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Introduction: Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that are stratified into high-risk (HR-MDS) and low-risk (LR-MDS) categories. Until recently, LR-MDS has been typically managed by supportive measures and erythropoiesis-stimulating agents (ESAs); whereas management of HR-MDS typically included hypomethylating agents and allogeneic hematopoietic stem cell transplant. However, the limited rates and durations of response observed with these interventions prompted the search for targeted therapies to improve the outcomes among patients with MDS., Areas Covered: Here, we review the current landscape of targeted therapies in MDS. These include pyruvate kinase and hypoxia-inducible factor (HIF) activators; TGF-beta, telomerase, BCL2 and isocitrate dehydrogenase (IDH) inhibitors; as well as novel approaches targeting inflammation, pyroptosis, immune evasion, and RNA splicing machinery., Expert Opinion: This review highlights the progress and challenges in MDS treatment. Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.

Anti-synthetase syndrome (AS) is a subset of idiopathic inflammatory myopathy (IIM) characterized by the presence of anti-aminoacyl-transfer RNA synthetase accompanied by myositis, interstitial lung disease and other clinical features. According to a recent multicentric study, 31% of AS patients present skin lesions compatible with dermatomyositis, but sclerodermiform features are rare. Therefore, we aimed to report the case of a patient with simultaneous diagnosis of AS, deep morphea, vasculitic neuropathy, and myelodysplastic syndrome and review the current literature regarding these uncommon associations. A 57 year old man with axial and symmetrical proximal muscle weakness, skin thickening and B symptoms, later diagnosed with PL7 + AS, deep morphea, myelodysplastic syndrome (MDS) and vasculitic neuropathy documented by histopathologic studies and immunologic assessments. Since both AS and deep morphea share the vasculopathic changes and type II interferon-induced inflammation, we hypothesize that they may share pathogenic mechanisms. The muscle biopsy of the patient was consistent with AS and showed focal neutrophil infiltration. The patient received intensive immunosuppressive therapy for AS and vasculitic neuropathy, with high dose steroids, intravenous immunoglobulin (IVIg) and rituximab. Nonetheless, he suffered an unfavorable evolution with a fatal outcome due to septic shock. Albeit sclerodermiform features are rare in patients with AS, we propose a pathogenic link among AS, deep morphea and the autoimmune/autoinflammatory signs of MDS. The vasculopathic changes along with the activation of the innate and adaptive immune system leading to the production of proinflammatory cytokines may have been one of the contributing factors for the coexisting diagnosis of the patient., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Regular monitoring of CD34 donor chimerism (DC) is a highly sensitive method of predicting relapse in allogeneic stem cell transplant (alloHSCT) recipients with AML/MDS. A fall of CD34 DC below 80% is an indicator of ensuing relapse. There are limited studies assessing the efficacy of donor lymphocyte infusion (DLI) triggered by mixed CD34 DC (MDC), in addressing falling chimerism., Patients and Methods: We performed a retrospective analysis of consecutive alloHSCT patients between 2012 to 2023 who received DLI (with or without azacitidine) for CD34 MDC without morphologic relapse at the time of infusion., Results: Of the 21 patients with follow up CD34 DC available, 14 (66.7%) achieved CD34 full donor chimerism (FDC) following DLI with or without azacitidine (dli-FDC), while 7 (33.3%) did not (dli-MDC). The 2-year cumulative incidence of relapse (CIR) was significantly lower in dli-FDC compared to dli-MDC (21.4% vs. 85.7%, P < 0.001), correlating with superior overall survival (OS; median years not reached vs. 0.67 years [95% CI, 0.58-ND], P < .001). Rates of grade II-IV acute GVHD post-DLI were 14.9%, and moderate-severe cGVHD was 42.8% in the dli-FDC group. The 5-year nonrelapse mortality (NRM) of the dli-FDC group was 7.1% following DLI., Conclusion: Our study shows the restoration of CD34 FDC post-DLI is associated with reduced relapse and improved overall survival, with low NRM., Competing Interests: Disclosure All authors listed above do not have any conflicts of interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics, and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory hematologic malignancies., Patients and Methods: In the monotherapy cohort (n = 61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, during a 3-week cycle. In the combination cohort (n = 17), patients with acute myeloid leukemia and myelodysplastic syndrome received escalating doses of AZD5991 and venetoclax during either a 3- or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma pharmacokinetics and antitumor activity., Results: The most common (≥30%) adverse events were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred because of adverse events: cardiac arrest, sepsis, tumor lysis syndrome, and acute respiratory failure; only tumor lysis syndrome was related to AZD5991. Dose-limiting toxicities occurred in five patients. Three patients with myelodysplastic syndrome achieved an objective response: one marrow complete remission without hematologic improvement, one partial remission with AZD5991 monotherapy, and one marrow complete remission with AZD5991 + venetoclax. Asymptomatic elevations of troponin I or T were observed in eight (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after Cycle 1. No associations were found between elevated troponin and cardiovascular risk factors., Conclusions: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background and Objectives: Acute myeloid leukemia and myelodysplastic syndrome are both clonal hematologic malignancies that primarily affect older adults. Current treatments for AML/MDS are both limited in number and efficacy. This study aims to evaluate venetoclax-based therapies in AML/MDS, focusing on overall survival and recurrence-free survival rates, and to expand real-world data on its use. Materials and Methods: Clinical and laboratory data on patients with AML/MDS aged 18≥ treated with venetoclax between January 2019 and July 2022 were included. Survival analysis was calculated based on the period from 2019 to December 2023. Results: A total of 161 AML and 40 patients with MDS were included. The median age was 63.53 ± 15.30 years for AML and 70.12 ± 10.21 years for MDS. In both groups, over 55% are male. A total of 77.6% of patients with AML and 75% of patients with MDS received treatment prior to venetoclax. Venetoclax was administered in combination with azacitidine to 84.5% of AML and 67.5% of MDS. The relapse rate in AML is approximately 15%. Overall, the 2-year survival rate is 46% and 18.73 months. The overall CR/CRi rate for patients with AML is 49.1%, while for patients with MDS, it is 50%. The 2-year survival rate for patients with MDS is 52.7%. The 2-year RFS rate was 75.5% for AML and 90.9% for MDS. The relapse rate in AML is approximately 15%. The percentage of adverse events leading to treatment discontinuation among those with grade 3-4 toxicity is low; 26.7% for AML ( n = 43) and 15% for MDS ( n = 6). Conclusions: Our real-world data demonstrate that venetoclax has the potential to improve overall survival rates when used in combination with HMAs and supports its use in patients with AML/MDS.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Lenalidomide (LEN) can induce red blood cell-transfusion independence (RBC-TI) in 60-70% of del(5q) myelodysplastic neoplasm (MDS) patients. Current recommendation is to continue LEN in responding patients until failure or progression, with likelihood of toxicity and a high cost for healthcare systems. This HARMONY Alliance study investigated the outcome of MDS del(5q) patients who discontinued LEN while RBC-transfusion independent. We enrolled 118 patients with IPSS-R low-intermediate risk. Seventy patients (59%) discontinued LEN for intolerance, 38 (32%) per their physician decision, nine (8%) per their own decision and one (1%) for unknown reasons. After a median follow-up of 49 months from discontinuation, 50/118 patients lost RBC-TI and 22/30 who underwent cytogenetic re-evaluation lost complete cytogenetic response. The median RBC-TI duration was 56 months. In multivariate analysis, RBC-TI duration after LEN discontinuation correlated with low transfusion burden before LEN therapy, treatment ≥ 12 LEN cycles, younger age and higher Hb level at LEN withdrawal. Forty-eight patients were re-treated with LEN for loss of response and 28 achieved again RBC-TI. These data show that stopping LEN therapy in MDS del(5q) patients who reached RBC-TI allows prolonged maintenance of TI in a large subset of patients., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Favourable outcomes with CPX-351 versus conventional 7 + 3 were demonstrated in the pivotal phase III trial in adults aged 60-75 years with newly diagnosed, highrisk/secondary acute myeloid leukaemia (AML). As a complement to the clinical trial and to address important data gaps, the CPX-351 Real-World Effectiveness and SafeTy (CREST-UK; NCT05169307) study evaluated the use of CPX-351 in routine clinical practice in the UK, in 147 patients with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Best response of complete remission or complete remission with incomplete platelet or neutrophil recovery was achieved by 53% of evaluable patients. Kaplan-Meier median overall survival (OS) was 12.8 months (95% confidence interval 9.2-15.3). Fifty (34%) patients proceeded to haematopoietic cell transplantation (HCT); median OS landmarked from the HCT date was not reached. There were no new safety concerns with CPX-351 identified in CREST-UK. Patients treated with CPX-351 in the outpatient setting spent an average of 24.4, 16.7, 