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Introduction Treatment of chronic phase (CP) chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) proved to be almost equally effective in young and elderly patients. Three TKIs, imatinib (IM), dasatinib (DAS) and nilotinib (NIL), are approved for frontline therapy in Italy. Choice of frontline TKI is based on a combined evaluation of patient's characteristics and expectations, with age usually playing a prominent role. However, to date, few data are available on patterns of TKI selection in very elderly patients. Aim To analyse the use of frontline TKI therapy in a large and unselected cohort of very elderly CP-CML patients Methods We retrospectively evaluated 332 patients aged ≥75 year diagnosed from 1/2012 to 12/2019 at 36 Hematology Centres participating at the "Campus CML" project. Results Clinical features at diagnosis for the whole cohort and according to frontline TKI are reported in Table 1. As to frontline TKI, 285 patients (85.8%) received IM and 47 (14.2%) a 2G-TKI (DAS n=28, 59.5%; NIL n=19, 40.5%). Of the 285 IM-treated patients, 192 (67.3%) started with standard dose (400 mg/day) and 93 (32.7%) with a reduced dose (300 mg/day n=64, 22.5%; Following widespread introduction of generic IM in Italy in early 2018, patients were divided in 2 groups: among 238 patients diagnosed from 2012 to 2017, 198 (83.1%) received IM and 40 (16.9%) a 2G-TKI, while patients diagnosed in 2018-2019 were treated with IM in 87/94 (92.5%) cases and with a 2G-TKI in 7 (7.5%) cases only (p=0.028). Conclusions IM remains the frontline drug of choice in very elderly CML patients, and this trend seems to increase after the introduction of the generic formulation. However, 2G-TKI are used in a small but sizeable group of patients, without a clear correlation with baseline CML features, thus probably reflecting a physician's evaluation of patient's fitness and/or expectation. Efficacy and safety of initial reduced TKIs doses in the setting of very elderly patients warrant further analyses. Figure 1 Figure 1. Disclosures Latagliata: Novartis: Honoraria; BMS Cellgene: Honoraria; Pfizer: Honoraria. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Elena: CELGENE: Other: funding for meeting participation; PFIZER: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; GILEAD: Membership on an entity's Board of Directors or advisory committees. Iurlo: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; InCyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Abruzzese: Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Breccia: Bristol Myers Squibb/Celgene: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria.

Background Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML). However, the first months of therapy are crucial, as optimal response is defined as the achievement of molecular milestones at 3, 6 and 12 months (mo.) and as many toxicities, also causing a TKI switch, are more frequent in the 1st year. Methods To evaluate achievement of early molecular response (MR) and incidence of events leading to a TKI change during the 1st year of therapy, we retrospectively studied 1650 CP-CML patients diagnosed from 2012 and 2019 at 31 Hematology Centres and treated with frontline imatinib (IM) or second-generation (2G) TKIs dasatinib or nilotinib. Optimal MR at 3, 6 and 12 mo. were assessed according to 2020 ELN recommendations. Results Frontline TKI was IM in 926 (56.1%) and 2G-TKIs in 724 (43.9%) cases: the main clinical features at diagnosis of the entire cohort and according to frontline treatment is reported in the Table 1. Commonest comorbidities were arterial hypertension (38.7%), previous neoplasm (13.6%), diabetes (11.3%), peripheral vascular diseases (7.8%), COPD (7.5%) and ischemic heart disease (6.8%). IM-treated patients were older (p Optimal MR was achieved at 3 mo. by 1186/1430 (82.9%), at 6 mo. by 1025/1352 (75.8%) and at 12 mo. by 826/1264 patients (65.3%), respectively. Total number of patients discontinuing TKI in the 1st year was 321/1650 (19.4%), being higher with IM (237/926, 25.5%) than 2G-TKIs (84/724, 11.6%) (p0.001), hematologic toxicity (1.7%, 2.0% IM vs 1.4% 2G-TKIs, p=0.25) and progression (1.0%, 1.2% IM vs 0.8% 2G-TKIs, p=0.56). Cumulative incidence of discontinuation at 3, 6 and 12 mo. were 5.6%, 10.7% and 19.3%, respectively; values for IM and 2G-TKIs at the three timepoints were 8.1%, 15.0%, 25.5% and 2.5%, 5.3%, 11.5% (p Conclusions This real-world study on over 1600 CML patients shows that almost 20% discontinue frontline TKI during the 1st year, mostly for primary resistance or toxicity. Discontinuation rates are higher with IM compared to 2G-TKIs, mostly at 3 mo. and are probably due to a lower attainment of early MR. The impact of older age, higher risks and heavier burden of comorbidities in IM patients should be considered and need deeper investigation. Figure 1 Figure 1. Disclosures Elena: GILEAD: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; CELGENE: Other: funding for meeting participation. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Pfizer: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Bonifacio: Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Abbvie: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Novartis: Honoraria. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria.

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0; BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL; indeed, pts with at least major molecular response (MMR; BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48; TFR rate at wk 96 and 144; BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Interim results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. Figure 1 Figure 1. Disclosures Breccia: Abbvie: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau; Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is an adverse risk factor. Treatments in this setting are scarce. In a randomized international phase 2 trial (EQoL-MDS, EudraCT number 2010-022890-33), we reported effecacy and safety of eltrombopag for the treatment of thrombocytopenia in the first 90 patients with lower-risk MDS with a platelet (PLT) count < 30 Gi/L (Oliva et al. Lancet Hem 2017). However, there are concerns of regulatory agencies regarding the use of thrombopoetin rececptor agonists in MDS due to previous reports signalling disease progression in clinical trials with the use of romiplostim and of eltrombopag, the latter in high risk MDS. Objective: We are further evaluating safety by conducting a comprehensive analysis of mutations in a panel of major driver or candidate driver genes in cases enrolled in the EQoL-MDS trial using targeted-capture sequencing. Methods: Serial (every 3 months) sequencing was performed using the SureSelect custom kit (Agilent Technologies), for which 350 genes were selected from known oncogenes or tumour suppressor genes in haematological malignancies. Relevant somatic mutation data with (i) VAF > 0.05; (ii) depth > 100; (iii) P value for EBCall < 0.0001, were filtered by exclusion based on (i) synonymous SNVs; (ii) variants present only in unidirectional reads; (iii) variants occurring in repetitive genomic regions; (iv) missense SNVs with VAF of 0.4-0.6 or Results: We present preliminary results of the first 21 cases (13 eltrombopag, 9 placebo) enrolled in the trial and with biological samples. Mean age was 62 (± 15) and 13 patients were male. According to the WHO 2016 classification, 11 patients had MDS with single lineage dysplasia (SLD), 7 had multi lineage dysplasia (MLD), 1 placebo case had excess blasts-1, and 1 placebo case had unclassifiable. IPSS-R risk was very low, low and intermediate in 4, 8 and 1 eltrombopag cases, respectively, and 5, 2 and 1 placebo cases, respectively. Karyotype was normal in 16 cases, del(20q) was detected in 4 cases and +14 in 1 case. At study entry, in total 49 genes were mutated (Figure), where one or more of the 49 driver genes were mutated in all but 1 placebo patient (Table). The table shows characteristics and events of patients according to treatment arm. Noteworthy, in the eltrombopag arm, two cases experienced a loss of gene mutations, one obtaining International Working Group defined complete remission of MDS, while 1 MDS EB-1 case had a gain in ZRSR2. Two placebo cases experienced a gain in mutations Conclusions: Treatment with eltrombopag in lower risk MDS is effective and safe. Preliminary analyses do not suggest that eltombopag induces disease progression neither at a clinical, nor a molecular level. Loss of mutations may occur during eltrombopag treatment with complete remission. Figure 1 Figure 1. Disclosures Oliva: Novartis: Other: Advisory Board; Celgene BMS: Consultancy, Other: Advisory Board, Patents & Royalties; Alexion: Other: Advisory Board; Argenx: Other: Advisory Board; Daiichi: Other: Advisory Board; Amgen: Other: Advisory Board. Nannya: Otsuka Pharmaceutical Co., Ltd.: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Kulasekararaj: Alexion, AstraZeneca Rare Disease Inc.: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; Ra Pharma: Consultancy, Honoraria, Speakers Bureau; Alexion: Consultancy, Honoraria, Speakers Bureau; Achilleon: Consultancy, Honoraria, Speakers Bureau; Biocryst: Consultancy, Honoraria, Speakers Bureau; Akari: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy; F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Speakers Bureau. Latagliata: Novartis: Honoraria; Pfizer: Honoraria; BMS Cellgene: Honoraria. Santini: Astex: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ogawa: Eisai Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kan Research Laboratory, Inc.: Consultancy, Research Funding; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; ChordiaTherapeutics, Inc.: Consultancy, Research Funding; Ashahi Genomics: Current holder of individual stocks in a privately-held company. OffLabel Disclosure: Eltrombopag (Revolade) is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients aged 1 year and above who are refractory to other treatments (e.g. corticosteroids, immunoglobulins).Revolade is indicated in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy.Revolade is indicated in adult patients with acquired severe aplastic anaemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for haematopoietic stem cell transplantation.

