ALBERT

Description: 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. Method: We present here the prospective epidemiologic analysis of 1116 adult patients affected by MPNs (PV=289, ET=550, PMF=209) diagnosed according to 2008 WHO criteria, from January 2011 to December 2015 in 15 hematological Centers (5 academic and 10 community-based Hospitals) in Latium. A total of 289 PV, 550 ET and 209PMF were identified. The overall incidence rate of 289PV was 1.0/105 in 2011 and 2012, 1.1/105 in 2013, 0.9/105 in 2014 and 2015. The overall incidence rate of 550ET was 2.0/105 in 2011, 2.4/105 in 2012, 2.2/105 in 2013, 1.8/105 in 2014 and 1,2/105 in 2015 and the overall incidence rate of 209PMF was 0.7/105 in 2011 and 2012, 1.0/105 in 2013, 0.7/105 in 2014 and 0.5/105 in 2015. We have observed also 63 cases of MPNu (36M/32F) and the incidence rate was 0.3/105 in 2011 and 2012, 0.14/105 in 2013, 0.24/105 in 2014 and 0.22/105 in 2015. Baseline features of PV, ET and PMF patients are summarized in table 1. We have also analyzed the presence of comorbidities including obesity, arhythmia and neoplasia observed at the diagnosis in 1.6, 6.2 and 4% of all population, respectively; thirty-five percent of 1116 pts presented other comorbidities such as diabetes, inflammatory bowel disease, renal and liver failure. As thrombotic risk factors we considered diabetes, dislipidemia, smoke, essential hypertension and thrombophilia observed in 11,8, 16,2, 13,2, 51,7 and 3% of total pts, respectively. Conclusions: We confirm in our prospective observational protocol the overall incidence of MPN Ph negative, previously reported in the literature and the major incidence of male gender in PV and PMF, female in of ET. The annual incidence from 2011-2015 in Latium is remained substantially the same during the observation period. The decreasing trend observed in 2015 is probably due to the different update of some Centers that was done in October 2015 not including patients diagnosed in the last two months. Disclosures 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.

Description: Background Thrombotic 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. Methods To address this issue, we report on 1087 patients [M/F 508/579, median age 67.6 years, interquartile range (IQR) 55.2 - 75.9] with newly diagnosed MPN enrolled in the prospective database of our regional cooperative group since January 2011. Of them, 571 (52.5%) had Essential Thrombocythemia (ET), 303 (27.9%) Polycythemia Vera (PV) and 213 (19.6%) Primary Myelofibrosis (PMF). The main clinical features at diagnosis of the whole cohort and according to the different MPNs are reported in the Table 1. Results On the whole, 22 episodes of thrombotic complications were reported in 1087 patients (2.0%) at a median interval from diagnosis of 18.2 months (IQR 7.4 - 29.7): in particular, 15 (68.1%) were arterial (8 cerebral, 2 coronaric, 4 in the lower limbs, 1 splancnic) and 7 (31.9%) venous (5 in the lower limbs and 2 in the upper limbs). As to the incidence of early thrombosis in the different MPNs, they were 13/571 (2.2%) in ET patients, 5/303 (1.6%) in PV patients and 4/213 (1.8%) in PMF patients (p=0.810): median time from diagnosis to thrombotic event was also similar in the 3 MPNs (p=0.311). The 4-year cumulative Thrombosis-Free Survival (TFS) of the whole cohort was 97.3% (95%CI 96.0 - 98.6): there was no difference among the 3 MPNs as to 4-year TFS [96.7% (95%CI 94.8 - 98.6) in ET, 97.8% (95%CI 95.9 - 99.7) in PV and 98.7% (95%CI 96.9 - 100) in PMF, respectively, p=0.668). Several clinical features at diagnosis (age, gender, Hb levels, WBC and PLT counts, spleen enlargement, JAK-2 V617F mutation and previous thrombotic events) were evaluated for a role in predicting thrombotic events: only age (p=0.009) and previous thrombotic events (p=0.009) were significant. Conclusions The incidence of early thrombosis seems low in the first 4 years after diagnosis of MPN based on our prospective database, without any difference among ET, PV and PMF: it is worth of note that only age and previous thrombotic events had a predictive role, thus confirming many retrospective reported data and reinforcing the prognostic value of old scoring system for thrombotic risk in MPN. Table 1 Table 1. Disclosures 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.

