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ABSTRACTSome preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.

To elucidate the biologic and clinical heterogeneity of adult pro-B acute lymphoblastic leukemia (ALL) (ie, terminal deoxynucletidyl-transferase–positive[TdT+], CD19+, CD10–, surface immunoglobulin–negative [SIg–]), we evaluated 66 patients enrolled in the Italian multicentric Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 study between October 1996 and December 1999. The ALL1/AF4 fusion transcript, originating from the t(4;11) translocation, was detected in 24 patients (36.4%), and the BCR/ABL chimeric product was found in 6 patients (9%), while the remaining 36 cases (54.6%) were ALL1/AF4-BCR/ABL–negative. A white blood cell (WBC) count higher than 50 × 109/L was found in 13 of 24, 2 of 6, and 6 of 36 of the ALL1/AF4-positive, BCR/ABL-positive, and ALL1/AF4-BCR/AB–negative patients, respectively (P = .007). None of the 24 ALL1/AF4-positive patients coexpressed the CD13 and/or CD33 myeloid antigens. By contrast, CD13 and CD33 molecules were detected, respectively, in 3 of 6 and in 14 of 33 cases of the BCR/ABL-positive patient group, and in 2 of 6 and 9 of 35 cases of the ALL1/AF4-BCR/ABL–negative patient group. These differences still remained statistically significant even if the BCR/ABL-positive patients were excluded from the analysis. A complete remission (CR) was achieved in 52 (83.4%) of the 62 patients with ALL evaluable for response to treatment. CR rates were similar in the 3 genotypic groups. By contrast, comparing patients with or without the ALL1/AF4 gene the probability of remaining in continuous complete remission (CCR) at 3.5 years was 16% and 49.8%, respectively (P = .005). Our data demonstrate that in adult pro-B-ALL a distinction should be made between pro-B-ALL cases with and without the ALL1/AF4 or the BCR/ABL chimeric genes, since the absence of both of these fusion genes correlates with a significantly better clinical outcome after intensive polychemotherapy treatment without hematopoietic stem cell transplantation.

To elucidate the biologic and clinical heterogeneity of adult pro-B acute lymphoblastic leukemia (ALL) (ie, terminal deoxynucletidyl-transferase–positive[TdT+], CD19+, CD10–, surface immunoglobulin–negative [SIg–]), we evaluated 66 patients enrolled in the Italian multicentric Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) 0496 study between October 1996 and December 1999. The ALL1/AF4fusion transcript, originating from the t(4;11) translocation, was detected in 24 patients (36.4%), and the BCR/ABLchimeric product was found in 6 patients (9%), while the remaining 36 cases (54.6%) were ALL1/AF4-BCR/ABL–negative. A white blood cell (WBC) count higher than 50 × 109/L was found in 13 of 24, 2 of 6, and 6 of 36 of the ALL1/AF4-positive, BCR/ABL-positive, and ALL1/AF4-BCR/AB–negative patients, respectively (P= .007). None of the 24 ALL1/AF4-positive patients coexpressed the CD13 and/or CD33 myeloid antigens. By contrast, CD13 and CD33 molecules were detected, respectively, in 3 of 6 and in 14 of 33 cases of the BCR/ABL-positive patient group, and in 2 of 6 and 9 of 35 cases of the ALL1/AF4-BCR/ABL–negative patient group. These differences still remained statistically significant even if the BCR/ABL-positive patients were excluded from the analysis. A complete remission (CR) was achieved in 52 (83.4%) of the 62 patients with ALL evaluable for response to treatment. CR rates were similar in the 3 genotypic groups. By contrast, comparing patients with or without the ALL1/AF4gene the probability of remaining in continuous complete remission (CCR) at 3.5 years was 16% and 49.8%, respectively (P= .005). Our data demonstrate that in adult pro-B-ALL a distinction should be made between pro-B-ALL cases with and without the ALL1/AF4or the BCR/ABLchimeric genes, since the absence of both of these fusion genes correlates with a significantly better clinical outcome after intensive polychemotherapy treatment without hematopoietic stem cell transplantation.

Background.Adverse events are relatively more common in the follow-up of primary myelofibrosis (PMI) than in other Ph- myeloproliferative neoplasms, with higher morbidity and mortality rates, as reported in several retrospective studies. At present, however, prospective data on the early incidence (<4 years from diagnosis) of these complications in PMI are not available.

Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria.

Breccia: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Ariad: Honoraria. Cimino:Celgene: Honoraria; Bristol-Mayer: Honoraria. Lo Coco:Pfizer: Consultancy; Baxalta: Consultancy; Novartis: Consultancy; Lundbeck: Honoraria, Speakers Bureau; Teva: Consultancy, Honoraria, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Tiribelli:Novartis: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Cavo:Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Research Funding; Takeda: Honoraria; Celgene: Honoraria, Research Funding. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

Breccia: Ariad: Honoraria; Pfizer: Honoraria; Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria.

Median age of CML patients at diagnosis is reported to be around 66 years. Few data about the characteristics and outcome of patients younger than 40 years are available, and the clinical trials of dasatinib and nilotinib as first line treatment were not stratified by age.

BackgroundThrombotic episodes are the major complication in the follow-up of Philadelphia negative Myeloproliferative Neoplasms (MPN), with high morbidity and mortality, as reported in several retrospective studies. At present, however, few prospective data are available on the early incidence of these complications.

Palumbo: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Shire: Honoraria; Roche: Honoraria. Bonifacio:Novartis: Research Funding; Bristol Myers Squibb: Consultancy; Amgen: Consultancy; Ariad Pharmaceuticals: Consultancy; Pfizer: Consultancy. Tiribelli:Bristol-Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Gilead: Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Fanin:Novartis: Speakers Bureau. Merli:Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cavo:Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Breccia:Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

To evaluate the prognosis of patients with Essential Thrombocythemia (ET) in the first decade of the century we assessed retrospectively the thrombosis free survival (TFS) and the overall survival (OS) of the patients diagnosed from 01/01/2000 to 31/12/2009 and collected in the database of our group. The diagnosis of ET was performed with PVSG, WHO 2001 or WHO 2008 criteria, according to the period of the first observation. The whole population of 757 patients was then divided in two groups: the first (group I) with the diagnosis performed between 01/01/2000 to 31/12/2005 (334 patients) with a median follow-up of 111,9 months, the second (group II) diagnosed between 01/01/2006 to 31/12/2009 (385 patients) with a median follow-up of 58,2 months. The main clinical features of the two groups of patients are reported in the Table 1. No difference was observed between the two groups as to age, gender, platelet and WBC count, Hb level, Cardio-Vascular Risk Factors (CVRF), spleen enlargement and occurrence of previous thrombotic events. The frequency of the JAK-2 V617Fmutation resulted significantly different (49.1% vs 68.4%) but in the group I the search of the mutation was never performed at the diagnosis. The TFS and OS were calculated from the date of diagnosis to the date of any appropriate event or to the date of last follow-up with Kaplan-Meier product limit method; the comparison of proportions and median values was computed with the Chi-squared and the Mann-Withney tests, as indicated. No significant difference emerged neither for TFS (p= 0,09, HR 1,42, 95% C.I. 0.89-2.30) nor for OS (p= 0,15, HR 1,34, 95% C.I. 0,87-2,06). We also considered the type of treatment used in the two groups to assess the potential link between the therapy and TFS or OS. No difference emerged between the two groups as to anti-aggregating treatment (mainly ASA), equally utilized in both groups [287/369, 77,8%, and 330/383, 78,3%, respectively (p = 0,95)]. As for the cyto-reductive therapy, Hydroxyurea was used in 74.8% vs 67.9% (p= 0.60) and alkylating agents in 1.9% vs 2.1% (p= 0.85), whereas Anagrelide was used in 10,6% vs 3,9% (p= 0,001) and Interferon in 9,5% vs 5,2% (p= 0,037), respectively. This more frequent use of Anagrelide and Interferon in the first group (2000-2005) did not modify TFS and OS of the patients. In conclusion, no improvement was observed in the prognosis of ET patients in the recent years: thus, new efforts to identify patients at risk and the introduction of new drugs as JAK-2 inhibitors are warranted to improve the prognosis of these patients.

Background: MPNs including Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), are clonal hematopoietic diseases in which the discovery of molecular driver mutations (JAK2, CALR, MPL) has deeply modified diagnostic approach in recent years. To date available data on epidemiology of MPNs and perspective analysis are rare. Our aim is to study the incidence of MPN Ph negative in a specific region of Italy named Latium and its variability across five years. Moreover we prospectively report the general features of our population.