Background We already showed that in CML pts peripheral blood CD34+/CD38-/CD26+ cell population represent a "CML specific" leukemia stem cell (LSC) circulating compartment. Indeed, we demonstrated that CD26+LSCs are measurable by flow-cytometry in 100% of CML pts at diagnosis the latter representing an alternative and rapid diagnostic tool. In addition, in a cross-sectional study we were able to spot peripheral blood CD26+LSCs also in about 65% of CML during TKI treatment regardless of type and length of TKI treatment and degree of molecular response. However, no prospective data are available regarding the behavior of PB CD26+LSCs in terms of rate and timing of reduction during TKI therapy and the correlation, if any, with the attainment of response according to ELN guidelines. Interestingly, even CML patients in stable TFR may harbor circulating CD26+LSCs thus suggesting a probable active role of the immune system in the control of residual disease. One hypothesis could reside in the presence or absence on the LSCs of molecules (such as PD-L1) able to hamper an anti-leukemic T cell response. From Jan 2018 we conducted a prospective multicenter Italian study including CML pts at diagnosis treated and managed by each of 15 participating center according to ELN guidelines. We here present the first interim analysis after a median time of treatment of 12 mos. Aims The main goals of this study were to prospectively monitoring PB CD26+LScs in CML pts during TKI treatment and to correlate the behavior of LSCs with molecular response. In a proportion of pts PD-L1 expression on CD26+ LSCs at diagnosis was also evaluated. Methods At diagnosis and during TKI treatment, pts have been centrally evaluated in Siena lab for flow-cytometry PB CD26+ LSCs (+3, +6, +12, +18, +24 mos) and PD-L1 expression (at diagnosis). At each time point molecular BCR-ABL/ABLIS ratio was monitored locally in each center. Results 176 consecutive CML pts (IMA 92; NILO 61; DASA 23) were enrolled in the study so far (table 1). PB CD26+LSCs were measured at time 0 (baseline) in all 176 CML pts and in 165/176 (94%), 142/176 (81%) and 112/176 (71%) at +3, +6, +12 mos of TKI treatment, respectively. Median CD26+LSCs absolute number/µL at baseline was 6.96/µL (range 0.0126-64429), at +3 mos 0.0137/µL (range 0-6,49), at +6 mos 0.0056/µL (range 0-1.188), and at +12 mos 0.0112/µL (range 0-0.1824). No significant correlation between number of CD26+LSC, degree of response and BCR-ABL copies was found (Table 2). Interestingly, median CD26+LSCs at diagnosis was found significantly higher in NILO and DASA treated pts (12, 48/µL and 17,48/µL, respectively) than in IMA pts (4,58/µL). So far, 20/176 (11.4%) pts switched to different TKIs, due to failure/suboptimal response: of note, median CD26+ LSCs of this cohort at diagnosis was the highest (23.12/µL). Starting from Jun 2019, 44/176 (25%) CML pts have been evaluated also for PD-L1 expression at diagnosis: of these, 23/44 (52%) resulted PD-L1 positive and 21/44 (48%) resulted negative with a median of CD26+LSCs of 15.39/µL (range 1.28-635.5) and 4.45/µL (range 0.234-113.9), respectively. Conclusions After a sensible drop observed at 3 mos of any TKI treatment, CD26+LSCs are fluctuating and measurable at low level in most of pts (> 65%) even at 18 and 24 mos. We confirmed no correlation between the absolute number of persisting CD26+LSCs and BCR-ABL copies. However, pts with failure or suboptimal response showed the highest level of CD26+ at diagnosis. CD26+LSCs were found PD-L1+ in about half of 44 pts tested. At diagnosis higher CD26+LSCs number, PD-L1 positivity or both may correlate with a lower probability to achieve an optimal response; interim data of this first report will be presented; enrolment and follow up are ongoing. Disclosures Bocchia: Incyte: Honoraria; CELGENE: Honoraria. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Liberati:MORPHOSYS: Honoraria, Research Funding; ONCONOVA: Honoraria, Research Funding; INCYTE: Honoraria; VERASTEM: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; ONCOPEPTIDES AB: Honoraria, Research Funding; TAKEDA: Honoraria, Research Funding; FIBROGEN: Honoraria; BIOPHARMA: Honoraria; ARCHIGEN: Honoraria; BEIGENE: Honoraria; BMS: Honoraria; AMGEN: Honoraria; CELGENE: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria, Research Funding; NOVARTIS: Honoraria, Research Funding; KARYOPHARM: Honoraria, Research Funding.

Background. The Philadelphia (Ph) chromosome (chr.) is the hallmark of chronic myeloid leukemia (CML) and typically results from the reciprocal translocation t(9;22)(q34;11.2). Complex variant translocations (CVT) involving one or more additional chr. are identified in less than 5% of newly diagnosed CML. There are conflicting reports about the prognostic impact of CVT in the achievement of optimal response to tyrosine kinase inhibitor (TKI), and very few studies addressed the role of frontline treatment with imatinib or second generation (2G)-TKI in patients with CVT. Aims. To assess the response to imatinib or 2G-TKI in a large cohort of newly diagnosed CML with CVT, and to explore the impact of the different chr. translocations on outcome. Methods. This observational retrospective study was conducted in 19 hematologic centers in the framework of Campus CML, a network of Italian physicians involved in the management of CML patients. All newly diagnosed CML from 2000 to 2019 were evaluated and patients with CVT were selected for the present analysis. Karyotypes were defined according to the 2016 International System for Human Cytogenetic Nomenclature. Responses to frontline treatment were retrospectively categorized according to the 2013 ELN recommendations, as they include cytogenetic milestones. Deep molecular response (DMR, i.e. MR4or better) was defined as BCR-ABLIS ratio ≤0.01% or undetectable disease with ≥10,000 ABL copies. Patients with DMR lasting ≥2 years and at least a Q-PCR test every 6 months were defined as stable DMR responders. Failure-free survival (FFS) was calculated from the start of frontline TKI treatment to progression to advanced phase, death, or switch to other treatments for resistance. For FFS calculation, patients were censored at TKI stop for treatment-free remission (TFR) or in case of switch for intolerance only. Differences between subgroups according to the partner chr. were presented for descriptive purposes. Results. CVT were identified in 109 (3.2%) patients from a whole population of 3,361 subjects with newly diagnosed CML. Ninety-five out of 109 patients (87%) exhibited three-way translocations, with chr. 1, 4, 6, 10, 11, 12, 14, 15 and 17 representing the most common additional partners (figure). Four- and five-way translocations were identified in 13 and 1 patients, respectively. Additional chr. abnormalities (ACA) in the Ph+ cells were observed in 15/109 (13.8%) patients and were more common in older individuals (p=0.018). Overall, median age at diagnosis was 50.6 years (range 20-90). Risk distribution according to the ELTS score was 54%, 28% and 8% for L, I and H risk, respectively (10% missing). Cytogenetic result was available before the choice of frontline treatment in 45% of cases and represented a decisive factor in 28% of them (i.e. clinicians selected a 2G-TKI or high-dose imatinib, according to the available options). Frontline TKI treatment was imatinib in 80 cases (73%) and 2G-TKI (nilotinib n=22, dasatinib n=6, bosutinib n=1) in the remaining cases. The frequency of optimal response at 3, 6 and 12 months was 48%, 45% and 53%, respectively, for imatinib-treated patients, and 76%, 83% and 76%, respectively, for the 2G-TKI cohort (p The subtype of CVT had an impact on response and long-term outcome. Patients with CVT involving chr. 1, 4, 6, 11 or 12 had a higher frequency of MMR at 12 months than patients with CVT involving chr. 10, 14, 15 or 17 (75.8% vs 30.4%, respectively, p=0.001), higher frequency of stable DMR (48.7% vs 22.2%, respectively; p=0.04) and tended to have better median FFS (p=0.07), regardless of the type of frontline TKI and of the ELTS score. Conclusions. Due to its retrospective nature, this study does not allow to define which is the optimal therapy for CML harboring CVT at diagnosis. However, our data reinforce the usefulness of bone marrow karyotyping in CML. The observed differences between partner chr. may also depend on the breaking points, which are variable. Further dissection of CVT will help to identify which are associated to a poor response to TKIs. Figure Disclosures D'Adda: Incyte: Other: Advisory board; Novartis: Other: Advisory board; Pfizer: Other: Advisory board. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Crugnola:Celgene: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Bocchia:Incyte: Honoraria; CELGENE: Honoraria. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Breccia:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Saglio:Novartis: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte: Research Funding; Roche: Research Funding.

