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Background Ruxolitinib (Ruxo), an orally bioavailable and selective inhibitor of JAK1 and JAK2, significantly reduces splenomegaly and disease-related symptoms in patients with myelofibrosis (MF). However, no clear survival benefit has been demonstrated, which may in part reflect suboptimal drug exposure related to lower dosages needed to minimize hematological toxicity, specifically cytopenias. Furthermore, the optimal management of specific conditions such as leukocytosis or thrombocytosis in patients under ruxolitinib therapy is still undefined. In these cases, combining ruxolitinib with a cytoreductive agent like hydroxyurea (HU) might improve hematological response. Aims: To evaluate the efficacy and safety of Ruxo and HU combination. Methods This observational multicenter study, conducted from April 2012 to April 2017, enrolled 20 adult patients with a confirmed diagnosis of primary myelofibrosis (PMF), post-polycythemia vera (PPV-MF), or post-essential thrombocythemia (PET-MF) with hyperproliferative manifestations of the disease not controlled by Ruxo therapy. All patients we enrolled into the study had received Ruxo at a starting dose based on baseline platelet count. Patients were included into the study when Ruxo proved to be unable to reduce WBC and/or platelet count to within normal range (WBC Results The addition of HU was started after a median time of ruxolitinib monotherapy of 6.5 months (range 1-49.6 months): 17 patients (85%) started HU treatment due to lack of WBC control, whereas the remaining 3 patients (15%) started for the lack of platelet control. While on Ruxo monotherapy, ten patients (50%) needed a dose reduction due to hematological toxicity and three patients temporarily discontinued Ruxo due to severe thrombocytopenia (15%). After 14.5 months (range 2-195) median time of combination therapy in 8 patients the Ruxo daily doses increased (mean increase = 5.1 mg BID), in 9 the dose was unchanged despite the addition of HU, and only in three cases the ruxolitinib dose had to be reduced (mean reduction = 3.4 mg BID). Overall, the mean daily dose of Ruxo administered to the whole cohort of patients increased by 1.8 mg BID (P=.013), and only one patient had to discontinue Ruxo, due to severe thrombocytopenia. Non-hematological adverse events were not observed. Among the 17 patients who started combination therapy to control WBC count, 14 (82.3%) obtained a WBC response, whereas, among the three patients who started HU in association with Ruxo in order to reduce platelets count, two (66.6%) achieved a platelet response. In addition, 12 patients of the whole study cohort had clinical improvement in MF-associated symptomatic burden, with 9 of them showing spleen and symptoms response and the remaining three only spleen response. Thus, a clinical response of any type was obtained in 8 patients (40%) during Ruxo monotherapy and in 17 patients (85%) during Ruxo-HU combination (P=.003). Of note, all 8 patients in which Ruxo dose was increased during combination had at least one type of drug-related clinical response. Conclusion In conclusion, the combination of HU with Ruxo yielded a high clinical response rate and increased Ruxo exposure in patients with hyperproliferative forms of MF. The association was very well tolerated, and the hematological toxicities mostly and were generally manageable with dose reductions and/or supportive treatment. Disclosures Pane: AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau.

Plasmablastic multiple myeloma is an uncommon morphological variant of multiple myeloma with aggressive clinical course and poor outcome. Its differential diagnosis includes plasmablastic lymphoma, a variant of diffuse large B-cell lymphoma with frequent extranodal presentation, which usually affects immunosuppressed patients and is virtually indistinguishable from plasmablastic multiple myeloma on the basis of histology solely. Differential diagnosis relies on close clinical-pathological correlation. Herein, the authors report a case of aggressive multiple myeloma occurring in a 48-year-old patient with pure plasmablastic morphology, expression of T-cell markers CD3 and CD4, and cutaneous involvement as first presenting sign. Heterotopic expression of T-cell markers has been described in literature for both plasmablastic multiple myeloma and plasmablastic lymphoma. The causative mechanisms underlying this aberrant phenotype have not yet been elucidated; nevertheless the possibility of this rare finding should be considered to avoid misinterpretations. Remarkably, despite occurring rarely, cutaneous involvement could be observed at an early stage or even be the first manifestation of disease in particularly aggressive forms of myeloma. As a consequence, the presence of cutaneous lesions should not favor a straightforward diagnosis of plasmablastic lymphoma. The importance of a correct differential diagnosis lies in its therapeutical implications.

Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine–rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008–2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43–86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity

BACKGROUND: The combination schedule of rituximab, fludarabine and cyclophosphamide is considered the standard therapy for fit and young untreated chronic lymphocytic leukemia (CLL) patients. However, although this therapy improves progression free survival (PFS) and overall survival (OS), it has been associated with increased toxicity: 76% of the patients experienced at least one grade 3 or 4 event. Recently, encouraging clinical results in terms of safety and efficacy have been obtained using bendamustine in combination with rituximab (R-B) in untreated CLL patients. PURPOSE: We performed a multicentre retrospective study to assess safety and efficacy of R-B in a large group of untreated CLL patients. METHODS: One hundred and thirty six untreated CLL patients were recruited from 16 Italian Institutions and included in the present analysis. The median age was 69 years (range 43–85), with 49.3% of patients older than 70 years; 53.7% of cases were male. All patients had active disease as defined by the NCI-WG, and 27.2% were at Binet stage C. FISH data, available in 86/136 cases, identified a del(17p) in 5.1% of the patients and del(11q) in 5.9%. Sixty-four patients (47.1%) had a creatinine clearance ≤70 mL/min. Fifty-six % of cases showed a WHO performance status (PS) of I-II and 61% a CIRS comorbidity index >0. RESULTS: Among the 136 patients, 90 cases (66.2%) received B at the dosage of 90 mg/m2 on day 1 and 2 every 28 days, the remaining 46 cases received B at the dosage of 70 or 80 mg/m2. R was administered at the dosage of 375 mg/m2 on day 1 of all cycles in 59.6% of cases, while 40.4% received 375 mg/m2 on day 1 of the first cycle and 500 mg/m2 on day 1 of the other cycles. A total of 725 cycles were administered with a median number of 6 cycles per patient. Eighteen patients (13.2%) required early discontinuation of therapy before the sixth cycle for serious infections (n=7), persistent hematological toxicity (n=5), grade 4 dermatological toxicity (n=3), withdrawal of consent (n=2), hypersomnia and depression (n=1). Grade 3 or 4 adverse events for neutropenia, thrombocytopenia, and anemia were documented in 25.8%, 25.8%, and 16.2% of patients, respectively. Grade 3 or 4 severe infections occurred in 6.6% of patients. The overall response rate (ORR) was 93.4%, 48 patients (35.3%) achieved a complete response (CR), 79 (58.1%) a partial response (PR), 8 (5.9%) a stable disease (SD) and in 1 patient (0.7%) no response assessment was performed due to death prior to terminating therapy. In the high-risk group with del17p, 5/7 (71.4%) cases achieved a PR and 2 a SD. Age >70 years (P=0.026) and del17p (P=0.007) were the only two parameters significantly associated with a lower response rate, while del11q and unmutated IGHV, as well as creatinine clearance 0 did not seem to impact on achievement of response. The only parameter predictive of the probability of achieving a CR was an age CONCLUSIONS: The clinical practice of the Italian centers taking part in the study confirms that chemoimmunotherapy with R-B was an effective and well-tolerated treatment for untreated CLL patients. In patients with del17p the therapy appears to be less efficacious. Disclosures Off Label Use: Bendamustine in diffuse large B-cell lymphoma. Zinzani:Genentech, inc.: Membership on an entity's Board of Directors or advisory committees.

