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Competing Interests: KW and MG declares funding, advisory board honoraria and other financial support (eg, travel support) from Amgen, AOP Orphan, Novartis, BMS, AbbVie, Pfizer, Roche, Janssen, Gilead, AstraZeneca, Lilly. SI declares honoraria from Pfizer, AOP Orphan, Novartis, Incyte and Abbvie, advisory board honoraria from Pfizer, Novartis, GSK and Incyte and other financial support (travel support) from Pfizer, Novartis, AOP Orphan and Alexion. SK reports funding from Novartis, Bristol-Myers Squibb, Janssen/Geron; advisory board honoraria from Pfizer, Incyte, Ariad, Novartis, AOP Pharma, BMS, Celgene, Geron, Janssen, CTI, Roche, Baxalta, Sanofi, Sierra Oncology, and GSK; patent for BET inhibitor at RWTH Aachen University; honoraria from Novartis, BMS, Celgene, Geron, Janssen, Pfizer, Incyte, Ariad, Shire, Roche, AOP Pharma, Sierra Oncology, Karthos, Imago Bioscience, and GSK; serves as an editor for HemaSphere; and other financial support (eg, travel support) from Alexion, Novartis, BMS, Incyte, Ariad, AOP Pharma, Baxalta, CTI, Pfizer, Sanofi, Celgene, Shire, Janssen, Geron, Abbvie, Karthos, Sierra Oncology, Imago Biosciences, and GSK. KD declares consulting/advisory role/honoraria from AbbVie, Celgene/BMS, Novartis, CTI BioPharma Corp, and Roche. J-JK declares consulting/advisory role/honoraria from AbbVie, BMS, Novartis, AOP Health. All the other authors have no conflicts of interest to disclose.

The coronavirus disease 2019 (COVID-19) pandemic indirectly resulted in missed therapeutic opportunities for many diseases. Here we focus on community-acquired respiratory viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) [respiratory syncytial virus, parainfluenza and influenza A], and highlight the pandemics impact on clinical trials to develop novel therapies for other severe respiratory viral infections. We retrospectively reviewed inclusion rates within respiratory antiviral clinical trials in comparison with all other clinical trials in our clinical investigations center, before and during the COVID-19 pandemic. As opposed to the remaining clinical trials developed within our unit, respiratory antiviral trials inclusion rates did not recover after the initial recruitment decrease observed across all trials during the first pandemic wave. These results were discussed in the context of non-COVID-19 respiratory viral infection rates within our center, showing a general decline in seasonal respiratory viruses spread since the COVID-19 pandemic onset. Virus epidemiology changes upon the wide SARS-CoV-2 expansion as well as the lifestyle changes globally adopted to prevent SARS-CoV-2 transmission could have therefore contributed to the negative impact of the COVID-19 pandemic on antiviral drug development. Our study highlights the peculiarity of respiratory antiviral drug development during the COVID-19 pandemic era and describes potential explanations for such drug development halting., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Myeloproliferative neoplasms (MPNs) are the most common etiologies of primary splanchnic vein thrombosis, present in almost forty percent of patients with Budd-Chiari syndrome or portal vein thrombosis. Diagnosis of MPNs can be difficult in these patients because key characteristics, such as elevated blood cell counts and splenomegaly, are confounded by portal hypertension or bleeding complications. In recent years, diagnostic tools have improved to provide more accurate diagnosis and classification of MPNs. Although bone marrow biopsy findings remain a major diagnostic criterion, molecular markers are playing an increasing role not only in diagnosis but also in better estimating prognosis. Therefore, though screening for JAK2V617F mutation should be the starting point of the diagnostic workup performed in all patients with splanchnic vein thrombosis, a multidisciplinary approach is needed to accurately diagnose the subtype of myeloproliferative neoplasm, recommend the useful additional tests (bone marrow biopsy, search for an additional mutation using targeted next-generation sequencing), and suggest the best treatment strategy. Indeed, providing a specific expert care pathway for patients with splanchnic vein thrombosis and underlying myeloproliferative neoplasm is crucial to determine the optimal management to reduce the risk of both hematological and hepatic complications., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Myelofibrosis (MF)-associated constitutional symptoms can severely impact health-related quality of life. Clinical trials in MF traditionally measure symptom response to treatment as a landmark endpoint of total symptom score (TSS) reduction ≥50% from baseline. However, this dichotomous assessment provides a limited view of clinically relevant symptomatic changes. Herein we evaluated longitudinal change from baseline in TSS over the continuous 24-week period and individual symptom scores to obtain a more comprehensive understanding of symptom benefits experienced by patients with MF receiving therapy., Methods: Longitudinal symptom change was evaluated using mixed-effect model repeated measure (MMRM) methodology with individual item-level analyses to complement the interpretation of the landmark symptom results in the completed phase III SIMPLIFY studies of momelotinib in MF. MMRM compared mean change in TSS from baseline with Week 24 using data from all patient visits. Generalized estimating equations were used to estimate item-level odds ratios using multiple predictive imputations for missing data., Results: Momelotinib and ruxolitinib groups reported similar overall symptom improvements, with a TSS difference of <1.5 points between groups for each post-baseline visit in SIMPLIFY-1. In SIMPLIFY-2, the improvement in TSS observed in momelotinib-treated patients was consistent with that observed in SIMPLIFY-1, whereas progressive TSS deterioration was observed with control. Item-level scores were heterogeneous in both studies. A similar and greater proportion of momelotinib-treated patients were categorized as "improved" or "stable" compared with control in SIMPLIFY-1 and SIMPLIFY-2, respectively. Odds ratios for between-group comparison ranged from 0.75 to 1.21 in SIMPLIFY-1, demonstrating similarity in likelihood of symptom improvement. In SIMPLIFY-2, the likelihood of symptom improvement in each item was higher in the momelotinib arm., Conclusions: These findings suggest that momelotinib provides clinically relevant symptom benefits in the JAK inhibitor-naïve and JAK inhibitor-exposed settings., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Myeloproliferative neoplasms are characterized by the acquisition at the hematopoietic stem cell level of driver mutations targeting the JAK/STAT pathway. In addition, they also often exhibit additional mutations targeting various pathways such as intracellular signalling, epigenetics, mRNA splicing or transcription. The natural history of myeloproliferative neoplasms is usually marked by a chronic phase of variable duration depending on the disease subtype, which can be followed by an accelerated phase or transformation towards more aggressive diseases such as myelofibrosis or acute leukemia. Besides, recent studies revealed important new information about the rates and mechanisms of sequential acquisition and selection of mutations in hematopoietic cells of myeloproliferative neoplasms. Better understanding of these events has been made possible in large part with the help of novel techniques that are now available to precisely decipher at the single cell level both the clonal architecture and the mutation-induced cell modifications. In this review, we will summarize the most recent knowledge about the mechanisms leading to clonal selection, how clonal architecture complexity can explain disease heterogeneity, and the impact of clonal evolution on clinical evolution., (© 2023. The Author(s).)

Myelofibrosis (MF) is a myeloproliferative disorder that exhibits considerable biological and clinical heterogeneity. At the two ends of the disease spectrum are the myelodepletive or cytopenic phenotype and the myeloproliferative phenotype. The cytopenic phenotype has a high prevalence in primary MF (PMF) and is characterized by low blood counts. The myeloproliferative phenotype is typically associated with secondary MF (SMF), mild anemia, minimal need for transfusion support, and normal to mild thrombocytopenia. Differences in somatic driver mutations and allelic burden, as well as the acquisition of non-driver mutations further influences these phenotypic differences, prognosis, and response to therapies such as JAK2 inhibitors. The outcome of patients with the cytopenic phenotype are comparatively worse and frequently pose a challenge to treat given the inherent exacerbation of cytopenias. Recent data indicate that an innate immune deregulated state that hinges on the myddosome-IRAK-NFκB axis favors the cytopenic myelofibrosis phenotype and offers opportunity for novel treatment approaches. We will review the biological and clinical features of the MF disease spectrum and associated treatment considerations., (© 2022. The Author(s).)

