Abstract: Introduction. Azacitidine (AZA) as single agent has been shown to improve overall survival in high-risk myelodysplastic syndromes (MDS), with an overall response rate (ORR) of 50-60% (Silverman 2002; 2006; Fenaux 2009). However as a significant proportion of patients (pts) do not respond to treatment, and moreover, as the the duration of therapeutic response to AZA is limited, several attempts have been made to associate AZA with other drugs, with the aim to improve the outcome. In particular, the addition of lenalidomide (LEN) to AZA, either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), has shown promising results, although these data await confirmation by larger series of pts. The aim of this study was to evaluate the efficacy (ORR) and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts. Moreover, as in previous studies we demonstrated that the increase in PI-PLCβ1 gene expression during AZA treatment is related to haematological response and frequently anticipates the response (Follo, 2009; 2012), another aim of our study was to assess the evaluation of PI-PLCβ1 expression as early predictive biomarker of response also with the association of AZA and LEN, and to look for other possible biomarkers able to predict response, as the mutational status assessed by next generation sequency (NGS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (according to WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The treatment for both arms was planned for 8 cycles (32 weeks) in the absence of disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 40 pts (23 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: Refractory Cytopenia with Multilineage Dysplasia (RCMD): 3 pts; Refractory Anemia with Excess of Blasts-1 (RAEB-1): 9 pts; RAEB-2: 23 pts; MDS-unclassified (MDS-U): 5 pts; IPSS risk was: Intermediate-2: 29 pts; High: 6 pts; not determined (N.D.) (because of lack of cytogenetic data): 5 pts. (all with RAEB-2). IPSS cytogenetic risk was: intermediate in 10 pts and high in 9 pts (3 with complex karyotypes and 6 with isolated -7 or 7q-). 5 pts showed del5q (in 3 cases in the context of a complex karyotype, and in 1 case associated with another single additional cytogenetic alteration). 2 pts had therapy-related MDS. 21 pts (52.5%) were transfusion-dependent at baseline. 19 pts were randomly assigned to ARM 1, and 21 pts to ARM 2. At the time of this analysis, 22/40 pts (55%) completed ≥ 6 cycles of treatment, and are evaluable for response. 13/22 pts (59,1%) showed a favourable response to treatment, following the International Working Group (IWG) criteria (Cheson, 2006): 2 pts achieved Complete Remission (CR), 2 pts attained Partial Remission (PR), 2 pts showed Marrow Complete Remission (mCR), and 7 pts obtained Hematological Improvement (HI), while the 9 non responder pts maintained a Stable Disease (SD). Responder pts were 7/10 (70%) in ARM 1 (2 CR; 1 PR; 4 HI), and 6/12 (50%) in ARM 2 (1 CR; 1 PR; 2 mCR; 2 HI), respectively. Median time to first response: 2 (2-7) months. A significant toxicity (grade 〉 2) was observed in 10/40 (25%) pts. 15/40 pts (37,5%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 8 pts (20%) early discontinued therapy before completing the planned 8 cycles, because of prolonged thrombocytopenia (1 pt), death (3 pts), evolution into acute myeloid leukemia (AML) (2 pts) and withdrawal of consent (2 pts), respectively. Causes of death were: febrile neutropenia, myocardial infarction and sudden death, respectively . Conclusions. Our results, although preliminary, seem to confirm the feasibility of the association of AZA and LEN in high-risk MDS pts. More data are needed in order to compare the efficacy and safety of combined vs sequential treatment and vs AZA monotherapy. Moreover, possible relationships with signal transduction pathways and with mutational status are under evaluation. Disclosures Finelli: Celgene: Research Funding, Speaker Other; Novartis: Speaker, Speaker Other; Janssen: Speaker, Speaker Other. Off Label Use: Lenalidomide in higher-risk MDS and AML. Cavo:Celgene: Consultancy, Honoraria, Speakers Bureau.

