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The frequency of thrombosis in AML has been evaluated only in a few studies and no validated predictive model is currently available. Recently, DIC score was shown to identify patients at higher thrombotic risk. We aimed to evaluate the frequency of thromboembolism in AML patients treated with intensive chemotherapy and to assess the ability of genetic and clinical factors to predict the thrombotic risk. We performed a retrospective observational study including 222 newly diagnosed adult AML (210) and high-risk MDS (12), treated with intensive chemotherapy between January 2013 and February 2020. With a median follow-up of 44 months, we observed 50 thrombotic events (90% were venous, VTE). The prevalence of thrombosis was 22.1% and the 6-months cumulative incidence of thrombosis was 10%. The median time to thrombosis was 84 days and 52% of the events occurred within 100 days from AML diagnosis. Khorana and DIC score failed to stratify patients according to their thrombotic risk. Only history of a thrombotic event (p = 0.043), particularly VTE (p = 0.0053), platelet count above 100 × 10

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P

Background Erythropoiesis‐stimulating agents effectively improve the hemoglobin levels in a fraction of anemic patients with myelodysplastic syndromes (MDS). Higher doses (HD) of recombinant human erythropoietin (rhEPO) have been proposed to overcome suboptimal response rates observed in MDS patients treated with lower “standard doses” (SD) of rhEPO. However, a direct comparison between the different doses of rhEPO is lacking. Methods A cohort of 104 MDS patients treated with HD was retrospectively compared to 208 patients treated with SD in a propensity score‐matched analysis to evaluate hematological improvement‐erythroid (HI‐E) rate induced by the different doses of rhEPO. The impact of rhEPO doses on survival and progression to leukemia was also investigated. Results Overall HI‐E rate was 52.6%. No difference was observed between different rhEPO doses (P = .28) in matched cohorts; in a subgroup analysis, transfusion‐dependent patients and patients with higher IPSS‐R score obtained a higher HI‐E rate with HD, although without significant impact on overall survival (OS). Achievement of HI‐E resulted in superior OS. At univariate analysis, a higher HI‐E rate was observed in transfusion‐independent patients (P, When compared in a propensity‐score matched analysis, standard doses of rhEPO showed similar effects to those of higher doses in anemic MDS patients. Achievement of favorable response with hematologic improvement in this clinical scenario is possible by reducing drug doses and costs.

In IgM monoclonal gammopathies MYD88L265P is a prognostic and predictive biomarker of therapy response. MYD88L265P detection is mainly performed by allele-specific quantitative PCR (ASqPCR), however recently, droplet digital PCR (ddPCR) has been proved to be suitable for MYD88L265P screening and minimal residual disease monitoring (MRD). This study compared ASqPCR and ddPCR to define the most sensitive method for MYD88L265P detection in bone marrow (BM), peripheral blood (PB) sorted or unsorted CD19+ cells, and in plasma cell-free DNA (cfDNA). Overall, the analysis showed a good concordance rate (74%) between the two methods, especially in BM samples, while discordances (26%) were mostly in favor of ddPCR (ddPCR+ vs. ASqPCR-) and were particularly evident in samples with low mutational burden, such as PB and cfDNA. This study highlights ddPCR as a feasible approach for MYD88L265P detection across different specimen types (including cfDNA). Interestingly, its high sensitivity makes CD19+ selection dispensable. On the other hand, our results showed that MYD88L265P detection on PB samples, especially with ASqPCR, is suboptimal for screening and MRD analysis. Finally, significantly different MYD88L265P mutational levels observed between Waldenström Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance patients suggest the need for further studies in order to identify possible correlations between mutational levels and risk of progression to Waldenström.

Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients. However, its tolerability in elderly patients is still debated. Methods: An observational, retrospective study was carried out, patients with chronic lymphocytic leukemia (CLL) or lymphoma, aged ≥ 65 years old, treated with bendamustine-based regimens in first or subsequent lines between 2010 and 2020 were considered eligible. Results: Overall, 179 patients aged ≥ 65 years were enrolled, 53% between 71 and 79 years old. Cumulative Illness Rating Scale (CIRS) comorbidity score was ≥6 in 54% patients. Overall survival (OS) at 12 months was 95% (95% confidence interval [CI]: 90–97%), after a median follow up of 50 months, median OS was 84 months. The overall response rate was 87%, with 56% complete responses, the median time to progression (TTP) was 61 months. The baseline factors affecting OS by multivariable analysis were sex, histological diagnosis, renal function, and planned bendamustine dose, while only type of lymphoma and bendamustine dose impacted on TTP. Main adverse events were neutropenia (grade ≥ 3: 43%) and infections (any grade: 36%), with 17% of patients requiring hospital admission. Conclusions: The responses to bendamustine, as well as survival, are relevant even in advanced age patients, with a manageable incidence of acute toxicity.

© 2021 by the authors., In IgM monoclonal gammopathies MYD88L265P is a prognostic and predictive biomarker of therapy response. MYD88L265P detection is mainly performed by allele-specific quantitative PCR (ASqPCR), however recently, droplet digital PCR (ddPCR) has been proved to be suitable for MYD88L265P screening and minimal residual disease monitoring (MRD). This study compared ASqPCR and ddPCR to define the most sensitive method for MYD88L265P detection in bone marrow (BM), peripheral blood (PB) sorted or unsorted CD19+ cells, and in plasma cell-free DNA (cfDNA). Overall, the analysis showed a good concordance rate (74%) between the two methods, especially in BM samples, while discordances (26%) were mostly in favor of ddPCR (ddPCR+ vs. ASqPCR-) and were particularly evident in samples with low mutational burden, such as PB and cfDNA. This study highlights ddPCR as a feasible approach for MYD88L265P detection across different specimen types (including cfDNA). Interestingly, its high sensitivity makes CD19+ selection dispensable. On the other hand, our results showed that MYD88L265P detection on PB samples, especially with ASqPCR, is suboptimal for screening and MRD analysis. Finally, significantly different MYD88L265P mutational levels observed between Waldenström Macroglobulinemia and IgM monoclonal gammopathy of undetermined significance patients suggest the need for further studies in order to identify possible correlations between mutational levels and risk of progression to Waldenström., This research was supported by: a grant from the International Waldenstrom’s Macroglobulinemia Foundation and the Leukemia & Lymphoma Society, Fondi di Ricerca Locale, Università degli Studi di Torino, Italy; Fondazione CRT (projects code: 2018.1284), Torino, Italy; Damiano per l’Ematologia (C.F. 91062500557).

Simple Summary The better understanding of disease biology, the availability of new effective drugs and the increased awareness of patients’ heterogeneity in terms of fitness and personal expectations has made the current treatment paradigm of AML in the elderly very challenging. Here, we discuss the evolving criteria used to define eligibility for induction chemotherapy and transplantation, the introduction of new agents in the treatment of patients with very different clinical conditions, the implications of precision medicine and the importance of quality of life and supportive care, proposing a simplified algorithm that we follow in 2021. Abstract Acute myeloid leukemia (AML) in older patients is characterized by unfavorable prognosis due to adverse disease features and a high rate of treatment-related complications. Classical therapeutic options range from intensive chemotherapy in fit patients, potentially followed by allogeneic hematopoietic cell transplantation (allo-HCT), to hypomethylating agents or palliative care alone for unfit/frail ones. In the era of precision medicine, the treatment paradigm of AML is rapidly changing. On the one hand, a plethora of new targeted drugs with good tolerability profiles are becoming available, offering the possibility to achieve a prolonged remission to many patients not otherwise eligible for more intensive therapies. On the other hand, better tools to assess patients’ fitness and improvements in the selection and management of those undergoing allo-HCT will hopefully reduce treatment-related mortality and complications. Importantly, a detailed genetic characterization of AML has become of paramount importance to choose the best therapeutic option in both intensively treated and unfit patients. Finally, improving supportive care and quality of life is of major importance in this age group, especially for the minority of patients that are still candidates for palliative care because of very poor clinical conditions or unwillingness to receive active treatments. In the present review, we discuss the evolving approaches in the treatment of older AML patients, which is becoming increasingly challenging following the advent of new effective drugs for a very heterogeneous and complex population.