Background: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis., Methods: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting., Findings: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%])., Interpretation: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia., Funding: Sierra Oncology., Competing Interests: Declaration of interests SV reports consulting fees from Bristol Myers Squibb/Celgene, Incyte, Novartis, and Sierra Oncology. ATG reports consulting fees from AbbVie, Bristol Myers Squibb, Constellation/MorphoSys, CTI Biopharma, Novartis, Pharma Essentia, and Sierra Oncology. ATK reports grants from AbbVie, Bristol Myers Squibb, Prelude, and Sierra; consulting fees from AbbVie and Prelude; honoraria from Bristol Myers Squibb, Incyte, and Novartis; and participation on a data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb, CTI Biopharma, Geron, Imago, and Incyte. MLF reports payment for expert testimony from OncLive; meeting attendance or travel support from Novartis; and participation on a data safety monitoring board or advisory board for Bristol Myers Squibb, Novartis, and Sierra Oncology. DM reports research grants from Bristol Myers Squibb/Celgene, and Constellation Biopharma; honoraria from AbbVie, Celgene, Jazz, and Novartis; meeting attendance or travel support from Jazz; participation on a data safety monitoring board or advisory board for the ALL-RIC study; and leadership role with the European Society of Hematology and the EBMT Chronic Malignancies Working Party. AP reports honoraria, meeting attendance and travel support, and participation on an advisory board from Novartis Oncology. S-SY reports research grants from Kyowa Kirin and Roche/Genentech; consulting fees from Astellas, Amgen, Antengene, and Celgene; and honoraria from Novartis. VG reports consulting fees from AbbVie, Bristol Myers Squibb/Celgene, Constellation Biopharma, Novartis, Pfizer, and Sierra Oncology; honoraria from Bristol Myers Squibb, Constellation Biopharma, and Novartis; and participation on data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb/Celgene, Pfizer, and Roche. J-JK reports honoraria from Novartis; participation on a data safety monitoring board or advisory board for AbbVie, Bristol Myers Squibb, Incyte, and Novartis. NG reports consulting fees from Alexion, Bristol Myers Squibb/Celgene, Incyte, and Novartis; honoraria from Bristol Myers Squibb/Celgene, Janssen, and Novartis; leadership or fiduciary role for Alexion, Incyte, and Novartis; and meeting attendance or travel support from AbbVie, Genzyme, and Sanofi. FP reports research grant from Bristol Myers Squibb/Celgene; consulting fees from AbbVie, APO, Bristol Myers Squibb/Celgene, Karyopharm, Kyowa Kirin, MEI, Novartis, and Roche; and honoraria from Bristol Myers Squibb/Celgene, Janssen, and Novartis. CNH reports grant support from Bristol Myers Squibb/Celgene, Constellation Biopharma, and Novartis; consulting fees from AOP, Galecto, Keros, and Roche; honoraria from AbbVie, Celgene, Constellation Biopharma, CTI Biopharma, Janssen, and Novartis; participation in data safety monitoring board or advisory board for AbbVie, AOP, CTI Biopharma, Geron, Promedior, Roche, and Sierra Oncology; and leadership or fiduciary role in the European Hematology Association and MPN Voice. BJK, SR, and RD report employment and stock or stock options at Sierra Oncology. JK reports employment and stock or stock options at Sierra Oncology and former employment and stock and stock options from Gilead. RM reports research grants from AbbVie, Celgene, CTI Biopharma, Constellation Biopharma, Genotech, Incyte, Promedior, Samus, and the Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174); and consulting fees from Constellation Biopharma, LaJolla, Novartis, and Sierra Oncology. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Myelofibrosis (MF) is a clonal hematologic malignancy with progressive bone marrow fibrosis. Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival. The only curative treatment for MF is allogenic stem cell transplantation; however, few patients are eligible. Disease management strategies for MF-related anemia have limited effectiveness, and Janus kinase (JAK) inhibitors may induce or worsen related anemia. Thus, there is a significant unmet need for the treatment of patients with MF-related anemia. This review summarizes current and emerging treatments for anemia in MF, including luspatercept and KER-050 (transforming growth factor-β ligand traps), momelotinib and pacritinib (JAK inhibitors), pelabresib (a bromodomain extra-terminal domain inhibitor), PRM-151 (an antifibrotic agent), imetelstat (a telomerase inhibitor), and navitoclax (a BCL-2/BCL-xL inhibitor). Therapeutic combinations with ruxolitinib may offer another treatment approach., Competing Interests: Declaration of Competing Interest Francesco Passamonti has been a member of a speakers’ bureau for AbbVie, BMS, Celgene, Janssen, and Novartis; has consulted for AbbVie, AOP Orphan, BMS, Celgene, Janssen, Karyopharma, Kyowa Kirin, MEI Pharma, Novartis, and Roche; and has received research grants from BMS. Claire N. Harrison has received honoraria from AbbVie, AOP Orphan, BMS, Constellation Pharmaceuticals, CTI BioPharma Corp, Janssen, Novartis, and Sierra Oncology; has consulted for AbbVie, AOP Orphan, CTI BioPharma Corp, Galecto, Geron, and Sierra Oncology; has received support for travel from BMS and Novartis; has been a member of an advisory board for Galecto; and has received research grants from BMS, Constellation Pharmaceuticals, and Novartis. Ruben A. Mesa has consulted for Constellation Pharmaceuticals, La Jolla Pharmaceutical, Novartis, Pharma, and Sierra Oncology; and has received research grants from AbbVie, Celgene, Constellation Pharmaceuticals, CTI BioPharma Corp, Genotech, Incyte, Mays Cancer Center P30 Cancer Center Support Grant from the National Cancer Institute (CA054174), Promedior, and Samus. Jean-Jacques Kiladjian received honoraria from Novartis; and has been a member of an advisory board for AbbVie, AOP Orphan, BMS, Incyte, and Novartis. Alessandro M. Vannucchi has been a member of an advisory board for AbbVie, AOP Orphan, Blueprint Medicines, Celgene, Incyte, and Novartis; and has received lecture fees from AbbVie, AOP Orphan, Blueprint Medicines, BMS, GSK, Incyte, and Novartis. Srdan Verstovsek has received research support for the conduct of clinical studies from BMS., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Patients with myelofibrosis (MF) who discontinue ruxolitinib due to progression/resistance have poor prognoses. JAK inhibitors control symptoms and reduce spleen volumes with limited impact on underlying disease pathophysiology. Murine double minute 2 (MDM2), a negative regulator of p53, is overexpressed in circulating malignant CD34 + MF cells. The oral MDM2 inhibitor navtemadlin (KRT-232) restores p53 activity to drive apoptosis of wild-type TP53 tumor cells by inducing expression of pro-apoptotic Bcl-2 family proteins. Navtemadlin demonstrated promising clinical and disease-modifying activity and acceptable safety in a phase II study in patients with relapsed/refractory MF. The randomized phase III BOREAS study compares the efficacy and safety of navtemadlin to best available therapy in patients with MF that is relapsed/refractory to JAK inhibitor treatment.

Despite much of the past 2 years being engulfed by the devastating consequences of the SAR-CoV-2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show-cased at the 15th Post-American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th-10th December 2020 and 7th-10th October 2021, respectively. The inaugural Post-ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases., (© 2022 John Wiley & Sons Ltd.)

Patients with Philadelphia-negative myeloproliferative neoplasms are at high risk of thrombotic events (TEs). Predisposing factors have been identified in essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (primary MF, PMF), while yet not recognized in post PV/ET-MF (known as secondary MF, SMF). Within the 1258 SMF of the MYSEC (MYelofibrosis SECondary to PV and ET) dataset, 135 (10.7%) developed a TE at a median follow-up of 3.5 years (range, 1-21.4), with an incidence of 2.3% patients per year. Venous events accounted for two-thirds of the total. Cox multivariable analysis, supported by Fine-Gray models with death as competitive risk, showed that being on cytoreductive therapy at time of SMF evolution is associated with an absolute risk reduction of thrombosis equal to 3.3% within 3 years. Considering individually cytoreductive therapies, univariate regression model found that both conventional cytoreduction, mainly hydroxyurea, (HR 0.41, 95% CI: 0.26-0.65, p = 0.0001) and JAK inhibitors, mostly ruxolitinib, (HR 0.50, 95% CI: 0.24-1.02, p = 0.05) were associated with fewer thrombosis. Our study informs treating physicians of a non-low incidence of TEs in post PV/ET-MF and of the potential protective role of cytoreductive therapy in terms of thrombotic events., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response., Methods: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability., Discussion: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population., Trial Registration: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421)., (© 2022. The Author(s).)

