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Limited information is available on the impact of the COVID-19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on 8665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS-CoV-2-positive patients (2·5%). Most patients (57%) were diagnosed as having SARS-CoV-2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65years with a male prevalence (73%). Fifty-six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS-CoV-2 infection was six years (three months to 18years). Twenty-one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty-three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID-19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS-CoV-2 infection and an impact of the pandemic on the overall management of CML patients.

To evaluate the role of bosutinib in elderly patients aged >65 years with chronic myeloid leukemia (CML), a real-life cohort of 101 chronic-phase CML patients followed up in 23 Italian centers and treated with bosutinib in second or a subsequent line was retrospectively evaluated. Starting dose of bosutinib was 500 mg/day in 25 patients (24.8%), 400 mg/day in 7 patients (6.9%), 300 mg/day in 33 patients (32.7%), 200 mg/day in 34 patients (33.6%), and 100 mg/day in 2 patients (2.0%). Grade 3/4 hematological toxicity occurred in 7/101 patients (6.9%) and grade 3/4 extra-hematological toxicity in 19/101 patients (18.8%). Permanent bosutinib discontinuation due to toxicity was needed in 12 patients (11.9%). Among the 96 patients evaluable for response, 74 (77.0%) achieved a complete cytogenetic response (CCyR), while 64 of these 74 patients in CCyR (66.6% of all 96 evaluable patients) also achieved a molecular response (MR) (major MR [MR 3.0] in 21 [21.8%], deep MR [MR 4.0/4.5] in 43 [44.8%]). The 3-year event-free survival and overall survival of the whole patients' cohort from bosutinib start were 60.9% (CI 95% 49.3-72.5) and 86.4% (CI 95% 77.2-95.6), respectively. Our real-life data show that bosutinib is effective, with a favorable safety profile, also in elderly patients with important comorbidities and resistance and/or intolerance to previous tyrosine-kinase inhibitor treatments. As a consequence, it could play a significant role in current clinical practice for frail patients.

An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2nd generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p

Background There is now great interest in using digital health tools to monitor patients' health status in real-world practice. Such tools often include electronic-patient-reported outcome (ePRO) systems in which symptoms questions are included into online interfaces for patient self-reporting, with real-time alerts triggered to the treating physician if severe symptoms or problems are reported. However, there is little information about the clinical utility and user perceptions of these systems, and this is particularly true in the area of hematology. Objectives This study investigates physicians' perceptions of usability and clinical utility of using remote ePROs in routine practice of patients with hematologic malignancies and explored implications in the delivery of patient care. Patients and Methods Remote ePROs are being gathered since December 2020 by the ALLIANCE Digital Health Platform, whose details of the development process have been previously described (Efficace F. et al., JMIR Res Protoc. 2021 Jun 1;10:e25271). Adult patients diagnosed with any hematologic malignancy are eligible to enter the platform, after having provided written informed consent. Aspects related to health-related quality of life (HRQoL), symptoms and medication adherence are assessed via validated PRO measures. The platform allows for real-time graphical presentation to physicians of individual patient symptoms and HRQoL outcomes. Based on a pre-defined algorithm, which includes the presence of clinically important problems and symptoms, the platform triggers automated alerts to the treating haematologists and medical staff. The definition of clinically important problems and symptoms is based on previously defined evidence-based thresholds (Giesinger J. et al., J Clin Epidemiol. 2020 Feb;118:1-8). We asked treating haematologists a feedback about their experience in using the platform, by an ad hoc web-survey consisting of 27 items covering several domains, including: usability and benefits, current use, evaluation of patient health-status, symptoms and adverse events, as well as physician-patient communication. We summarized characteristics of enrolled patients and treating haematologists by proportions, mean, median and range. We also used logistic regression analysis to check the possible association of characteristics of haematologists with survey results. Results Of the 201 patients invited to participate between December 2020 and June 2021 (cut-off date for current analysis), 180 (90%) accepted to enter the ALLIANCE platform, currently activated in 19 centers. The median age of patients was 57 years (range 21-91) and 58% were males. The majority were diagnosed with chronic myeloid leukemia (n=32, 18%) and multiple myeloma (n=31, 17%) and were in stable disease (n=89, 49%). Twenty-three hematologists (44% males) with a median age of 42 years (range 31-63) and an average 17 years (range 5-34) of experience in clinical practice, completed the survey. The majority of physicians (78%) accessed the platform at least once per month (of whom 39% at least once per week), regardless the alerts sent by the system about patients' clinically relevant problems. The frequency of access on a regular basis was also independent of physician sex (p=0.393) and years of experience in clinical practice (p=0.404). Overall, 57% of hematologists discussed often or very often ePROs with their patients, while 83% and 61% deemed this information helpful to better identify symptomatic adverse events (AEs) of grade 1-2 or of grade 3-4, respectively (see figure). Also, 87% and 91% of hematologists found ePROs useful to improve physician-patient communication and the accuracy of documentation of symptomatic AEs (regardless of severity), respectively. Physicians' responses to selected items of the survey are reported in the figure. Conclusions: Current findings support the clinical utility, from the perspective of the treating physician, of integrating ePROs into routine cancer care of patients with hematologic malignancies. Figure 1 Figure 1. Disclosures Efficace: Takeda: Consultancy; Janssen: Consultancy; Abbvie: Consultancy, Other: Grants (to Institution); Amgen: Consultancy, Other: Grants (to Institution). Breccia: Bristol Myers Squibb/Celgene: Honoraria; Pfizer: Honoraria; Abbvie: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Fazio: Janseen: Honoraria. Petrucci: Karyopharm: Honoraria, Other: Advisory Board; GSK: Honoraria, Other: Advisory Board; Amgen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Janssen-Cilag: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: 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, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tafuri: Roche: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Patriarca: Incyte: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Argenix: Honoraria. Luppi: Abbvie: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; MSD: Honoraria; Gilead Science: Honoraria, Other: Travel grant; Daiichi-Sankyo: Honoraria; Jazz Pharma: Honoraria. Vignetti: Novartis: Honoraria; Incyte: Honoraria; Amgen: Consultancy, Honoraria.