Background. The therapeutic approach in thrombocythemic patients with Philadelphia negative chronic myeloproliferative neoplasms (Ph- MPN), in order to result cost-effective (primum non nocere), is commonly driven by the risk factors considered in the gradually updated guidelines. However, no studies were addressed to evaluate if and how the real-life therapeutic approach changed in the last decades. Objective. To evaluate, in a large series of thrombocythemic patients with Ph- MPN, the impact of clinical and biological characteristics at diagnosis on the therapeutic approach adopted before and after the publication of the Italian guidelines for essential thrombocythemia therapy [1]. Methods. The analysis considered, in the patients of the Registro Italiano Trombocitemie (RIT), the clinical and biological characteristics at diagnosis, and the treatment ongoing after 3, 6, 12, and >12 months from diagnosis (antiplatelet alone [AntiPLT]; cytoreductive alone [CYT]; CYT+AntiPLT). Results. The analyzed patients were 2418, 914 (38%) males and 1504 (62%) females, with a diagnosis (PVSG or WHO criteria) performed before and after 2005 in 51% and 49% of cases, respectively. The rate of ongoing treatment with AntiPLT, CYT, and CYT+AntiPLT increased as follows: at 3rd month 16%, 12%, and 31%; at 12th month 17%, 14%, and 39%; after 12 months 19%, 16%, and 55%, respectively. Patients treated with CYT or CYT+AntiPLT did not significantly differ in their characteristics at diagnosis. The analysis of data at the 3rd month (initial phase) showed that: 1) CYT±AntiPLT treatment, ongoing in 43% of patients, was significantly related, in univariate analysis, to male gender, older age, prior thrombosis, higher thrombocytosis, leukocytosis, higher HCT level, CVRFs, comorbidities, symptoms, splenomegaly, hepatomegaly, and bone marrow fibrosis grade >0 (no relationship with JAK2 V617F mutation, and prior hemorrhage); in multivariate analysis, it was significantly related to age >60 y, age 40-60 y, prior thrombosis, PLT >1000 x109/L, PLT 700-1000 x109/L, symptoms, and comorbidities. 2) patients with standard high risk (age >60 y, and/or prior thrombosis, and/or PLT >1500 x109/L ) were receiving CYT±AntiPLT (59%), AntiPLT (7%), and no treatment (34%). 3) patients with standard low risk were receiving CYT±AntiPLT (22%), AntiPLT (27%), and no treatment (51%). Low risk patients receiving CYT±AntiPLT had age 40-60 y (73%), CVRFs (59%), symptoms (53%), comorbidities (42%), PLT 1000-1500 x109/L (35%), PLT 700-1000 x109/L (42%), JAK2 V617F mutation (30%), WBC >10 x109/L (22%). 4) in patients receiving CYT±AntiPLT, the initial cytoreductive drug and the median age were: hydroxycarbamide (80%, 68 y), anagrelide (6%, 49 y), interferon alpha (9%, 42 y), pipobroman (2%, 72 y), busulfan (3%, 70 y). The AntiPLT drug mostly used was low dose ASA (86-90% of cases, at any age). 5) Patients diagnosed after 2005, compared with those diagnosed before, showed a higher rate of CYT±AntiPLT treatment when at standard high risk ( 64% vs 53 % p Conclusion. The initial (within the 3rd month) therapeutic approach in the thrombocythemic Ph- MPN patients of the RIT was after 2005 relatively compliant with the 2004 Italian guidelines. In fact, the rate of CYT±AntiPLT treatment in patients with standard high risk was higher than before (64% vs 53%, p [1] Barbui T et al. Haematologica 2004; [2] Harrison C et al. NEJM 2005; [3] Gisslinger H et al. NEJM 2013; [4] Passamonti F et al. Blood 2012; [5] Barbui T et al. Blood 2012 *The RIT is a project of the GIMEMA Foundation Disclosures Gugliotta: Shire : Honoraria.

The present management of onco-haematologic patients may require continuous infusion of cytotoxic drugs, use of drugs or concentrated ion solutions which are toxic for the endothelial wall of small vessels, infusion of large amounts of antibiotics or antimycotics, red blood cell and platelet transfusion, and not rarely parenteral nutrition. Such a complex therapy needs a vascular access by a central vein catheter (CVC) insertion. Many types of CVC are available at present: tunnelled Hickman or Hickmanlike catheters, subcutaneous ports, tunnelled catheters with Groshong valve, external untunnelled catheters.