Description: 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. Patients and Methods. For AML patients eligible to an allogeneic transplant, the RTN policy consists of an algorithm of donor choice based on a hierarchy according to the following criteria: 1) HLA identical sibling; 2) MUD ≥8/10 HLA 3) UCB as single unit selected on the base of cell dose and number of HLA disparities (0-1/6 HLA: TNC ≥2.5x107/kg and CD34 ≥1x105/kg; 2/6 HLA: TNC ≥3.5x107/kg and CD34 ≥2x105/kg); 4) G-CSF primed, unmanipulated bone marrow Haplo donor. Myeloablative (MAC) or reduced intensity (RIC) TBF (Tiothepa, Busulfan, Fludarabine) conditioning regimen was identical for all patients, GVHD prophylaxis was uniform for each categories. of transplant Results. From January 2006 to December 2014, 238(89%) out of 303 adult patients candidates to an allogeneic transplant for high-risk AML were considered eligible. Overall, a donor was available for 205 (86%) of 238 eligible patients. At time of the analysis, 17 of these 205 patients (8%) had lost the transplant eligibility and 4 (2%) were still scheduled for transplant, therefore 184/205 (90%) patients with an available donor were finally transplanted from Id-sib (n=76), MUD (n=38), UCB (n=17) or Haplo (n=53) donors. The 8-yrs overall survival (OS) of the 238 eligible patients from time of HLA typing and of the 184 transplanted patients from time of the graft was 40±4%and 43±4%, respectively. By excluding the low number of UCB recipients (n=17), the OS was particularly dismal for the 34 patients transplanted in advanced disease phase (7±4% at 4 yrs), whereas for the 132 patients transplanted in early (CR1+ CR2) phase the 8-yr OS was 56±5%: 58±7% for 61 HLA Id-sib, 50±8% for 40 Haplo and 63±10% for 27 MUD recipients (P=NS). The OS of patients transplanted in early phase was 63±5% for 97 patients receiving MAC and 33±9% for RIC recipients. For these 97 patients, the survival by type of donor was 62±10% either for 47 Id-sib or 28 Haplo and 70±10% for 22 MUD recipients (P=NS). The results were analyzed by various donor/recipient (D/R) combinations such as age, sex and CMV status. The median donor age was 39 years (range, 18-70) and the median patient age was 43 years (range, 16-59): the 8-yr OS of patients (n=30) with younger D/R combination (D

Description: Therapy with Tyrosine Kinase Inhibitors (TKIs) changed the fate of Philadelphia-positive Chronic Myeloid Leukemia (CML). At present, the therapeutic strategy aims to improve the management of the disease and the quality of life of the patients. In July 2015, we started a prospective multicentric randomized trial with the aim to validate the policy of the intermittent de-escalation treatment and to explore the impact of this strategy on the Quality of Life. To this purpose, CML patients older than 60 years in stable (≥2 years) MR3.0 or MR4.0 molecular response were randomized to receive a FIXED intermittent TKIs regimen (one month ON and one month OFF), as previously published (Russo D, Blood 2013; Russo D, BCJ 2015), versus a PROGRESSIVE intermittent TKIs regimen (one month ON and one month OFF for the 1st year; one month ON and two months OFF for the 2nd year; one month ON and three months OFF from the 3rd year) (OPTkIMA study, ClinicalTrials.gov: NCT02326311). Molecular monitoring was performed according to the 2015 ELN guidelines, every 3 months by RT-PCR on peripheral blood (Baccarani M,Blood 2013). In case of MR3.0 (MMR) loss, checked in two monthly consecutive RT-PCR analysis, patients were planned to exit the study and to resume TKIs daily. This first interim report have been focused on the patients who, by intention to treat, have completed the first year of the study for an historical comparison with the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). During the first year, both the patients randomized in the FIXED and in the PROGRESSIVE arms were given the TKIs treatment one month ON and one month OFF. Up to June 2018, 177 patients have been enrolled by 26 Italian Hematological Centers (first patient randomized in July 2015) and 121/177 patients (68%) completed the first year of OPTkIMA study. The median age was 71 years (range 60-89) and 64% of the patients were belonging to the Sokal intermediate/high risk goup. 96/121 (79%), 14/121 (12%) and 11/121 (9%) patients were receiving imatinib (IMA), nilotinib (NILO) and dasatinib (DAS), at the time of enrollment. Overall, 59/121 (49%) and 62/121 (51%) patients have been randomized in the FIXED and PROGRESSIVE arm, respectively. 41/62 patients (66%) randomly assigned to the PROGRESSIVE arm have entered the second year of therapy. 34/121 patients (28%) went out of the study during the first year. The reasons for protocol discontinuation were: informed consent withdrawn (2 cases), second cancer (4 cases), loss of MR3.0 (28 cases). (Table 1). Among the 28 patients who lost the MMR, 17 and 11 were in MR4.0 and MR3.0, respectively, when they were enrolled into the study. Thus the probability of loosing the MR3.0 while on OPTkIMA was 21,7% at one year (Figure 1). All the 28 patients resumed TKIs continuously and all obtained at least the MR3.0 response, within 6 months and are currently included in the study follow up. The intermittent treatment was well tolerated, with 4 serious adverse events (1 appendicitis, 1 atrial fibrillation, 1 cardiac failure, 1 hip fracture) and 3 adverse events (1 diarrohea, 1 pruritus and 1 fever), none of which have been considered treatement-related. None of the patients experienced the TKI withdrawn syndrome. According to this first interim report, we found that a policy of intermittent TKIs administration in elderly patients is safe and well tolerated. Analysis of patient-reported QoL outcomes is ongoing and will further add information on the overall treatment effectivness of the new PROGRESSIVE intermittent TKI administration. After the 1st year, 28/121 patients (23%) lost MR3.0 and all of them re-gained the major molecular response within 6 months from resumption of continuous treatment. The probability of MR3.0 loss while on OPTkIMA at 1 year was 21,7% and this is quite comparable with the 20% MR3.0 loss observed in the previous INTERIM trial (Russo D, Blood 2013; Russo D, BCJ 2015). Disclosures Efficace: Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Research Funding; TEVA: Research Funding; AMGEN: Research Funding; Incyte: Consultancy; Amgen: Consultancy; TEVA: Consultancy; Orsenix: Consultancy. Abruzzese:Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy; Ariad: Consultancy. Bonifacio:Incyte: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Bristol Myers Squibb: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Giai:Novartis: Consultancy; Pfizer: Consultancy.

