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Background: the Registro Italiano Trombocitemie (RIT) was activated mainly to evaluate the diagnosis and therapy appropriateness in the thrombocythemic patients with Ph-negative myeloproliferative neoplasm (MPN) observed in the adhering centers. Objective: to evaluate how the diagnostic and therapeutic approach changed in the RIT patients diagnosed with thrombocythemic MPN in the last two decades. Methods: the RIT centers registered by a web-based system during the years 2005-2014 their thrombocythemic MPN patients, and semesterly updated their follow-up data. For patients diagnosed before 2005, the data on diagnosis and prior follow-up were retrospectively collected. The diagnostic process and the initial treatment (started into the first year after diagnosis) were comparatively analyzed in the patients diagnosed before and after 2005. Results: the RIT centers registered 2629 patients. 2388 of them, object of this analysis, were diagnosed between1995 and 2014: 1098 (46%) in the decade 1995-2004 (Group I), and 1290 (54%) in the decade 2005-2014 (Group II). The diagnostic process in the patients of Group II and Group I included bone marrow biopsy (BMB, performed into 1 year and before any cytoreduction): 85% vs 80%, p The patients of Group II, as compared with those of Group I, showed a similar gender distribution (M/F ratio 0.61 vs 0.65, p 0.452), and had at diagnosis: a higher age (median 60 vs 57 years, p 60 years in 50% vs 45% of cases, p Moreover, they had: a lower platelet (PLT) count (median 737 vs 775 x 109/L, p 10 x 109/L in 28% vs 26% cases); a similar median levels of hematocrit (HCT %, in females 41.4 vs 41.0; in males 44.7 vs 44.6) and hemoglobin (Hb g/dL, in females 13.8 vs 13.6; in males 15.0 vs 14.9). The BMB, revised according to the WHO 2008 criteria, showed a not different distribution (p 0.21) of ET (64% vs 61%), ep-PMF (16% vs 17%), PMF (3% vs 2%), PV (4% vs 4%), and U-MPN (13% vs 16%. The JAK2 V617F mutation in patients of Group II (at diagnosis) and of Group I (after diagnosis) was found in 62% and in 58% of tested cases (p 0.054), respectively. The patients at high standard thrombotic risk were 58% vs 52%, p 0.004. In the patients of Group II and Group I the distribution of the treatment started into the first year was significantly different (p The treatment CYT ± AntiPLT was started in the patients at high standard thrombotic risk with a rate of 81% vs 80%, respectively, and in the patients at low standard thrombotic risk in 37% vs 43% of cases, respectively. The initial treatment CYT±AntiPLT was related, in multivariate analysis, both in patients of Group II and Group I, with older age (>60 and 40-60 vs 1000 and 700-1000 vs Conclusion: in the studied thrombocythemic MPN patients the real-life diagnostic approach was improved after 2005 not only due to the routine use of JAK2 tests, but also due to the higher rate of BMB done (85% vs 80%). The appropriateness of the cytoreductive treatment (CYT±AntiPLT started into one year from diagnosis) remained high in patients at high standard thrombotic risk (over 80% of cases were treated). Concomitantly, the inappropriate use of the cytoreductive drugs in patients at low standard thrombotic risk appreciably decreased (from 43% to 37% of cases). Moreover, it has to be remarked that the therapeutic approach was significantly influenced not only by older age and prior thrombosis, but also by thrombocytosis (PLT count >700 x 109/L), disease-related symptoms, and inconstantly by leukocytosis and CVRFs. Table Table. Disclosures Gugliotta: SHIRE Co.: Honoraria. Gugliotta:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Abstract 1973 