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Giulia Benevolo, Francesco Vassallo, Irene Urbino, Valentina Giai Division of Haematology, Città della Salute e della Scienza, Turin, ItalyCorrespondence: Giulia BenevoloHematology, Città della Salute e della Scienza, Corso Bramante 88/90, Turin, 10126, ItalyEmail gbenevolo@cittadellasalute.to.itAbstract: Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by exuberant red cell production leading to a broad range of symptoms that compromise quality of life and productivity of patients. PV reduces survival expectation, primarily due to thrombotic events, transformation to blast phase and post-PV myelofibrosis or to development of second cancers, which are associates with poor prognosis. Current therapeutic first line recommendations based on risk adapted classification divided patients into two groups, according to age (< or > 60 years) and presence of prior thrombotic events. Low-risk patients (age < 60 years and no prior history of thrombosis) should be treated with aspirin (81– 100 mg/d) and phlebotomy, to maintain hematocrit < 45%. High-risk patients (age > 60 years and/or prior history of thrombosis), in addition to aspirin and phlebotomies, should receive cytoreductive therapy in order to reduce thrombotic risk. Nowadays hydroxyurea still remains the cytoreductive agent of first choice, reserving Interferon to young patients or childbearing women. During the last years, ruxolitinib emerged as a new treatment in PV patients, as second line therapy: it appeared especially effective in patients with severe pruritus, symptomatic splenomegaly, or post-PV myelofibrosis symptoms. Currently, in PV treatment, several molecules have been tested or are under investigation. At present, the drug that has shown the most encouraging results is givinostat.Keywords: polycythemia vera, therapy, ruxolitinib, interferon, givinostat

BACKGROUND Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor. METHODS We conducted a phase 3, randomized, double-blind, placebo-controlled trial of the oral formulation of azacitidine (CC-486, a hypomethylating agent that is not bio-equivalent to injectable azacitidine), as maintenance therapy in patients with AML who were in first remission after intensive chemotherapy. Patients who were 55 years of age or older, were in complete remission with or without complete blood count recovery, and were not candidates for hematopoietic stem-cell transplantation were randomly assigned to receive CC-486 (300 mg) or placebo once daily for 14 days per 28-day cycle. The primary end point was overall survival. Secondary end points included relapse-free survival and health-related quality of life. RESULTS A total of 472 patients underwent randomization; 238 were assigned to the CC-486 group and 234 were assigned to the placebo group. The median age was 68 years (range, 55 to 86). Median overall survival from the time of randomization was significantly longer with CC-486 than with placebo (24.7 months and 14.8 months, respectively; P<0.001). Median relapse-free survival was also significantly longer with CC-486 than with placebo (10.2 months and 4.8 months, respectively; P<0.001). Benefits of CC-486 with respect to overall and relapse-free survival were shown in most subgroups defined according to baseline characteristics. The most common adverse events in both groups were grade 1 or 2 gastrointestinal events. Common grade 3 or 4 adverse events were neutropenia (in 41% of patients in the CC-486 group and 24% of patients in the placebo group) and thrombocytopenia (in 22% and 21%, respectively). Overall health-related quality of life was preserved during CC-486 treatment. CONCLUSIONS CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment. (Supported by Celgene; QUAZARAML-001 ClinicalTrials.gov number, NCT01757535.) [ABSTRACT FROM AUTHOR]

The article focuses on the use of the recombinant fusion protein luspatercept to treat patients with lower-risk myelodysplastic syndromes. It discusses the method and design of the randomized, double-blind, placebo-controlled trial conducted in eleven countries and notes that 229 patients with lower-risk myelodysplastic syndromes with ring sideroblasts were enrolled. Adverse events and transfusion independence are mentioned.

Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Patients with chronic myeloid leukemia (CML) treated with nilotinib or ponatinib may experience arterial occlusive events (AOEs). It is currently recommended to thoroughly assess cardiovascular risk factors before treating CML. We identified 455 consecutive CML adult patients, 335 treated with nilotinib and 120 with ponatinib; 380 patients without previous cardiovascular diseases or diabetes were stratified according to the Systematic Coronary Risk Evaluation (SCORE2) and SCORE2-Older Persons (SCORE2-OP). This updated algorithm from the European Society of Cardiology (ESC) estimates a 10-year risk of fatal and non-fatal cardiovascular diseases. It is based on sex, age, smoking habits, systolic blood pressure, non-high-density lipoprotein cholesterol, and European geographical region of cardiovascular risk. The SCORE2/SCORE2-OP algorithm translated more patients (50.2%) to the high-very high cardiovascular risk category than the previous SCORE (25.3%). Patients with a high to very high SCORE2/SCORE2-OP risk showed a significantly higher incidence rate of AOEs (69.2% vs. 46.5%, p < 0.001). The older SCORE was less specific in estimating AOEs in patients classified as low-intermediate risk (69.8 vs. 54.2%). In multivariate analysis, no associations were found between AOEs and gender, age, and type or dose of tyrosine kinase inhibitor. Only the SCORE2/SCORE2-OP risk was confirmed as a significant predictive factor (p = 0.028; hazard ratio = 2.2; 95% confidence interval = 1.1-4.5). Patients with AOEs required, in most cases, imaging diagnostic tests, additional drugs, and sometimes invasive procedures, increasing access to visits and hospital management. This real-life study suggested that the SCORE2 and SCORE2-OP charts could help identify cardiovascular fragility in CML patients providing them with more attention and a proper TKI selection., (© 2023. The Author(s).)

Background: The authors assessed the clinical utility of patient-reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy., Methods: The authors conducted an international prospective study that included patients with newly diagnosed, chronic-phase CML. Before clinical consultation, patients were provided a tablet computer to self-rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self-reported questionnaire. The proportions of optimal responders at 3 and 6 months were assessed according to the European LeukemiaNet criteria., Results: Between July 2020 and August 2021, 94 patients with a median age of 57 years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6-month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3 months and by 61 of 81 patients (75.3%) at 6 months., Conclusions: Patient-reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848)., (© 2023 American Cancer Society.)

Competing Interests: Declaration of Competing Interest None.

Purpose: In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia., Methods: In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10 3 /mm 3 ) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10 3 /mm 3 or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics., Results: From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ 2 = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times., Conclusion: Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.

An accurate estimation of AML prognosis is complex since it depends on patient-related factors, AML manifestations at diagnosis, and disease genetics. Furthermore, the depth of response, evaluated using the level of MRD, has been established as a strong prognostic factor in several AML subgroups. In recent years, this rapidly evolving field has made the prognostic evaluation of AML more challenging. Traditional prognostic factors, established in cohorts of patients treated with standard intensive chemotherapy, are becoming less accurate as new effective therapies are emerging. The widespread availability of next-generation sequencing platforms has improved our knowledge of AML biology and, consequently, the recent ELN 2022 recommendations significantly expanded the role of new gene mutations. However, the impact of rare co-mutational patterns remains to be fully disclosed, and large international consortia such as the HARMONY project will hopefully be instrumental to this aim. Moreover, accumulating evidence suggests that clonal architecture plays a significant prognostic role. The integration of clinical, cytogenetic, and molecular factors is essential, but hierarchical methods are reaching their limit. Thus, innovative approaches are being extensively explored, including those based on "knowledge banks". Indeed, more robust prognostic estimations can be obtained by matching each patient's genomic and clinical data with the ones derived from very large cohorts, but further improvements are needed.

Objectives: Chemotherapy-induced neutropenia in acute myeloid leukaemia (AML) is a risk factor for life-threatening infections. Early diagnosis and prompt interventions are associated with better outcomes, but the prediction of infection severity remains an open question. Recently, National Early Warning Score (NEWS) and quick sequential organ failure assessment (qSOFA) scores were proposed as warning clinical instruments predicting in-hospital mortality, but their role in the haematological context is still unknown., Methods: We retrospectively assess the predictive role of NEWS and qSOFA in a large and homogeneous cohort of adult AML patients treated with intensive chemotherapy. In a total of 1048 neutropenic episodes recorded in 334 consecutive patients, the scores were applied to predict outcomes on the same day of fever onset, and after 24 and 48 h from score calculation., Results: Both NEWS and qSOFA significantly predicted death, with more accuracy on the same day (NEWS AUROC 0.984 and qSOFA AUROC 0.969) and after 24 h (NEWS AUROC 0.928 and qSOFA AUROC 0.887), while remained moderately accurate after 48 h. Furthermore, also ICU admission was accurately predicted at fever onset and after 24 h., Conclusions: Both scores were useful tools in the management of post chemotherapy neutropenic febrile AML patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR. Methods: CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation. Results: After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found ( p = 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib ( p = 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss. Discussion: Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pacelli, Santoni, Sicuranza, Abruzzese, Giai, Crugnola, Annunziata, Galimberti, Iurlo, Luciano, Sorà, Fava, Bestoso, Marzano, Cartocci, Defina, Sammartano, Cencini, Raspadori and Bocchia.)