The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Thrombocytopenia is a common feature of myelofibrosis (MF), a myeloproliferative neoplasm driven by dysregulated JAK/STAT signaling; however, pivotal trials assessing the efficacy of ruxolitinib (a JAK1/2 inhibitor) excluded MF patients with low platelet counts (<100 × 10 9 /L)., Objectives: Determination of the maximum safe starting dose (MSSD) of ruxolitinib was the primary endpoint, with long-term safety and efficacy as secondary and exploratory endpoints, respectively., Design: EXPAND (NCT01317875) was a phase 1b, open-label, ruxolitinib dose-finding study in patients with MF and low platelet counts (50 to <100 × 10 9 /L)., Methods: Patients were stratified according to baseline platelet count into stratum 1 (S1, 75 to <100 × 10 9 /L) or stratum 2 (S2, 50 to <75 × 10 9 /L). Previous analyses established the MSSD at 10 mg twice daily (bid); long-term results are reported here., Results: Of 69 enrolled patients, 38 received ruxolitinib at the MSSD (S1, n  = 20; S2, n  = 18) and are the focus of this analysis. The incidence of adverse events was consistent with the known safety profile of ruxolitinib, with thrombocytopenia (S1, 50%; S2, 78%) and anemia (S1, 55%; S2, 44%) the most frequently reported adverse events and no new or unexpected safety signals. Substantial clinical benefits were observed for patients in both strata: 50% (10/20) and 67% (12/18) of patients in S1 and S2, respectively, achieved a spleen response (defined as ⩾50% reduction in spleen length from baseline) at any time during the study., Conclusion: The final safety and efficacy results from EXPAND support the use of a 10 mg bid starting dose of ruxolitinib in patients with MF and platelet counts 50 to <100 × 10 9 /L., Registration: ClinicalTrials.gov NCT01317875., Competing Interests: Competing interests: PG reports payment of honoraria from Abbvie and Novartis; travel support from Abbvie, Novartis and Sanofi; participation in advisory boards from Abbvie and Novartis. JJK reports consulting fees from Abbvie and Novartis; payment of honoraria from AOP Orphan and Novartis; participation in advisory boards from BMS/Celgene and Incyte. AMV reports consulting fees from Abbvie, Blueprint, BMS/Celgene, Incyte, Novartis and Roche; payment of honoraria from Abbvie, BMS and Novartis. HM reports payment of honoraria from Novartis. LP reports payment of honoraria from Novartis. GH reports payment of honoraria from Novartis. SV reports research grants from AstraZeneca, Blueprint, Celgene, CTI BioPharma Corp., Genentech, Gilead, Incyte, Italpharma, Novartis, NS Pharma, Pharma Essentia, Promedior, Protagonist Therapeutics, Roche, Sierra Oncology; consulting fees from Celgene, Constellation, Incyte, Novartis, Pragmatist, Sierra. FBoyer reports consulting fees from Novartis. DN reports research funding from Daiichi; participation on speaker’s bureau from Amgen and Novartis; membership on an entity’s board of directors or advisory committees from Cellectis. AML reports institutional grants from Abbvie, Archigen, Beigene, Celgene, Fibrogen, GSK, Incyte, Janssen, Karyopharm, Morphosys, Novartis, Onconova, Oncopeptides, Pfizer, Roche, Sanofi, Servier, Takeda, Verastem; consulting fees from Incyte; payment of honoraria from Abbvie, BMS, Celgene, IQVIA, Janssen, Servier; travel support from Abbvie, BMS, Celgene, IQVIA, Janssen, Novartis, Roche, Sanofi, Takeda, Verastem; participation in advisory boards from Amgen and Servier. CH reports institutional grants from BMS/Celgene, Constellation Pharmaceuticals and Novartis; consulting fees from Novartis; payment of honoraria from Abbvie, AOP Orphan Pharmaceuticals, BMS/Celgene, CTI BioPharma Corp, Incyte, Janssen and Novartis; participation in advisory boards from AOP Orphan Pharmaceuticals, Celgene, Constellation Pharmaceuticals, CTI BioPharma Corp, Galecto, Geron, Incyte, Keros, Novartis, Promedior, Roche, Sierra Oncology. PR, MW, DK, and KS are employers and stockholders of Novartis. PAWTB reports participation in advisory boards from BMS/Celgene. HG reports research grants from AOP Orphan and Novartis; consulting fees from AOP Orphan, Myelopro, Novartis; payment of honoraria from AOP Orphan, BMS/Celgene, Janssen, Novartis. FBarraco, MD, and EP report no conflicts of interest., (© The Author(s), 2022.)

Janus kinase inhibitors (JAKi) approved for myelofibrosis provide spleen and symptom improvements but do not address anemia, a negative prognostic factor. Momelotinib, an inhibitor of ACVR1/ALK2, JAK1 and JAK2, demonstrated activity against anemia, symptoms, and splenomegaly in the phase 3 SIMPLIFY trials. Here, we report mature overall survival (OS) and leukemia-free survival (LFS) from both studies, and retrospective analyses of baseline characteristics and efficacy endpoints for OS associations. Survival distributions were similar between JAKi-naïve patients randomized to momelotinib, or ruxolitinib then momelotinib, in SIMPLIFY-1 (OS HR = 1.02 [0.73, 1.43]; LFS HR = 1.08 [0.78, 1.50]). Two-year OS and LFS were 81.6% and 80.7% with momelotinib and 80.6% and 79.3% with ruxolitinib then momelotinib. In ruxolitinib-exposed patients in SIMPLIFY-2, two-year OS and LFS were 65.8% and 64.2% with momelotinib and 61.2% and 59.7% with best available therapy then momelotinib (OS HR = 0.98 [0.59, 1.62]; LFS HR = 0.97 [0.59, 1.60]). Baseline transfusion independence (TI) was associated with improved survival in both studies (SIMPLIFY-1 HR = 0.474, p = 0.0001; SIMPLIFY-2 HR = 0.226, p = 0.0005). Week 24 TI response in JAKi-naïve, momelotinib-randomized patients was associated with improved OS in univariate (HR = 0.323; p < 0.0001) and multivariate (HR = 0.311; p < 0.0001) analyses. These findings underscore the importance of achieving or maintaining TI in myelofibrosis, supporting the clinical relevance of momelotinib's pro-erythropoietic mechanism of action, and potentially informing treatment decision-making., (© 2022. The Author(s).)

Myelofibrosis (MF) is a clonal myeloproliferative neoplasm, typically associated with disease-related symptoms, splenomegaly, cytopenias and bone marrow fibrosis. Patients experience a significant symptom burden and a reduced life expectancy. Patients with MF receive ruxolitinib as the current standard of care, but the depth and durability of responses and the percentage of patients achieving clinical outcome measures are limited; thus, a significant unmet medical need exists. Pelabresib is an investigational small-molecule bromodomain and extraterminal domain inhibitor currently in clinical development for MF. The aim of this article is to describe the design of the ongoing, global, phase III, double-blind, placebo-controlled MANIFEST-2 study evaluating the efficacy and safety of pelabresib and ruxolitinib versus placebo and ruxolitinib in patients with JAKi treatment-naive MF. Clinical Trial Registration: NCT04603495 (ClinicalTrials.gov).