Background. Hematological and extra-hematological adverse events associated to Hydroxyurea (HU) treatment in patients with chronic myeloproliferative neoplasms (MPN) are object of particular interest in the Ph-negative MPN since they can significantly limit the HU use. Objective. To evaluate the extra-hematological adverse events associated to HU treayment in a large cohort of Essential Thrombocythemia (ET) patients. Material and Methods. One thousand and seventy-five out of the 2005 ET patients registered in the RIT were treated with HU and are the object of this report. The patients, 641 females (59.6%) and 434 males (40.4%), diagnosed according to the PVSG or WHO criteria in 54 hematological centers of the RIT, started treatment with HU as first (92%) or second (8%) line, at median age of 65 years.The mean duration of HU treatment was 3.3 years. The HU treatment was withdrawn in 221 (20.5%) patients after a mean of 3.0 years.The administered dose of HU was 0.25–3.0 g/day (median 1), and a mean cumulative dose was 1113 g. The extra-hematological adverse events (EHAEs) observed during the HU treatment were distinguished in HU related AEs (HU-EHAEs), ET related AEs (ET-EHAEs) and HU or ET unrelated AEs (U-EHAEs).Results. During the HU treatment (3587 pt-y) 378 EHAEs were reported in 207 (19.3%) patients, being the HU-EHAEs 244 (6.8/100 pt-y) in 170 (15.8%) patients. In detail, the HU-EHAEs were: dermatological in 108 (48.3%) cases (38 hyperpigmentation, 26 leg ulcers, 22 maculo-papular rash, 10 lichenoid eruptions, 5 skin cancer, 4 alopecia); gastro-intestinal in 80 (32.8%) cases (37 nausea/vomiting, 30 diarrhea, 13 gastro-intestinal intolerance); systemic in 35 (14.3%) cases (28 fever, 7 fatigue); neurological in 19 (7.8%) cases (headache); miscellanea in 2 (0.8%) cases. Conclusion. This preliminary analysis in 1075 ET patients of the Registro Italiano Trombocitemia (RIT) treated with HU shows that the extra-hematological adverse events referred to the HU (HU-EHAEs) occurred with not negligible rate (6.8/100 pt-y) and need to be object of attention in the management of ET patients. Disclosures: No relevant conflicts of interest to declare.

Background Initial analysis of the combination melphalan, prednisone, plus lenalidomide (MPR) showed significant antimyeloma activity in patients with untreated multiple myeloma, with neutropenia and thrombocytopenia as the most frequent side effects. This updated analysis reassessed the kinetics of neutropenia and thrombocytopenia as well as the safety and efficacy of MPR. Patients and Methods A total of 21 patients with newly diagnosed myeloma received melphalan 0.18 mg/kg on days 1-4, prednisone 2 mg/kg on days 1-4, and lenalidomide 10 mg daily on days 1-21 for nine 28-day cycles, followed by maintenance therapy with lenalidomide 10 mg daily on days 1-21. Results Grade 3/4 neutropenia occurred in 52% of the patients, and granulocyte colonystimulating factor was administered in 43%. The mean neutrophil counts at the start of each MPR cycle, during nadir, and after 6 months of maintenance were 2.69 × 10 9 /L, 1.43 × 10 9 /L, and 2.11 × 10 9 /L, respectively. Grade 3/4 thrombocytopenia occurred in 24% of the patients. Platelet transfusions were required by 1 patient (5%) with a platelet count of 16 × 10 9 /L; however, no thrombocytopenia-associated bleeding was reported. The mean platelet counts at the start of each cycle, during nadir, and after 6 months of maintenance were 174 × 10 9 /L, 121 × 10 9 /L, and 158 × 10 9 /L, respectively. Median follow-up was 29.6 months, median progression-free survival was 28.5 months, and 2-year overall survival was 91%. Conclusion MPR is a promising regimen with manageable hematologic toxicity.