Introduction : therapy of chronic phase (CP) chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKIs) in virtually all patients. Three TKIs are approved for first-line therapy in Italy: imatinib and two second-generation (2G) TKIs, dasatinib and nilotinib. Choice of the front-line TKI is based on a combined evaluation of patient's and disease characteristics, age, risk, comorbidities and concomitant medications. Treating physician's preference and, in some cases, economic considerations, particularly after the advent of generic imatinib, may play a role in TKI selection. However, to date, few data are available on TKI use in a whole nation and on the possible drivers of treatment choice. Aim of the present work was to analyse the use of front-line TKI therapy in a large, unselected cohort of Italian CP-CML patients, correlating patient's features to drug choice. Methods: in the framework of the national Campus CML program, we retrospectively evaluated 1422 patients with CP-CML diagnosed from 2012 and 2019 in 21 haematologic Centres, mostly in academic and/or tertiary hospitals, widespread through the entire Italian territory and treated frontline with imatinib, dasatinib or nilotinib. Results: median age at diagnosis was 59.9 years [interquartile range (IQR) 47.1 - 71.7], with 317 (22.3%) patients under 45 years, 552 (38.8%) between 45 and 65 years and 553 (38.9%) older than 65 years; 821 (57.7%) patients were males. Among 1364 evaluable patients, CML risk according to Sokal score was low in 540 (39.6%), intermediate in 610 (44.7%) and high in 214 (15.7%) patients respectively; the number at low, intermediate or high risk according to the novel ELTS score among 1325 evaluable patients was 759 (57.3%), 402 (30.3%) and 164 (12.4%) respectively. Considering comorbidities, 1003 (70.6%) patients had at least one active disease at the time of CML diagnosis, the most common being hypertension (n=547, 38.5%), previous neoplasms (n=185, 13.0%), diabetes (n=150, 10.6%), chronic bronchopulmonary diseases (n=114, 8.0%), acute myocardial infarction (n=95, 6.7%), previous stroke (n=36, 2.5%) and other vascular diseases (n=98, 6.9%). Among 1335 evaluable patients, 813 (60.9%) were taking at least one concomitant medication, with 280 (21.0%) taking 3-5 drugs and 140 (10.5%) taking 6+ drugs at time of TKI start. As to the frontline therapy, 794 (55.8%) received imatinib and 628 (44.2%) were treated with 2G-TKIs, (226 dasatinib and 402 nilotinib) respectively. According to age, 2G-TKIs were chosen for majority of patients aged 100,000/mm3 vs 38.2% if WBC 10 g/dl; p=0.001) and bigger spleen (65.1% if spleen >5 cm vs 44.8% if spleen 1-5 cm vs 37.3% if spleen not palpable; p5 drugs, respectively (p 45 years, intermediate or high Sokal risk, presence of some comorbidities (2nd neoplasia and stroke) and number of concomitant medications. Conclusions: preliminary results of this observational study on almost 1500 patients show that around 55% of newly diagnosed Italian CP-CML patients receive imatinib as front-line therapy, and that the use of 2G-TKI is prevalent in the younger patients and in those with no concomitant clinical conditions. The counterintuitive finding of imatinib prevalence as frontline treatment in high risk patients might be explained by the older age of these patients. Introduction of the generic formulation in 2018 seems to have fostered the use of imatinib. Figure Disclosures Breccia: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Roche: Research Funding.

Introduction. New guidelines for the management of dyslipidemia and lipid modification in order to reduce the risk of cardiovascular (CV) events have been recently published by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). New recommendations regarding the target value of plasma lipids in very high and high CV risk patients have been provided, in addition to an estimate of the CV risk with a new Systematic Coronary Risk Evaluation (SCORE) chart. Few data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib, and the association with arterial occlusive events (AOEs). We therefore analyzed a large real-life cohort of Italian patients with CML treated with nilotinib outside of clinical trials and evaluated the association between AOEs and plasma lipoproteins levels; moreover, we estimated the prognostic value of the new SCORE chart to predict AOEs. The secondary endpoint was to report the management of dyslipidemia in the clinical practice. Methods. We identified 233 adult patients with CML who were treated in 20 Italian centers with nilotinib. All patients were stratified into low to moderate (SCORE ≤ 5%) or high to very high (SCORE risk >5%) CV risk, according to the new version of the SCORE 2019. We recorded concentration levels of cholesterol, high-density lipoproteins (HDL), low-density lipoproteins (LDL) and triglycerides at diagnosis of CML, before starting ponatinib and therefore after 3, 6 and 12 months of treatment. All AOEs (cerebrovascular, peripheral vascular and CV events excluding hypertension) were considered. Results. The median age was 50 years (range 20-88) and the Sokal score was intermediate-high in 45.5% of patients. The median follow-up was 5 years (range 3.4-10.5). Nilotinib was administered as first line of therapy in (72%) of cases or second or subsequent lines of treatment for inefficacy (20.9%) or intolerance (7.1%). At baseline, nilotinib was administered at the following doses: 800 mg/day in 9.3% of patients, 600 mg/day in 87% of patients, 400 mg/day in 3.1% of patients and 300mg in 0.6% of patients, respectively. The median time of drug exposure was 60 months (range 2-155). The 48-month cumulative incidence rate of AOEs was 14.1±2.7%. Patients with cholesterol plasma levels > 200 mg/dL and LDL >70 mg/dL at baseline and 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (24.5±7.3% vs 11±2.7%, P=0.02 and 22.3±4.9% vs 5.9±2.6, P=0.003, respectively) Figure 1. Patients with triglycerides levels > 200 mg/dL 3 months after starting nilotinib, showed a significantly higher incidence of AOEs (56±20.5% vs 13.3±2.7%, P=0.011) Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (32.8.1±9% vs. 9±1%±2.6%, p=0.001). In multivariate analysis, statistical significance of cholesterol plasma levels > 200 mg/dL and LDL >70 mg/dL after 3 months and high-very-high SCORE was maintained (P=0.018, HR=3.4, 95% CI=1.2-9.4 and P=0.004, HR=3.5, 95% CI=1.5-8.2, respectively). Overall, 46 patients (20.5%) presented dyslipidemia at CML diagnosis and 65 (29%) at the start of treatment with nilotinib. Despite dyslipidemia, only 6 patients were taking statins during the treatment with nilotinib and only 5 started it after 3 months of nilotinib: 3 patients were treated with rosuvastatin and 2 with pravastatin. Conclusions. Our findings suggest that a proper control of dyslipidemia, keeping cholesterol and triglycerides plasma levels ≤ 200 mg/dL and LDL ≤70 mg/dL is associated with reduced risk of AOEs in CML patients treated with nilotinib. An under estimation of the clinical importance of elevated plasma lipids as a risk factor for AOEs events represents a possible issue in the real-life. Figure 1 Disclosures Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Galimberti:Incyte: Honoraria; Novartis: Speakers Bureau. Castagnetti:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Pregno:Incyte-Italy,: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Novartis-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports; Pfizer-Italy: Membership on an entity's Board of Directors or advisory committees, Other: conference reports. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Gugliotta:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION: Frontline therapy with second generation (2G) tyrosine-kinase inhibitors (TKIs) in chronic phase (CP) chronic myeloid leukemia (CML) patients demonstrated higher efficacy as compared to imatinib, with less patients experiencing treatment failure and progression to advanced disease. However, limited information are currently available on the management and outcome of those CML pts not achieving an optimal response to first-line treatment with a 2G-TKI. AIM: To describe the clinical outcome of CP CML patients without an optimal response to a frontline 2G-TKI that switched to alternative TKIs. METHODS: We performed a retrospective analysis in 22 Centers cooperating within the Italian CML Campus Project. Main inclusion criteria were: 1) diagnosis of CP-CML after 2010; 2) first-line treatment with a 2G-TKI; 3) switch to second-line treatment in case of non-optimal response (either following ELN recommendations or as for clinical practice); 4) CML in CP at the time of switching to second-line treatment. The main exclusion criteria were a switch to second-line treatment for intolerance or for low adherence to therapy. RESULTS: The main findings of this analysis are summarized in the table. Seventy-one pts meeting the inclusion/exclusion criteria were identified; the median age of pts at CML diagnosis was 46 (21-80) years. Sokal risk score was low, intermediate, and high in 24 (34%), 30 (42%), and 17 (24%) pts, respectively. First-line treatment was performed with nilotinib in 47 (66%) pts and dasatinib in 24 (34%) pts. According to the ELN 2020 recommendations, 51 (72%) pts fulfilled the criteria for "failure" and 20 (28%) pts those for "warning". BCR-ABL mutations were identified in 12 of 65 (18%) evaluable pts (T315I in 1 pt). Additional chromosomal abnormalities in Ph+ cells were identified in 6 of 54 (11%) evaluable pts. Second-line treatment was started after a median time of 16 (4-72) months, with ponatinib (40 pts, 56%), dasatinib (21 pts, 30%), nilotinib (7 pts, 10%), or bosutinib (3 pts, 4%). Median follow-up from start of second-line treatment was 25 (2-90) months. Best response to second-line treatment was MR2 in 18 (25%) pts and MR3 in 37 (51%) pts. Nineteen (27%) pts (13 for resistance and 6 for intolerance) switched to third-line treatment (ponatinib, 11 pts; nilotinib, 3 pts; dasatinib, 4 pts; imatinib, 1 pt), after a median time of 8 (1-72) months. Mutations were identified in 2 of 17 evaluable pts, and both patients harbored a T315I mutation. MR3 was reached by 9 (47%) of these pts. Lastly, 7 (10%) pts switched (6 for resistance and 1 for intolerance) to fourth-line treatment (asciminib, 4pts; dasatinib, 2 pts, nilotinib, 1 pt). Overall, 44 (62%) patients reached with sequential TKI treatments a MR3 (31/51 pts among "failures"; 13/20 among "warnings"). Allogeneic stem-cell transplantation (SCT) was performed in 7 (9.5%) pts (6 among "failures"), after a median time of 20 (15-60) months from CML diagnosis. Progression to advanced phase occurred in 2 (3%) pts; both pts previously met the ELN2020 "failure" criteria. Estimated 4-y PFS was 92.5%. Death occurred in 3 (4%) pts (1 after progression to blast phase, 2 for cardiovascular adverse events). Estimated 4-y OS was 93.7% CONCLUSION Our findings show that CP-CML patients not achieving an optimal response to frontline 2G-TKI therapy, despite a complex management, still have a favorable prognosis and survival due to the availability of both multiple TKI options and SCT. Figure Disclosures Gugliotta: Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Abruzzese:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Di Raimondo:Amgen, Takeda, Novartis: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; GILEAD, Incyte: Research Funding; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Rosti:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Saglio:Pfizer: Research Funding; Ariad: Research Funding; Roche: Research Funding; Incyte: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Breccia:Abbvie: Consultancy; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