BACKGROUND Azacitidine (AZA) is the standard treatment for myelodysplastic syndromes (MDS); however, many patients prematurely stop therapy and have a dismal outcome. METHODS The authors analyzed outcomes after AZA treatment for 402 MDS patients consecutively enrolled in the Italian MDS Registry of the Fondazione Italiana Sindromi Mielodisplastiche, and they evaluated the North American MDS Consortium scoring system in a clinical practice setting. RESULTS At treatment discontinuation, 20.3% of the patients were still responding to AZA, 35.4% of the cases had primary resistance, and 44.3% developed adaptive resistance. Overall survival (OS) was better for patients who discontinued treatment while in response because of planned allogeneic hematopoietic stem cell transplantation (HSCT; median OS, not reached) in comparison with patients with primary resistance (median OS, 4 months) or adaptive resistance (median OS, 5 months) or patients responsive but noncompliant/intolerant to AZA (median OS, 4 months; P = .004). After AZA discontinuation, 309 patients (77%) received best supportive care (BSC), 60 (15%) received active treatments, and 33 (8%) received HSCT. HSCT was associated with a significant survival advantage, regardless of the response to AZA. The North American MDS Consortium scoring system was evaluable in 278 of the 402 cases: patients at high risk had worse OS than patients at low risk (3 and 7 months, respectively; P < .001). The score was predictive of survival both in patients receiving BSC (median OS, 2 months for high-risk patients vs 5 months for low-risk patients) and in patients being actively treated (median OS, 8 months for high-risk patients vs 16 months for low-risk patients; P < .001), including transplant patients. CONCLUSIONS Real-life data confirm that this prognostic scoring system for MDS patients failing a hypomethylating agent seems to be a useful tool for optimal prognostic stratification and for choosing a second-line treatment after AZA discontinuation.

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.

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Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring >= 2 mutations had a worse outcome than patients with

Clinical guidelines recommend the use of erythropoietin-stimulating agents (ESA) in anemic patients with lower risk myelodysplastic syndrome (MDS)[1][1]–[4][2] and two registration trials for ESA have just been completed.[5][3],[6][4] We conducted a retrospective study in MDS patients selected by

Discontinuation of tyrosine kinase inhibitors (TKIs) therapy is now feasible for patients with chronic myeloid leukemia (CML) with deep and longstanding molecular response (MR 4/4.5); around 40–60%...

Prognosis of elderly acute myeloid leukemia (AML) patients remains dismal with less than 15–20% of long-term survivors. Though challenged by hypomethylating agents (HMA), intensive chemotherapy (IC...

Although genetics is a relevant risk factor in acute myeloid leukemia (AML), it can be minimally informative and/or not readily available for the early identification of patients at risk for treatment failure. In a randomized trial comparing standard vs high-dose induction (ClinicalTrials.gov #NCT00495287), we studied early peripheral blast cell clearance (PBC) as a rapid predictive assay of chemotherapy response to determine whether it correlates with the achievement of complete remission (CR), as well as postremission outcome, according to induction intensity. Individual leukemia-associated immunophenotypes (LAIPs) identified pretherapy by flow cytometry were validated and quantified centrally after 3 days of treatment, expressing PBC on a logarithmic scale as the ratio of absolute LAIP+ cells on day 1 and day 4. Of 178 patients, 151 (84.8%) were evaluable. Patients in CR exhibited significantly higher median PBC (2.3 log) compared with chemoresistant patients (1.0 log; P < .0001). PBC < 1.0 predicted the worst outcome (CR, 28%). With 1.5 log established as the most accurate cutoff predicting CR, 87.5% of patients with PBC >1.5 (PBChigh, n = 96) and 43.6% of patients with PBC ≤1.5 (PBClow, n = 55) achieved CR after single-course induction (P < .0001). CR and PBChigh rates were increased in patients randomized to the high-dose induction arm (P = .04) and correlated strongly with genetic/cytogenetic risk. In multivariate analysis, PBC retained significant predictive power for CR, relapse risk, and survival. Thus, PBC analysis can provide a very early prediction of outcome, correlates with treatment intensity and disease subset, and may support studies of customized AML therapy.

