ALBERT

Description: Key Points Previously untreated patients with severe hemophilia A caused by F8 null mutations show a more severe phenotype than previously untreated patients with non-null mutations. The phenotypic differences are modest, and as such not likely to affect decisions regarding when and how to start prophylaxis.

Description: Introduction The standard treatment for elderly untreated diffuse large B-cell lymphoma (DLBCL) is RCHOP21, however up to 40% of patients experienced failures. Lenalidomide showed activity in heavily pretreated DLBCL and in vivo and in vitro data demonstrated a synergism with rituximab. In the phase I trial REAL07 (Chiappella et al, Haematol 2013), FIL demonstrated that the association of LRCHOP21 was feasible in elderly untreated DLBCL and identified 15 mg lenalidomide from day 1 to day 14 as the maximum tolerated dose in combination with RCHOP21. Patients and methods. The phase II trial REAL07 was designed based on Simon's two stage design to demonstrate an improvement of overall response rate (ORR) of 15% in LRCHOP21 compared to 70% of standard RCHOP21. Secondary endpoints were progression-free survival (PFS), overall survival (OS), event-free survival (EFS) and to correlate outcome with cell of origin (COO) profile. Response was evaluated according to 2007 Cheson criteria. Inclusion criteria were: age 60-80 FIT at the comprehensive geriatric assessment; untreated CD20+ DLBCL; Ann Arbor stage II/III/IV; international prognostic index (IPI) at low-intermediate/intermediate-high/high (LI/IH/H) risk. Treatment plan was: RCHOP21 plus 15 mg lenalidomide from day 1 to 14 for 6 courses. All cases were centrally reviewed by expert pathologist; COO profile analysis was conducted with immunohistochemistry according to Hans' algorithm and with gene expression profile (DASL assay). Results. From April 2010 to May 2011, 49 patients were enrolled. Clinical characteristics were: median age 69 years (range 61-80); stage III/IV 43 (88%), IPI IH/H 30 (61%). At the end of 6 LRCHOP21, ORR was 92%. Complete remissions (CR) were 42 (86%) and partial remission 3 (6%); 3 patients (6%) did not respond and one (2%) died for homicide. At a median follow-up of 28 months, 2-year OS was 92% (95% CI: 79-97), 2-year PFS was 80% (95% CI: 64-89) and 2-years EFS was 70% (95% CI: 55-81); 2-year PFS for IPI LI was 89% (95% CI: 62-97) and for IPI IH 76% (95% CI: 47-90) and for IPI H 72% (95% CI: 36-90). Hematological and extra-hematological toxicities were mild, with no grade IV extra-hematological events and no toxic deaths during treatment. Of the 294 planned courses of LRCHOP21, 277 (94%) were administered; median dose of lenalidomide delivered was 1185 mg (94% of the planned dose); at least 90% of the planned dose of each drug was administered in 91% of the RCHOP21 courses. Median interval time between RCHOP21 courses was 21 days (range 19-48). All 49 cases underwent central pathology review and diagnosis of DLBCL was confirmed. Regarding COO analysis, tissue block or stained slides were collected in 40/49 (82%), of which 32 were adequate for analysis. At the time of this abstract, COO analysis was reported according to immunohistochemistry data; DASL analysis is ongoing. Clinical characteristics between germinal center (GCB, 16 patients) and non-GCB (16 patients) were superimposable, excepted for a majority of H IPI risk in non-GCB group (p 0.067). ORR for GCB and non-GCB were 88% (CR 81%) and 88% (CR 88%), respectively. At a median follow-up of 28 months, 2-year PFS was 71% (95% CI: 40-88) in GCB-group and 2-years PFS was 81% (95% CI: 51-93) in non-GCB-group (Figure 1). Conclusions. In conclusion, LRCHOP21 is effective, also in poor risk patients, namely in non-GCB subgroup. These encouraging data warrant a future phase III randomized trial comparing LRCHOP21 vs. RCHOP21 in untreated non-GCB DLBCL. Disclosures: Off Label Use: lenalidomide in first line DLBCL is off lable. drug provided free by Celgene. Vitolo:Roche: Speakers Bureau; Celgene: Speakers Bureau; Takeda: Speakers Bureau.