Background: In the PEGASUS trial, the complement C3 inhibitor, pegcetacoplan, showed superiority to eculizumab in improving haematological outcomes in adult patients with paroxysmal nocturnal haemoglobinuria and suboptimal response to eculizumab at 16 weeks. The aim of the open-label period was to evaluate the long-term efficacy and safety of pegcetacoplan through to 48 weeks., Methods: PEGASUS was a phase 3, randomised, open-label, active-comparator controlled trial conducted in 44 centres in Australia, Belgium, Canada, France, Germany, Japan, Russia, South Korea, Spain, the UK, and the USA. Eligible participants were aged 18 years or older, had paroxysmal nocturnal haemoglobinuria, and had a haemoglobin concentration of less than 10·50 g/dL after 3 months or longer of stable eculizumab treatment. After a 4-week run-in with eculizumab plus pegcetacoplan, patients were randomly assigned (1:1) by interactive response technology to pegcetacoplan (1080 mg subcutaneously twice weekly) or eculizumab (according to their regimen at enrolment) for 16 weeks and could continue to the open-label period (32 weeks of pegcetacoplan monotherapy [pegcetacoplan-to-pegcetacoplan] or 28 weeks of pegcetacoplan monotherapy [eculizumab-to-pegcetacoplan]). Randomisation was stratified by platelet count and number of previous blood transfusions. The primary endpoint was change from baseline in haemoglobin at week 16, which has previously been reported. The outcomes of the open-label period (week 16 to week 48) are reported here. At 48 weeks, efficacy (including mean haemoglobin concentration and quality of life measured on the Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue scale) was assessed in the intention-to-treat population and safety was assessed per protocol. This trial was registered with ClinicalTrials.gov, NCT03500549, and has been completed., Findings: Between June 14, 2018, and Nov 14, 2019, 80 patients were randomly assigned to receive treatment with pegcetacoplan (41 patients) or eculizumab (39 patients). Most participants were women (49 [61%]) and 31 (39%) were men; 12 (15%) were Asian, two (3%) were Black, 49 (61%) were White, and 17 (21%) were another race or did not report their race. The open-label period had 77 participants (38 pegcetacoplan-to-pegcetacoplan, 39 eculizumab-to-pegcetacoplan). Patients in the pegcetacoplan-to-pegcetacoplan group maintained high mean haemoglobin concentrations between 16 weeks (11·54 g/dL [SD 1·96]) and 48 weeks (11·30 g/dL [1·77]; p=0·14). Patients in the eculizumab-to-pegcetacoplan group had significantly greater mean haemoglobin concentrations at 48 weeks (11·57 g/dL [2·21]) versus 16 weeks (8·58 g/dL [0·96]; p<0·0001). Clinically meaningful improvements in FACIT-Fatigue scores were observed at 48 weeks, with a mean change from baseline for all patients receiving pegcetacoplan monotherapy of 9·89 points (SD 9·63), for patients in the pegcetacoplan-to-pegcetacoplan group mean 10·14 points (9·06), and for patients in the eculizumab-to-pegcetacoplan group mean 9·62 points (10·34). During the entire study period, 13 (16%) of 80 patients discontinued treatment (three [7%] of 41 through to week 16 due to breakthrough haemolysis, and ten [13%] of 77 due to severe treatment-emergent adverse events) and 18 patients (eight pegcetacoplan-to-pegcetacoplan, ten eculizumab-to-pegcetacoplan) had at least one serious treatment-emergent adverse event during the open-label period, four were considered to be related to pegcetacoplan treatment. The most common treatment-emergent adverse events (in ≥10% patients) among both pegcetacoplan-treated groups during the open-label period were injection site reactions (in 20 [26%] of 77 patients), haemolysis (15 [19%]), nasopharyngitis (12 [16%]), and diarrhoea (ten [13%]). No treatment-related deaths occurred throughout the duration of the study., Interpretation: The durability of improved haematological outcomes and favourable safety profile over 48 weeks of treatment suggests that pegcetacoplan has the potential to improve treatment benefit and alter treatment goals in patients with paroxysmal nocturnal haemoglobinuria., Funding: Apellis Pharmaceuticals., Competing Interests: Declaration of interests RPdL reports consultancy at Novartis, Pfizer, Amgen, Alexion Pharmaceuticals, Apellis Pharmaceuticals, and Swedish Orphan Biovitrum; honoraria from Novartis, Pfizer, Amgen, Alexion Pharmaceuticals, Apellis Pharmaceuticals, and Swedish Orphan Biovitrum; research funding from Novartis, Pfizer, Amgen, and Alexion Pharmaceuticals; and grants from Alexion Pharmaceuticals, Amgen, Novartis, and Pfizer. JS reports consultancy at Novartis, Alexion Pharmaceuticals, and Apellis Pharmaceuticals; honoraria from Takeda, Pfizer, Novartis, Prevail Therapeutics, and Alexion Pharmaceuticals; speakers’ bureau at Takeda, Pfizer, Novartis, and Alexion Pharmaceuticals; and membership on an entity's board of directors or advisory committees at Prevail Therapeutics and Alexion Pharmaceuticals. ICW reports consultancy at Alexion Pharmaceuticals, Apellis Pharmaceuticals, Biocryst, Novartis, and Sanofi Genxyme; honoraria from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Biocryst, Novartis, and Sanofi Genxyme; and speakers’ bureau at Alexion Pharmaceuticals. AR reports personal fees from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Kira, Novartis, Roche, Swedish Orphan Biovitrum, Sanofi, Bioverativ, and Grifols; and grants from Roche. BH reports honoraria and advisory board member at Novartis, Roche, Alexion Pharmaceuticals, and Apellis Pharmaceuticals. JP reports consultancy and honoraria at Blueprint Medicines, Amgen, F Hoffmann-La Roche, MSD, Bristol Myers Squibb, Alexion Pharmaceuticals, Novartis, Pfizer, Gilead, Boehringer Ingelheim, Swedish Orphan Biovitrum, and Apellis Pharmaceuticals; and honoraria from SwixxBiopharma. KU reports grants from Alexion Pharmaceuticals, Apellis Pharmaceuticals, Chugai, and Novartis; and personal fees from Novartis, Chugai, and Alexion Pharmaceuticals. MG reports consultancy at Biocryst and Regeneron Pharmaceuticals; honoraria from Alexion Pharmaceuticals and Swedish Orphan Biovitrum; advisory board member at Novartis, Biocryst, Alexion Pharmaceuticals, and Swedish Orphan Biovitrum; and educational work sponsored by Apellis with unrestricted grant paid to Medscape. J-JK reports membership on an entity's board of directors or advisory committees at AbbVie, Novartis, Bristol Myers Squibb, and AOP Orphan. CMdC reports consultancy at Apellis Pharmaceuticals; honoraria from Novartis, Alexion Pharmaceuticals, Biocryst, and Apellis Pharmaceuticals; and research funding from Alexion Pharmaceuticals, and Apellis Pharmaceuticals. TA reports current employment and current equity holder at Apellis Pharmaceuticals. MA-A reports current employment at Apellis Pharmaceuticals. PD reports being a founder, Chief Scientific Officer, and current equity holder at Apellis Pharmaceuticals. CF and FG report current employment and current equity holder at Apellis Pharmaceuticals. AMR reports consultancy at Novartis and Amyndas; membership on an entity's board of directors or advisory committees at Novartis, Alexion Pharmaceuticals, Samsung, Biocryst, Achillion, Roche, Sanofi, and Apellis Pharmaceuticals; and grants from Alexion Pharmaceuticals, Novartis, Alnylam, and Rapharma. PH reports consultancy at Alexion Pharmaceuticals, Apellis Pharmaceuticals, AbbVie, AstraZeneca, Janssen, and Roche; research funding from Alexion Pharmaceuticals, Apellis Pharmaceuticals, AbbVie, Gilead, Janssen, Pharmacyclics, and Roche; and speakers bureau at Alexion Pharmaceuticals, Apellis Pharmaceuticals, AbbVie, AstraZeneca, Janssen, and Roche. HN declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Imetelstat, a first-in-class telomerase inhibitor, demonstrated meaningful clinical benefit including a robust symptom response rate and potential overall survival benefit in IMbark, a phase II study in intermediate-2 or high-risk myelofibrosis (MF) patients who have relapsed after or are refractory to JAK inhibitors. We describe the rationale and design for the phase III trial, IMpactMF (NCT04576156), an open-label evaluation of imetelstat versus best available therapy, excluding JAK inhibitors, in MF patients refractory to JAK inhibitor. Imetelstat 9.4 mg/kg is administered as an intravenous infusion every 21 days. Primary objective is to assess overall survival. Secondary objectives include symptom and spleen responses, progression-free survival, clinical response assessment, bone marrow fibrosis reduction, safety and pharmacokinetics. Biomarker, cytogenetics and mutation analyses will be performed.

Fedratinib, an oral Janus kinase-2 (JAK2) inhibitor, is approved for patients with myelofibrosis (MF) and platelet counts ≥50 × 10 9 /l, based on outcomes from the phase 3, placebo-controlled JAKARTA trial in JAK-inhibitor-naïve MF, and the phase 2, single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. We evaluated the efficacy and safety of fedratinib 400 mg/day in patients with baseline platelet counts 50 to <100 × 10 9 /l ("Low-Platelets" cohorts), including 14/96 patients (15%) in JAKARTA and 33/97 (34%) in JAKARTA2. At 24 weeks, spleen response rates were not significantly different between the Low-Platelets cohort and patients with baseline platelet counts ≥100 × 10 9 /l ("High-Platelets" cohort), in JAKARTA (36% vs. 49%, respectively; p = 0.37) or JAKARTA2 (36% vs. 28%; p = 0.41). Symptom response rates were also not statistically different between the Low- and High-Platelets cohorts. Fedratinib was generally well-tolerated in both platelet-count cohorts. New or worsening thrombocytopaenia was more frequent in the Low-Platelets (44%) versus the High-Platelets (9%) cohort, but no serious thrombocytopaenia events occurred. Thrombocytopaenia was typically managed with dose modifications; only 3/48 Low-Platelets patients discontinued fedratinib due to thrombocytopaenia. These data indicate that fedratinib 400 mg/day is safe and effective in patients with MF and low pretreatment platelet counts, and no initial fedratinib dose adjustment is required for these patients., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Myeloproliferative neoplasms (MPN) are mainly sporadic but inherited variants have been associated with higher risk development. Here, we identified an EPOR variant (EPOR P488S ) in a large family diagnosed with JAK2 V617F -positive polycythaemia vera (PV) or essential thrombocytosis (ET). We investigated its functional impact on JAK2 V617F clonal amplification in patients and found that the variant allele fraction (VAF) was low in PV progenitors but increase strongly in mature cells. Moreover, we observed that EPOR P488S alone induced a constitutive phosphorylation of STAT5 in cell lines or primary cells. Overall, this study points for searching inherited-risk alleles affecting the JAK2/STAT pathway in MPN., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Thrombocytopenia is common in patients with myelofibrosis (MF) and is a well-established adverse prognostic factor. Both of the approved Janus kinase (JAK) inhibitors, ruxolitinib and fedratinib, can worsen thrombocytopenia and have not been evaluated in patients with severe thrombocytopenia (platelet counts <50×109/L). Pacritinib, a novel JAK2/interleukin-1 receptor-associated kinase 1 inhibitor, has been studied in two phase III trials (PERSIST-1 and PERSIST- 2), both of which enrolled patients with MF and severe thrombocytopenia. In order to better characterize treatment outcomes for this population with advanced disease, we present a retrospective analysis of efficacy and safety data in the 189 patients with severe thrombocytopenia treated in the PERSIST studies. The proportion of patients in the pacritinib group meeting efficacy endpoints was greater than in the BAT group for ≥35% spleen volume reduction (23% vs. 2%, P=0.0007), ≥50% modified Total Symptom Score reduction (25% vs. 8%, P=0.044), and self-reported symptom benefit ("much" or "very much" improved; 25% vs. 8%, P=0.016) at the primary analysis time point (week 24). The adverse event profile of pacritinib was manageable, and dose modification was rarely required. There was no excess in bleeding or death in pacritinib-treated patients. These results indicate that pacritinib is a promising treatment for patients with MF who lack safe and effective therapeutic options due to severe thrombocytopenia.

Background: Access to clinical trials and especially early-phase trials (ECT) is an important issue in geriatric oncology. As cancer can be considered an age-related disease because the incidence of most cancers increases with age, new drugs should also be evaluated in older patients to assess their safety and efficacy. The EGALICAN-2 study was primarily designed to identify social and/or regional inequalities regarding access to ECT. We focused on the factors of inequalities in access to ECT in older patients., Patients and Methods: During a 1-year period (2015-2016), a survey was conducted in 11 early-phase units certified by the French National Cancer Institute., Results: A total of 1319 patients were included in the analyses: 1086 patients (82.3%) were <70 years and 233 patients (17.7%) were >70 years. The most common tumor types at referral in older patients were gastrointestinal (19.3%), hematological (19.3%), and thoracic tumors (18.0%). Most patients referred to the phase I unit had signed informed consent and the rate was similar across age (92.7% in younger patients versus 90.6% in older patients; P = 0.266). The rate of screening failure was also similar across age (28.5% in younger patients versus 24.3% in older patients; P = 0.219). Finally, in older patients, univariate analyses showed that initial care received in the hospital having a phase I unit was statistically associated with first study drug administration (odds ratio 0.49, 90% confidence interval 0.27-0.88; P = 0.045)., Conclusions: Older patients are underrepresented in early clinical trials with 17.7% of patients aged ≥70 years compared with the number of new cases of cancer in France (50%). However, when invited to participate, older patients were prone to sign informed consent., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856., (© 2022 by The American Society of Hematology.)