Introduction. The association of Azacitidine (AZA) and Lenalidomide (LEN), either administered concurrently or sequentially, 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). Moreover, the aim of this analysisis is to enucleate the clinical and biological features of pts who showed long-lasting (≥ 20 cycles) responses. 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 pts 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. 21 pts were randomly assigned to ARM 1, and 23 pts to ARM 2. Treatment was given for a median of 8.5 (1-68) cycles; in ARM 1: 9 (1-68) cycles; in ARM 2: 8 (1-63) cycles, respectively. Median follow-up: 15 (2-77) months. 10/44 pts (22.7%) did not complete at least 6 cycles of treatment for causes other than disease progression, 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%). Median duration of hematologic response: 10.5 months. 37 pts (84.1%) died , and 20 pts (45.4%) showed progression to AML. Grade >2 non haematological toxicity: 54.5%. Median OS: 15 months. OS was significantly longer in responder pts as compared to the other pts (28 vs 7 months, p2 non haematological toxicity (ARM 1: 66.7%; ARM 2: 43.5%), AML incidence (ARM 1: 33.3%; ARM 2: 56.5%; p=0.2150) and OS (ARM 1: 14 months; ARM 2: 16 months). However, among responder pts, sequential treatment showed a longer clinical benefit, as compared to combined treatment. Responder pts of ARM 2 showed a significantly longer median duration of response (18 vs 6 months, p=0.0481), a longer median duration of therapy (28 vs 10 months, p=0.0870; 20 vs 10 cycles, p=0.1181), more long-lasting (≥ 20 cycles) responses (34.8% vs 9.5%, p=0.1017) and a longer OS (35 vs 26 months, p=0.3868), as compared to responder pts of ARM 1. Overall, 10/44 long-responder pts (22.7%) received ≥ 20 cycles; 5/10 pts (50%) achieved CR. IPSS risk: Intermediate-2 (8 pts); High (2 pts); IPSS-R risk: Intermediate (2 pts); High (6 pts); Very High (2 pts); IPSS cytogenetic risk: Good (5 pts); Intermediate (3 pts); Poor (2 pts); IPSS-R cytogenetic risk: Good (5 pts); Intermediate (4 pts); Very Poor (1 pt); 4/6 patients with altered karyotype achieved cytogenetic remission; it is noteworthy that the only 3 pts of the entire series who showed no gene mutations at baseline are included in this subset of long-responders pts, while 5/10 pts showed at baseline ≥ 1 prognostically unfavorable gene mutations (none with TP53 mutations), with variable VAFs during treatment. Moreover all long-responder pts showed a common gene mutation on SOD2 gene, and mutations on PLCG2 gene. Conclusions. Our results confirm the efficacy of both AZA+LEN treatment regimens in higher-risk MDS pts, in terms of ORR and OS, although sequential treatment was associated with a longer clinical benefit among responder pts. A subset of pts (22,7 %) with less unfavorable cytogenetic and molecular characteristics showed a long-lasting response to treatment. Disclosures Finelli: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Rigolin:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria.

Background: Successful tyrosine-kinase inhibitors (TKIs) discontinuation has been obtained in some patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML). Careful molecular monitoring after discontinuation is the key to guarantee the safety, in terms of prompt resumption of therapy according to retreatment threshold criteria. It was observed that the majority of relapses usually occur during the first 6 months after TKI discontinuation [Saussele S, Lancet Oncol 2018; Etienne G, JCO 2017], accounting for the monthly quantitative PCR (qPCR) that all prospective protocols included in the trial design at least during the first half-year. Two studies [Kong HJ, Cancer 2017; Shanmuganathan N, Blood 2019] investigated if performing molecular analysis with a different and less "cautious" timeframe yields comparable efficacy with logistical issues reduction. Here we retrospectively evaluated how molecular monitoring has been conducted in Italy on a cohort of patients not included in any prospective trial with follow-up visits. Methods: The outcome of Italian patients with CP-CML who discontinued TKIs per clinical practice has recently been reported [Fava C, Haematologica 2019]. For the purpose of the present study, all the 32 participating centers were required to provide dates and molecular results available for each enrolled patient in the first 24 months after TKI stop. Descriptive analysis was carried out. The average time to the loss of major molecular response (MMR), the frequency of the visits (monitoring) and the occurrence of loss of MMR within the first 6 months, between 6-12 months, and 13-24 months were computed. When appropriate non-parametric tests were used to test for differences. Results: 227 chronic phase CML pts were included in this sub-analysis. Median age at TKI discontinuation was 58.73 years and median follow up since TFR was 2.03 years. In this timeframe every patient had a mean of 7.95 appointments for molecular evaluation. Overall, 1804 analysis were performed, of which 18.2% happened in the first three months and 38.2% in the first six months. During the first three months of TKI discontinuation, 40 pts (17.6%) didn't have any molecular assessment; 78 pts (34.4%) had only 1 qPCR performed, 77 pts (33.9%) 2 qPCR, 31 pts (13.7%) 3 qPCR and 1 pt (0.4%) 4 qPCR. For the first six months after TKI stop, 7 pts (3.1%) didn't undergo any BCR-ABL1 evaluation; 37 pts (16.3%) had only 1 analysis, 60 pts (26.4%) 2 analysis, 37 pts (16.3%) 3 analysis, 28 pts (12.3%) were evaluated 4 times, 40 pts (17.6%) 5 times, 17 pts (7.5%) 6 times and only 1 pt (0.4%) 7 times. The majority of visits fell between the 3rd and the 7th month after TKI interruption (Figure 1) with 84 pts (52.2%) being evaluated at month 3, 96 pts (59.6%) at month 4, 80 pts (49.7%) at month 5, 89 pts (55.3%) at month 6, 101 pts (62.7%) at month 7. In the first six months the visits occurred with a mean interval of 1.44 months; between months 7-12 molecular evaluations were performed every 1.94 months; during the second year of discontinuation (months 13-24) every 2.89 months (p Discussion: The safety of TFR relies consistently on the management of patients off-therapy especially during the first 6 months, when molecular relapses more often occur. Our retrospective analysis showed that a less intense frequency of monitoring did not affect the success of TFR nor put pts at risk of progression. However, these data confirm that the first 6 months off-treatment require a more stringent follow-up for early detection of MMR loss. Disclosures Rosti: BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnetti:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria. Capodanno:Novartis: Honoraria; Incyte: Honoraria. Ferrero:Novartis: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Elena:Pfizer: Consultancy; Novartis: Consultancy. Breccia:Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Bocchia:BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Cedrone:BMS: Honoraria; Novartis: Honoraria. Sgherza:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Santoro:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Giai:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Levato:Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Saglio:Pfizer: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Jansen: Consultancy; Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy. Fava:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria.