Description: Background. Ara-c based chemo-immunotherapy followed by autologous stem cell transplantation (ASCT) is the most effective approach in young mantle cell lymphoma (MCL) patients, though few if any patients are cured. Recent data indicate that subsequent Rituximab maintenance (RM) prolongs PFS and OS (Le Gouill NEJM 2017). Lenalidomide is an oral agent effective in MCL, considered suitable for prolonged maintenance programs, but has never been tested in this setting. The FIL MCL0208 trial (NCT02354313) is a prospective, international randomized, phase III trial, comparing Lenalidomide maintenance (LM) vs observation (OBS) after an intensive Ara-c containing chemo-immunotherapy (R-HDS) program, followed by ASCT in previously untreated MCL patients. Patients and Methods. Adult patients aged 18-65 years, with advanced stage MCL without clinically significant comorbidities were enrolled. Patients received 3 R-CHOP-21, followed by R-HDS i.e. R-high-dose Cyclophosphamide (R-HD-CTX) (4g/m2), 2 cycles of R-high-dose Ara-C (R-HDAC) (2g/m2 q12x3 d). CD34+ cells were collected after the first course of R-HDAC. The conditioning regimen for ASCT was BEAM. After ASCT, responding patients were randomized between LM (15 mg days 1-21 every 28 days) for 24 months or observation. Primary endpoint analysis was scheduled at the occurrence of the 60th PFS event in the randomized population, which occurred on June 20th, 2017 and data were analyzed for the present abstract on March 3rd 2018. Results. Three-hundred three patients were enrolled from May 2008 to August 2015 by 48 Italian and 1 Portuguese Center. Three patients were excluded after central histological review. Median age was 57 years (IQR 51-62), M/F ratio 3.6/1. Ninety-two percent of patients had stage IV, 33% bulky disease (〉5 cm), 33% elevated LDH, and 75% BM infiltration. Ki67 ≥30% was observed in 32%, MIPI was low (L) in 54%, intermediate in 31% and high (H) in 15% of patients. MIPI-c was L in 49%, low-intermediate (LI) in 29%, high-intermediate (HI) in 14%, H in 9%. Nine percent had blastoid variant. Fifty-two (17%) patients interrupted treatment before randomization (8 toxic deaths, 1 death for car accident, 24 progressions and 19 toxicity/refusals). On an ITT basis, the R-HDS + ASCT program induced 78% of CR, 7% of PRs, 10% of PD, 3% of toxic deaths (TRM) and 2% NA. Median follow-up (mFU) from inclusion was 51 months. Three years PFS and OS for the enrolled population were 67% and 84%, respectively. Of 248 patients who received ASCT, 205 were randomized either to LM (n=104) or OBS (n=101) and 43 (17%) were not because of: lack of response (8), refusal/PI decision/delay (8), unresolved infections (3) and inadequate hematopoietic recovery (24). Feasibility and efficacy were assessed on an ITT basis while toxicity was analyzed on subjects receiving at least one Lenalidomide dose. In the LM arm, 53 out of 104 patients did not start or complete the planned maintenance because of death (2), AE (26), PD (7), still ongoing (2), other causes (16). In the OBS arm 32 patients did not complete the observation phase because of death (1), AE (1), PD (20), still ongoing (10), other causes (1). Overall 28% of patients received less than 25% of the planned Lenalidomide dose. Despite suboptimal exposure to study drug, with a mFU from randomization of 35 months, 22 PFS events were recorded in the LM cohort vs 38 in the OBS arm, resulting in a 3y-PFS of 80% (95% CI; 70%-87%) in the LM arm vs. 64% in the OBS arm (95% CI; 53%-73%), stratified HR 0.51; 95% CI 0.30-0.87; p=0.013 (Fig 1A). OS was superimposable in the two arms: 93% vs 86%, stratified HR 0.96, 95% CI 0.44-2.11, p= 0.91 (Fig1B). Two deaths were observed in the LM arm due to pneumonia and thrombotic thrombocytopenic purpura and one in the OBS arm due to pneumonia. Grade 3-4 hematological toxicity was seen in 63% of patients in LM vs 11% in the OBS arm with 59% vs 10% of patients experiencing granulocytopenia. Non-hematological grade 3 toxicity was comparable in the two arms except grade 3-4 infections (11% vs. 4%; Fisher's p=0.10). Second cancers occurred in 7 patients in the LM and 3 in the OBS arm (Fisher's p=0.20). Conclusions. Results from the MCL0208 trial indicate that LM has a