Introduction. Lenalidomide (RevlimidR) is a novel, orally active immunomodulatory drug effective for the treatment of refractory myeloma. In this multicenter trial, we evaluate the potential additive and synergistic effect of the combination RevlimidR, melphalan and prednisone (R-MP). Materials and Methods. Patients (pts) with newly diagnosed symptomatic multiple myeloma older than 65 years were treated with 9 courses of RevlimidR (5–10 mg/day for 21days every 4–6 weeks) plus MP (melphalan 0.18–0.25 mg/kg and prednisone 2 mg/kg for 4 days every 4–6 weeks). The trial was designed to define the toxicity profile of R-MP and to analyze the efficacy of this combination. Four different dose levels were tested: 1. melphalan 0.18 mg/kg + RevlimidR 5 mg/day; 2. melphalan 0.25 mg/kg + RevlimidR 5 mg/day; 3. melphalan 0.18 mg/kg + RevlimidR 10 mg/day; 4. melphalan 0.25 mg/kg + RevlimidR 10 mg/day. Each cohort included 6 pts. Dose limiting toxicity (DLT) was defined as: any grade ≥ 3 non-hematologic toxicity; grade 4 neutropenia lasting >7 days; any other grade 4 hematologic toxicity and any treatment delay due to toxicity that occurred during the first cycle. All pts received ciprofloxacin and aspirin as prophylaxis. Results. At present, 24 pts (median age 72, range 61–77) received at least one R-MP course and were evaluated. No DLTs were observed in the first 2 dose levels; 1 DLT was observed with melphalan 0.18 mg/Kg and RevlimidR mg/kg (grade 4 neutropenia lasting> 7 days); 2 DLTs were reached with melphalan 0.25 and RevlimidR 10 mg (1 neutropenic fever, 1 grade 3 cutaneous toxicity). After 1 cycle of R-MP, no one was in complete remission (according to the EBMT/IBMTR criteria), 2 pts (9.5%) showed a myeloma protein reduction of 75–99%, 7 pts (28.6%) a response of 50–74%, and 15 (61.9%) a response of 7 days, 1 treatment delay due to toxicity, 2 grade 3 dermatological toxicities). Conclusions. R-MP was well tolerated with a manageable toxicity. Significant response rate was observed. It represents a feasible and promising approach for newly diagnosed pts who are not candidates for transplant. Fifteen additional pts were treated with the fix dose of melphalan 0.18 mg/kg + RevlimidR 10 mg/day, results are too premature to assess efficacy. An update of these data will be presented.

High dose therapy represents the gold standard therapy for newly diagnosed multiple myeloma (MM) patients (pts), with no definite agreement about the adoption of single or double transplant. From January 2000 to December 2004, 151 consecutive MM pts aged ≤65 years in stage II, III or I in progression according to Durie-Salmon were enrolled in a multicenter no randomised high dose program including a tandem transplant (Tx1; Tx2). The protocol was designed as follows: 2 pulse-VAD as induction, 2 DCEP to mobilise peripheral blood stem cells (PBSC), double auto-transplant 3-6 months apart each conditioned with high-dose Melphalan at the dose of 200 mg/m2. Patients characteristics at the enrolment: males 76 (51%), females 75 (49%), median age 55 (range: 35–65), stage I in progression 26 (17%), stage II 25 (16%), stage III 100 (67%). Response rates after each phase for the evaluable patients are reported in the table below VAD (151 pts) DCEP (146 pts) Tx1 (119 pts) Tx2 (63 pts) CR (%) 4 9 18 29 VGPR (%) 28 35 48 60 PR (%) 44 30 25 9 SD (%) 18 10 2 0 Progr (%) 6 16 7 0 Patients not addressed to transplant for mobilization failure were only 5%. Most of the patients (75%) collected ≥ 4x106CD34+cells/Kg after each DCEP-cycle which were considered adequate to rescue hemopoiesis after each transplant. The whole protocol was well-tolerated. In particular, no therapy related mortality was associated to pulse-VAD, or DCEP, and no difference between Tx1 and Tx2 as far the transplant related mortality was registered (1.5% after each transplant). Second transplant was not performed in 48 pts for the following reasons: 8 pts (7%) did not collect enough PBSC, 8 pts (7%) have had severe toxicity with the first transplant; 8 pts (7%) underwent allo-TMO; 7 pts (6%) had progressive disease and 15 pts (12%) refused Tx2. Finally only 76 pts (50% of the enrolled pts) completed the program with the second transplant. Analysing data on an intention-to-treat basis, median follow-up was 30 months, median Progression Free Survival (PFS) was 31 months, median overall survival (OS) was not reached. The median Event Free Survival (calculated from the completion of Tx1 to progression or any other event) was 20 months. No difference in terms of PFS and EFS was found comparing pts who finally received only Tx1, with those who completed the protocol (p=0.9; p=0.5). The EFS was not statistically different for patients receiving one or two transplant even when the analysis was performed according to the type of response achieved after Tx1. In conclusion, despite higher percentage of good quality responses (CR+VGPR) can be obtained with 2 transplants with respect to 1 (66% vs 89%) without additional toxicity, no difference in terms of PFS or EFS were observed between the patients who underwent 1 or 2 transplants. Thus, keeping into account the more complex management of patients in a tandem transplant program, it might be more advantageous to perform as initial therapeutic approach, high-dose protocol including only 1 transplant procedure.