Background Bosutinib is a 2nd generation tyrosine-kinase inhibitor (TKI) active in Chronic Myeloid Leukemia (CML) patients resistant or intolerant to frontline imatinib, dasatinib or nilotinib; the favourable toxicity profile makes bosutinib potentially useful in elderly patients, but at present there are no data in unselected cohorts of these subjects. Aim To highlight this issue, a real-life cohort of 91 patients followed in 21 Italian Centers and treated with bosutinib when aged > 65 years was retrospectively evaluated. Patients The main clinical features of the whole cohort at diagnosis and at baseline of bosutinib treatment are reported in the Table; all patients were in CP when bosutinib was started. Median interval from diagnosis to bosutinib treatment was 49.7 months [interquartile range (IQR) 14.2 - 117.5]. Results Starting dose of bosutinib was 500 mg/day in 20 patients (22.0%), 400 mg/day in 7 patients (7.7%), 300 mg/day in 28 patients (30.8%), 200 mg/day in 34 patients (37.3%) and 100 mg/day in 2 patients (2.2%), respectively. After a median period of treatment of 18.1 months (IQR 9.4 - 27.7) all patients were evaluable for toxicity; on the whole, all grade hematological and extra-hematological toxicities were reported in 12/91 (13.1%) and 45/91 (49.4%) patients, respectively. A grade 3 - 4 hematological toxicity occurred in 5/91 patients (5.4%); a grade 3 - 4 extra-hematological toxicity occurred in 16/91 patients (17.5%). Overall, 46 patients (50.5%) never discontinued bosutinib: a temporary discontinuation < 6 weeks was needed in 19 patients (20.9%) and a temporary discontinuation > 6 weeks in 2 patients (2.2%). A permanent bosutinib discontinuation was needed in the remaining 24 patients (26.4%): in particular, 11 patients (12.1%) permanently discontinued bosutinib due to toxicity (skin rash in 3 cases, gastro-intestinal toxicity in 3 cases, pleural effusion in 2 cases, transaminitis, QTc prolongation and myalgia in 1 case each), 6 patients (6.6%) due to resistance and 7 patients (7.7%) due to other reasons (unrelated death in 6 cases and patient decision in 1 case). As to response, 5 patients (5.5%) were considered too early for assessment (< 3 months of treatment); among the 86 patients evaluable for response, 11 patients (12.7%) did not have any response (including 6 patients who discontinued bosutinib for early toxicity), 4 (4.6%) achieved hematological response only, and 71 (82.5%) achieved Cytogenetic Response (CyR) (Major CyR in 4, Complete CyR in 67). Among the 67 patients in Complete CyR, 58 (67.4% of all 86 evaluable patients) also achieved Molecular Response (MR) [Major MR (MR 3.0) in 19 (22.1%), Deep MR (MR 4.0/4.5) in 39 (45.3%)]. The 3-year Overall Survival and Event-Free Survival of the whole cohort of patients from bosutinib start were 83.0% (CI95% 71.6 - 94.4) (Figure 1) and 59.5% (CI95% 39.9 - 72.1), respectively. Conclusions Our real-life data show that bosutinib is effective, even if initial doses in many cases were lower than recommended, with a favourable safety profile also in elderly patients with important comorbidities resistant/intolerant to previous TKI treatments,: as a consequence, it could play a significant role in the current clinical practise for these frail patients. Disclosures Latagliata: Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Annunziata:Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Elena:Novartis: Consultancy; Pfizer: Consultancy. Crugnola:Incyte: Honoraria; Novartis: Honoraria. Bonifacio:Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; BMS: Honoraria. Sgherza:Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Iurlo:Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria. Breccia:Celgene: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; 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; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino:Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation

Background and Rationale. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) are 2nd generation TKIs with similar second-line efficacy. The use of DAS and NIL may be burdened by pulmonary, infectious, cardiovascular and metabolic complications; these complications are more frequent and more clinically relevant in the elderly. BOS could represent an important therapeutic option in elderly patients intolerant to or failing a first-line TKI, but the dose of 500 mg OAD may be higher than necessary. Aims. All TKIs have been tested at a fixed initial dose, with dose adjustment in case of toxicity or treatment failure. On the contrary, the aim of our study was to evaluate in elderly CML patients if second-line BOS was effective and better tolerated at doses lower than 500 mg OAD, beginning with 200 mg OAD, then increasing the dose to 300 OAD or 400 mg OAD according to the molecular response, to find the minimum effective dose. Methods. A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: all patients started with 200 mg OAD for 2 weeks ("run-in" period), then the dose was increased to 300 mg OAD; after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD. In responsive patients, BOS dose was maintained, 300 mg or 400 mg OAD. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Sixty-three patients have been enrolled. The primary endpoint was the proportion of patients in MR3 at 1 year. Definitions: MR3, BCR-ABLIS < 0.1%; MR4, BCR-ABLIS < 0.01% with > 10.000 copies; MR4.5, BCR-ABLIS < 0.0032% with > 32.000 copies. Results. Median age: 73 yrs (range 60-90). Age distribution: 60-69 yrs, 18 pts (29%); 70-79 yrs, 31 pts (49%); > 80 yrs, 14 pts (22%). Sokal score at diagnosis: low 19%, intermediate 49%, high 32%. Reasons for switching to BOS: intolerance 63%, resistance 37%. First-line TKI: imatinib 83%, DAS 11%, NIL 6% (same TKI distribution in intolerant and resistant patients). Median follow-up: 9 mos (range 1-30). Overall, 10/63 patients had a dose-increase to 400 mg OAD, 49/63 to 300 mg OAD, while 4/63 continued on BOS 200 mg OAD without any dose increase. At baseline, 13 patients were already in MR3. The MR3 rates by 3 and 6 months were 43% and 56%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 60% (65% in intolerant and 52% in resistant patients, p = 0.31). Interestingly, only 21% of patients > 80 yrs old achieved or maintained a MR3 (p < 0.001, compared to younger patients). Patients achieving MR4 or MR4.5 were 38% and 19%, respectively. Overall, 22%, 27% and 11% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level. Selected adverse events: cardiac ischemia, 2 patients; pericardial effusion, 2 patients; no pleural effusions. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events (3 hypertransaminasemia, 1 nephrotoxicity, 1 diarrhea, 1 skin rash, 1 myalgia/fatigue), 3 unsatisfactory responses (without progressions). Fifty-one out of 63 patients are still on BOS at the last contact: 6 on 400 mg OAD, 34 on 300 mg OAD, 11 on 200 mg OAD. Conclusions. A gradual dose increase, based on prospective molecular monitoring, allowed the great majority of enrolled patients (approximately 70%) to remain on treatment with BOS 300 mg OAD or less, achieving a major molecular response (MR3) in 60% of the cases. These results trial showed that, in elderly patients intolerant to or failing a first-line TKI, BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD. Disclosures Castagnetti: Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria. Gugliotta:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Trawinska:Novartis: Consultancy, Honoraria. Bonifacio:Novartis: Honoraria, Research Funding; Amgen: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Elena:Novartis: Consultancy; Pfizer: Consultancy. Lucchesi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Albano:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Lunghi:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Stagno:BMS: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Incyte: Consultancy, Honoraria. Iurlo:Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Ferrero:Novartis: Honoraria. Cavo:janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau. Saglio:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Jansen: Consultancy; Incyte: Consultancy. Pane:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: research founding; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Baccarani:Novartis: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Takeda: Consultancy. Rosti:BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: Bosutinib is a second generation TKI already registered for the treatment of adult patients with chronic phase CML with resistance or intolerance to prior therapy. In the present study the initial dose is 200 mg instead of 500 mg OAD. A dose increase to 300 or 400 mg is scheduled according to molecular response and tolerabiliy