Background: Acute myeloid leukemia (AML) patients are at high risk of infections during post-induction neutropenia. Recently, the role of antibacterial prophylaxis has been reconsidered due to concerns about the emergence of multi-resistant pathogens. The aim of the present study was to evaluate the impact of avoiding prophylaxis on the rate of induction death (primary endpoint), neutropenic fevers, bloodstream infections (BSIs), resistant pathogens BSIs and septic shocks (secondary endpoints)., Methods: We performed a retrospective single-center study including 373 AML patients treated with intensive induction chemotherapy, divided into two groups according to levofloxacin prophylaxis given (group A, gA) or not (group B, gB)., Results: Neutropenic fever was observed in 91% of patients in gA and 97% in gB (OR 0.35, IC95% 0.08 - 1.52, p=0162). The rate of BSIs was 27% in gA compared to 34% in gB (OR 0.69, 0.38 - 1.25, p=0.222). The induction death rate was 5% in gA and 3% in gB (OR 1.50, 0.34 - 6.70, p=0.284). Fluoroquinolones (FQ) resistant pathogens were responsible for 59% of total BSIs in gA and 22% in gB (OR 5.07, 1.87 - 13.73, p=0.001); gram-negative BSIs due to multi-drug resistant organisms were 31% in gA and 36% in gB (OR 0.75, 0.15 - 3.70, p=0.727)., Conclusions: Despite its limitations (retrospective nature, single-center, different cohort size), the present study showed that avoiding levofloxacin prophylaxis was not associated with an increased risk of induction death. The cumulative incidence of neutropenic fever was higher in non-prophylaxis group, while no difference was observed for BSIs. In the prophylaxis group we observed a higher incidence of FQ-resistant organisms., Competing Interests: Competing interests: The authors declare no conflict of Interest.

Background: Accurate assessment of elderly acute myeloid leukemia (AML) patients is essential before intensive induction chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation. In this context, we investigated the capacity of three scores for frailty prediction., Methods: At diagnosis, 197 patients were clinically evaluated for appropriate treatment intensity. In parallel and independently, the G8-score, the Hematopoietic Stem Cell Index (HCT-CI) and the AML-score for CR were determined for each patient and analyzed with respect to overall survival (OS)., Results: The G8-score and the HCT-CI were able to significantly separate "fit" from "unfit" patients, <0.001 and p = 0.008. In univariate Cox models, the predictive role for OS was confirmed: for the G8-score (HR: 2.35, 95% CI 1.53-3.60, p < 0.001), the HCT-CI (HR: 1.91, 95% CI 1.17-3.11, p = 0.009) and the AML-score (HR: 5.59, 95% CI 2.04-15.31, p = 0.001), the latter was subsequently used to verify the cohort. In the multivariate Cox model, the results were confirmed for the G8- (HR: 2.03, p < 0.001) and AML-score (HR: 3.27, p = 0.001). Of interest, when combining the scores, their prediction capacity was significantly enhanced, p < 0.001., Conclusions: The G8-, the HCTCI and the AML-score represent valid tools in the frailty assessment of elderly AML patients at diagnosis.