Background:Response to ruxolitinib (RUX), the only JAK1/2 inhibitor commercially available for the treatment of Myelofibrosis (MF) may vary among patients (pts) and is largely unpredictable at therapy start. Therefore, pts' selection is based only on clinical needs.

Background.Ruxolitinib (RUX) is the first commercially available JAK1/2 inhibitor that may control splenomegaly and systemic symptoms related to myelofibrosis (MF). Despite MF occur frequently in elderly patients (pts), no data are yet available on RUX efficacy and safety in this particularly frail population.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

INTRODUCTION:Essential Thrombocytemia (ET) is the most common of the myeloproliferative neoplasms, vascular complications contribute mostly to both morbidity and mortality. The ability to identify thrombotic risk of the individual patient is necessary for a correct therapeutic management. Traditionally, risk stratification for thrombosis in ET pts was based on the respective absence and/or presence of either age >60 years or history of thrombosis. Recently, the IPSET score (International Prognostic Score Of Thrombosis for ET) was developed to better predict the occurrence of thrombotic events in ET patients. Risk factors included in the new score were: age, cardiovascular risk factors, previous thrombosis, presence of JAK 2 V617F mutation.

Thrombotic events are major complications in patients (pts) affected by Essential Thrombocytemia (ET) and Polycytemia Vera (PV). To compare thrombotic risk in these 2 groups, we evaluated retrospectively our database of 1249 ET and 623 PV pts diagnosed and followed in 11 hematological centers in the Latium region between 1/1980 and 12/2010: the diagnosis was done according to PVSG, WHO 2001 and 2008criteria based on the time of first observation. Baseline features of ET pts:797F/452M,median age 62.9 yrs (range 19-96),median WBC count 8.8 x 109/L (range 1.2-57.7), median PLT count 812 x 109/L (range 457-3582), median Hb level 14.0 g/dl (range 6-20.5), JAK-2V617Fpositivity 59.7% with a median allele burden of 19,6% (range 0.2- 99.9), spleen enlargement in 18.7% of pts, previous thrombosis223/1239 evaluable pts (17.9%) [arterial 176/223 (14.1%), venous 47/223 (3.8%)]. Baseline features of PV pts:289F/334M, median age 63.0yrs (range 21-91), median WBC count 10.1 x 109/L (range 3.5-37.6), median PLT count 457 x 109/L (range 169-1790), median Hb level 18.2 g/dl (range 10.5-24.8), JAK-2V617Fpositivity 94.3% with a median allele burden of 59.1% (range 0.3-99.9), spleen enlargement in 42% of patients, previous thrombosis 146/617 evaluable pts (23.7%)[arterial 114/617 (18.5%), venous 32/617 (5,2%)].in the ET cohort, after a median follow-up of 7.7 yrs, thrombotic complications were seen in 107/1141 evaluable pts (9.4%) [arterial60 (5.25%), venous 47 (4.11%)]; in the PV cohort, after a median follow-up of 8.5 yrs, thrombotic complications were seen in 107/623pts (17.2%) [arterial 67 (10.8%),venous 40 (6.4%)].All common risk factors for thrombosis were evaluated in multivariate analysis, searching the cut-off number for continuous variables with ROC curves. The significant variables at multivariate analysis for ET and PV pts are shown in the table; age, previous thromboses and spleen enlargement were risk factors in ET pts, while previous thromboses and JAK-2V617Fallele burden were risk factors in PV pts. PLT count above ROC value seemed to be a protective factor in both cohorts. In conclusion, in contrast with the tendency to evaluate in a similar manner the thrombotic risk of PV and ET, data from our retrospective database showed that these 2 groups should be considered populations with different risk factors for thrombosis. Table 1Putative prognostic factorsPolycythemia VeraEssential ThrombocythemiaHR95% C.I.pHR95% C.I .pPrevious thromboses2,311,13 - 4,740,021,871,08 -3,230,026Age ≥ 60 y1,540,79 - 2,990,211,901,18 - 3,060,009JAK2V617FPV: allelic burden ≥ 81% ET: pos1,951,03 - 3,710,040,760,48 - 1,210,25Plt countPV ≥ 452.109/L ET ≥ 944.109/L0,490,25 - 0,950,040,520,31 - 0,890,017Spleen enlargement0,670,34 -1,310,241,711,02 - 2,890,04CV risk factors (at least 1)0,920,41 - 2,030,830,870,51 - 1,490,62WBCPV ≥ 10,175.109/L ET ≥ 9,630.109/L1,090,57 - 2,080,801,410,89 -2,260,15