clinically meaningful anti-lymphoma activity in MCL. However, the applicability of LM has some limitations in the context of patients undergoing intensified chemoimmunotherapy. Overall these data support the use of a maintenance regimen after ASCT in young MCL patients. Disclosures Ladetto: Roche: Honoraria; Celgene: Honoraria; Acerta: Honoraria; Jannsen: Honoraria; Abbvie: Honoraria; Sandoz: Honoraria. Di Rocco:Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Chiappella:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: lecture fees; Teva: Other: lecture fees; Nanostring: Other: lecture fees; Amgen: Other: lecture fees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: lecture fees. Rusconi:Celgene: Research Funding. Gomes da Silva:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Institution's payment for consultancy, Travelling support; Celgene: Other: Travelling support; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees; Roche: Other: Institution's payment for consultancy, Travelling support; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: lecture fees, Research Funding. Vitolo:Takeda: Speakers Bureau; Sandoz: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Speakers Bureau. Martelli:Sandoz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Background. Recent studies have described the landscape of recurrently mutated genes in mantle cell lymphoma (MCL), including genes involved in DNA damage response/cell cycle (ATM, TP53, CCND1), epigenetic regulation (KMT2D also known as MLL2, WHSC1), and cell signaling (BIRC3, TRAF2, NOTCH1). However, with the exception of TP53 abnormalities, little is known about the clinical relevance of recurrent mutations in MCL. Thus, we performed deep sequencing analysis of a MCL gene panel in the prospective series of patients enrolled in the ongoing FIL-MCL0208 phase III trial (EudraCTNumber: 2009-012807-25). Patients and Methods. The study included untreated, advanced stage 70% of cases. The gene panel was analyzed in tumor DNA from baseline bone marrow CD19+ purified MCL cells and, for comparative purposes to filter out polymorphisms, in the paired normal genomic DNA (available in 55% of cases) using a TruSeq Custom Amplicon target enrichment system followed by deep next generation sequencing (Illumina, median depth of coverage 2356x). Variants represented in 〉10% of the alleles were called with VarScan2 with the somatic function when the paired germline DNA was available. For patients lacking germline DNA, a bioinformatic pipeline including a number of stringent filters was applied to protect against the misclassification of polymorphisms as somatic variants. Primary endpoint of the analysis was progression free survival (PFS). Results. Out of the enrolled patients, 151 are currently evaluable for mutations and clinical outcome (median age: 57 years, range 35-66; males 75%). Among prognostic factors, the MIPI was intermediate or high-risk in 49% of patients, the Ki67 ≥30% in 39%, and blastoid histology occurred in 8%. At the first planned interim analysis, median follow-up of alive patients was 26 months. At 2-years, 79% of patients were progression free and 91% alive (Cortelazzo et al EHA 2015). Overall, at least one mutation was detected in 106/151 cases (70%), including mutations of ATM in 42% of cases, CCND1 in 14%, WHSC1 in 13%, KMT2D in 12%, TP53 in 7%, NOTCH1 in 6%, BIRC3 in 5% and TRAF2 in 1% (Figure 1A). By univariate analysis, mutations of TP53 (2-years PFS 48% vs 82%; p

Description: Anemia is one of the most prevalent clinic condition leading to a specialist medical consult. In 2014 our Internal Medicine unit started a Multidisciplinary Anemia Ambulatory (Internist, Immune-Hematologist, Hematologist) with the purpose to rapidly manage, diagnosis and treatment of anemic patients, giving a direct connection between general practitioners and hospital services. We treated and collected data on patients come to our attention in a tertiary care hospital in Genoa (Liguria), an area characterized by elderly population, which often carries more than one comorbidity with the purpose of better define the epidemiology of such a prevalent but underestimated issue. From January 1st 2014 a total of 212 patients came to our