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 9 /L at diagnosis (p = 0.036) and active smoking (p = 0.025) significantly and independently increased the risk of thrombosis, the latter particularly of arterial events. AML genetic profile did not affect thrombosis occurrence. Results were confirmed considering only thromboses occurring within day 100 from diagnosis. DIC score at diagnosis, but not thrombosis, was independently associated with reduced survival (p = 0.004). Previous VTE, platelet count above 100 × 10 9 /L and active smoking were the only factors associate with increased thrombotic risk in AML patients treated intensively, but further studies are needed to validate these results., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: Myelodysplastic Syndromes (MDS) are a heterogenous group of clonal hematopoietic stem cell malignancies. Previous studies showed that Reactive Oxygen Species (ROS) play a role in the pathogenesis and clinical evolution of MDS, contributing to Hematopoietic Stem and Progenitor Cells (HSPC) genetic instability. Less is known about ROS levels in the various sub-populations of MDS HSPC and how they correlate with clinical data in MDS patients. Our study aims to analyze ROS levels in MDS Hematopoietic Stem Cells (HSC), common myeloid progenitors (CMP), Granulocyte Macrophages Progenitors (GMP) and megakaryocyte-erythrocyte progenitors (MEP); afterwards, we looked at the relationship between ROS levels and clinical data., Methods: thirty-eight MDS and 27 Normal Bone Marrow (NBM) samples were collected; ROS levels were analyzed via multicolor flow cytometry., Results: In both NBM and MDS, HSC showed much higher ROS levels than progenitors (3 to 4 folds, p < 0.0001); HSC ROS were significantly more elevated in MDS-no excess blasts versus MDS with excess blasts and versus NBM. GMP from MDS-no excess blasts showed higher ROS compared to NBM GMP. The 3 MDS with Ringed Sideroblasts (RS) showed more elevated ROS in HSC and GMP compared to the not RS low/intermediate-1 MDS; the 2 monosomy 7 patients displayed higher ROS levels in each subpopulation compared to the normal karyotype MDS; the only del(5q) patient did not show relevant differences in ROS levels compared to the median of the normal karyotype MDS ROS. The 9 high transfusion burden patients exhibited higher ROS in HSC and GMP compared to NBM HSC and GMP. These data were not confirmed in low transfusion burden (n:2) and non-transfused patients (n:26). In low/intermediate-1 MDS, a direct correlation between ferritin values and ROS levels in progenitors, but not in HSC, was detected. Interestingly, low/intermediate-1 risk patients that are no longer responding to recombinant human erythropoietin (rh-EPO) showed higher ROS levels in GMP and HSC., Conclusions: Our data showed that ROS can play a role in the pathogenesis and maintenance of low and intermediate-1 risk MDS clone; ROS status can be influenced by several clinical factors as ferritin levels and rh-EPO treatment. In this scenario, high ROS levels can contribute to genetic instability and influence progression to AML. Further biological studies are needed to elucidate ROS role in MDS pathogenesis and analyze the possible benefit of antioxidant drugs added to the standard MDS treatments.

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.

Philadelphia negative Myeloproliferative Neoplasms (MPN) are a heterogeneous group of hematopoietic stem cell diseases. MPNs show different risk grades of thrombotic complications and acute myeloid leukemia evolution. In the last couple of decades, from JAK2 mutation detection in 2005 to the newer molecular trademarks studied through next generation sequencing, we are learning to approach MPNs from a deeper perspective. Here, we intend to elucidate the important factors affecting MPN clonal advantage and the reasons why some patients progress to more aggressive disease. Understanding these mechanisms is the key to developing new treatment approaches and targeted therapies for MPN 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 2 nd 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<0.001), while age (per year, HR=1.03; 95%CI 1.00-1.06; p=0.064), CCI (4-5 vs 2, HR=5.22; 95%CI 2.56-10.65; p<0.001), ELTS score (high risk vs low, HR=3.11; 95%CI 1.52-6.35, p=0.002) and 2GTKI vs IMA (HR=0.26; 95%CI 0.10-0.65, p=0.004) were associated to an increased risk of non-related CML mortality. The ELTS score showed a better discriminant ability than the Sokal score in all comparisons., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Specchia, Pregno, Breccia, Castagnetti, Monagheddu, Bonifacio, Tiribelli, Stagno, Caocci, Martino, Luciano, Pizzuti, Gozzini, Scortechini, Albano, Bergamaschi, Capodanno, Patriarca, Fava, Rege-Cambrin, Sorà, Galimberti, Bocchia, Binotto, Reddiconto, DiTonno, Maggi, Sanpaolo, De Candia, Giai, Abruzzese, Miggiano, La Barba, Pietrantuono, Guella, Levato, Mulas, Saccona, Rosti, Musto, Di Raimondo, Pane, Baccarani, Saglio and Ciccone.)