Background.Similar probabilities of survival have been reported for patients transplanted from Matched Unrelated Donor (MUD), Umbilical Cord Blood (UCB) or Haploidentical (Haplo) donors as alternative hematopoietic stem cell sources. However, few studies have compared these results with those obtained in patients transplanted from HLA Id-siblings (Id-sib). Moreover, all reported studies are retrospective and the criteria of donor selection were not predefined. We report the intention to treat (ITT) analysis results on 238 patients with high-risk acute myeloid leukemia (AML) prospectively transplanted according to the policy of the Rome Transplant Network (RTN), a metropolitan transplant program established in Rome in 2006.

Breccia: novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.

No relevant conflicts of interest to declare.

Patients and Methods.At the Rome Transplant Network, a JACIE accredited metropolitan transplant program, a matched-pair analysis has been conducted on 116 of 255 patients transplanted between January 2008 and December 2012. The patients transplanted from Id Sib (n=58) or Haplo related donors (n=58) were completely matched for the following features: patient age, gender, diagnosis (7 subgroups), disease phase (early: CR1+CR2; advanced: >CR2+active disease), myeloablative or reduced intensity conditioning regimen consisting of Thiotepa, i.v. Busulphan and Fludarabine (TBF) association, donor age and donor/recipient sex, AB0 and CMV combinations. As GVHD prophylaxis, all patients received the standard CSA and MTX combination with the addition of ATG, MMF and Basiliximab in Haplo bone marrow recipients. The transfusion policy, supportive care and antinfectious prophylaxis were identical for all patients.

Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by trilinear marrow expansion and an increased susceptibility to thrombo-embolic complications. Data of 623 patients (pts) followed in 11 Hematological centers of our region from 1978 to December 2010 were collected in our database. The diagnosis was made according to PVSG criteria, WHO 2001 and 2008 criteria, respectively, based on the year of diagnosis. The main epidemiological and clinical features of all pts are reported in table.

Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be useful to monitor the local epidemiology ,the frequency and the disease patterns.

Survival of Essential Thrombocytemia (ET) patients in the first 10 years of disease follow-up is similar to the general population one. While it is well known that alkylating agents (given alone or sequentially) increase the risk for acute myeloid leukemia, the specific role of different therapies on the development of secondary malignancies (SM) in ET patients, is still under investigation.

Prognosis of patients with myeloproliferative neoplasms developing blast phase (MPN-BP) is very poor. Median survival of these patients is about 2-3 months (Cervantes F, Acta Hemathol 1991; Mesa RA, Blood 2005; Kantajian HM, Leukemia 1997; Tam CS, Blood 2008) and nowadays no drug can induce a durable complete response (CR) in patients who are not candidate to BMT. A phase II study (Thepot S., Blood 2010, 116, 3735) recently reported on 54 patients with MPN-BP treated with 5-AZA, showing a median survival of 9 months with an Overall Response Rate (ORR) of 52% (24% complete response).

Clinical diagnosis of IFI is difficult ,due to lack of sensitive and specific diagnostic tools. An assessment of trends concerning the prevalence of IFI is a challenge and postmortem data may be useful to monitor the local epidemiology ,the frequency and the disease patterns.The aim of this retrospective analysis is to determinate the local epidemiology and the prevalence at autopsy of IFI, occurring in hematological malignancies at a single center  over a eleven years period.We have retrospectively reviewed 161 patients – median age  62,5 yrs, range 22 -83 - with hematological malignancies, who underwent autopsy between 2002 -2012. Acute Myeloid Leukemia (AML) were 77, Acute Lymphoid  Leukemia (ALL) 11,  Lymphoproliferative disorders (LPD) 56 and other disorders 17. Acute leukemia pts received systemic antifungal  prophilaxis, whereas the others not absorbable prophilaxis. None patients received transplant procedures. An experienced pathologist evaluated the organ involvement and the IFI pathologic pattern. Fisher’s Exact test was used to recognize the IFI prevalence, the main occurring pathogens and the involved site; a p-value of <0.05 was considered statistically significant.The analysis of 161 consecutive autopsies identified 40  pts.(25%)resulting to have IFI; of these, 22 were AML (55%) ,6 ALL (15%),11LPD (28%) and 1 other. Aspergillus  spp. infection was detected in 20 cases (50%), Mucor spp in 8 (20%) and Candida spp. in 12 (30%). Moulds  were prevalent in acute leukemia pts. and Aspergillus spp. is the leading pathogen with respect to Candida and Mucor spp. (p 0,0396),with a statistically significant prevalence in ALL (p 0,0186).The site more involved resulted lung (p 0.0002). Whereas the standardized EORTC/MSG criteria applied in vivo were conclusive for  IFI in 6  pts ( 15%) only, the postmortem findings revealed fungal infections in further 34  pts (85%).This analysis confirms that the IFI diagnosis is still an unresolved issue in hematological malignancies. Acute leukemias remain the subset with the higher prevalence of mould infections. As in other largest studies, in our experience Aspergillus spp and lung proved to be the most recurrent pathogen and site of involvement. At now, the diagnostic methods are not still completely able to identify the underlying IFI, thus  the autopsy rate should be increased to achieve a better knowledge of epidemiology and to critically review previous misdiagnosis.No relevant conflicts of interest to declare.