attention for internist consult due to anemia: 165 female and 47 male, medium age 63,23 years (F 58,86, M 78,57, range 19-100). A precise classification of anemia was determined for 187 patients: 130 had iron deficiency anemia (IDA, 61,32%), 17 multifactorial anemia (inflammatory disorders, chronic kidney disease and combined deficiency, 8,02%), 16 combined deficiency anemia (iron and vitamins, 7,55%), 9 chronic kidney disease related anemia (4,25%), 7 anemia secondary to inflammatory chronic disorder (3,30%), 5 B12 deficiency (2,36%), 2 both folate and B12 deficiency (0,94%), 1 folate deficiency (0,47%). Twenty-five patients were not classified due to lack of data. Severity of anemia was defined according to WHO criteria: 53 patients (25%) presented mild anemia (Hb 129 - 110 g/L), 123 (58%) moderate anemia (Hb 109 - 80 g/L), 33 (15,6%) severe anemia (Hb 〈 80 g/L). Three patients were not anemic at the baseline evaluation. We considered comorbidities of internistic relevance, which could be worsened by anemia: cardiovascular (coronary heart disease, arrhythmias, heart failure), 30 patients; neurologic (ischemic and degenerative diseases), 19 patients; respiratory disease (COPD and asthma), 11 patients. Eleven patients had 2 comorbidities (cardiovascular and respiratory or neurological) and 3 patients had all three comorbidities. Patients were treated according to clinical practice in relation to type, severity and clinical manifestation of anemia. One hundred and thirty patients needed more than one access to ambulatory to correct anemia; data from the second access were: patient responders (normalization of Hb levels or improvement of at least 20 g/L): 78 patients; partial responders (improvement of Hb levels from 5 to 20 g/L): 34 patients; non responders: 18 patients. Fourteen patients needed at least 1 blood red cells transfusion, 12 with severe anemia and 2 with moderate anemia. A total of 93 patients needed deep diagnostic insight through specialist pathways, such as hematologic (4 patients), gastroenterologic (39 patients), gynecologic (37 patients), both gastroenterologic and gynecologic (13 patients). All patients were managed as outpatients, except for 8 patients which required hospitalization due to severity of clinical findings: 4 patients were hospitalized in Internal Medicine ward, 1 patients in Gynecology and 3 patients needed access through Emergency Care Unit. Among IDA patients, 92 were treated with intravenous iron supplement: 32 with sodium ferric gluconate (SFG) (medium 16,68 vials, range 8-43) and 50 with ferric carboxymaltose (FC) (medium 1,04 vials). Nine patients treated with SFG experienced allergic reaction, so they were switched to FC. Patients treated with SFG were successfully treated for 69,56% and 26,08% responded partially. One patient treated with FC experienced allergic reaction, so he was switched to oral therapy. FC patients fully responded in 76% and 22% were partial responders. These preliminary data shows that Multidisciplinary Anemia Ambulatory and its diagnostic-therapeutic path, with the involvement of different Specialists and Operative Unit, resulted in an improvement of the coordination and continuity of care, reducing sanitary cost in terms of hospitalization, drugs rationalization and quality of life for patients. More data will derive from the newborn Anemia Regional Register, which will lead to a better comprehension of the real size of anemia in our local epidemiology, in which health derived costs are rising together with ageing of the comorbid population which often needs longitudinal assistance, coordination and continuity of care. Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND Essential Thrombocythemia (ET) is a Philadelphia-negative chronic myeloproliferative neoplasm characterized by haemorrhagic and thrombotic complications. Haemorrhagic events and arterial and venous thrombosis, including microcirculation transient occlusions, are the major causes of morbidity in ET patients. The control of these events represents the goal of standard therapeutic approaches. MATERIALS AND METHODS We retrospectively analysed data about 107 ET patients who received diagnosis between January 1980 and June 2014. Median follow-up was 80 months,16 patients were lost during follow-up. The medium age at diagnosis was 60 years, with a prevalence of female (66 patients).We recorded adverse cardiovascular events at diagnosis and during follow-up, assessing whether cytoreductive ad antiplatelet therapy could reduce such events and improve quality of life. Finally, we evaluated the impact of additional cardiovascular risk factors. OBJECTIVES to observe incidence and kind of thrombotic events in patients affected by ET at diagnosis and during follow-up. RESULTS 30 patients (27.7%) had a history of thrombosis at diagnosis (8 transient cerebral ischemia, 7 myocardial infarction/unstable angina, among them 7 patients experienced a rethrombosis during follow-up. 16 patients (15%) developed a first thrombotic event, all patients were under cytoreductive treatment. 21 patients with a history of thrombosis had more than 60 years at diagnosis, 19 patients (63%) had at least one additional cardiovascular risk factor among arterial hypertension, dyslipidemia, diabetes, obesity, hyperuricemia and smoking. Median platelet count was 813000/mm3, leukocyte count greater was more than 10000/mm3 in half of patients. Evolution to acute leukemia/myelofibrosis occurred in 3 (2,7%) and 7 (6,5%) patients of total. CONCLUSIONS The occurrence of thrombotic events even in patients with good hematologic response of disease and during antiplatelet and cytoreductive therapy, indicates the presence of a residual risk of thrombosis. This risk is not yet fully clarified by retrospective studies published until now. Prospective studies will be useful to evaluate the role and the importance of comorbidity in these patients with long-prognosis, in order to optimize therapy, reduce cardiovascular events and improve quality of life Disclosures No relevant conflicts of interest to declare.

Description: BACKGROUND: Iron overload from chronic transfusion therapy can be extremely toxic and most patients (pts) do not receive adequate iron chelation therapy (ICT) despite evidence of transfusional iron overload (IOL). Deferasirox (DFX) is the principal option currently available for ICT in the management of IOL due to transfusion dependent anemia, such as in MDS pts. The most common adverse events (AEs) are gastrointestinal disorders, skin rash, elevations in liver enzymes levels and non-progressive transient increases in serum creatinine also in MDS pts, most of whom are elderly with significant comorbidities and side effects of other concomitant therapies. In order to achieve effective ICT with minimal toxicity in individual pts, regular monitoring to assess IOL and adverse effects of DFX treatment is essential. METHODS: The safety and efficacy of DFX were examined in a retrospective multicenter observational study of transfusion-dependent (TD) MDS pts with International Prognostic Scoring System (IPSS) low-or Int-1-risk. We included all pts treated with DFX up to 12 months, divided into two groups; the first one (group A) not under a multidisciplinary assessment, including pts not adequately treated, in terms of dosing and discontinuation of ICT and the second one (group B) with pts under multidisciplinary control. The DFX starting dosing was 10 mg/kg/die in all pts. The aim of our retrospective analysis was to assess the effectiveness of ICT in relation of dosing and right management of AEs. RESULT: We evaluated 45 MDS pts (12F/33M); 27 belonging to the group A and 18 to group B. The age was 74.2±8.8 and 77.3±4.8 respectively. The ECOG 0-1 was 85,1% in group A and 88,9% in group B. The transfusion episodes prior starting DFX were22.1±12.1 and 24.5±35.4 in the first and in the second group, respectively. The serum ferritin level at baseline was respectively 1285.1±489.6 ng/mL and 1452.6±748.1 ng/mL. The mean serum ferritin level increased from 1285.1+489.6 ng/mL to 1412.1+842.8 ng/mL in group A while decreased from 1452.6+748.1 ng/mL to 1166.1+ 723.4 ng/mL in group B. The rate of inadequate therapy, in terms of dosing and/or discontinuation ICT, was 85% in group A compared to 60% in group B (p= 0.086).The rate of severe SAE observed in all pts was 10%.The most common AEs were diarrhea, nausea, upper abdominal pain, serum creatinine increase. The positive hematological