Purpose: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia., Methods: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI)., Results: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 10 9 /L, and absolute neutrophil count was 1.3 × 10 9 /L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI ( P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 10 9 /L., Conclusion: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of CC-486 in MDS is needed., Competing Interests: Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbvieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol-Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, Abbvie, Bristol-Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Valeria SantiniHonoraria: Celgene/Bristol-Myers Squibb, Novartis, Janssen-CilagConsulting or Advisory Role: Celgene/Bristol-Myers Squibb, Novartis, Menarini, Takeda, Pfizer, Geron, Gilead SciencesResearch Funding: CelgeneTravel, Accommodations, Expenses: Janssen-Cilag, Celgene Antonio AlmeidaHonoraria: Novartis, CelgeneConsulting or Advisory Role: Novartis, CelgeneSpeakers' Bureau: Novartis, CelgeneTravel, Accommodations, Expenses: Bristol-Myers Squibb Uwe PlatzbeckerHonoraria: Celgene/JazzConsulting or Advisory Role: Celgene/JazzResearch Funding: Amgen, Janssen, Novartis, BerGenBio, CelgenePatents, Royalties, Other Intellectual Property: part of a patent for a TFR-2 antibody (Rauner et al. Nature Metabolics 2019)Travel, Accommodations, Expenses: Celgene Lewis R. SilvermanResearch Funding: Celgene, MedImmune, Onconova Therapeutics, BayerPatents, Royalties, Other Intellectual Property: Patent for the combination of azacitidine and rigosertib Francesco BuccisanoConsulting or Advisory Role: NovartisSpeakers' Bureau: Novartis Pierre FenauxHonoraria: CelgeneResearch Funding: Celgene Rena BucksteinHonoraria: Celgene, Taiho PharmaceuticalConsulting or Advisory Role: CelgeneResearch Funding: Celgene, Takeda, Otsuka USUncompensated Relationships: Celgene/Jazz Maria Diez CampeloHonoraria: Celgene, NovartisConsulting or Advisory Role: Celgene, Takeda, Novartis, BerGenBioTravel, Accommodations, Expenses: Celgene, Novartis David ValcarcelConsulting or Advisory Role: Celgene, Amgen, GlaxoSmithKline, Novartis, Takeda, Pfizer, Bristol-Myers Squibb, Sanofi, Jazz Pharmaceuticals, SOBISpeakers' Bureau: Celgene, Novartis, Amgen, GlaxoSmithKline, Astellas Pharma, Pfizer, Jazz Pharmaceuticals, Sanofi/Aventis, Bristol-Myers SquibbTravel, Accommodations, Expenses: Celgene, Amgen, Pfizer, GlaxoSmithKline, Jazz Pharmaceuticals Paresh VyasStock and Other Ownership Interests: OxStemHonoraria: Celgene, Pfizer, Jazz Pharmaceuticals, Abbvie, Daiichi SankyoResearch Funding: Celgene, Forty SevenPatents, Royalties, Other Intellectual Property: Patent for flow cytometric detection of leukaemic stem cells Esther Natalie OlívaHonoraria: Celgene, Novartis, Amgen, Alexion PharmaceuticalsConsulting or Advisory Role: Amgen, Celgene, NovartisSpeakers' Bureau: Celgene, NovartisPatents, Royalties, Other Intellectual Property: Royalties for QOL-E instrument Jake ShorttConsulting or Advisory Role: Astellas Pharma, NovartisSpeakers' Bureau: Bristol-Myers SquibbResearch Funding: Astex Pharmaceuticals, Amgen, Celgene/Bristol-Myers Squibb Dietger NiederwieserConsulting or Advisory Role: Cellectis, Amgen, NovartisSpeakers' Bureau: NovartisResearch Funding: Daiichi Sankyo Moshe MittelmanHonoraria: CelgeneConsulting or Advisory Role: Onconova TherapeuticsSpeakers' Bureau: NovartisResearch Funding: Novartis, Takeda, Janssen-Cilag, Roche, Medison, Abbvie, Gilead Sciences Luana FianchiConsulting or Advisory Role: SanofiTravel, Accommodations, Expenses: Celgene Ignazia La TorreEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Jianhua ZhongEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Eric LailleEmployment: Bristol-Myers Squibb, Celgene, Catalent,Stock and Other Ownership Interests: Bristol-Myers Squibb, Moderna Therapeutics, Catalent Daniel Lopes de MenezesEmployment: Celgene, Bristol-Myers SquibbStock and Other Ownership Interests: Celgene, Bristol-Myers Squibb, NovartisPatents, Royalties, Other Intellectual Property: Published and Issues patents at BMS, Novartis Barry SkikneEmployment: Celgene/Bristol-Myers SquibbConsulting or Advisory Role: Celgene/Bristol-Myers SquibbResearch Funding: Daiichi Sankyo/UCB Japan C.L. BeachEmployment: Bristol-Myers SquibbStock and Other Ownership Interests: Bristol-Myers Squibb Aristoteles GiagounidisStock and Other Ownership Interests: Novartis, RocheHonoraria: Celgene, Amgen, NovartisConsulting or Advisory Role: CelgeneNo other potential conflicts of interest were reported.

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-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-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.