Survival of Essential Thrombocytemia (ET) patients in the first 10 years of disease follow-up is similar to the general population one. While it is well known that alkylating agents (given alone or sequentially) increase the risk for acute myeloid leukemia, the specific role of different therapies on the development of secondary malignancies (SM) in ET patients, is still under investigation.To retrospectively evaluate the role of different treatments on the development of SM in a large population of ET patients.We collected a series of 1026 ET patients (diagnosis period 1980-2010), followed in 11 Hematological Centers (universities 5, general hospitals 6) from the region Lazio in Central Italy. Median age at ET diagnosis is 62.5 years (range 17-93); 392 males, 634 females; median follow-up of the entire population is 6.2 years (range 0.1 – 31.9). Seventy/1026 patients (6.8%) developed 71 SM during follow-up.  Observed SM were grouped as follows: genito-urinary 15, breast 14, non-melanoma skin cancer 12, lung 11, gastro-intestinal 8, hematologic 5, thyroid 3, central nervous system 1, soft tissue 1 and unknown 1.Taking in consideration the different treatment approach, we divided our population in 5 different groups: group 0, no treated patients; group 1, patients treated either with Hydroxiurea (HU) alone or in combination/sequentially  with Interpheron (IFN)/Anagrelide (ANA); group 2, patients treated either with alkylating agents (ALK) alone or in combination/sequentially  with IFN/ANA; group 3, patients treated with ALK + HU sequentially; group 4,  patients treated with ANA and/or IFN only. Characteristics of the patients are shown in the table.Taking into account every single treatment group, although we observed an increased rate in the ALK one (4/26, 15.4%), we could not find a statistically significant difference in the risk of SM development. Instead, combining  different groups we obtained the subsequent results: group 0 + 4 versus group 1, no statistically significant difference (p= 0.174); group 0 + 4 versus 2 + 3 statistically significant difference (p= 0.031). Compared to anagrelide, interferon or no treatment, alkylating agents alone or given  sequentially with hydroxiurea, seem to increase the risk of SM development,  while HU treatment alone do not.No relevant conflicts of interest to declare.

To highlight the role of 5-AZA in this subset, we evaluated retrospectively 16 patients (M/F 12/4, median age 63.5 years, range 51 - 81) with MPN-BP according to standard definition (Mascarenhas J et al., Leuk Res. 2012 Dec;36(12):1500-4) treated with 5-AZA in the last 3 years and reported in the database of Gruppo Laziale for the study of Ph- SMPC. Primitive MPN diagnosis was Essential Thrombocythemia in 5 cases, Primary Myelofibrosis in 6, Polycythemia Vera in 1 and MDS/MPN in 4; the JAK-2 V617F mutation was present in 7/14 patients tested (50%); all, but 1, patients received a previous treatment during chronic myeloproliferative phase [12 patients with Hydroxyurea (HU) alone, 1 with HU + Anagrelide, 1 with HU + Pipobroman and 1 with Melphalan + Allogeneic bone marrow transplantation]. Median time from diagnosis to BP evolution was 47 months (range 12 - 317). All patients were treated with 5-AZA at the dosage of 75 mg/m2: as to the schedule, 13 patients received a 7-day schedule and 3 patients a 5-day schedule every 28 days. At the time of evolution, median WBC value was 17.1 x 106/L (range 5.0–89.5), median Hb level 9.9 g/dl (range 6.6–12.7) and median PLT value 155 x 106/L (range 7–434). Two patients died early after 5-AZA initiation from pulmonary fungal infection and respiratory failure respectively, 4 patients had a disease progression, 4 patients a stable disease, 2 patients(14%) had an hematological improvement and 4 pts (28.5%) a complete response after 4, 4, 5, and 12 months; median survival of patients in CR is 19.6 months. The overall survival from BP evolution was 8.1 months (range 1–49.5 months) and 3/4 patients in CR are still alive after 15, 24 and 49.5 months, respectively.Our data confirm the relative efficacy and safety of 5-AZA in this group of patients with otherwise dismal prognosis, underlining the possible achievement of long-lasting responses in a sizeable portion of them.Off Label Use: Bendamustine.