response rate was observed in 15% of all pts. CONCLUSIONS: The study showed that group B obtained advantage in terms of efficacy and toxicity. The difference between the two groups derived from the ability to manage comorbidities, concomitant therapies and AEs, in particular the rise in serum creatinine, the most common cause DFX discontinuation or dosing reduction. In this setting, the most important specialist was the nephrologist. In our multidisciplinary group experts in management of ICT were hematologist, internist, immune-hematologist and nephrologist. We shared how we monitored kidney function and managed a possible nephrotoxicity (table.2), in order to ensure DFX efficacy. Positive hematological responses were observed, and a subset of pts achieved transfusion independence. The timing of future multidisciplinary evaluation is set on 24 and 36 months, time in which we expect the best response to DFX therapy. Table 1. Ferritin trend group A (n27) group B (n18) Ferritin N mean±SD Median (range) N mean±SD Median (range) Baseline 27 1285.1±489.6 1134 (388-2099) 18 1452.6±748.1 1515 (160-3018) 3 months 22 1451.5±720.5 1247.5 (529-2791) 13 1312.7±909.8 1064 (521-3859) 6 months 23 1850.5±1079.1 1419 (374-4185) 11 1168.4±648.4 1300 (160-2409) 12 months 17 1412.1±842.8 1372 (111-3127) 9 1166.1±723.4 930 (277-2536) Table 2. Management of renal changes during therapy with DFX Creatinine and urine examination:1) in two successive determinations prior to initiation of therapy, then every month 2) in pts with other risk factors for kidney disease, every week for 1 month after start of DFX or dose increase and, subsequently, every month Changes in creatinine:1) increased by 33% in two successive determinations: reduce DFX dose of 5 mg/kg 2) progressive increase of creatinine: interrupt DFX and then re-challenge it at a lower dose with gradual increase if the clinical benefits outweigh the risks Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Myelodysplastic syndromes (MDS) are a highly heterogeneous group of clonal disorders, with very different prognosis in given individuals, overall survival (OS) ranging from more than 10 years (y) for the more indolent conditions to only few months (m) for the forms approaching AML; beside of the well-established disease-related prognostic systems (classical IPSS or its revised form [IPSS-R], the prognostic implication of comorbidities is emerging as a relevant patient-related factor influencing clinical outcome. Aim of our study was to evaluate the clinical impact of comorbidities in a series of MDS patients whatever treated in a “real-life” setting. Methods: this retrospective cohort study involved the MDS patients consecutively registered between Jan 2011 and Dec 2013 into the Registro Ligure delle Mielodisplasie database, a regional registry established within the framework of the Italian Network of regional MDS registries. Data of 318 patients (pts) with available complete assessment of comorbidities at diagnosis were included into the study. The clinical characteristics and comorbidities were all considered into the analysis. Comorbidities were evaluated according to both hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and MDS-specific comorbidity index (MDS-CI). All survival analyses were made from the date of diagnosis to last follow-up, death, or progression to AML. Unless specified, survival analyses were Cox models using continuous variables accounting for interactions. Results: Our cohort mainly consisted of older (median age 75y (range 40-98) “lower-risk” MDS pts: according to IPSS stratification, 151 (54.7%) pts were classified as low-risk, 86 (31.2%) as intermediate-1, 32 (11.6%) as intermediate-2 and 7 (2.5%) were in the high-risk group. One or more comorbidity of any grade of severity was seen in 177 (55.7%) pts at diagnosis. The more common comorbidity was cardiac (26.5%). At least a single comorbidity was present in 61.2% of pts older than 75y and in 50.6% of younger pts (p=0.07). Cardiovascular disorders were more frequent among older (32.9% for 〉75y vs 15.1% for ≤ 75y, p75 y (48% vs. 28.9% for 〈 75 y (p=0.001). A lower comorbidity score impacted on the clinical choice for active forms of therapy, while pts with an higher