28.2, and 27.7 fewer days on the ward compared with inpatients during first induction, second induction, first consolidation, and second consolidation, respectively. The results from CREST-UK provide valuable insights into the effectiveness, safety, and outpatient delivery of CPX-351 in routine clinical practice in the UK., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Introduction: Luspatercept is approved for patients with very low-to intermediate-risk myelodysplastic syndrome (MDS). Dosing is based on pre-dose hemoglobin levels and transfusion requirements. This study aims to evaluate if a site with a pharmacist prospectively reviewing luspatercept doses achieves dose optimization, compared to a site that does not have a pharmacist prospectively reviewing doses. Methods: We performed a retrospective chart review involving patients age ≥18 years or older with MDS at a major academic medical center main campus, which does not have a pharmacist prospectively review luspatercept doses, and a satellite campus infusion center, which has a pharmacist prospectively reviewing doses. Patients included received at least one dose of luspatercept between January 1, 2017 through August 31, 2022. The primary endpoint is the percentage of off-label luspatercept doses not consistent with prescribing information (PI) recommended dose adjustments. Results: The study included 17 patients. Of the 162 doses evaluated, 37 (23%) were off-label. Off-label dosing at the main campus was more common than at a satellite location (29.6% vs. 2.4%; p < 0.003). More patients achieved transfusion independence at the satellite compared to the main campus (83.3% vs. 27.3% p < 0.39). Conclusions: There was a higher percentage of off-label dosing at a center without a pharmacist's prospective review vs. a center with a pharmacist's prospective review. On-label dose optimization may lead to a higher percentage of patients achieving transfusion independence. Enhancements in the current ordering and review process can be improved with the involvement of a pharmacist's prospective involvement at both centers., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Structural variations involving enhancer hijacking induce aberrant oncogene expression and cause tumorigenesis. A rare translocation, t(3;8)(q26.2;q24), is associated with MECOM and MYC rearrangement, causing myeloid neoplasms with a dismal prognosis. The most recent World Health Organization classification recognises myeloid neoplasms with MECOM rearrangement as acute myeloid leukaemia (AML) with defining genetic abnormalities. Recently, the increasing use of induced pluripotent stem cell (iPSC) technology has helped elucidate the pathogenic processes of haematological malignancies. However, its utility for investigating enhancer hijacking in myeloid neoplasms remains unclear. In this study, we generated iPSC lines from patients with myelodysplastic syndromes (MDS) harbouring t(3;8)(q26.2;q24) and differentiated them into haematopoietic progenitor cells to model the pathophysiology of MDS with t(3;8)(q26.2;q24). Our iPSC model reproduced the primary patient's MECOM expression changes and histone H3 lysine 27 acetylation (H3K27ac) patterns in the MECOM promoter and MYC blood enhancer cluster (BENC). Furthermore, we revealed the apoptotic effects of the bromodomain and extra-terminal motif (BET) inhibitor on iPSC-derived MDS cells by suppressing activated MECOM. Our study demonstrates the usefulness of iPSC models for uncovering the precise mechanism of enhancer hijacking due to chromosomal structural changes and discovering potential therapeutic drug candidates for cancer treatment., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Myelodysplastic syndromes (MDS) are myeloid malignancies with heterogeneous genotypes and phenotypes, characterized by ineffective haematopoiesis and a high risk of progression towards acute myeloid leukaemia (AML). Prognosis for patients treated with hypomethylating agents (HMAs), as is azacytidine, the main drug used as frontline therapy for MDS is mostly based on cytogenetics and next generation sequencing (NGS) of the initial myeloid clone. Although the critical influence of the epigenetic landscape upon cancer cells survival and development as well on tumour environment establishment is currently recognized and approached within current clinical practice in MDS, the heterogenous response of the patients to epigenetic therapy is suggesting a more complex mechanism of action, as is the case of RNA methylation. In this sense, the newly emerging field of epitranscriptomics could provide a more comprehensive perspective upon the modulation of gene expression in malignancies, as is the proof-of-concept of MDS. We initially did RNA methylation sequencing on MDS patients (n = 6) treated with azacytidine and compared responders with non-responders. Afterwards, the genes identified were assessed in vitro and afterwards validated on a larger cohort of MDS patients treated with azacytidine (n = 58). Our