Abstract: Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012; 2017), or sequentially (Platzbecker, 2013; Di Nardo 2015; Mittelman 2016; Narayan 2016) has proven effective in Myelodysplastic Syndromes (MDS), however the optimum dose and schedule remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the IWG criteria (Cheson, 2006). Secondary endpoints: a) rate of CR; b) duration of responses; c) overall survival (OS). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS with IPSS risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles. For responder patients the same treatment was continued until disease progression or unacceptable toxicity. Results. From March 2013, 44 pts (27 males), median age: 72 (48-83 yrs) were enrolled, from 13 hematologic Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present (additional cytogenetic alterations: 1 in 1 pt, and 〉 1 in 4 pts , respectively). 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-52) cycles; in ARM 1: 9 (1-51) cycles; in ARM 2: 8 (1-52) cycles, respectively. Median follow-up: 15 (2-54) months; 47 (37-54) months for survivors. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression (6 pts for adverse events, 2 pts for consent withdrawal and 2 pts for medical decision), and were not considered evaluable for response. Among the 34/44 pts (77.3%) evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. Intention-to-treat (ITT) analysis: ORR: 59.1%. First response was observed after a median of 2 (1-8) cycles. The Best Response achieved was: CR: 8 pts (23.5%) (ITT: 18.1%), PR: 1 pt (2.9%) (ITT: 2.2%), mCR: 3 pts (8.8%) (ITT: 6.8%), HI: 8 pts (23.5%) (ITT: 18.1%), mCR+HI: 6 pts (17.6%) (ITT: 13.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). Among the 27 pts (21 evaluable for response) with an abnormal karyotype at baseline, ORR was 66.7% (ITT: 51.8%) and 4 pts achieved complete cytogenetic response. Median duration of hematologic response: 10.5 months. 34 pts (77,3%) died , and 17 pts (38.6%) showed progression to AML. Grade 〉 2 non haematological toxicity: 54.5%. Median OS: 15 months. No significant differences between the 2 arms were observed, in terms of ORR (ARM 1: 76.5%, ITT: 61.9%; ARM 2: 76.5%, ITT: 56.5%), CR rate (ARM 1: 17.6%, ITT: 14.3%; ARM 2: 29.4%, ITT: 21.7%), grade 〉 2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 28.6%; ARM 2: 47.8%) and OS (ARM 1: 14 months; ARM 2: 16 months), but the median response duration was significantly longer in ARM 2 (18 months) as compared to ARM 1 (6 months) (p=0.0459). At the time of last analysis, 5/44 (11.4%) patients, 1/21 (4.8%) in ARM 1, and 4/23 (17.4%) in ARM 2, were still maintaining the haematological response, and were still in treatment, after 54, 54, 52, 51 and 37 months, and after 52, 51, 33, 48 and 35 cycles of therapy, respectively. The changes observed during treatment in mutational status of inositide-specific genes and microRNA expression profiling were related to clinical outcome, predicting a negative response to therapy. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although pts treated with the sequential regimen showed a significantly longer duration of haematological response. Disclosures Finelli: Celgene: Other: speaker fees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: speaker fees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fees. Candoni:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Merck SD: Honoraria, Speakers Bureau. Gobbi:Novartis: Consultancy; Janssen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees. Rigolin:Gilead: Research Funding. Cavo:GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction. Azacitidine (AZA) is the standard of care of higher-risk myelodysplastic syndromes (MDS), but the duration of clinical response is limited, and outcome after AZA failure is dismal. Several studies have demonstrated the efficacy and safety of combining AZA with Lenalidomide (LEN), either administered concurrently or sequentially, however the optimum dose and schedule for this combination remains unknown. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in higher-risk MDS pts (IPSS score risk: High or INT-2), and to look for possible biomarkers able to predict response. Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts. In 5 pts (11.4%) del(5q) was present. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8.5 (1-37) cycles; in ARM 1: 9 (1-32) cycles, in ARM 2: 8 (1-37) cycles, respectively. 6 pts (ARM 1: 2; ARM 2: 4) are still on treatment. Pts have been followed for a median of 15 (2-37) months for all subjects, for a median of 32 (18-37) months for survivors. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. The median duration of hematologic response was 10.5 months. A grade 〉 2 non hematologic toxicity was observed in 54.5 % of pts, and an emerging (from grade 0-2 to 〉 2) hematologic toxicity in 27.3% of pts. In 61.4% of pts LEN dose was reduced because of hematologic or non-hematologic toxicity. 32 pts (72.7%) died , and 17 pts (38.6%) showed progression to AML. Median overall survival (OS) was 15 months. No significant differences between the 2 arms were observed, in terms of ORR, CR rate, toxicity, AML incidence and OS, but there was a trend (although still not significant) towards a longer median duration of response in the sequential arm: ARM 1: 6 months; ARM 2: 18 months (p=0.0847). MDS cells showed alterations of the inositide-dependent signalling as well as an altered microRNA profile. In particular, responder cases showed a frequent downregulation of miR-3613 and mir-4668, that were upregulated in non responder cases. Further analyses are ongoing. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR, although the sequential schedule seems to induce more durable responses. Moreover, possible relationships with signal transduction pathways and microRNA profile are under evaluation. Disclosures Finelli: Novartis: Other: Speaker fees; Celgene: Other: Speaker fees; Celgene: Research Funding. Gobbi:Janssen: Consultancy, Honoraria; Novartis: Consultancy, Research Funding; Roche: Honoraria; Takeda: Consultancy; Gilead: Honoraria; Celgene: Consultancy; Mundipharma: Consultancy, Research Funding. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

Abstract: Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by genetic and clinical heterogeneity and high mortality. Despite the recent introduction of novel pharmaceutical agents in hemato-oncology, few advancements have been made in AML for decades. In the last years, the therapeutic options have rapidly changed, with the approval of innovative compounds that provide new opportunities, together with new challenges for clinicians: among them, on 1 September, 2017 the Food and Drug Administration granted approval for Gemtuzumab Ozogamicin (GO) in combination with daunorubicin and cytarabine for the treatment of adult patients affected by newly diagnosed CD33+ AML. Benefits of GO-based regimens were also reported in the pre- and post-transplantation settings. Moreover, several biomarkers of GO response have been suggested, including expression of CD33 and multidrug resistance genes, cytogenetic and molecular profiles, minimal residual disease and stemness signatures. Among them, elevated CD33 expression on blast cells and non-adverse cytogenetic or molecular risk represent largely validated predictors of good response.

Abstract: We analyzed clinical and molecular follow-up of 16 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT). The median interval between allogeneic SCT and relapse was 26 months (7–162). Two patients had failed treatment with donor lymphocyte infusions prior to Imatinib; four patients had received therapy with IFN alpha. All patients were treated with Imatinib (400 or 600 mg/daily). One patient had received Imatinib before allogeneic SCT. The overall complete hematological (CHR) and cytogenetic responses (CCyR) were 100% for all patients either relapsed in CP or AP. All patients achieved complete molecular response (CMR), intended as 3 logs reduction of BCR-ABL/B2M within 18 months; 8/16 patients obtained a CMR within three months, independently of the phase of the disease at of relapse. Median follow-up after start of Imatinib therapy was 24 months (range 6–36). Chimerism status evaluated in 9 patients showed conversion to full donor chimerism after therapy in all but one of them. Imatinib has significant activity against CML in relapse after allogeneic bone marrow transplantation with durable cytogenetic and molecular remissions obtainable in all patients.