burden of comorbidities were preferentially treated with supportive care, even if difference did not reach significance (p=0.07). Overall survival and risk of non-leukemic death (NLD) were analyzed (median f.u. 26.9 m (range 1-220). HCT-CI did not significantly correlated with OS nor NLD (p= 0.1 and p= 0.07, respectively), while MDS-CI was found to be of prognostic significance both for OS (mean 136.6 (95%CI 116-157) m for the low-risk group, 81.3 (95%CI 61-102) m for the intermediate group and 48.1 (95%CI 30-66) m for the high-risk group, p=0.001) and for NLD (mean 159.6 (95%CI 139-180) m for the low-risk group, 96.5 (95%CI 72-121) m for the intermediate group and 49 (95%CI 31-67) m for the high-risk group (p

Description: Backgroud: The appearance of inhibitors (INH) is the most serious complication in hemophilia A (HA) patients. The primary objective is their eradication. Usually the primary ITI was performed with the same concentrate causing INH development, but which replacement factor to be use in case of ITI-R is still debatable. We report two successful cases of ITI-R with simoctocog alfa (rhFVIII) performed in two different Italian Hemophilia Centers, while three other cases are still ongoing. Case Report: Case-1: Adult man with moderate HA who developed INH after surgery and concomitant switch to another concentrate (octocog-alfa 2nd gen). The patient refused the ITI treatment immediately after the inhibitors appearance, and was then put on prophylaxis with bypassing agents for several months. First ITI was then started with pdFVIII/vWF at 200 IU/kg/day, inhibitor titer reached its historical peak (134 BU/ml) two months later and progressively decreased to 15 BU/ml, but without ever disappearing. This ITI was stopped after nineteen months. A second ITI was then tried with high dose regimen of morocotocog-alfa, but also in this case the mean INH titer remained steadily high (21 BU/ml) and this treatment was considered failed after fifteen months from the onset. A new ITI-R was then started when the INH titer was 74 BU/ml, with simoctoctocog-alfa (rhFVIII), at 200 IU/kg/day. INH progressively decreased and 7 months later disappeared (

Description: Introduction Limited stage follicular lymphoma (FL) is usually managed with involved field radiotherapy (IFRT), although different approaches are currently carried out, ranging from watch and wait to combined treatment. RT on involved lymph nodes allows eradication of the disease only in 40-50% of patients. Anti-CD20 monoclonal antibodies (MoAb), widely used in advanced stage FL, are likely to be effective in reducing the relapse risk, although no scientific evidence of their role has been provided. The aim of this multicenter phase II prospective study was to evaluate the role of MRD in identifying patients unlikely to be cured by RT, for whom an immunotherapy-based consolidation could improve outcome. Methods 110 patients with stage I/II FL were enrolled. IFRT was administered to all patients at a dose of 24 Gy. Peripheral blood (PB) and bone marrow (BM) samples were centralized to the Italian FIL (Federazione Italiani Linfomi) MRD Network of EuroMRD-certified laboratories: the presence of a BCL2/IGH rearrangement was investigated at baseline in all patients by nested PCR (NEST) and RQ-PCR (RQ), the latter according to the EuroMRD guidelines. In patients BCL2/IGH+ at baseline by both NEST and RQ in BM and/or PB, MRD was analyzed in both tissues after IFRT and every 6 months over a three-year follow-up period. Patients with positive MRD by both NEST and RQ in BM and/or PB after IFRT or who became positive during the follow-up were treated with 8 weekly doses of the anti-CD20 MoAb ofatumumab. The primary objective of the study was to define the efficacy of immunotherapy in obtaining the disappearance of BCL2/IGH rearranged cells. Results Preliminary data are available for 107 patients, 57 males, 50 females. Median age was 55 years (29-83). 17% had G1 FL, 32% G2, 40% G3A, 11% NOS. The FLIPI score was 0 in 59% of patients, 1 in 35%, 2 in 6%. 