The mechanisms of transformation of chronic myeloproliferative neoplasms (MPN) to leukemia are largely unknown, but TP53 mutations acquisition is considered a key event in this process. p53 is a main tumor suppressor, but mutations in this protein per se do not confer a proliferative advantage to the cells, and a selection process is needed for the expansion of mutant clones. MDM2 inhibitors may rescue normal p53 from degradation and have been evaluated in a variety of cancers with promising results. However, the impact of these drugs on TP53-mutated cells is underexplored. We report herein evidence of a direct effect of MDM2 inhibition on the selection of MPN patients' cells harboring TP53 mutations. To decipher whether these mutations can arise in a specific molecular context, we used a DNA single-cell approach to determine the clonal architecture of TP53-mutated cells. We observed that TP53 mutations are late events in MPN, mainly occurring in the driver clone, whereas clonal evolution frequently consists of sequential branching instead of linear consecutive acquisition of mutations in the same clone. At the single-cell level, the presence of additional mutations does not influence the selection of TP53 mutant cells by MDM2 inhibitor treatment. Also, we describe an in vitro test allowing to predict the emergence of TP53 mutated clones. Altogether, this is the first demonstration that a drug treatment can directly favor the emergence of TP53-mutated subclones in MPN., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The COVID-19 pandemic has created enormous challenges for the clinical management of patients with hematological malignancies (HMs), raising questions about the optimal care of this patient group., Methods: This consensus manuscript aims at discussing clinical evidence and providing expert advice on statements related to the management of HMs in the COVID-19 pandemic. For this purpose, an international consortium was established including a steering committee, which prepared six working packages addressing significant clinical questions from the COVID-19 diagnosis, treatment, and mitigation strategies to specific HMs management in the pandemic. During a virtual consensus meeting, including global experts and lead by the European Society for Medical Oncology and the European Hematology Association, statements were discussed and voted upon. When a consensus could not be reached, the panel revised statements to develop consensual clinical guidance., Results and Conclusion: The expert panel agreed on 33 statements, reflecting a consensus, which will guide clinical decision making for patients with hematological neoplasms during the COVID-19 pandemic., Competing Interests: DIsclosure CB reports honoraria from Roche/Genentech, Janssen, BeiGene, Novartis, Pfizer, Incyte, AbbVie, Gilead Sciences, Celltrion, MorphoSys, Regeneron; he reports consulting or advisory role: Gilead Sciences, Janssen, Roche, Pfizer, BeiGene, Celltrion, AbbVie, Incyte, Regeneron, MorphoSys, Novartis; he reports speaker’s engagement: Roche, Janssen, BeiGene, Celltrion, AbbVie, Pfizer, Gilead Sciences; he reports research funding: Roche/Genentech, Janssen, Celltrion, Merck Sharp & Dohme (MSD), Pfizer, Amgen. MD reports honoraria as Advisory Board Member of AstraZeneca, Bayer, BeiGene, Celgene, Genmab, Gilead, Incyte, Janssen, Lilly, MorphoSys, Novartis, Roche; he reports honoraria for speaker’s engagement from Amgen, AstraZeneca, Bayer, Celgene, Gilead, Janssen, Novartis, Roche; he reports institutional research grants from AbbVie, Bayer, Gilead, Celgene, Janssen, Roche. AA-L has declared no conflicts of interest. JA reports personal financial interests as advisory board and invited speaker from Incyte, advisory board from Mallinckrodt, advisory board and invited speaker from Novartis, advisory board and invited speaker from Pfizer; she reports non-financial interests as principal investigator from Incyte, principal investigator from Novartis. LA received advisory honoraria from Roche, Celgene, Janssen-Cilag, Verastem, Eusa Pharma, Incyte, ADC Therapeutics and Gilead; research support from Gilead, and travel expenses from Roche, Celgene, Janssen-Cilag, and Eusa Pharma; speakers bureau from Novartis. CB has declared no conflicts of interest. LB reports Advisory Committee activities for AbbVie, Amgen, Astellas, Bristol Myers Squibb (BMS), Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics and has research support from Bayer and Jazz Pharmaceuticals. PC has declared no conflicts of interest. MGDP has declared no conflicts of interest. MD reports personal fees from Amgen, personal fees from Takeda, personal fees from Janssen, personal fees from BeiGene, personal fees from BMS, outside the submitted work. SD reports personal financial interests as advisory board, invited speaker, fellow funding, and coordinating PI from BeiGene, writing engagement from Karger, advisory board and coordinating PI from Sanofi, funding, and other from Janssen; she reports non-financial interests as advisory role at British Society for Haematology Lymphoma Special Interest Group, advisory role at Lymphoma Action, member of board of directors at WMUK Charity. HTE has declared no conflicts of interest. RF reports honoraria for advisory boards and/or speaker bureau from Janssen, Gilead, AbbVie, Amgen, Novartis, Roche, Incyte, Pfizer, all outside the submitted work. PG reports grants and personal fees from AbbVie, grants and personal fees from Acerta/AstraZeneca, personal fees from BeiGene, personal fees from Celgene/Juno/BMS, grants and personal fees from Janssen, personal fees from Lilly/Loxo, personal fees from MEI, personal fees from Roche, personal fees from Sanofi, personal fees from ArQule/MSD, outside the submitted work; MGdS reports grants, personal fees, non-financial support and other from Gilead Sciences, grants from AstraZeneca, personal fees, non-financial support, and other from Janssen Cilag, personal fees and non-financial support from Roche, non-financial support from AbbVie, personal fees and non-financial support from BMS, personal fees and non-financial support from MSD, personal fees and non-financial support from Takeda, personal fees from Novartis, personal fees from ADC Therapeutics, outside the submitted work. JG reports personal fees from AbbVie, grants and personal fees from AstraZeneca, grants and personal fees from BMS/Celgene, grants and personal fees from Janssen, personal fees from Kite/Gilead, personal fees from MorphoSys, personal fees from Novartis, personal fees from TG Therapeutics, outside the submitted work. RH has had a consultant or advisory relationship with Janssen, Amgen, Celgene, AbbVie, BMS, Novartis, PharmaMar, and Takeda; has received honoraria from Janssen, Amgen, Celgene, BMS, PharmaMar, and Takeda; has received research funding from Janssen, Amgen, Celgene, BMS, Novartis, and Takeda. CH reports grants and personal fees from Novartis, grants and personal fees from BMS, personal fees from Sierra Oncology, personal fees from CTI pharmaceuticals, personal fees from Jannsen, personal fees from Geron, grants and personal fees from AOP Orphan Pharma, personal fees from Galecto, grants, personal fees and other from Constellation, outside the submitted work. MH reports personal fees from Novartis, personal fees from Pfizer, personal fees from Roche, personal fees from AbbVie, personal fees from Daiichi Sankyo, personal fees from Bayer Pharma AG, personal fees from Jazz Pharmaceuticals, personal fees from BMS, personal fees from Tolremo, outside the submitted work. BK has received honoraria for lectures from Ipsen, Novartis and MSD (all outside of the submitted work). J-JK reports consulting fees and honoraria from Novartis, consulting fees from AbbVie, honoraria from AOP Orphan Pharma, participation on a monitoring board or advisory board from BMS/Celgene, participation on a monitoring board or advisory board from Incyte. NK reports grants and honoraria from Neovii, honoraria from Sanofi, grants and honoraria from Jazz, grants and honoraria from Celgene, grants and honoraria from Riemser, honoraria from Gilead/Kite, honorarium from AOP Oprhan Pharma, grants and honorarium from Novartis, honorarium from Amgen. PM reports personal fees from Celgene, Amgen, Janssen, AbbVie, Sanofi, outside the submitted work. JP has declared no conflicts of interest. FP has declared no conflicts of interest. DR received honoraria from Incyte, Novartis Pharma, Pfizer; clinical trial steering committee membership: Novartis; membership on advisory boards: Incyte, Novartis Pharma, Pfizer. J-MR reports grants and honoraria from Novartis, Amgen, Pfizer, Takeda, Incyte, and Servier. TR has declared no conflicts of interest. JF-M reports consulting and advisory boards honoraria (received by CUN ) from AbbVie, Amgen, BMS, Celgene, Janssen, GlaxoSmithKline, Karyopharm, MSD, Novartis, Takeda, Sanofi, SecuraBio, Regeneron, Roche, outside the submitted work. VS has declared no conflicts of interest. GFS reports personal fees and other from AbbVie, other from Amgen, other from Astellas, other from Boehringer-Ingelheim, grants, personal fees and other from Celgene, other from Helsinn Healthcare, grants, personal fees, and other from Janssen-Cilag, grants and other from Novartis, other from Onconova, grants, personal fees and other from Roche, and other from Takeda, outside the submitted work. PS reports honoraria from Amgen, Celgene, Janssen, Karyopharm, SkylineDx, Takeda, and