immunophenotyping, viral sierology resulted within normal range. Abdominal ultrasound showed about 95 cm2 homogeneous splenomegaly and revealed an hyperechogenic rounded mass measuring 5–6 cm that completely embraced the splenic hilum. Splenic vein at the source was not visible and splenic flow was not measurable because of the hilum compression. Splenic vein in the retropancreatic site was measurable only partially: it presented thin caliber with normal directed blood flow inside. The abdominal CT exam confirmed the presence of a 5.6×7 cm solid tissue mass embracing the pancreatic tail and the splenic vessels and it extended across the spleno-pancreatic ligament. Moreover, the mass also involved the upper part of the left adrenal gland expanding until peri-renal space. Radiologically the mass was considered as RPF. In this case the retroperitoneal fibrotic tissue compresses the splenic hilum reducing the blood flow through the spleen thus causing congestive splenomegaly. The increase size of the spleen is responsible for thrombocytopenia as well as for leucopenia. The mechanism underlying splenomegaly-related thrombocytopenia is an induction of a reversible pooling of up to 90 percent of total body platelets. Both platelet production and the survival of platelets within the spleen are normal. Pooling is the major factor responsible for thrombocytopenia in uncomplicated splenomegaly. In this patient no hematologic specific treatment is indicated since neither thrombocytopenia nor leucopenia have clinical relevance. The aim of the therapy should be to reduce the progression of the fibrotic tissue to prevent further organ-related damages.

Combination therapy is commonly used in the treatment of advanced and aggressive cutaneous T-cell lymphomas (CTCL), like Mycosis Fungoides (MF) and Sézary Syndrome (SS). Alemtuzumab, the humanized anti-CD52 antibody primarily developed for the treatment of B-CLL, has been also administered effectively in patients with CTCL as monotherapy, but it might be an ideal candidate for combination therapy either with a biological immune response modifier like interferon (IFN)-α, or with a drug known to be particularly active in CTCL like gemcitabine. No data on the activity of combination schemes including alemtuzumab in CTCL seem to be available. The aim of this study was to explore the clinical activity of alemtuzumab in two combination modalities, including either IFN-α or gemcitabine. We enrolled 5 patients, 4 males and 1 female, affected by SS/erythrodermic MF, with a median age of 57 yrs (43–74) and a median disease history of 21 mo.s (9–95). Two patients were treated with both combination schemes. Before starting therapy, all patients except one had a rapidly progressive disease, relapsed or refractory to previous treatments, and had previously received three or more systemic chemotherapy regimens. Most patients had reduced performance status and all had severe itching. Four patients received alemtuzumab in combination with IFN-α: subcutaneous alemtuzumab was administered at 3 mg on day 1, 10 mg on day 3, followed by 15 mg on alternating days for 7 total doses; after a further 3 months of treatment with IFN-α (3 MU three times weekly) the patients received reinduction with alemtuzumab (10 mg weekly for another month). Three patients received alemtuzumab in combination with gemcitabine: subcutaneous alemtuzumab was given at 10 mg on days 1, 8 and 15 of a 28-day schedule in combination with gemcitabine at a dose of 1200 mg/m2 intravenously (median number of cycles=4). Trimethoprim/sulphamethoxazole (twice daily 2 times per week) and valacyclovir (500 mg twice daily) were administered from day 2 until at least 2 months after alemtuzumab discontinuation. The response (complete/CR, partial/PR, stable disease/SD) was assessed in skin, lymph nodes and peripheral blood, by using the SWAT criteria and by comparing the absolute number of circulating Sezary cells (SC) detected by flow-cytometry before and after treatment. The overall response (OR) was determined as the worse result obtained in the different sites. The OR rate was 57.1% (4 PR vs 3 SD), higher in the group treated with alemtuzumab and gemcitabine (66.7%: 2 PR vs 1 SD) than in the group treated with alemtuzumab and IFN-α(50%, 2 PR and 2 SD). The better response rate obtained in the group treated with gemcitabine was due to the higher activity in the skin (2 CR, 1 SD vs 2 PR, 2 SD) and in the lymph nodes (3 PR vs 3 PR, 1 SD). The circulating SC count was low at the end of therapy (median, 164, range, 24–530), with a lower median value in the group treated with gemcitabine (131), than in the group treated with IFN-α (303). Itching, self-assessed on a 0 to 10 visual analog scale, was significantly reduced from a median score of 9 before treatment, to 1 at the end of therapy. Both combination treatments were well tolerated. Infusion-related adverse events were not reported. Grade 3–4 hematologic toxicity was observed only in one case treated by alemtuzumab and gemcitabine (grade 3 leukopenia). One patient from the group treated with alemtuzumab and IFN-α had infectious complications (CMV pneumonitis and pulmonary aspergillosis). Two patients treated with gemcitabine showed CMV detectable viral load in peripheral blood without any occurrence of complications. All patients treated with alemtuzumab and IFN-α experienced a progressive disease, respectively at 5, 9, 11, 12 months, whereas the 3 patients treated with alemtuzumab and gemcitabine are still in PR at 4, 10, 12 months (median overall PFS: 9 mo.s). At last follow-up, 3 patients are still alive with disease, while two had died, one for unrelated causes and the other for progressive disease. Although the present series is small, our observations point towards a potential role of alemtuzumab in combination schemes in heavily pretreated CTCL patients, as the response rate (57%) appears better than that reported in the literature for alemtuzumab alone (OR 33%), and the toxicity profile of both combination seems to be fairly acceptable. Moreover, gemcitabine might be a better candidate than IFN-α for combination therapy with alemtuzumab, since the progression-free survival seems to be prolonged.

The oral anticoagulant therapy (OAT) in oncologic patient is often problematic because both the haemorragic risk and the thrombotic risk, i.e. the recurrence of venous thromboembolism, are increased. Many studies have been conducted in patient with solid neoplasms; it remains still unclear whether these results could be entirely extrapolated to patients with haematological malignancies. Our aim was to analyse the clinical outcomes and the control of anticoagulation, measured as % time in target INR range, in the patients with cancer compared to patients without cancer; moreover we focused on patients with haematological neoplasms. A total of 500 patients were recruited in 6 years, regardless of the indication for OAT; 146 (29%) of them were affected by cancer (47 haematological and 99 solid neoplasms); those being treated with warfarin for less than 1 month were excluded from this analysis. It resulted that patients affected with cancer had a worse anticoagulation control, compared to those without cancer (55% vs 60%; p