In chronic-phase chronic myeloid leukemia (CML), tyrosine kinase inhibitors (TKIs) are the standard of care, and treatment-free remission (TFR) following the achievement of a stable deep molecular response (DMR) has become, alongside survival, a primary goal for virtually all patients. The GIMEMA CML working party recently suggested that the possibility of achieving TFR cannot be denied to any patient, and proposed specific treatment policies according to the patient’s age and risk. However, other international recommendations (including 2020 ELN recommendations) are more focused on survival and provide less detailed suggestions on how to choose first and subsequent lines of treatment. Consequently, some grey areas remain. After literature review, a panel of Italian experts discussed the following controversial issues: (1) early prediction of DMR and TFR: female sex, non-high disease risk score, e14a2 transcript and early MR achievement have been associated with stable DMR, but the lack of these criteria is not sufficient to exclude any patient from TFR; (2) criteria for first and subsequent line therapy choice: a number of patient and drug characteristics have been proposed to make a personalized decision; (3) monitoring of residual disease after discontinuation: after the first 6 months, the frequency of molecular tests can be reduced based on MR4.5 persistence and short turnaround time; (4) prognosis of TFR: therapy and DMR duration are important to predict TFR; although immunological control of CML plays a role, no immunological predictive phenotype is currently available. This guidance is intended as a practical tool to support physicians in decision making.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200mg/dL and LDL > 70mg/dL 3months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P= 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P< 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P= 0.008; HR = 3.5; 95% CI = 1.4–8.7 and P < 0.001; HR = 4.4; 95% CI = 2–9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins. Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported&mdash, 281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months&mdash, 65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

Purpose The aim of the study was to evaluate the feasibility and the potential effects of the Haematological Home Care (HHC) programme for acute leukaemia (AL) patients, either in active chemotherapy or in the terminal phase of disease. Methods We retrospectively assessed a group of AL patients assisted at home in terms of number of hospitalisations, accesses to emergency department and place of death. We also used historical data to evaluate potential effects of HHC. Results The study group consisted of 44 patients, 36 of whom (82%) required palliative treatment, and eight (18%) had ongoing active chemotherapy. The mean number of hospitalisations was 0.64 (range 0-7) per patient, and the number of emergency department (ED) visits was 0.82 (range 0-4) per patient. Place of death was at home for 51.4% of patients and in hospital for 40.5%. Considering a historical group of 17 patients assisted at home the rate of hospitalisations and ED visits were 2.53 (range 0-9) and one (range 0-3), respectively. Place of death was home and hospital in 6% and 65%, respectively. Conclusions Haematological Home Care for AL patients is feasible and has potential positive effects in terms rate of hospitalisations and place of death.