Here we evaluated whether sequential high-dose chemotherapy (sHD) increased the early complete remission (CR) rate in acute myelogenous leukemia (AML) compared with standard-intensity idarubicin-cytarabine-etoposide (ICE) chemotherapy. This study enrolled 574 patients (age, 16-73 years; median, 52 years) who were randomly assigned to ICE (n = 286 evaluable) or sHD (2 weekly 3-day blocks with cytarabine 2 g/m2 twice a day for 2 days plus idarubicin; n = 286 evaluable). Responsive patients were risk-stratified for a second randomization. Standard-risk patients received autograft or repetitive blood stem cell-supported high-dose courses. High-risk patients (and standard-risk patients not mobilizing stem cells) underwent allotransplantation. CR rates after 2 induction courses were comparable between ICE (80.8%) and sHD (83.6%; P = .38). sHD yielded a higher single-induction CR rate (69.2% vs 81.5%; P = .0007) with lower resistance risk (P < .0001), comparable mortality (P = .39), and improved 5-year overall survival (39% vs 49%; P = .045) and relapse-free survival (36% vs 48%; P = .028), despite greater hematotoxicity delaying or reducing consolidation blocks. sHD improved the early CR rate in high-risk AML (odds ratio, 0.48; 95% confidence interval [CI], 0.31-0.74; P = .0008) and in patients aged 60 years and less with de novo AML (odds ratio, 0.46; 95% CI, 0.27-0.78; P = .003), and also improved overall/relapse-free survival in the latter group (hazard ratio, 0.70; 95% CI, 0.52-0.94; P = .01), in standard-risk AML, and postallograft (hazard ratio, 0.61; 95% CI, 0.39-0.96; P = .03). sHD was feasible, effectively achieved rapid CR, and improved outcomes in AML subsets. This study is registered at www.clinicaltrials.gov as #NCT00495287.

Very elderly (> 75years) chronic myeloid leukaemia (CML) patients at diagnosis are sometimes treated with different doses of imatinib (IM) based on concomitant diseases and physicians’ judgement. However, data on long-term follow-up of these patients are still lacking. To investigate treatment response and outcome, we retrospectively revised an Italian database of 263 very elderly CML patients receiving IM from the time of diagnosis. Median age at diagnosis was 78.5years and 56% of patients had 2 or 3 comorbidities. A complete haematological and cytogenetic response were achieved in 244 (92.8%) and 184 (69.9%) patients, respectively. In 148 cases (56.2%), a major molecular response was observed, which was deep in 63 cases (24%). A blastic phase occurred in 11 patients (4.2%). After a median follow-up of 45.0months, 93 patients have died (9 from disease progression) and 104 (39.5%) are still in treatment with IM. Incidence of grades 3–4 haematological and non-haematological toxicity was similar to those reported in younger patients. Five-year event-free survival was 54.5% and 45.2% in patients ≤80years and > 80years, respectively (p = 0.098). Five years OS was 75.7% and 61.6% in patients ≤80years and > 80years, respectively (p = 0.003). These findings show that IM plays an important role in frontline treatment of very elderly CML patients without increased toxicity and any effort to treat these patients with standard doses should be made in order to achieve responses as in younger subjects.