research support from Celgene, Janssen, Amgen, Takeda, BMS, SkylineDx, Karyopharm, all outside the submitted work. MvL-T has received travel grants and honoraria from Celgene, Gilead, Chugai, Janssen, Novartis, Amgen, Takeda, BMS, Medac, Oncopeptides, Merck, CDDF, Pfizer, Medac, Thermo Fisher, AstraZeneca; is a consultant for Celgene, Gilead, Oncopeptides, MSD, 4D Pharma, Janssen, Shionogi and received research funding from BMBF, Deutsche Jose Carreras Leukämie-Stiftung, IZKF Jena, Novartis, Gilead, Deutsche Krebshilfe, Celgene, Oncopeptides, Deutsche Forschungsgemeinschaft (DFG). CW has declared no conflicts of interest. GP reports grants from Amgen, grants, personal fees and non-financial support from Merck, grants and non-financial support from AstraZeneca, grants and personal fees from Roche, grants and personal fees from BMS, grants from Lilly, grants and personal fees from MSD, grants and personal fees from Novartis, outside the submitted work. FP reports grants from Novartis, Celgene, BMS, Abbvie, Karyopharma, Janssen., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Polycythaemia vera is associated with a reduced quality of life, a high rate of vascular events, and an intrinsic risk of disease evolution. The results of several randomised trials for the treatment of this disorder are now available, and both a new ropegylated formulation of interferon alfa-2b (ropeginterferon alfa-2b; 2018) and ruxolitinib (2015) have been approved in Europe. European LeukemiaNet (ELN) investigators have therefore deemed it appropriate to provide recommendations for the use of these drugs in clinical practice. An expert panel of 14 senior haematologists from ELN centres that had actively participated in previous ELN projects or relevant randomised trials, chaired by a member of the ELN Steering Committee, developed a list of clinical questions, and a methodologist established three patient, intervention, comparator, outcome (PICO) questions and systematically reviewed the evidence. Recommendations were approved by six Delphi consensus rounds and two virtual meetings (on Jan 26, 2021, and June 24, 2021). The expert panel recommended that patients with polycythaemia vera who are younger than 60 years and have not had previous thrombotic events should start cytoreductive drug therapy if at least one of the following criteria are fulfilled: strictly defined intolerance to phlebotomy, symptomatic progressive splenomegaly, persistent leukocytosis (>15 × 10 9 white blood cells per L), progressive leukocytosis (at least 100% increase if baseline count is <10 × 10 9 cells per L or at least 50% increase if baseline count is >10 × 10 9 cells per L), extreme thrombocytosis (>1500 × 10 9 platelets per L), inadequate haematocrit control requiring phlebotomies, persistently high cardiovascular risk, and persistently high symptom burden. Recombinant interferon alfa, either in the form of ropeginterferon alfa-2b or pegylated interferon alfa-2a, is the recommended cytoreductive treatment for these patients. The expert panel suggested that either interferon alfa or ruxolitinib should be considered for patients who are being treated with hydroxyurea but require a therapy change., Competing Interests: Declaration of interests MM has received consulting fees from Gilead Sciences, speaker fees from Amgen, support for attending meetings from Takeda, and is a member of the guideline committee of the Italian Society of Hematology. AMV has received speaker fees from Novartis, AOP Health, Incyte, AbbVie, GlaxoSmithKline (GSK), and Bristol Myers Squibb (BMS); and has participated on the advisory boards of Novartis, Incyte, AOP Orphan Pharmaceuticals, AbbVie, GSK, BMS, and Roche. MG has received consulting and speaker fees, support for attending meetings, and participated on advisory boards for AOP Health, Novartis, Celgene, Amgen, AstraZeneca, CTI BioPharma, Shire, Pfizer, Roche, Janssen Pharmaceuticals, and Gilead Sciences. CH has received grants or contracts with payment to her institution from Novartis, Celgene, and Constellation Pharmaceuticals; consulting fees from Keros Therapeutics, Galecto Biotech, and Roche; speaker fees from Novartis, Celgene, CTI BioPharma, AbbVie, Gilead Sciences, Janssen Pharmaceuticals, Promedior, and Geron Corporation; support for attending meetings from Novartis and Celgene, and has participated on advisory boards for Roche, CTI Biopharma, Geron Corporation, Promedior, AbbVie, AOP Orphan Pharmaceuticals, and Galecto. SK has received research grants from AOP Health, Novartis, Janssen Pharmaceuticals, and Imago BioScience; consulting fees from Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, and Janssen Pharmaceuticals; speaker fees from Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, Janssen Pharmaceuticals, Kartos Therapeutics, and Imago BioScience; support for attending meetings from Alexion Pharmaceuticals, Novartis, BMS/Celgene, Incyte/ARIAD, AOP Orphan Pharmaceuticals, CTI BioPharma, Pfizer, Sanofi, Janssen Pharmaceuticals, Geron Corporation, Kartos Therapeutics, Sierra Oncology, Imago BioScience; has participated on advisory boards for Pfizer, CTI BioPharma, Sanofi, Novartis, BMS/Celgene, Incyte/ARIAD, Roche, AOP Orphan Pharmaceuticals, Kartos Therapeutics, and Imago BioScience; has patents planned, issued, or pending from Rheinisch-Westfalische Technische Hochschule Aachen; and has a leadership role in Deutsche Gesellschaft fur Hamatologie und Medizinische Onkologie. HG has received research grants and support for attending meetings from AOP Orphan Pharmaceuticals and Novartis; consulting fees from AOP Orphan Pharmaceuticals, Novartis, and BMS/Celgene; and speaker fees from AOP Orphan Pharmaceuticals, Novartis, BMS/Celgene, and Janssen. AÁ-L has participated on advisory boards and has received speaker fees from Novartis, AOP Orphan Pharmaceuticals, and Celgene; and has received support for attending meetings from Novartis and Pfizer. VDS has received speaker fees from AbbVie and Novartis, and participated on advisory boards of AOP Health and Novartis. PG has received speaker fees from AbbVie and Novartis, and support for attending meetings from Sanofi. FPal has received speaker fees from Novartis and Incyte; consulting fees from AOP Health, CTI BioPharma, Novartis, and Celgene/BMS; and support for attending meetings from Celgene/BMS. FPas has received consulting fees from AbbVie, Novartis, BMS, and Amomed Pharma; and speaker fees from AbbVie, Janssen Pharmaceuticals, Novartis, and BMS. RTS has received research grants from the Cancer Research & Treatment Fund and Johns Family Fund, received speaker fees and payment for expert testimony from PharmaEssentia, participated on an advisory board for PharmaEssentia, and has a leadership role (Vice-President and Medical Director) at the Cancer Research & Treatment Fund. J-JK received consulting fees from AbbVie and Novartis; speaker fees from AOP Orphan Pharmaceuticals, Novartis, and BMS; and has participated on advisory boards for Incyte. TB has received research grants and speaker fees from AOP Orphan Pharmaceuticals and Novartis, and consultancy fees from AOP Orphan Pharmaceuticals. GB and RH declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Target identification and drug discovery roads have been widely improved over the past decades in onco-hematology. In this review, we summarize recent improvements in the use of physio-pathologically relevant models and innovative screening approaches to accelerate efficient drug development. Using acute myeloid leukemia as an example, we also discuss the main encountered pitfalls and propose alternative roads to improve the drug discovery journey in onco-hematology., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Purpose: This phase I, dose-escalation study investigated the recommended dose for expansion (RDE) of siremadlin, a p53-MDM2 inhibitor, in patients with wild-type TP53 advanced solid or hematologic cancers., Patients and Methods: Initial dosing regimens were: 1A (day 1; 21-day cycle; dose 12.5-350 mg) and 2A (days 1-14; 28-day cycle; dose 1-20 mg). Alternative regimens included 1B (days 1 and 8; 28-day cycle) and 2C (days 1-7; 28-day cycle). The primary endpoint was incidence of dose-limiting toxicities (DLT) during cycle 1., Results: Overall, 115 patients with solid tumors and 93 with hematologic malignancies received treatment. DLTs occurred in 8/92 patients with solid tumors and 10/53 patients with hematologic malignancies. In solid tumors, an RDE of 120 mg was defined in 1B. In hematologic tumors, RDEs were defined in 1A: 250 mg, 1B: 120 mg, and 2C: 45 mg. More patients with hematologic malignancies compared with solid tumors experienced grade 3/4 treatment-related adverse events (71% vs. 45%), most commonly resulting from myelosuppression. These were more frequent and severe in patients with hematologic malignancies; 22 patients exhibited tumor lysis syndrome. Overall response rates at the RDEs were 10.3% [95% confidence interval (CI), 2.2-27.4] in solid tumors and 4.2% (95% CI, 0.1-21.1), 20% (95% CI, 4.3-48.1), and 22.2% (95% CI, 8.6-42.3) in acute myeloid leukemia (AML) in 1B, 1A, and 2C, respectively., Conclusions: A common safety profile was identified and preliminary activity was noted, particularly in AML. Comprehensive investigation of dosing regimens yielded recommended doses/regimens for future combination studies., (©2021 The Authors; Published by the American Association for Cancer Research.)