The role of caregivers in homecare settings is relevant to the patient&rsquo, s wellbeing and quality of life. This phenomenon is well described in the literature for the oncological setting but not specifically for that of hematological malignancies. The aim of this study was to explore the experience of primary caregivers of patients with hematological malignancies within home care. We conducted a phenomenological study based on interviews with 17 primary caregivers of hematological patients. Analysis of the contents led to the identification of five main themes. Perhaps, the innovative aspects of this study can be summarized in three points: This service was demonstrated to fulfil the ethical aspects of providing the patient with a dignified accompaniment to the end of life. Secondly, the efficiency of the service and the benefit are directly dependent on the caregivers&rsquo, wellbeing, so knowledge of the dynamics and emotions involved can lead to the development and implementation of programs for hematological malignancies. Lastly, a collaborative caregivers&ndash, professionals relationship can improve a sense of accomplishment for all parties involved, lessening the family&rsquo, s frustration related to not having done their best. Home care brings significant benefits for both the patient and the caregivers and fulfils the ethical obligation of providing the patient dignified end-of-life care.

Hypertension is a commonly reported comorbidity in patients diagnosed with chronic myeloid leukemia (CML), and its management represents a challenge in patients treated with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs), considering their additional cardiovascular (CV) toxicity. The renin angiotensin system (RAS) contributes to hypertension genesis and plays an important role in atherosclerosis development, proliferation, and differentiation of myeloid hematopoietic cells. We analyzed a cohort of 192 patients with hypertension at CML diagnosis, who were treated with 2nd- or 3rd-generation TKIs, and evaluated the efficacy of RAS inhibitors (angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-II receptor blockers (ARBs)) in the prevention of arterial occlusive events (AOEs), as compared with other drug classes. The 5-year cumulative incidence of AOEs was 32.7 ± 4.2%. Patients with SCORE ≥ 5% (high-very-high) showed a significantly higher incidence of AOEs (33.7 ± 7.6% vs 13.6 ± 4.8%, p = 0.006). The AOE incidence was significantly lower in patients treated with RAS inhibitors (14.8 ± 4.2% vs 44 ± 1%, p < 0.001, HR = 0.283). The difference in the low and intermediate Sokal risk group was confirmed but not in the high-risk group, where a lower RAS expression has been reported. Our data suggest that RAS inhibitors may represent an optimal treatment in patients with hypertension and CML, treated with 2nd or 3rdG TKIs.

BACKGROUND Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). CONCLUSIONS For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.

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.

We aimed to compare fatigue of newly diagnosed patients with myelodysplastic syndromes (MDS) with that of the general population (GP). We also investigated the ability of the IPSS and IPSS-R to capture severity of patient-reported fatigue at diagnostic workup. A sample of 927 newly diagnosed patients with MDS was consecutively enrolled in a large international observational study and all patients completed the FACIT-Fatigue questionnaire at baseline. Fatigue was compared with that of the GP (N = 1075) and a 3-point difference in mean scores was considered as clinically meaningful. Fatigue of MDS patients was on average 4.6 points below the mean of the GP (95% CI, −5.9 to −3.2, p < 0.001), reflecting clinically meaningful worse fatigue. Unlike the IPSS, the IPSS-R identified clearly distinct subgroups with regard to burden of fatigue. Mean scores differences compared with GP ranged from nonclinically relevant for very low risk (Δ = −1.8, 95% CI, −4.0 to 0.5, p = 0.119) to large clinically meaningful differences for very highrisk IPSS-R patients (Δ = −8.2, 95% CI, −10.3 to −6.2, p < 0.001). At diagnostic workup, fatigue of MDS is clinically meaningful worse than that reported by the GP. Compared with the IPSS classification, the IPSS-R provides a better stratification of patients with regard to fatigue severity.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Not available.