Next-Generation Sequencing (NGS)-based BCR-ABL1 kinase domain (KD) mutation screening has been shown to enable greater accuracy and sensitivity and straightforward identification of compound mutants (CM) as compared to Sanger sequencing (seq). However, the prevalence of CMs has never been assessed in prospective studies, and although in vitro data suggest that many of them may be challenging for all tyrosine kinase inhibitors (TKIs) including ponatinib, attempts to correlate such data with in vivo responses have never been made. To address these issues, we have reviewed the results of routine NGS-based BCR-ABL1 KD mutation screening performed over the past 3 years. Between 2015 and 2018, we have prospectively used NGS to analyze a consecutive series of 751 Ph+ leukemia patients (pts) on TKI therapy who were eligible for BCR-ABL1 KD mutation screening according to ELN/NCCN/ESMO recommendations. The study population included 664 chronic myeloid leukemia (CML) pts with failure or warning response (chronic phase [CP], n=593; accelerated or blastic phase [AP/BP], n=71) and 87 Ph+ acute lymphoblastic leukemia (ALL) pts with relapsed/refractory disease. NGS of ≈400bp amplicons generated by nested RT-PCR was performed on a Roche GS Junior (until April 2017) or on an Illumina MiSeq (from May 2017 on) using custom protocols whose accuracy, sensitivity and reproducibility was checked by national and international (EUTOS) control rounds. Read alignment and variant calling was done using the AmpSuite software (SmartSeq srl), with a lower detection limit set to 3%. Cis or trans configuration of mutation pairs, indicating CMs or polyclonality, respectively, was determined correcting for the likelihood of PCR recombination. The 35INS insertion/truncation mutant was excluded from the analysis. NGS identified mutations in the BCR-ABL1 KD in a total of 313/664 (47%) CML pts (255/593 [43%] CP-CML and 58/71 [82%] AP/BP-CML) and 69/87 (79%) Ph+ ALL pts. Ninety-one percent of the mutations could be recognized as conferring resistance to at least one TKI on the basis of publicly available IC50 data or published reports. In 42/593 (7%) CP-CML, 6/71 (8.5%) AP/BP-CML and 12/87 (14%) Ph+ ALL pts, low burden mutations (i.e., mutations carried by a proportion of transcripts 15% - hence detectable by Sanger seq). Fifty-five (9.2%) CP-CML, 51 (72%) AP/BP-CML and 56 (49%) Ph+ ALL pts had ≥2 mutations (CP-CML: 1-5 mutations; AP/BP-CML: 1-6 mutations; Ph+ ALL: 1-13 mutations). Identification of CMs in pts with ≥2 mutations was fully possible (i.e., all the candidate pairs mapped within a distance of 400bp) in 71% of cases and partially possible (i.e., some, but not all the candidate pairs mapped within a distance of 400bp) in another 12% of cases. A total of 86 CMs (85 double and 1 triple) in 73 pts (21 [3.5%] CP-CML, 23 [32%] AP/BP-CML and 29 [37%] Ph+ ALL pts) could be catalogued (Figure 1A). All but two (T315I+D276G, M244V+E255K) were detected in pts who had received ≥2 TKIs and all included at least a 2nd-generation TKI-resistant mutation. The most frequent CMs were T315I+E255K, T315I+E255V, T315I+F359V, F317L+Y253H (Figure 1A). The triple CM, detected in a ponatinib-resistant pt, was F317I+Y253F+Q252H. Correlation of IC50 data with in vivo responses (the TKIs pts were clinically resistant to) confirmed only partially in vitro predictions (Figure 1B). In particular, although ponatinib was shown in vitro to be poorly effective against several CMs, only the T315I+E255V was consistently found to be associated with ponatinib failure. In conclusion, our results in a large unselected series of TKI-resistant pts analyzed by NGS show that:CMs are relatively infrequent in CP-CML, but may be a relevant issue in AP/BP-CML and Ph+ ALL;among pts with multiple mutations, those who have failed 1 line of therapy have most often polyclonality, whereas those who have failed ≥2 lines of therapy may have CMs or polyclonality;in vitro predictions of sensitivity and insensitivity based on IC50 data should be regarded with caution. In particular, the only compound mutant that we consistently found to be associated with ponatinib failure was the T315I+E255V. Supported by EUTOS 2016. Disclosures Soverini: Novartis: Consultancy; Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy. Pagano:Pfizer: Speakers Bureau; Gilead: Speakers Bureau; Basilea: Speakers Bureau; Merck: Speakers Bureau; Janssen: Speakers Bureau. Gugliotta:Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Castagnetti:Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Angelucci:Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board; Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC. Martinelli:Abbvie: Consultancy; Ariad/Incyte: Consultancy; Janssen: Consultancy; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy. Cavo: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; Bristol-Myers Squibb: 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; Amgen: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: Understanding health-related quality of life (HRQOL) profile, including functional aspects and symptom burden, of yet untreated patients with myelodysplastic syndromes (MDS) is important to help clinicians to better identify subgroup of patients in need of special attention from the very beginning of therapy. Aims: The primary objective of this study was to investigate baseline (i.e., pretreatment) HRQOL profile of untreated patients with lower-risk MDS, examining differences by age, gender, risk score category and comorbidity. A secondary objective was to provide age and sex baseline reference HRQOL values, according to the EORTC QLQ-C30 questionnaire, to be used as benchmark comparisons in future MDS studies. Methods: This analysis is based on 443 newly diagnosed adult MDS patients with International Prognostic Scoring System (IPSS) risk score of low (46 %) or intermediate-1 (54%), enrolled in an international prospective cohort observational study. Median age was 75 years (range 32-94), with 261 men (59%) and 182 (41%) women. HRQOL was assessed by the EORTC QLQ-C30 questionnaire at study entry, before any treatment (except for transfusions). This well validated questionnaire consists of five functioning scales: physical, role, emotional, cognitive and social; three symptom scales: fatigue, nausea/ vomiting and pain; six single item scales: dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact; and the global health status/HRQOL scale. The items were scaled and scored using the recommended EORTC procedures. At the time of baseline HRQOL assessment, 111 (25%) patients had received at least one red blood cell transfusion. We used Wilcoxon-Mann-Whitney and Kruskal-Wallis tests for all comparisons. We used the false discovery rate approach to account for multiple testing, with a nominal α-level=0.05. In addition to statistical significance, clinically relevant HRQOL differences were also evaluated based on previously published criteria (Cocks K, et al, J Clin Oncol 29:89-96, 2011). Results: There were not statistically significant differences in any of the HRQOL scales measured by the EORTC QLQ-C30, by the specific IPSS risk category (i.e., low risk vs intermediate-1 risk score). Overall, women reported worse HRQOL scores than men, with clinically relevant differences for physical (Δ=-7.1, P=0.002), role (Δ=-9.9, P=0.002) and emotional functioning, (Δ=-10, P Conclusion: Pretreatment HRQOL profile in lower-risk MDS patients vary substantially by age group categories, sex and number of comorbidities, and these differences should be highly considered at the time of treatment start. As in MDS research, the EORTC QLQ-C30 is currently one of the most frequently used HRQOL measure, our baseline reference values provide benchmark data against which other MDS studies using this questionnaire may be compared. Disclosures Efficace: Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Orsenix: Consultancy; Incyte: Consultancy; TEVA: Research Funding; TEVA: Consultancy; Lundbeck: Research Funding; Amgen: Consultancy; AMGEN: Research Funding. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Platzbecker:Celgene: Research Funding. Stauder:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Voso:Celgene: Research Funding, Speakers Bureau. Santini:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Novartis: Honoraria. Lubbert:Teva: Other: Study drug; Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding. Cuneo:Gilead: Other: advisory board, Speakers Bureau; Abbvie: Other: advisory board, Speakers Bureau; Roche: Other: advisory board, Speakers Bureau; janssen: Other: advisory board, Speakers Bureau.

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.

Purpose: Since July 2012, the Haematological Home Care (HHC) program was activated in our Institution to improve quality of assistance of patients with haematological malignancies, both in the terminal phase of disease and during active chemotherapy. Methods: We conducted a retrospective study to describe the 3-year experience of our HHC program; its efficacy was measured for acute leukaemia patients only analysing number of hospitalizations, number of accesses to the Emergency department and place of death. Our study population was also compared with historical data from a small group of 17 patients with acute leukaemia assisted at home, by their general practitioner, in the previous 3 years, when the HHC program was not available. Results: The study group consisted of 44 patients, 36 of whom (82%) needed a palliative treatment, while 8 (18%) had an ongoing active chemotherapy. The mean number of hospitalizations was 0.64 (range 0-7) per patient and the number of emergency department visits was 0.82 (range 0-4) per patient. Place of death was home environment in 51.4% and hospital in 40.5% of patients. When compared to data of the historical group, HCC program significantly reduced the number of hospitalizations (0.64 vs 2.53 per patient, range 0-9; P 0.001), significantly increased the number of patients who died at home (51.5% vs 6%; P=0.003) and reduced those who died in hospital (40.5% vs 65%; P 0.003). Conclusions: Home care for patients with acute leukaemia is feasible, decreases the number of hospitalizations, and increases the number of patients who die in their own home. Figure. Figure. Disclosures Luminari: Servier: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Roche: Consultancy; Sandoz: Consultancy.