Description: 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 V617F mutation 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. Table Table. Disclosures 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.

Description: Background Deferasirox (DFX) is an oral iron chelator widely employed in the treatment of iron overload during thalassemic syndromes and myelodysplastic syndromes. Aim At present, very few data are available on the treatment with DFX in patients with Ph- Myeloproliferative Neoplasms(MPN) and transfusional requirement. Methods To address this issue, we report here on 41 patients (M 31; F 10) with MPN and iron overload secondary to transfusional requirement enrolled in the database of our regional cooperative group who received a treatment with DFX. Of them, 36 had a primary Myelofibrosis, 4 a post Essential Thrombocythemia myelofibrotic phase and 1 a post Polycythemia Vera myelofibrotic phase. Results According to IPSS classification, 8 patients (19.5%) resulted low/intermediate-1 risk, 14 (34.1%) intermediate-2 risk and 19 (46.4%) high-risk. The main features of the patients at diagnosis and at baseline of DFX treatment are reported in the Table. Treatment with DFX was started after a median interval from diagnosis of 13.3 months [interquartile range (IR) 7.3 - 41.1] and from start of transfusion dependence of 11.5 months (IR 5.8 - 20.2), with a median of 27 packed red cells units received (IR 18 - 37). The starting DFX dose was 20 mg/Kg in 16 patients (39.1%), 15 mg/Kg in 20 patients (48.8%) and 10 mg/Kg in 5 patient (12.1%). All patients were evaluable for toxicity:extra-hematological toxicity of all WHO grades was reported in 20/41 patients (48.8%) and consisted of gastro-intestinal symptoms in 7 patients, transient renal impairment in 10 patients and skin reactions in 3 patients: however, only 3 patients (7.3%) needed a permanent discontinuation for toxicity. Thirty-nine out 41 patients were evaluable for response (〉 6 months of treatment). As to chelation efficacy, after a median treatment period of 15.4 months (IR 8.1 - 22.3), 4 patients achieved ferritin levels 〈 500 ng/ml, 10 patients ferritin levels 〈 1,000 ng/ml and 2 patients presented a reduction 〉 50% of basal ferritin but with levels 〉 1,000 ng/ml, with a global response rate of 16 out 39 patients (41.0%): among the remaining 23 patients, 2 discontinued for early toxicity, 20 did not have any ferritin reduction and 1 had an early unrelated death (〈 6 months of treatment). As to hematological improvement, 7/39 patients (17.9%) showed an unexpected and persistent rise of Hb levels 〉 1.5 g/dl, with disappearance of transfusional requirement in 5 cases. The median overall survival of the whole cohort from DFX initiation was 20.7 months (95% CI 16.0 - 25.3): the median overall survival from DFX initiation in patients with chelation response was 46.9 months (95% CI 10.7 - 83.0) compared to 14.0 months (95% CI 5.6 - 22.3) in patients without chelation efficacy (p=0.002). Conclusions Treatment with DFX is feasible and effective in MPN with iron overload. Moreover, also in this setting an hematological improvement can occur in a sizeable rate of patients. Disclosures 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.