Tafuri: Sigma Tau Pharmaceuticals: Research Funding.

Abstract 5062

Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 4445

Abstract 5157

Abstract 3854This icon denotes a clinically relevant abstract

In our opinion, this casistic of patients with different types of MPNs reflects clinical presentation and evolution of three variants of the same disease. Many clinical findings in our unselected cohort of patients are similar to those reported in literature; in particular, thrombotic events were seen in about 13 – 17% of patients, without any correlation with Jak-2 status in both pre-diagnosis and follow-up. However, 2 main differences were noted: a lower incidence of JAK-2 V617F mutation among our PV patients and a lower rate of evolution in myelofibrosis and AML among our ET and PV patients. Both these features warrant further insights to be fully elucidated.No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Abstract 5065

Abstract 3077

Single or tandem Autologous Stem Cell Transplantation (ASCT) has been considered standard approach in adult (<65y) Multiple Myeloma (MM) patients (pts), however post ASCT disease progression occurs in the majority of cases suggesting that post ASCT maintenance treatment might be useful. The role of Bortezomib in the post-ASCT context is still not well defined. In December 2007 this single center study was activated in the aims to assess the impact of Bortezomib maintenance a) on time to progression (TTP), b) the possible toxicity related to a prolonged administration of the agent.Between October 2002 and July 2008, at Hematology Unit of S. Giovanni Hospital, 24 pts (median age 59.5y, min 38-max 67y) with newly diagnosed intermediate/advanced MM underwent single (8), or tandem (16) ASCT, respectively. Of these, 13 pts autotransplanted (8 single and 5 tandem) between 2002 and 2007, who did not receive any treatment post-ASCT, were considered as historic control group, while the remaining 11 autotransplanted from December 2007 to September 2008, received Bortezomib as maintenance treatment. Maintenance schedule consisted of Bortezomib as single agent given at dosage 1.5 mg (total dose) every 15 days until progression. Response was evaluated according to the International Myeloma Working Group uniform response criteria, while minimal residual disease (MRD) was assessed every 3 months on bone marrow (BM) samples by 6-colour BDFACS CANTO II. Abnormal plasma cells (APC) were identified using an Ab panel against the following markers: CD38, CD138, CD19, CD20, CD45, CD56, CD117, CD28, CD200. The condition was optimized in order to obtain a sensitivity level ' 1×10-3 (<0.01). Moreover, the presence of peripheral neuropathy (PN) was monitored before maintenance start, then every 3 mo by neurophysiologic tests including motor and sensory conducting studies.In the Bortezomib group, post -2nd ASCT, 5 pts achieved complete (CR) or a very good partial response (VGPR), 4 partial response (PR), and 2 maintained stable disease (SD), respectively; the overall response rate was 82%, with 45% CR+VGPR. Maintenance was started in a median time of 3.8 mo (min 1.7 - max 13.7 mo). As of July 2009, after a median maintenance length of 16.2 mo (min 4.1 - max 19 mo), all 11 pts are alive. As disease status, of the 4 pts in PR after 2nd ASCT, 1 achieved stringent CR (sCR), 1 CR and 2 progressed, respectively. The 5 pts who were previously in CR/VGPR maintained the same type of response, with no detectable MRD (< 0.01), except 1 pt who shifted to PR. Finally, of the 2 pts in SD, 1 persisted in SD after 10 months from the beginning of the Bortezomib maintenance, while the other one progressed. Thus, to date, of the 11 pts entered in the study, 55% are sCR+CR+VGPR, with an overall response rate of 63%. It is noteworthy that the 3 pts who relapsed (at 3, 4, 16 mo from maintenance start) had chromosome 13 deletion at diagnosis. Considering that not all pts underwent 2nd ASCT, TTP was evaluated from 1st ASCT. In the Bortezomib group (median follow-up 26 mo; range: 15 – 33 mo), median TTP has not yet been reached, whereas in the control group (median follow-up 34 mo; range: 14 – 62 mo), median TTP was 13 mo (log-rank P<0.01) (Fig 1). Finally, none of the pts in the Bortezomib group experienced grade 3 or 4 haematologic toxicity and/or PN requiring dose reduction or discontinuation of the drug.The preliminary results of this single center study, even though limited to a small cohort of pts, suggest that Bortezomib as single agent in post-ASCT maintenance may improve the quality of previously achieved response and prolong TTP. However, these preliminary results need to be confirmed by a longer follow-up and a randomized multicenter study.No relevant conflicts of interest to declare.