Background. The availability of multiple tyrosine kinase inhibitors (TKIs) and precise molecular monitoring has dramatically changed the prognosis in CML patients. With proper medical management, the planning of a pregnancy in both male (M) and female (F) patients is now possible. Towards this goal, the GIMEMA CML working party initiated a retrospective and prospective study to describe all male conceptions/female pregnancy outcomes in the CML Italian population from January 2013. Aims. The specific aims of this study were to analyze conceptions and pregnancies in male and female patients with regard to 3 general issues: 1) Illness issues, including CML treatment prior to conception/during/after pregnancy, transcript kinetics, the recovery of a lost response after therapy cessation, and the effects of treatment modifications (e.g., resistance, switching); 2) Conception/pregnancy issues, including planned, unplanned, spontaneous and medically assisted pregnancies (MAP), spontaneous/elective abortions, pregnancy progression, delivery, and breast feeding; and , 3) Post-natal health issues from birth to walking including speaking and academic performance. Patients and methods. Patients included in the study had to meet the following criteria A) Age >18 yrs; B) Confirmed CML diagnosis; C) Conception or pregnancy; D) TKI treatment before, during and/or after pregnancy; and E) Signed, IRB-approved written informed consent form. Of the 143 enrollees, data were obtained from 135 patients (83M and 52F). A total number of 166 cases were analyzable. Male conceptions were 106, and female pregnancies 60. Results 1) At time of conception 34 patients had no treatment (TF), 8 received interferon-a (IFN), and the remaining were treated with a TKI (Table 1). Considering only female patients, all stopped TKI treatment when pregnancy was discovered at 3-6 weeks (w). After placental maturation (>20w) 13 patients were treated with IFN (10), 2 with Imatinib, and 1 with Nilotinib (N). In this latter patient N concentration was tested in maternal plasma and cord blood at delivery and showed no transfer to the baby. Kinetics of rise was calculated in a subgroup of 17 patients. Doubling time [DT = duration x log(2) /log (final ratio)-log (initial ratio)] exhibits a bimodal trend, very short for some patients (5.8 days mean, range 4.5-8.2) and much longer for others (182 days mean, range 59.2-328.4), This result does not correlate with molecular status pre TF. Furthermore 76.5% of patients will not lose Major Molecular Response during pregnancy, while in TF, that is more than expected when compared to non pregnant controls (TFR). No cases of CML progression or resistance to re-treatment were observed. CML transcript ratios during pregnancy are shown in Fig.1. 2) The majority of pregnancies were planned. MAPs were reported in 5M and 3F. Two spontaneous conceptions occurred in 2M after allogeneic transplant. Eleven abortions before 12 w (2 M ,induced; 9F, 5 induced) were reported (not included in the 166 cases). Pregnancies in all cases progressed normally. In F there were 2 pre-eclampsia, 2 oligohydramnios, 1 abruption placenta. In 8M and 8 F babies were born pre term and 1M and 2F were small at birth with no further consequences. Forty-two F (70%) delivered spontaneously. Babies were born at a mean 40 w (34-44) in M, 39 w (33-42) in F. Breast feeding information was collected for 45F of which18 (29%) breast feed for at least one month (range 1-28 mo). 3) Post-natal information showed normal child development and growth. One respiratory arrest was noted at birth with rapid recovery and 1 macrocephaly was described with no further consequences. Of the 56 children >3 yrs old attending school (44M,12F), 2M presented with language problems and in one case autism was diagnosed. Other reported outcomes include 1 child diagnosed as having rheumatoid arthritis at 2 yr (F), and 1 diagnosed with celiac disease (M). Conclusions TKI therapy has allowed CML patients to pursue a normal life including planning/managing a family. Males do not need to stop therapy to conceive due to the therapy's non-genotoxic nature, in contrast to females who must cease therapy due to the teratogenic nature of TKIs. Kinetics of regrowth of the CML residual disease during pregnancy in female patients is different than in TFR patients. To our knowledge this is the largest multicentric study regarding CML and reproduction. Results and practical management will be presented. Disclosures Abruzzese: Novartis: Research Funding; Pfizer: Consultancy; Ariad: Consultancy; BMS: Consultancy. Castagnetti:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy. Rambaldi:Pfizer: Consultancy; Novartis: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Celgene: Consultancy; Amgen Inc.: Consultancy. Gaidano:Roche: Consultancy, Honoraria; Morphosys: Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, 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. We retrospectively analyzed 251 young patients with CML in chronic phase from 12 different Italian Institutions, diagnosed between October 2001 and October 2016. Up to 2011 all patients were treated frontline with imatinib while from January 2011 onwards with imatinib or a second generation TKI (nilotinib or dasatinib), based on clinical judgment. At diagnosis median age was 32,6 years [interquartile range (IQR) 27,6- 36,9]; 143 (57%) were male. Splenomegaly was found in 129 out of 233 evaluable patients, in 29,2% of the cases spleen was palpable >5 cm below the costal margin. The risk score was low in most of the cases (low risk Sokal 71%, low risk Eutos 91,3% vs high risk Sokal 9,8%, high risk Eutos 8,7%). Clinical features of the patients in treatment with different inhibitors are summarized in table 1. There were two main statistically significant differences in the group of patients treated with dasatinib: a higher proportion of high risk (30,8%) according to Eutos score and a lower median Hb level at diagnosis (8,5 gr/dL). These features probably reflected the trend of using dasatinib in patients with a more aggressive disease, as this drug was shown to be more potent since the first in vitro studies. Out of 251 patients 179 were treated with imatinib, 57 (22%) with nilotinib, 15 (5,9%) with dasatinib. Median follow up of the whole cohort was 76,5 months (IQR 41- 116); as expected, the follow up was longer in the imatinib group compared to the nilotinib and dasatinib groups (100 months vs 39,6 and 23,0 respectively). In the whole cohort, the cumulative incidence of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMolR) were 90,4% and 75,7% respectively; a deep molecular response (negative nested PCR, MR4.0, MR4,5) was achieved by 52.2% of patients, without differences among the 3 groups. Primary resistance occurred in 12,4% of patients, without differences among the 3 groups: secondary resistance occurred in 15.9% of patients, with a higher rate in the imatinib group (19,5%) as compared with nilotinib (7,0%) and dasatinib (6,7%) (p=0.047). Treatment discontinuation due to toxicity was observed in 6.0% of patients, without differences among the 3 groups. Blast transformation occurred in 7 out of 251 patients (2,8%), all in the imatinib group, after a median time from the diagnosis of 31 months (range 4-110). The 4-year cumulative Event-Free Survival (EFS) and Overall Survival (OS) were 72,4% (95%CI 66,7 - 78,5) and 98,1% (95%CI 96,4 - 99,8) respectively, without differences among the 3 groups. All deaths were related to blast transformation in imatinib group. In conclusion, as expected in a younger population, response to treatment and OS were excellent. However, the 4-year EFS was lower than expected, in spite of the presence of patients with predominantly low risk score. Furthermore, while the higher rate of secondary resistance in the imatinib group probably reflects the longer follow-up, it is worth of note that no statistically significant difference was observed between imatinib and 2nd generation TKI groups in terms of OS and EFS. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

active and well tolerated single agent in the treatment of heavily pretreated Hodgkin lymphoma patients. In this pilot phase II study patients with previously untreated HL underwent sequential regimen consisting in 2 cycles of BV before doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) +/- radiotherapy (RT). The primary endpoint of the study was the response to BV assessed by positron emission tomography (PET) after the 2 cycles (PET2), defined as reduction of Deauville score or, in case of no change in Deauville score, as any reduction in standard uptake value (SUV) intensity compared to basal SUV. Between April and October 2013, 12 patients with a median age at diagnosis of 36 years (range, 19-70), 11 stage I-IIA and 1 stage IIIA, were enrolled. BV was administered as scheduled and at the full dose of 1.8 mg/kg in all patients. After the 2 cycles of BV, the overall response rate was 91%, comprising of ten (83%) complete responses and one (8%) partial metabolic response. The non responding patient had stage III and showed a new lesion at PET2. After ABVD +/- RT, the overall response rate was 100% with 11 complete responses and 1 partial response (converting from progression disease). At a median follow up of 8 months, all 11 patients are still in complete response, while the remaining one relapsed. During BV therapy, the only grade 3 adverse events were transient and asymptomatic increase in liver transaminases (n=3, 25%) and gamma glutamyl transpeptidase (n=2, 17%). During ABVD +/- RT grade III-IV neutropenia occurred in 9 (75%) patients. All toxicities were transient and resolved with growth factor support. Two cycles of BV as first line-treatment in limited stage HL induced an outstanding complete response rate with limited toxicity and reducing the need of chemotherapy. Waiting for a longer follow up to assess the duration of response, our data (sequential administration of immunotherapy and chemotherapy) should be considered the starting point for further studies in first line therapy for limited stage HL patients. Disclosures No relevant conflicts of interest to declare.