Rituximab (R) is an active and well tolerated agent in the treatment of Waldenstrom’s Macroglobulinemia (WM) whether used in untreated or in refractory/relapsed pts. Furthermore, there is evidence that the association of R with chemotherapy may improve the quality of responses. Fludarabine and Cyclophosphamide (FC) are synergistic with R in vitro in lymphoma cell lines, and the administration of the three drugs is associated with higher response rates in other lymphoprolipherative disorders. We updated our experience to define the efficacy and tolerability of FCR in symptomatic pts with WM. Patients: Nineteen pts, median age 57 y, received R 375 mg/sqm iv d 1, F 25 mg/sqm iv d 2–4, C 250 mg/sqm iv d 2–4 every 4 weeks. Anti-infective prophylaxis with cotrimoxazole and acyclovir was administered. Median time from diagnosis to FCR treatment was 46 m (range 1–156). Five pts received FCR as first line treatment while 14 pts, of whom 8 refractory, had been previously treated with a median of 2 lines of therapy (range 1–6), 5 having previous received monoclonal antibodies. Splenomegaly and lymphadenopathy were present in 32% and 36% of pts, respectively. In 42% of cases Hb was 3mg/dL. IgM median level was 4015 mg/dL (range 277– 10900), being > 4000 mg/dL in 53% of pts. Three pts were HCV-RNA positive and presented with cryoglobulinemia. Results: Pts received a median of 6 courses (range 3–6). Responses according to the IInd International Workshop on WM, updated in 2006, were categorized as follows: 15 PR (79%), 3 SD (16%), 1 PD (5%). Eight of the 15 PR pts could be considered as in “near CR”. In fact, the new response category could be justified by the achievement of complete resolution of symptoms, of adenopathy/organomegaly on CT scan, absence of malignant cells at BM immunophenotype and hystology, with only a persistence of a positive serum immunofixation (median serum MC protein of 0.3 g/dL). None of the variables considered (splenomegaly, lymphadenopathy, Hb level, serum albumin, β2M, IgM) was significantly associated with response. Ten pts showed a delayed response: 1 converted to CR after 4 m, in 9 a progressive reduction of MC is still detectable after a median follow-up of 10 m (range 4–31). Two pts underwent stem cell transplant (1 auto, 1 allo). Toxicity: Mild or moderate effects limited to the first and second R infusion, such as fever, hypotension, cutaneous rash, were seen in 5 pts (26%). None developed IgM “flare”. Neutropenia, observed in 82% of courses, was the main source of adverse effects. Two episodes of FUO and 1 clinically documented pneumonia were recorded. One pt died 3 m after the end of treatment while in PR for disseminated Aspegillosis. Conclusion: FCR regimen proved to be active and well tolerated even in previously heavily pre-treated WM pts; the response rate obtained is in line with clinical trials using R associated with other chemotherapeutic agents. A high percentage of near CRs and a progressive improvement of the quality of response has been observed even in pts with longer follow-up. The high incidence and long lasting episodes of neutropenia did not translate in major infectious episodes.