Abstract 4939

Background. Relapsed/refractory high grade NHL is a very aggressive pathology characterised by a poor prognosis. High dose therapy followed by peripheral blood stem cell (PBSC) rescue is to date the gold standard therapy. The results of high dose therapy are influenced by remission status after II line therapy as patients who undergo transplantation in complete response have better progression free survival with respect to those in partial response. While Rituximab+chemotherapy has become the approach of choice in 1st line-therapy, this type of schedule has not yet been largely applied in 2nd line therapy. In the aim of testing the efficacy of 2nd line-combined immuno-chemotherapy we designed a protocol including Rituximab + IEV/MINE. Methods. The planned treatment consists of 3 cycles of IEV or MINE (>65 y patients), plus Rituximab (375 mg/sqm) given on day +1 and on day +14 every cycle. G-CSF was administered from day 7 to ANC recovery and was continued until the CD 34+ collection after the third cycle. From April 2002 to July 2008 30 consecutive patients – 19 males and 11 females, median age 57 y (range 21–73 y) with refractory (12) and relapsed (18) Diffuse Large B Cell Lymphoma (DLBCL) entered the study. According to IPI score 20/30 patients were intermediatehigh risk; 21/30 had extranodal disease. Results. 27 patients completed treatment and are evaluable; 3 pts are not evaluable because of lethal infection after Ist cicle (2pts) and lost to follow up (1pt). 21/27 (78%) were responders: 12 (44%) achieved CR, 9 (33%) PR, while 6 progressive disease (PD) were withdrawn. Hematological toxicity including WHO grade III or IV neutropenia, anemia and thrombocytopenia was recorded in 19, 8 and 14 pts, respectively. Target CD 34 harvest was reached in 19/27 (70%) pts with CD 34+ median value 7,03 × 106/Kg. Among the responders 4 pts failed CD 34 harvest. 17/27 (63%) patients underwent transplantion, 11 autologous stem cell transplantation (ASCT) and 6 (>60 y) reduced intensity allogeneic-SCT. Of transplanted patients 4 (2 in CR post Mini Allo-SCT, 2 in relapse post ASCT) died 6, 2,10 and 10 months after transplantation, respectively. The remaining 13 (4 mini-alloSCT and 9 ASCT) are alive in CR which is lasting for 23 months median time (11–73). As of July 2008 15/27 (55%) patients are alive: 14 CR and 1 PR. Median follow up post R-IEV/MINE is 28 months (range 12–77), PFS was 38% and median OS is 32 months (range 7–90). Conclusions. Our experience, if limited to a small series of patients, shows that the addition of Rituximab to second line chemotherapy: increases response rate even in adverse IPI score cases, allows to obtain a good CD 34 harvest, represents an effective in vivo purging agent.

Background. Relapsed/refractory high grade NHL is a very aggressive pathology characterised by a poor prognosis. High dose therapy followed by peripheral blood stem cell (PBSC) rescue is to date the gold standard therapy. The results of high dose therapy are influenced by remission status after II line therapy as patients who undergo transplantation in complete response have better progression free survival with respect to those in partial response. While Rituximab+chemotherapy has become the approach of choice in 1stline-therapy, this type of schedule has not yet been largely applied in 2ndline therapy. In the aim of testing the efficacy of 2ndline-combined immuno-chemotherapy we designed a protocol including Rituximab + IEV/MINE.