Introduction Tyrosine kinase inhibitors (TKIs) have dramatically changed the outcome of chronic phase chronic myeloid leukemia patients (CP-CML),improving the long-term outcome; indeed, life expectancy is now very close to that of age matched individuals in the general population. Imatinib (IMA) the first generation TKI, increased the overall survival(OS)by more than 80%. Second-generation TKIs, (2gen TKIs) used in first line dasatinib and nilotinib, induced faster molecular responses, rapidly reducing the disease burden, but did not change the OS of CP-CML newly diagnosed patients. Most of the available data reported were extrapolated from sponsored clinical trials. The aim of this analysis is to detail and analyze the prognostic features influencing the OS in a large Italian CML cohort of patients prospectively enrolled in the GIMEMA CML Italian study. Methods Relevant clinical, demographic, biological and treatment-related information were web-based collected during a multicenter,observational Italian study that enrolled consecutive patients in each disease phase, at 68 Italian hematologic centers belonging to the GIMEMA network from January 2013 to June 2020. We analyzed prognostic factors influencing the OS by Kaplan Meier method and Cox multivariable models. Results A cohort of 1206 patients was prospectively analyzed, 608 of them received frontline IMA and 598 2genTKIs. Median age in the IMA cohort was 69 years (range 58-77) vs 52 years in the 2genTKIs cohort (range 41-63). The male/female ratio was 1.7 in the IMA group and 1.35 in the 2genTKIs cohort. Ninety-eight percent of patients were in CP. Results of molecular analysis of the BCR-ABL transcript at baseline showed: b2a2 in 33.1 % of patients and b3a2 in 59.9%, while an atypical transcript was found in 7%. The cytogenetic analysis at baseline showed major and minor additional aberrations in 5.7% and 1.6% of patients respectively. In the IMA cohort,according to the Sokal score, 27.7%, 57.3% and 15% of patients were stratified as low, intermediate and high risk, whereas according to the ELTS score 51.3%, 35.5% and 13.3%, of patients were classified as low, intermediate and high risk. In the 2genTKIs cohort, according to the Sokal score, 44.8%, 34.5% and 20.8%, were low, intermediate and high risk, respectively, whereas according to the ELTS score, 66.9%, 22% and 11% were assigned to the respective risk groups.The Charlson comorbidity index in the IMA cohort was 2-3 and 4-5 in 74% and 26% of patients respectively; in the 2genTKIs cohort the score was 2-3 in 89% and 4-5 only in 10% of patients. Overall, median follow-up of the whole population was 24.7 months (range 13.3-39.3).Seventy-three patients (6.1%) in the overall population died, the majority of them in the IMA cohort: 56 patients (9.2%), at median age of 80.5 years,11/608 (1.8%) due to CML-related causes. Conversely,in the 2genTKIs cohort only 17 patients (2.8%) died, at a median age of 62 years, 10/598 (1.7%) for CML-related causes. Estimated 60-months OS of the overall population was 86.4% (95% CI 81.3-90.2): 75.8% (95% CI 64.5-84) in the IMA cohort and 93.8% (95% CI 87.5-97) in the 2genTKIs group (p Conclusions In this first analysis of our study different clinical behaviors were observed among Italian hematologists, who prevalently prescribed IMA to older patients,with more comorbidities, as compared to 2genTKIs.These differences explain a better OS for patients treated with 2genTKIs vs IMA, however, the risk of death for CML related causes is quite similar between the two groups, all the differences being attributable to other causes of death.Prognostic baseline features associated to an increased OS confirmed that, in addition to age, the ELTS score and the comorbidities are the main clinical factors that independently influence the long-term OS Disclosures 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. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Abbvie: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Galimberti:Novartis: Speakers Bureau; Incyte: Honoraria. Bocchia:CELGENE: Honoraria; Incyte: Honoraria. Abruzzese:Incyte: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levato:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rosti:Pfizer: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Di Raimondo:GILEAD, Incyte: Research Funding; Amgen, Takeda, Novartis: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Pane:Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Foà:Incyte: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Saglio:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Roche: Research Funding; Novartis: Research Funding; Ariad: Research Funding.