Description: In the current clinical practice, imatinib is widely used also in very elderly patients with chronic myeloid leukemia (CML) at different doses based on concomitant diseases and physician' judgment. However, data on long-term follow-up of these patients are still lacking. To address this issue, we revised in our retrospective database 233 CML patients aged ≥ 75 years and treated with imatinib frontline in 34 italian hematological centers from 2/2002 to 7/2014. Median age at diagnosis was 78.4 years [interquartile range (IQR) 76.3 - 81.3], there were 113 males (48.5%) and 120 females (51.5%), median WBC, Hb and PLT counts were 45.0 x 109/l (IQR 29.4 - 83.4), 12,4 g/dl (IQR 11.0 - 13.6) and 375 x 109/l (IQR 238 - 680), respectively. Sokal Risk at diagnosis was low in 1 patient (0.4%), intermediate in 149 (67.4%), high in 71 (32.2%) and not evaluable in 12. One or more concomitant diseases requiring specific treatments were present in 225/233 patients (96.5%). Median interval from diagnosis to imatinib start was 0.7 month (IQR 0.2 - 1.4): the initial imatinib dose was 400 mg/day in 161 patients (69.1%), 300 mg/day in 57 (24.5%) and 〈 300 mg/day in 15 (6.4%). According to WHO, a grade 3 - 4 hematological and extra-hematological toxicity was reported in 44 (18.8%) and 41 (17.6%) patients, respectively. As to cumulative response, 13 patients (5.6%) discontinued IM due to early toxicity, 4 (1.7%) were resistant and 2 (0.8%) died from unrelated cause early after IM initiation: the remaining 214 patients (91.9%) achieved a complete haematological response (CHR). Among these 214 patients in CHR, 13 refused any other karyotipic or molecular evaluation, 23 achieved CHR only and 178 (76.4% of all 233 patients) achieved a cytogenetic response (CyR), which was partial in 16 patients and complete (CCyR) in 162 (69.5% of all 233 patients). In addition, among the 162 patients in CCyR, 125 (53.6% of all 233 patients) achieved a molecular response (MolR) (ratio 〈 0.1). A blastic phase occurred in 11 patients (4.7%). After a median follow-up from imatinib start of 45.0 months (IQR 22.3 - 72.0), 70 patients have died (9 from disease progression and 61 from unrelated causes), 16 patients were lost to follow-up and 147 are still alive (115 of them still in treatment with imatinib): 5-year event-free survival (EFS) and overall survival (OS) were 51.4% (CI95% 43.9 - 58.9) and 68.5% (CI95% 61.2 - 75.8), respectively. At univariate analysis, only the initial dose of imatinib (400 vs ≤ 300, p=0.03) was a significant predictive factor for CCyR achievement while only PLT count ≤ 500 x 109/l (p=0.031) was a significant predictive factor for MolR achievement. At multivariate analysis for EFS, achievement of a MolR (OR 0.25, 95%CI 0.14 - 0.43, p

Description: Unlike allogeneic transplant, autologous stem cell transplantation (ASCT) represents a procedure with a low-risk of cytomegalovirus (CMV) symptomatic reactivation-infection/end-organ disease (CMV complications) and invasive fungal disease (IFD). However, novel drugs for the treatment of lymphoproliferative malignancies could cause an increase of such opportunistic infections, even after ASCT. To the best of our knowledge, there are no published data demonstrating an association between CMV and IFD in the autologous setting, while this association has been widely reported in allogeneic transplantation. We have reviewed our series of 347 ASCT in myeloma and lymphoma patients performed over a period of 14 years with the aim of investigating the descriptive and analytical epidemiology of bacterial, CMV and IFD complications, focusing on the association between CMV and IFD. Patients with myeloma have significantly fewer bacterial infections and IFD than patients with lymphoma, but a similar rate of CMV complications. Descriptive epidemiological data are consistent with the literature, indicating an overall incidence of 36%, 3.5% and 15.5% for bacterial infections, IFD and CMV complications, with a case mortality rate of 4%, 16.7% and 3.7%, respectively. A strong correlation between CMV and IFD exists, with 8 cases of IFD out of a total of 12 presenting a CMV complication. At multivariate analysis, a diagnosis of lymphoma, ≥3 previous treatment lines and age ≥60 years were found to be independent risk factors for IFD. Duration of neutropenia (ANC 〈 500/mm3) ≥7 days represents an independent risk factor for CMV complications, where neutropenia most likely represents a crude surrogate biomarker indicating a deeper and longer state of overall immunosuppression. From our data we conclude that (1) myeloma patients are at lower risk of bacterial infections and IFD as compared with lymphoma patients but are at equal risk of CMV complications, most likely as a consequence of a selective impact of bortezomib on Herpes Viruses infection control; (2) a significant association exists between CMV and IFD, although a possible cause-effect relationship remains to be determined; (3) IFD is a rare complication after ASCT but burdened by a mortality rate of about 17%, with peak rates in older lymphoma patients who underwent more intensive therapeutic regimens.