data show that a more accurate prognosis could be based on analysing the methylome and thus we used methylation sequencing to differentially split high-grade MDS patients with identical demographical and cytogenetic features, between azacytidine responders and non-responders., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status., Patients and Methods: We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers., Results: A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers., Conclusions: The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lenalidomide is an immunomodulatory therapy used to treat multiple hematologic malignancies. The incidence of eosinophilia and hypereosinophilia during lenalidomide therapy, and the requirement for high-dose steroids are not well-defined PATIENTS AND METHODS: We retrospectively reviewed 44 patients with myelodysplastic syndromes who were treated with lenalidomide therapy from August 2006 and March 2023., Results: Eosinophilia (0.5-1.5 × 10 9 /L) and hypereosinophilia (>1.5 × 10 9 /L) were observed in 6 patients (14%) and 4 patients (9%), respectively. The median duration of lenalidomide therapy was 6.5 months. Backward multivariate ordinary logistic regression identified higher absolute eosinophil count (OR, 4759.986; 95% CI, 11.223-2018772.073; P = .006) and longer duration of lenalidomide therapy (OR, 1.148; 95% CI, 1.012-1.302; P = .032) as independent prognostic factors for the incidence of eosinophilia and hypereosinophilia. There was a trend for a higher use of high-dose steroids with hypereosinophilia. The median time to develop the first occurrence hypereosinophilia was 0.5 months. Steroids were used in 40% of patients with eosinophilia or hypereosinophilia. All events resolved with discontinuation of lenalidomide and/or use of steroids. No long-tern lasting adverse effects were recorded., Conclusion: Lenalidomide may induce or worsen existing eosinophilia which may lead to the need for steroids within a month of therapy., Competing Interests: Disclosures All authors declared no conflicts of interest related to this work. Koji Sasaki reports personal fees from Otsuka and Pfizer, outside the submitted work. Guillermo Garcia-Manero reports Gilead Sciences: Research Funding; Genentech: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Aprea: Honoraria; AbbVie: Honoraria, Research Funding; Astex: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy; Curis: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Elias Jabbour reports research funding from AbbVie, Adaptive Biotechnologies, Amgen, Bristol‐Myers Squibb, Cyclacel LTD, Pfizer, and Takeda; and personal fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol‐Myers Squibb, Pfizer, and Takeda, all outside the submitted work. Rashmi Kanagal-Shamanna received consultancy from Amgen, and Novartis, and served as Speakers Bureau for Aptitude Health, and Physicians Education Resource. Guillermo Montalban Bravo reports research funding from IFM Therapeutics. Lucia Masarova served as advisory committees at MorphoSys US. Hagop Kantarjian reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer and Sanofi; honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical and Takeda Oncology. WW reports Wierda:Gilead Sciences: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Miragen: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Kite, a Gilead Company: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; Xencor: Research Funding; Cyclacel: Research Funding; Genzyme: Consultancy; Genentech: Research Funding; Juno: Research Funding; Karyopharm: Research Funding; Sanofi: Consultancy; Oncternal Therapeutics, Inc.: Research Funding; Janssen: Research Funding; GSK/Novartis: Research Funding., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Higher-risk myelodysplastic syndromes (HR-MDS) are defined using a number of prognostic scoring systems that include the degree of cytopenias, percentage of blasts, cytogenetic alterations, and more recently genomic data. HR-MDS encompasses characteristics such as progressive cytopenias, increased bone marrow blasts, unfavorable cytogenetics, and an adverse mutational profile. Survival is generally poor, and patients require therapy to improve outcomes. Hypomethylating agents (HMAs), such as azacitidine, decitabine, and more recently, oral decitabine/cedazuridine, are the only approved therapies for HR-MDS. These are often continued until loss of response, progression, or unacceptable toxicity. Combinations including an HMA plus other drugs have been investigated but have not demonstrated better outcomes compared to single-agent HMA. Moreover, in a disease of high genomic complexity such as HR-MDS, therapy targeting specific genomic abnormalities is of interest. This review will examine the biological underpinnings of HR-MDS, its therapeutic landscape in the frontline and relapsed settings, as well as the impact of hematopoietic stem cell transplantation, the only known curative intervention for this disease.