We assessed the diagnostic performances of erythropoietin and JAK2 mutations in 1,090 patients with suspected polycythemia who were referred for red cell mass (RCM) measurement. In patients with a high haematocrit and/or haemoglobin level, a low erythropoietin level (<=3·3 mUI/ml) and JAK2 mutation showed comparable positive predictive value (PPV) for true polycythemia (RCM>=125%), 92·1% and 90% respectively. A very-low erythropoietin level (<=1·99 mUI/ml) had a PPV of 100% for polycythemia vera (PV) diagnosis. We confirmed the correlations between RCM, erythropoietin and JAK2 variant allelic frequency in PV patients. This study prompts the need to revisit the role of EPO in PV diagnostic criteria., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

In the MYF2001 trial, treatment of Janus kinase (JAK) inhibitor-relapsed/refractory intermediate-2 or high-risk myelofibrosis (MF) with imetelstat 9.4 mg/kg every 3 weeks demonstrated encouraging median overall survival of 29.9 months. To provide historical context, external real-world data (RWD) were collected from a study of 96 patients who had discontinued ruxolitinib and were subsequently treated with best available therapy (BAT) at Moffitt Cancer Center. A closely matched cohort was identified using the MYF2001 eligibility criteria, including patients with MF who had discontinued ruxolitinib due to lack or loss of response. Overall survival was measured from time of JAK inhibitor discontinuation to death or censored at last follow-up. To improve comparability, propensity score weighting approaches using average treatment effect for overlap population (ATO) and stabilized inverse probability treatment weighting (sIPTW) were used for 10 critical baseline covariates. Fifty-seven patients treated with imetelstat 9.4 mg/kg from MYF2001 and 38 patients treated with BAT from RWD were analyzed with improved balanced baseline covariates after propensity score adjustment, showing significantly lower risk of death with imetelstat compared with BAT (hazard ratio: 0.35; p = 0.0019). With sIPTW, results were similar. Results of sensitivity analyses were consistent with the primary analysis. In conclusion, treatment with imetelstat was associated with longer overall survival compared to BAT (30 vs 12 months, respectively) in closely matched patients with MF after JAK inhibitor failure, warranting further evaluation of imetelstat in this poor-prognosis patient population., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Over 95% of Polycythemia Vera (PV) patients carry the V617F mutation in the tyrosine kinase Janus kinase 2 (JAK2), resulting in uncontrolled erythroid proliferation and a high risk of thrombosis. Using mass spectrometry, we analyzed the RBC membrane proteome and showed elevated levels of multiple Ca 2+ binding proteins as well as endoplasmic-reticulum-residing proteins in PV RBC membranes compared with RBC membranes from healthy individuals. In this study, we investigated the impact of JAK2 V617F on (1) calcium homeostasis and RBC ion channel activity and (2) protein expression and sorting during terminal erythroid differentiation. Our data from automated patch-clamp show modified calcium homeostasis in PV RBCs and cell lines expressing JAK2 V617F , with a functional impact on the activity of the Gárdos channel that could contribute to cellular dehydration. We show that JAK2 V617F could play a role in organelle retention during the enucleation step of erythroid differentiation, resulting in modified whole cell proteome in reticulocytes and RBCs in PV patients. Given the central role that calcium plays in the regulation of signaling pathways, our study opens new perspectives to exploring the relationship between JAK2 V617F , calcium homeostasis, and cellular abnormalities in myeloproliferative neoplasms, including cellular interactions in the bloodstream in relation to thrombotic events.

Classical BCR-ABL-negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells (HSCs) caused mainly by recurrent mutations in genes encoding JAK2 (JAK2), calreticulin (CALR), or the thrombopoietin receptor (MPL). Interferon α (IFNα) has demonstrated some efficacy in inducing molecular remission in MPNs. To determine factors that influence molecular response rate, we evaluated the long-term molecular efficacy of IFNα in patients with MPN by monitoring the fate of cells carrying driver mutations in a prospective observational and longitudinal study of 48 patients over more than 5 years. We measured the clonal architecture of early and late hematopoietic progenitors (84 845 measurements) and the global variant allele frequency in mature cells (409 measurements) several times per year. Using mathematical modeling and hierarchical Bayesian inference, we further inferred the dynamics of IFNα-targeted mutated HSCs. Our data support the hypothesis that IFNα targets JAK2V617F HSCs by inducing their exit from quiescence and differentiation into progenitors. Our observations indicate that treatment efficacy is higher in homozygous than heterozygous JAK2V617F HSCs and increases with high IFNα dose in heterozygous JAK2V617F HSCs. We also found that the molecular responses of CALRm HSCs to IFNα were heterogeneous, varying between type 1 and type 2 CALRm, and a high dose of IFNα correlates with worse outcomes. Our work indicates that the long-term molecular efficacy of IFNα implies an HSC exhaustion mechanism and depends on both the driver mutation type and IFNα dose., (© 2021 by The American Society of Hematology.)

Purpose: Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086)., Patients and Methods: Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety., Results: Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias., Conclusion: In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway., Competing Interests: John MascarenhasConsulting or Advisory Role: Incyte, Geron, Celgene/Bristol Myers Squibb, Novartis, CTI BioPharma Corp, Kartos Therapeutics, Constellation Pharmaceuticals, Sierra Oncology, AbbVie, Roche/GenentechResearch Funding: Incyte, Pharmaessentia, Merck, Forbius, Geron, AbbVie, Kartos Therapeutics, Roche/Genentech, CTI BioPharma Corp Rami KomrokjiStock and Other Ownership Interests: AbbVieConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Jazz Pharmaceuticals, AbbVie, Geron, Acceleron PharmaSpeakers' Bureau: Jazz Pharmaceuticals, Bristol Myers Squibb, AgiosTravel, Accommodations, Expenses: Jazz Pharmaceuticals, Bristol Myers Squibb, Agios Dietger NiederwieserConsulting or Advisory Role: Cellectis, Amgen, NovartisSpeakers' Bureau: NovartisResearch Funding: Daiichi Sankyo Andreas ReiterHonoraria: Novartis, Blueprint Medicines, Incyte, Celgene/Bristol Myers Squibb, AOP Orphan PharmaceuticalsConsulting or Advisory Role: Novartis, Blueprint Medicines, Incyte, Celgene/Bristol Myers Squibb, AOP Orphan PharmaceuticalsResearch Funding: Blueprint Medicines, Deciphera, Novartis, Incyte, AOP Orphan PharmaceuticalsExpert Testimony: NovartisTravel, Accommodations, Expenses: Novartis, Deciphera, Blueprint Medicines, Incyte Bart ScottHonoraria: Bristol Myers SquibbConsulting or Advisory Role: Celgene, Acceleron Pharma, Astex Pharmaceuticals, NovartisSpeakers' Bureau: Alexion Pharmaceuticals, Celgene, Jazz Pharmaceuticals, NovartisResearch Funding: Celgene Maria BaerResearch Funding: AbbVie, AI Therapeutics, FORMA Therapeutics, Kite, a Gilead company, Oscotec, Takeda Ronald HoffmanConsulting or Advisory Role: Protagonist Therapeutics, NovartisResearch Funding: Novartis, Scholar Rock, Turning Point Therapeutics Olatoyosi OdenikeConsulting or Advisory Role: AbbVie, Impact Biomedicines, Celgene, Novartis, BMS, Taiho PharmaceuticalResearch Funding: Celgene, Incyte, Astex Pharmaceuticals, NS Pharma, AbbVie, Janssen Oncology, OncoTherapy Science, Agios, AstraZeneca, CTI BioPharma Corp, Kartos Therapeutics, Aprea AB Alessandro VannucchiConsulting or Advisory Role: Novartis, AbbVie, Roche, Incyte, CelgeneSpeakers' Bureau: Novartis, AOP Orphan Pharmaceuticals, Incyte, Roche, Celgene Jacqueline BussolariEmployment: Johnson & Johnson, Bristol Myers Squibb, HotSpot TherapeuticsLeadership: HotSpot TherapeuticsStock and Other Ownership Interests: Johnson & Johnson, Bristol Myers Squibb, HotSpot TherapeuticsTravel, Accommodations, Expenses: Johnson & Johnson Eugene ZhuEmployment: Johnson & JohnsonStock and Other Ownership Interests: Johnson & Johnson Esther RoseEmployment: Janssen Research & DevelopmentStock and Other Ownership Interests: Johnson & JohnsonConsulting or Advisory Role: Geron CorpTravel, Accommodations, Expenses: Janssen Research & Development Laurie ShermanEmployment: Geron, JanssenStock and Other Ownership Interests: Janssen, Geron Souria DoughertyEmployment: GeronStock and Other Ownership Interests: Geron Libo SunEmployment: GeronStock and Other Ownership Interests: Geron, Johnson & Johnson, Moderna TherapeuticsTravel, Accommodations, Expenses: Geron Fei HuangStock and Other Ownership Interests: Bristol Myers Squibb, Geron, Johnson & Johnson Ying WanEmployment: GeronStock and Other Ownership Interests: Geron Faye FellerEmployment: Geron, JanssenStock and Other Ownership Interests: Geron, JanssenTravel, Accommodations, Expenses: Geron, Janssen Aleksandra RizoLeadership: GeronStock and Other Ownership Interests: Geron, Johnson & Johnson Jean-Jacques KiladjianConsulting or Advisory Role: Novartis, Incyte, BMS, AOP Orphan Pharmaceuticals, AbbVie, PharmaessentiaNo other potential conflicts of interest were reported.