Abstract 2770 In the “real world” of clinical practice, often physicians choose to treat very elderly CML patients with imatinib (IM) at lower than standard (400 mg/day) dose, but there are no published data on the results. To highlight this issue, we retrospectively revised 200 > 75 years old CML patients in chronic phase treated with IM 29 haematological Italian Institutions. We compared 58 patients (29%) who received low-dose IM (≤ 300 mg/day) according to physician decision (LD group) with the remaining 142 patients (71%) who received standard dose IM (SD group). In the SD group, there were 73 males and 69 females with a median age at IM start of 77.9 years (IR 76.0–80.3), Sokal Risk at diagnosis was low in 3 patients, intermediate in 86, high in 39 and not evaluable in 12. Two or more concomitant diseases requiring specific treatments were present in 93/142 patients (65.4%), with 85 patients (59.8%) taking 3 or more concomitant drugs. Twenty-seven patients (19.0%) were in late chronic phase (≥ 12 months from diagnosis before starting IM); on the whole, median time from diagnosis to IM was 1.1 months (IR 0.5–3.0). In the LD group, there were 31 males and 27 females with a median age of 80.2 years (IR 77.9–84.5) at IM start, Sokal Risk at diagnosis was intermediate in 34 patients, high in 17 and not evaluable in 7. Two or more concomitant diseases requiring specific treatments were present in 43/58 patients (74.1%), with 43 patients (74.1%) taking 3 or more concomitant drugs. Fifteen patients (25.8%) were in late chronic phase; on the whole, median time from diagnosis to IM was 1.8 months (IR 0.7–10.4). Starting dose of IM was 300 mg/day in 44 patients (75.8%) and < 300 mg/day in 14 patients (24.2%). According to CTC-AE, grade 3–4 hematological and extra-hematological toxicities were observed in 29 (20.4%) and 30 (21.1%) patients in the SD group compared with 10 (17.2%) and 14 (24.1%) patients in the LD group, respectively. Overall, 63 patients in the SD group (44.3%) required a dose reduction compared to 13 (22.4%) in the LD group (p=0.004): eleven (7.7%) patients in the SD group discontinued IM for toxicity compared to 13 (22.4%) in the LD group (p=0.004). Response to IM in the 2 groups is detailed in the table.SD groupLD grouppN° patients evaluable for response13656Early discontinuation8 (5.8%)8 (14.3%)0.054Resistant disease3 (2.2%)1 (1.8%)0.859Complete haematological response only24 (17.6%)12 (21.4%)0.527Partial cytogenetic response9 (6.6%)6 (10.7%)0.329Complete cytogenetic response92 (67.6%)29 (51.8%)0.052Major molecular response69 (50.7%)17 (30.3%)0.012 After a median follow-up of 33.7 months (IR 18.1–64.7), in the SD group 35 patients died (5 from disease progression and 30 from unrelated causes), 5 patients were lost to follow-up and 102 are still alive: in the LD group, 15 patients died (3 from disease progression and 12 from unrelated causes), 3 patients were lost to follow-up and 40 are still alive. In the SD group, 2-year and 5-year overall survival were 93.2% (CI95% 88.6–97.2) and 65.7% (CI95% 55.0–76.3), respectively; in the LD group, 2-year and 5-year overall survival were 89.7% (CI95% 80.4–98.9) and 67.0% (CI95% 49.6–84.4), respectively. In conclusion, in very elderly CML patients even reduced IM dose appears to be safe and effective enough to achieve sustained cytogenetic and molecular responses with prolonged overall survival. Therefore, also very elderly patients with co-morbidities should have this chance of cure without no upper age limit. Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Abstract 5187 Introduction Tumor Volume (TV) is an important independent prognostic factor in patients with Hodgkin Lymphoma (HL) and can be calculated manually using Contrast Enhanced Computed Tomography (CT) scan as proposed by Gobbi et al. (Gobbi PG et al, JCO, 2001; Gobbi PG et al, Cancer 2004). Definition of CT based TV (CT-TV) however is difficult to assess being time consuming and complex procedure. Differently from CT, FDG-PET scan allows a better identification of tumor sites in HL and improves staging accuracy (Rigacci et al, Ann Hematol, 2007). Availability of digitalized images with PET makes it feasible to try to explore a PET based method to define TV (PET-TV). Patients and methods We performed a pilot study to compare CT-TV and PET-TV on a series of phantoms and on a series of patients, to “optimize” the calculation of PET-TV in humans and to compare the new PET-TV with CT-TV. For the first part of the study 12 fillable objects characterized by different known volumes (VL) (range 0.5–1700 ml), shape and complexity were filled with a solution of water and FDG and then acquired with PET/CT. For the second part of the study 20 patients with HL, for whom both baseline CT and PET were available, were identified. Patients had a median age of 34 years, 6 had stage I, 11 had stage II (2 with Bulky and 2 with subdiaphragmatic disease), 3 had stage III or IV. For both parts of the study CT-VL and PET-VL were calculated separately and blindly by a radiologist and a nuclear medicine physician. CT-VL was defined manually on CT as originally reported. For definition of PET-VL a semiautomatic segmentation software (PET VCAR - Volume Computer Assisted Reading - GE) was used; volume contouring was defined automatically using different SUV thresholds (35-40-45-50-55-60%) or semiautomatically using an operator aided approach. Results When used on phantoms both CT and PET allowed an accurate definition of VL with an overall difference with actual VL of +4% and +1%, respectively. The automatic approach for calculation of PET-VL was feasible with the best PET threshold for segmentation identified at 45%. Both CT and PET had the worst results with very small VL ( On patients CT-TV ranged from 13 to 840 ml. Regarding PET an automatic approach using 45% threshold defined with phantoms was first used but didn't allow sometimes to include all visible tumor; being the optimal threshold for patients variable an operator visual assessment evaluation was required. Final PET-TV ranged from 29 to 536 ml. Overall using CT-TV as comparator, the use of PET allowed the identification of lower TV (median −11%: −47% to + 86%); in 12/18 PET-TV was lower than CT-TV with differences ranging from −9% to – 47%. In 6 patients PET-TV was greater than CT-TV (+1% to +86). In patient with lower PET-TV than CT-TV, this was mainly due to the presence of “hot” and “cold” areas within the tumor (especially big mediastinal masses) that cannot be read by CT and takes PET-TV closer to a “functional volume”(FV) rather than an anatomical volume only. In one case with the PET-TV higher than CT-TV, PET also included extranodal sites (bone and tonsils) that were not identifiable at CT. Finally TV calculation time/patient was 10 minutes (5 to 15) with PET, much less than with CT. Conclusions: PET can be used to define VL in phantoms and TV in patients with HL. Although a fully automated method is feasible and effective in phantoms, a semiautomated approach must be used for PET-TV assessment in humans. With such approach PET-TV evaluation is feasible, easy and quick to assess. The use of PET-TV allows the identification of a new concept of “functional volume” (FV) that partially correlates with CT-TV but probably describes different aspects of the tumor. The clinical and prognostic relevance of FV in patients with HL must be further investigated. Disclosures: No relevant conflicts of interest to declare.

Abstract 4977 Introduction Lenalidomide (Len) is an immunomodulatory drug that has a selective inhibitory effect on the del(5q) clone. The exact mechanism of action has not been defined: Len is known to have multiple biologic activities and an impressive effect on myelodysplasia (MDS) with deletion of the long arm of chromosome 5, leading to transfusion-independence, a complete erythroid and cytogenetic response in over 65% of cases. Similar responses were also seen in patients with MDS and a complex karyotype including del(5q), which usually have a poor prognosis. Lenalidomide leads to an important myelotoxicity in 50% of patients, so the optimal schedule merits discussion. In this report we describe unexpected erythroid and cytogenetic responses in two elderly patients with del(5q) MDS treated with Len for less than 12 wks. Case Reports Since November 2008 we have been treating two female patients with a diagnosis of MDS and a deletion of the long arm of chromosome 5 [del(5q)] with Len. Both patients had a low-int-1 IPSS risk. At the time of diagnosis severe cardio-pulmonary co-pathologies were present, therefore we observed a very bad tolerance to anaemia. The monthly transfusion requirement before starting treatment was 6 packed RBC units. Len was started at a full dose (10 mg/d for 21 days every 4 wks). Patient 1 received a diagnosis of “5q- syndrome” (Fig. 1). She stopped therapy after only 10 days due to severe agitation and panic attacks; however, one month later we observed a progressive reduction of transfusion need. Two months later, the patient was transfusion-free and the response had been ongoing for 6 months; she obtained a very good partial cytogenetic response. After 6 months the anaemia worsened again; we started Len 10 mg/d, but after 15 days the therapy was stopped due to the same side effects. Forty days later, we observed transfusion-independence for another 6 months, and a very good partial cytogenetic response. When the patient's condition worsened again, she was treated with Len 10 mg on alternative days with a better tolerance. After the first cycle, she presented the same side effects. Again the karyotype analysis showed a very good partial cytogenetic response. In Patient 2 the morphologic analysis was compatible with RAEB-1 and the cytogenetic analysis showed a [del(16)(q22)] together with del (5q) (Fig. 2). Len was stopped after 15 days due to renal impairment, cardiopulmonary and cardiac failure; she was then given only palliative therapy, but four wks later she achieved a complete erythroid response and remained transfusion-free for one year. In January 2010 the patient worsened and started Len again (10 mg/d for 21 dd every 4 wks) with good tolerance, a complete hematologic response and a very good partial cytogenetic response. Hematologic responses are illustrated in Tab. 1 and Tab. 2. In these two patients, after a very short treatment with Len we observed a complete erythroid response and a very good partial cytogenetic response. The median time to achieve the response was 6 wks (range 4–8 weeks). Transfusion-independence was durable (24 and 38 weeks respectively). Discussion Giagounidis et al (Ann. Hematol, 2007) describe two similar cases in which short-time Len treatment was given and a good response was obtained. One of our patients experienced grade III hematologic toxicity during the first cycle of therapy; despite this, we did not observe severe infectious or hemorrhagic complications. Despite the very short duration of Len treatment in our two patients, in both cases we achieved a very good partial cytogenetic response. Conclusions We observed unexpected effects of Len in myelodysplastic patients with del(5q) and a low-int1 IPSS risk who were treated for a very short period; additionally, this response was observed again at least twice when treatment was begun again: although these patients obviously represent only selected cases, the good erythroid and cytogenetic responses suggest that some patients with MDS and del(5q) may benefit from Len treatment even if this must be discontinued. Disclosures: No relevant conflicts of interest to declare.