Erythropoiesis-stimulating agents (ESAs) were combined with ruxolitinib in 59 anaemic myelofibrosis patients (93% with Dynamic International Prognostic Scoring System [DIPSS] intermediate-2/high risk; 52·5% transfusion-dependent). Anaemia response (AR) rate was 54% and 76% of patients responded at 5 years. A further 15% displayed minor improvement in anaemia and 78% of patients reduced spleen size. Endogenous erythropoietin levels

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by ineffective hematopoiesis, cytopenia, and risk of evolution into Acute Myeloid Leukemia (AML). It was shown t...

Keywords: imatinib discontinuation; chronic myeloid leukaemia; tyrosine kinase inhibitor; treatment cessation

Purpose Most anemic patients with non-deleted 5q lower-risk myelodysplastic syndromes (MDS) are treated with erythropoiesis-stimulating agents (ESAs), with a response rate of approximately 50%. Second-line treatments, including hypomethylating agents (HMAs), lenalidomide (LEN), and investigational drugs, may be used after ESA failure in some countries, but their effect on disease progression and overall survival (OS) is unknown. Here, we analyzed outcome after ESA failure and the effect of second-line treatments. Patients and Methods We examined an international retrospective cohort of 1,698 patients with non-del(5q) lower-risk MDS treated with ESAs. Results Erythroid response to ESAs was 61.5%, and median response duration was 17 months. Of 1,147 patients experiencing ESA failure, 653 experienced primary failure and 494 experienced relapse after a response. Primary failure of ESAs was associated with a higher risk of acute myeloid leukemia (AML) progression, which did not translate into an OS difference. Of 450 patients (39%) who received second-line treatment, 194 received HMAs, 148 received LEN, and 108 received other treatments (MISC), whereas 697 received RBC transfusions only. Five-year AML cumulative incidence was 20.3%, 20.3%, and 11.3% for those receiving HMAs, LEN, and MISC, respectively ( P = .05). Five-year OS for patients receiving HMA, LEN, and MISC was 36.5%, 41.7%, and 51%, respectively ( P = .21). In a multivariable analysis adjusted for age, sex, revised International Prognostic Scoring System score, and progression at ESA failure, there was no significant OS difference among the three groups. Conclusion In this large, multicenter, retrospective cohort of patients with non-del(5q) lower-risk MDS treated with ESAs, none of the most commonly used second-line treatments (HMA and LEN) significantly improved OS. Early failure of ESAs was associated with a higher risk of AML progression.

Pleural effusion (PE) represents the leading cause of dasatinib (DAS) discontinuation. However, the pathogenic mechanism of this adverse event (AE) is unknown and its management unclear. We investigated if a DAS dose reduction after the first PE would prevent the recurrence of this AE. We retrospectively collected data on all the cases of PE in CML-chronic phase (CP) DAS-treated patients from November 2005 to February 2017 in 21 Italian hematological centers. We identified 196 cases of PE in a series of 853 CML-CP DAS-treated patients (incidence 23.0%). DAS starting dose was 100 mg/day in 70.4% of patients, less than 100 mg/day in 14.3%, and more than 100 mg/day in the remaining cases. Median time from DAS start to PE was 16.6 months. At first PE development, 28.6% of patients were in MMR, and 37.8% in deep molecular response (DMR). DAS was temporary interrupted in 71.9% of cases, with a dose reduction in 59.2%. Recurrence was observed in 59.4% of the cases. Treatment was definitively discontinued due to PE in 29.1% of the cases. Interestingly, among patients whose DAS dosage was reduced, 59.5% experienced PE recurrence. DAS dose reduction after the first episode of PE did not prevent recurrence of this AE. Therefore, once a MMR or a DMR is achieved, different strategies of DAS dose management can be proposed prior to the development of PE, such as daily dose reduction or, as an alternative option, an on/off treatment with a weekend drug holiday.