Recommendations regarding management of essential thrombocythaemia rely on studies done before the discovery of the CALR mutation. On May 20, 2020, the European LeukemiaNet annual meeting was held with the goal to identify unmet clinical needs in myeloproliferative neoplasms. Because patients with a CALR mutation have specific clinical characteristics, treatment of CALR-mutated essential thrombocythaemia was considered an unmet clinical need by the European LeukemiaNet. The elaboration of a consensus document with recommendations according to current evidence was proposed as a solution for resolving uncertainties in the treatment of CALR-mutated essential thrombocythaemia. A steering committee comprising four European LeukemiaNet members was then formed and a panel of ten experts in the field was recruited. The experts proposed 51 potential unmet clinical needs in the management of CALR-mutated essential thrombocythaemia and were asked to score the relevance of each topic. Those topics that obtained the highest scores as relevant unmet clinical needs were identified, including antiplatelet therapy in patients at low risk, definition of extreme thrombocytosis and its management in patients at low risk, indications of cytoreduction and targets of therapy, first-line treatment of choice in young patients (<60 years), and management of pregnancy. After the steering committee revised the available evidence for each topic, a consensus on management and proposal for improving knowledge was achieved by use of an email-based, two round, Delphi approach. Consensus was achieved when 90% of the panellists agreed with a statement and included 14 recommendations and six solution proposals. Key recommendations included careful observation for asymptomatic patients with classical, low-risk, CALR-mutated essential thrombocythaemia without cardiovascular risk factors; caution in the use of antiplatelet therapy for symptomatic patients at low risk with platelet counts of 1000-1500 × 10 9 platelets per L, in such cases cytoreduction is an adequate option, especially if adquired Von Willebrand disease is present; cytoreduction is recommended for extreme thrombocytosis (platelet count >1500 × 10 9 platelets per L) with pegylated interferon alfa being the preferred option for younger patients; both hydroxycarbamide and anagrelide might be given to patients ineligible for pegylated interferon alfa; and treatment algorithms for patients with high-risk pregnancies should not be changed according to genotype. The European LeukemiaNet proposes to use these recommendations in the routine management of patients with CALR-mutated essential thrombocythaemia, and designing new clinical studies in this field might be useful., Competing Interests: Declaration of interests AA-L participated in data safety monitoring boards and advisory boards and has received speaker and consulting fees from Novartis, AOP Orphan, and Celgene. CH had grants or contracts with payment to her institution from Novartis, Celgene, and Constellation, consulting fees from Keros, Galecto, and Roche, speaker fees from Novartis, Celgene, CTI BioPharma, Gilead, Jannsen, Promedior, and Geron, and participated on a data safety monitoring board and advisory board for Roche and Galecto. ER received speaker fees from Novartis and participated in the Abbvie advisory board. FP received speaker fees from Novartis, AOP, and Celgene. JCI received speaker fees from Novartis. J-JK received consulting fees from Abbvie and Novartis, speaker fees from AOP Orphan, Novartis, and Bristol Myers Squibb (BMS), and participated in advisory boards for Incyte. JN received grants from MPN Research Foundation, Alborada Trust, and Rosetrees Trust, and speaker fees from Jazz Pharmaceutical. MG received consulting and speaker fees, payment for expert testimony, support for attending meetings, and participated in data safety monitoring board and advisory board from AOP, Novartis, Celgene, BMS, Amgen, and AstraZeneca. RM received grants from Celgene, Incyte, Abbvie, Samus, Genotech, Promedior, and CTI BioPharma, consulting fees from Novartis, Sierra Onc, LaJolla, and Pharma. SK received grants from AOP, Janssen, and Novartis, consulting fees from Pfizer, CTI BioPharma, Baxalta, Sanofi, Novartis, BMS–Celgene, Incyte, Shire, Roche, AOP, and Janssen, speaker fees from Pfizer, CTI, Baxalta, Sanofi, Novartis, BMS–Celgene, Incyte, Shire, Roche, AOP, and Janssen, support from attending meetings from Pfizer, CTI BioPharma, Baxalta, Sanofi, Novartis, BMS–Celgene, Incyte, Shire, AOP, Janssen, Alexion, and Geron, patents planned, issued, or pending from Rheinisch-Westfälische Technische Hochschule Aachen, and leadership role in Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie. All other authors have no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This multicenter prospective phase 2 trial analyzed disease-free survival (DFS) in myelofibrosis patients receiving ruxolitinib for 6 months before transplantation. Seventy-six patients were recruited. Age-adjusted dynamic international prognostic scoring system was intermediate-1, intermediate-2, and high in 27 (36%), 31 (41%), and 18 (24%) patients. All patients received ruxolitinib from inclusion to conditioning regimen (fludarabine-melphalan) or to progression. A donor was found in 64 patients: 18 HLA-matched sibling donor (MSD), 32 HLA-matched unrelated (UD10/10), and 14 HLA mismatched unrelated donor (UD9/10. Among 64 patients with a donor, 20 (31%) achieved a partial response before transplantation and 59 (92%) could be transplanted after ruxolitinib therapy (18/18 MSD, 30/21 UD10/10, 11/34 UD9/10), of whom 19 (32%) were splenectomized. Overall survival from inclusion was 68% at 12 months. One-year DFS after transplantation was 55%: 83%, 40%, and 34% after MSD, UD10/10 or UD9/10, respectively. Cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 66% and non-relapse-mortality was 42% at 12 months. Short course of ruxolitinib before transplantation is followed by a high rate of transplantation. With the platform used in this protocol, outcome was much better in patients transplanted with HLA-matched sibling donor as compared to unrelated donor., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Myelofibrosis is a myeloproliferative neoplasm associated with constitutional symptoms, increasing splenomegaly, and worsening cytopenias. Janus kinase (JAK) inhibitors have been used for the treatment of myelofibrosis for several years, but there is a lack of comparative information between those treatments. A systematic review and network meta-analysis was performed on randomized controlled trials in patients with myelofibrosis receiving JAK inhibitor or placebo or control. Primary outcomes were efficacy on spleen volume reduction and total symptom score reduction. Additional analyses were conducted on anemia and thrombopenia events. Seven studies were included in the network meta-analysis including 1953 patients randomly assigned to four JAK inhibitors-ruxolitinib, fedratinib, pacritinib, momelotinib-or control. In first-line therapy, momelotinib and fedratinib were associated with comparable efficacy to ruxolitinib, and with less toxicity on erythrocytes and platelets, respectively. Pacritinib was less effective on splenomegaly than ruxolitinib as a first-line treatment but seemed effective in second line, after ruxolitinib exposure. Fedratinib and ruxolitinib that are FDA approved in myelofibrosis have both confirmed being valuable option to treat splenomegaly and constitutional symptoms, and their slightly different tolerance-profiles can guide therapeutic choice for first-line treatment, according to patient profile. Momelotinib could be another option especially due to its positive effect on anemia., (© 2021. The Author(s).)

Background: The Clinical Investigations Center of Saint-Louis Hospital (CIC-1427) is a structure dedicated to clinical trials and mainly early phase trials (first-in-man administration, phase 1 and 2). These trials are conducted in a French Regional Health Agency (ARS) authorized structure. In March 2020, faced to the global COVID-19 pandemic and the French national lockdown measures, the CIC-1427 had to rapidly adapt its operating procedures to ensure the safety of both patients and staff., Study Objective: Ensuring optimal management of patients included in early phase clinical trials, while respecting the good clinical and professional practices (GCP/GPP) of the CICs protocol sponsors' requirements, patients' safety and clinical research multidisciplinary staff safety (nurses, caregivers' assistants (AS), clinical research assistants (CRA), clinical trial coordinators (CTC), project leaders, health executive and investigating physicians), in the context of the health crisis related to COVID-19., Methods and Results: Due to their activity, requiring on-site presence, each staff member of the CIC-1427 clinical research team had to adapt their daily activity to the constraints of the health crisis. New specific procedures were quickly developed to deal with the pandemic. Most of the on-site medical visits were replaced by virtual consults with biological assessments in the local laboratories. "Remote monitoring" replaced on-site monitoring visits. Treatments were sent to each patient's home via couriers after agreement of the CPPs of each protocol (Committee for the Protection of Persons). The essential visits were maintained on site thanks to the unfailing involvement of our clinical care team, with implementation of a specific sanitary protocol., Conclusion: The involvement of our entire multidisciplinary research team ensured that each patient was able to benefit from a personalized follow-up and to continue the treatment on-trial. The newly introduced procedures also allowed collection of a maximum of safety and efficacy data for clinical trial sponsors while complying with good regulatory practices. This set of procedures developed during the first epidemic wave, fundamentally helped setting the frame for a better coping during the subsequent pandemic waves., (Copyright © 2021 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)