69% of patients had inguinal site involvement. Despite a negative BM biopsy, at baseline 30% of patients (n=32) had a BCL2/IGH rearrangement (30 MBR, 1 MBR and mcr, 1 mcr) in the BM and/or PB; the concordance between compartments was 90%, with 10% of negative PB showing a positive BM. No significant differences were observed in relapse probability between patients with or without a molecular marker. All patients were submitted to IFRT and all obtained a clinical response, which was complete in 79 of the 101 evaluated patients (78%) and partial in 22 (22%). MRD evaluation after treatment revealed the persistence of BCL2/IGH rearranged cells in the PB and/or BM in 60% of patients. According to the design of the protocol, MRD-positive patients, either after IFRT (n=18) or in case of conversion to a positive signal during the follow-up (n=7), received 8 weekly administration of ofatumumab. A conversion to MRD negativity, evaluated in 23 treated patients, was obtained in 20 (87% - CI 65.1-97.1). This result was significantly superior to the expected 50%. One death occurred after IFRT, due to ischemic stroke. Adverse events likely correlated to ofatumumab occurred in 7/25 treated patients, consisting of infusion reactions in 5, leading to a permanent interruption of immunotherapy in 3. After a median follow-up of 18 months, all patients who achieved a MRD negativity with ofatumumab underwent a regular molecular follow-up and are still MRD-negative. Overall, clinical relapse or progression were observed in 17 patients: 13 (18%) among the 73 "no marker" patients; 2 relapses (16%) were observed among the 12 MRD-negative patients after IFRT and 2 relapses were observed among the 23 patients treated with the anti-CD20 MoAb (8.7%), 1 having achieved a MRD negativity and 1 not. No significant differences in event-free survival have so far been observed between the three groups. Conclusions The MRD data of this phase II trial for early stage FL indicate that RT alone is often insufficient to eradicate the disease, being capable of inducing a negative MRD only in 40% of evaluable cases, with a long-lasting effect only in half of them. The primary objective of this study - MRD negativity after immunotherapy - was achieved, obtaining the disappearance of BCL2/IGH rearranged cells in the majority of patients treated with ofatumumab. The strategy of an immunotherapy consolidation after IFRT in MRD-positive patients allowed to increase molecular responses. A longer follow-up and further studies on larger patient populations will allow to conclusively define the impact of this MRD-driven strategy also on clinical outcome. Disclosures Pulsoni: Roche: Consultancy, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Gilead: Speakers Bureau; Merk: Consultancy; Bristol Meyer Squibb: Speakers Bureau. Ferrero:Servier: Speakers Bureau; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Gilead: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Luminari:ROCHE: Other: Role as Advisor ; CELGENE: Other: Role as Advisor & Travel Grant; TAKEDA: Other: Travel Grant; GILEAD: Other: Lecturer . Liberati:Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Janssen: Honoraria; Servier: 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, Other: Clinical trial support; Roche: Other: Clinical trial support; Novartis: Other: Clinical trial support. Ferreri:Roche: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Kite: Consultancy. Nassi:Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy. Corradini:Roche: Honoraria; Novartis: Honoraria; kite: Honoraria; KiowaKirin: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Servier: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Mannina:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Arcaini:Celgene: Speakers Bureau; Gilead Sciences: Research Funding; Bayer, Celgene, Gilead Sciences, Roche, Sandoz, Janssen-Cilag, VERASTEM: Consultancy; Celgene, Roche, Janssen-Cilag, Gilead: Other: Travel expenses. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Ladetto:AbbVie: Honoraria; Roche: Honoraria; ADC Therapeutics: Honoraria; Acerta: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; J&J: Honoraria; Celgene: Honoraria. Foà:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: The anti-CD20 MoAb Ofatumomab is employed to eradicate Minimal Residual Disease in early stage Follicular Lymphoma(FL). The drug is registered for Chronic Lymphocytic Leukemia, not for FL.