Introduction Dasatinib (DAS) is a second-generation (2G) tyrosine-kinase inhibitor (TKI) approved for the first- and second-line treatment of chronic myeloid leukemia (CML) patients. Though highly effective, DAS displays a distinct safety profile, with pleural effusion (PE) occurring in a significant proportion of patients. Among factors associated with DAS-related PE, concomitant pulmonary and cardiovascular diseases have emerged as the most common. Bosutinib (BOS) is another 2G-TKI that has proved to be effective in CML patients failing previous TKIs, with limited cardiac and pleural toxicity. Aims To analyse safety and efficacy of BOS therapy in chronic phase (CP) CML patients developing PE under DAS. Methods We retrospectively collected 20 CP-CML patients referring to several Italian hematology centers who have been receiving BOS in second- or subsequent line, after development of one or more PE with DAS. Cytogenetic and molecular responses were evaluated according to the ELN recommendations, with major molecular response (MMR) defined as BCR-ABLIS ratio Results Twenty patients (12 males and 8 females) with median age at CML diagnosis of 60 years (range: 44-78) were included in the present study. Four patients received DAS as first TKI, while 16 started imatinib and then switched to DAS, three of them after second-line nilotinib, for resistance (n=9) or intolerance (n=7); DAS starting daily dose was 100 mg in 15 patients, 80 mg in two and 50 mg in three. Median time to first PE was 20 months (range: 1-58). First PE grade was 1 in three, 2 in fifteen and 3 in two patients, respectively; 11/20 patients (55%) developed at least a second PE, with a median number of PE episodes of 2 (range: 1-6). Median duration of DAS therapy was 32 months (range: 6-75). Median age at BOS start was 68 years (range: 49-82), and 17/20 patients (85%) had at least one comorbidity requiring therapy, the most common being cardiovascular diseases (n=9), hypertension (n=8), diabetes (n=6), pulmonary diseases (n=4), secondary neoplasms (n=3) thyroid diseases (n=3). Median number of comorbidities and concomitant medications were 4 (range: 0-7) and 7 (range: 0-11), respectively. At BOS start 9 patients (45%) were at least in MMR (2 in DMR), 6 (30%) were in CCyR without MMR and 5 (25%) had less than a CCyR; two cases displayed ABL mutations (F317V in one, compound mutations in one). Only a minority of patients (n=4) commenced BOS at the canonical daily dose of 500 mg, while 10 and 6 cases started with 200 and 300 mg, respectively. After a median time from BOS start of 18 months (range: 3-39), 15 patients are still on treatment (median duration 13 months, range 3-38). 5 patients discontinued BOS for resistance (n=2) or toxicities (n=3); median actual BOS daily dose is 300 mg (range: 200-500). No patient progressed to accelerated/blast phase, 1 patient died of cerebral hemorrhage 6 months after BOS stop. Among the 15 patients still in BOS, 7 improved their response and 8 maintained response level: at last follow-up 9/15 (60%) were in DMR, 3/15 (20%) in MMR and 3/15 (20%) in CCyR. By all of 20 patients, 6 (30%) developed PE during BOS treatment, that was grade 1 in two cases and grade 2-3 in four; 3/4 of these latter patients permanently stopped BOS for this reason. Median time from BOS to 1st PE was 3 months (range:1-28). No patient experienced hematologic toxicities with BOS, while non-PE extra-hematologic side effects were recorded in 8 cases (diarrhea = 2, skin rash = 2, nausea = 1, increased creatinine = 1, increased lipase = 1, headache = 1); all these were grade 1-2 and none led to BOS discontinuation. Discussion With the limits of the retrospective nature and the small number of patients, our data suggest that BOS is a suitable therapeutic option in CML patients developing PE during DAS treatment. Of interest is the acceptable incidence of PE recurrence and lack of other serious toxicities even in a population of relatively elderly and with comorbidities. Disclosures Abruzzese: Novartis: Consultancy; Ariad: Consultancy; BMS: Consultancy; Pfizer: Consultancy.

Chronic myeloid leukemia (CML) treatment is based on company-sponsored and academic trials testing different tyrosine kinase inhibitors (TKIs) as first-line therapy. These studies included patients selected according to many inclusion-exclusion criteria, particularly age and comorbidities, with specific treatment obligations. In daily clinical practice (real-life), inclusion-exclusion criteria do not exist, and the treatment outcome does not only depend on the choice of first-line TKI but also on second- and third-line TKIs. To investigate in a real-life setting the response and the outcome on first-line imatinib, with switch to second generation TKIs in case of unsatisfying response or intolerance, we analyzed all newly diagnosed patients (N = 236), living in two Italian regions, registered in a prospective study according to population-based criteria and treated front-line with imatinib. A switch from imatinib to second-generation TKIs was reported in 14% of patients for side effects and in 24% for failure or suboptimal response, with an improvement of molecular response in 57% of them. The 5-year overall survival (OS) and leukemia-related survival (LRS) were 85% and 93%, respectively; the 4-year rates of MR3.0 and MR4.0 were 75% and 48%, respectively. Cardiovascular complications were reported in 4% of patients treated with imatinib alone and in 6% of patients receiving nilotinib as second-line. Older age (≥70 years) affected OS, but not LRS. These data provide an unbiased reference on the CML management and on the results of TKI treatment in real-life, according to ELN recommendations, using imatinib as first-line treatment and second-generation TKIs as second-line therapy. Am. J. Hematol. 92:82-87, 2017. © 2016 Wiley Periodicals, Inc.

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.