Abstract: Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

Abstract: Introduction. Azacitidine (AZA) is able to induce hematologic responses in 50-60 % of patients (pts) with Myelodysplastic Syndromes (MDS) and moreover to prolong survival in higher risk MDS pts. Recently, several studies have evaluated the efficacy and safety of combining, in high-risk MDS pts, AZA with Lenalidomide (LEN), either administered concurrently (Sekeres, 2010; 2012), or sequentially (Platzbecker, 2013), in both cases showing promising results, although in a limited number of pts. The aim of this study was to evaluate the efficacy and safety of the combination vs the sequential use of AZA and LEN in high-risk MDS pts (IPSS score risk: High or INT-2). Primary endpoint: ORR, defined as the Rate of Complete Remission (CR), Partial Remission (PR), Marrow Complete Remission (mCR), and Hematological Improvement (HI), following the International Working Group (IWG) criteria (Cheson, 2006). Methods. This is a randomized, phase II, multicenter, open label study, including pts with MDS (WHO 2008 classification) with International Prognostic Scoring System (IPSS) risk High or Intermediate-2, without previous treatment with AZA or LEN. ARM 1 (combined treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 1-21), orally, every 4 weeks. ARM 2 (sequential treatment): AZA: 75 mg/m2/day (days 1-5) I.C. + LEN: 10 mg/day (days 6-21), orally, every 4 weeks. The induction treatment was planned for 8 cycles (32 weeks). For responder patients (CR, PR, mCR, or HI) the same treatment was continued until disease progression or unacceptable toxicity. A sample size of 44 pts was planned. Results. From March 2013, 44 pts (27 males), with a median age of 72 (48-83 yrs) were enrolled, from 13 hematologic italian Centers. At baseline, WHO diagnosis was: RCMD: 2 pts; RCMD-RS: 1 pt ; RAEB-1: 11 pts; RAEB-2: 30 pts; IPSS risk was: Intermediate-2: 31 pts; High: 9 pts; not determined (N.D.) (because of lack of cytogenetic data): 2 pts. (all with RAEB-2). In 2 pts IPSS risk was Intermediate-1, but they were enrolled because of severe thrombocytopenia and neutropenia, respectively. IPSS-R risk was: intermediate: 8 pts; High: 16 pts; Very-High: 18 pts; N.D.: 2 pts; IPSS cytogenetic risk was: Good: 17 pts; Intermediate: 11 pts; Poor: 14 pts; N.D.: 2 pts. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. At the time of this analysis, enrolment of the planned 44 pts was completed. 34/44 pts (77.3%) completed ≥ 6 cycles of treatment, and are evaluable for response. The remaining 10 pts (4 in ARM 1 and 6 in ARM 2) are not evaluable for response, as they discontinued treatment before completing the 6th cycle because of adverse events (6 pts, 13.6%), consent withdrawal (2 pts, 4.5%) or medical decision (2 pts, 4.5%), respectively. Treatment was given for a median of 8 (1-28) cycles; in ARM 1: 9 (1-22) cycles, in ARM 2: 8 (1-28) cycles, respectively. Among the 34 pts evaluable for response, 26/34 pts (ORR: 76.5 %) showed a favourable response to treatment. The Best Response achieved was: CR: 8 pts (23.5%), PR: 1 pt (2.9%), mCR: 3 pts (8.8%), HI: 8 pts (23.5%), mCR+HI: 6 pts (17.6%). The remaining 8 pts showed either Stable Disease (SD) (6 pts, 17.6%) or Disease Progression (DP) (2 pts, 5.9%). First Response was detected after a median of 2 (1-8) cycles. Responder pts were: 13/17 (ORR: 76.5 %) in ARM 1 (3 CR; 1 PR; 1 mCR; 4 HI, 4 mCR+HI), and 13/17 (ORR: 76.5 %) in ARM 2 (5 CR; 2 mCR; 4 HI; 2 mCR+HI), respectively. Overall, the median duration of response was 8.5 (2-23) months: 6 (2-19) months in ARM 1; 16 (2-23) months in ARM 2. A grade 〉 2 non hematologic toxicity was observed in 24/44 (54.5 %) pts (ARM 1: 66.7%; ARM 2: 43.5%). 27/44 pts (61.4 %) (ARM 1: 61.9%; ARM 2: 60.9%) had a dose reduction of LEN because of hematologic or non-hematologic toxicity. 22 pts (50%) died (ARM 1: 47.6%; ARM 2: 52.2%). 14 pts (31.8%) (ARM 1: 23.8%; ARM 2: 39.1%) showed progression to AML. Overall, median survival was 13 (1-28) months; ARM 1: 13 (1-25) months; ARM 2: 14 (2-28) months. Conclusions. Our results confirm the efficacy of both AZA + LEN treatment regimens in high-risk MDS pts. Moreover, at a molecular level, a significant increase of phosphoinositide-specific phospholipase C (PI-PLC) beta1 and/or PI-PLCgamma1 expression was associated with a favourable clinical response to treatment. Responder cases also showed an increase of Beta-globin expression, hinting at a specific contribution of LEN on erythroid activation Disclosures Finelli: Janssen: Other: Speaker; Novartis: Other: Speaker; Celgene: Other: Speaker, Research Funding. Visani:Celgene: Research Funding. Cavo:Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.