We evaluated a maintenance, post-remission treatment with low-dose chemotherapy plus differentiating agents on poor-prognosis acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients ineligible to allografting. Patients had either age over 60 and/or secondary AML, therapy-related AML, previous relapse, high-risk MDS. Forty-five patients received the maintenance therapy based on two alternated schedules: (a) 6-thioguanine + 13-cis retinoic acid + dihydroxylated vitamin D3 and (b) low-dose cytarabine + 6-mercaptopurine + all-trans retinoic acid + dihydroxylated vitamin D3. We compared their outcome, at a median follow-up of 52 months, to that of a matched population of 49 patients who stopped treatments after consolidation. Maintenance group had a lower relapse incidence (70.3 vs. 86.4 % at 5 years p = 0.007) and a longer disease-free survival (median 21.2 vs. 8.7 months, p = 0.017). The relapse reduction improved overall survival: median 40.4 months (35.9 % at 5 years) for maintenance group vs. 15.8 (14.2 % at 5 years) for controls (p = 0.005). At multivariate Cox analysis, both cytogenetic and maintenance therapies resulted independent outcome predictors for overall survival. Maintenance treatment also reduced minimal residual disease (detected by WT1 and CBFβ-MYH11) in five of eight evaluable patients. The present results suggest that our strategy of maintenance therapy might improve the outcome of poor-risk AML/MDS patients.

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: 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

Introduction Patients with secondary acute myeloid leukemia (sAML) after myelodysplastic (MDS) or myeloproliferative neoplasms (MPN) treated with chemotherapy show poorer outcomes compared with de novo AML; consequently, these cases should be allocated to allogeneic stem cell transplant (alloSCT) whenever possible (Döhner H, Blood 2017). Some recent evidence suggested the potential of molecular characterization for implementing the current WHO definition (Arber DA, Blood 2016), since chromatin-splicing mutations have been reported to be highly specific for sAML (Lindsley RC, Blood 2015). However, this molecular signature has also been recognized in some clinically defined de novo AML cases (Papaemmanuil E, NEJM 2016). Based on this background, we assessed the clinical impact of chromatin-splicing mutational signature in clinically defined de novo AML patients enrolled into the prospective NILG 02/06 trial [ClinicalTrials.gov Identifier: NCT00495287]. Patients and Methods The trial (Bassan R, Blood Advances 2019) randomized 574 newly diagnosed AML patients to receive induction (standard vs high-dose) followed by consolidative chemotherapy and/or alloSCT. For the present analysis, only patients with de novo AML (n=313) and WHO-defined sAML after MDS or MPN (n=101) with a full genetic characterization have been considered. Studies performed at diagnosis included conventional karyotype (n=412) and molecular analysis (n=414) and/or targeted NGS (this latter performed on 197 patients with normal karyotype). Patients with WHO-sAML were defined by the presence of an antecedent history of MDS or MPN (n=21) and/or cytogenetic WHO criteria of AML with MDS-related changes (n=80). Chromatin-splicing mutational signature defined the molecular-sAML group and comprised ASXL1, STAG2, BCOR, KMT2A-PTD, EZH2, PHF6, SRSF2, SF3B1, U2AF1, ZRS2 and RUNX1, excluding patients with WHO recurrent abnormalities. Results Chromatin-splicing mutations were scored in 55/313 (17.6%) de novo AML patients (hereafter named molecular-sAML). The most frequently reported were KMT2A-PTD (45.5%), RUNX1 (44.4%) and ASXL1 (22.2%), while other mutations in the signature accounted for 5-17.5% of cases. Compared to de novo AML without chromatin-splicing mutations, patients with molecular-sAML and WHO-sAML were older (P Conclusions Chromatin-splicing mutational signature identifies a distinct high-risk group within de novo AML patients, which shows clinical characteristics and outcomes closer to sAML than to de novo AML patients. These data highlight the need to detect this molecular signature at diagnosis and support a molecular definition of sAML. Disclosures Ferrero: Novartis: Honoraria. Corradini:Celgene: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; Jazz Pharmaceutics: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Janssen: Honoraria, Other: Travel Costs; Roche: Honoraria; Sanofi: Honoraria; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs. Bassan:Incyte: Honoraria; Amgen Inc.: Honoraria; Pfizer: Honoraria; Shire: Honoraria. Rambaldi:Roche: Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding, Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau, travel support.