In patients with lower-risk myelodysplastic syndromes/neoplasms (MDS), response to first-line therapy is limited and transient. The MATTERHORN randomized, double-blind, phase 3 trial evaluated roxadustat versus placebo for patients with transfusion-dependent, lower-risk MDS. Eligible patients had very low-, low-, or intermediate-risk MDS with or without prior erythropoiesis-stimulating agent treatment, and a transfusion burden of 1-4 packed red blood cell (pRBC) units every 8 weeks (Q8W). Patients were randomized (3:2) to oral roxadustat (2.5 mg/kg) or placebo, both three times weekly, with best supportive care. Primary efficacy endpoint was transfusion independence (TI) for ≥56 days within 28 weeks (TI responders). MATTERHORN was terminated due to interim analysis outcomes not meeting statistical significance. In total, 272 patients were screened, and 140 patients were enrolled (82, roxadustat, and 58, placebo). At final analysis, 38/80 (47.5%) patients and 19/57 (33.3%) in the roxadustat and placebo arms, respectively, were TI responders (p = .217). A greater percentage of patients in the roxadustat arm with a transfusion burden of ≥2 pRBC units Q4W were TI responders (36.1%; 13/36) compared with the placebo arm (11.5%; 3/26; p-nominal = .047). The seven on-study deaths (4, roxadustat, and 3, placebo) were considered unrelated to treatment. Three roxadustat patients progressed to acute myeloid leukemia. Despite MATTERHORN not meeting its primary endpoint, a numerically higher TI rate was achieved with roxadustat treatment compared with placebo. Further analyses are needed to confirm the MDS patient subgroups deriving clinical benefit from this novel treatment., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: The preplanned interim analysis of the COMMANDS trial showed greater efficacy of luspatercept than epoetin alfa for treating anaemia in erythropoiesis-stimulating agent (ESA)-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. In this Article, we report the results of the primary analysis of the trial., Methods: COMMANDS is a phase 3, open-label, randomised, controlled trial conducted at 142 sites in 26 countries. Eligible patients were those aged 18 years or older, with myelodysplastic syndromes of very low risk, low risk, or intermediate risk (as defined by the Revised International Prognostic Scoring System), who were ESA-naive and transfusion dependent, and had a serum erythropoietin concentration of less than 500 U/L. Patients were stratified by baseline red blood cell transfusion burden, serum erythropoietin concentration, and ring sideroblast status, and randomly allocated (1:1) to receive luspatercept (1·0-1·75 mg/kg body weight, subcutaneously, once every 3 weeks) or epoetin alfa (450-1050 IU/kg body weight, subcutaneously, once a week; maximum total dose 80 000 IU) for at least 24 weeks. The primary endpoint was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), evaluated in the intention-to-treat population. The safety population included all patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT03682536; active, not recruiting)., Findings: Between Jan 2, 2019, and Sept 29, 2022, 363 patients were screened and randomly allocated: 182 (50%) to luspatercept and 181 (50%) to epoetin alfa. Median age was 74 years (IQR 69-80), 162 (45%) patients were female, and 201 (55%) were male. 289 (80%) were White, 44 (12%) were Asian, and two (1%) were Black or African American. 23 (6%) were Hispanic or Latino and 311 (86%) were not Hispanic or Latino. Median follow-up for the primary endpoint was 17·2 months (10·4-27·7) for the luspatercept group and 16·9 months (10·1-26·6) for the epoetin alfa group. A significantly greater proportion of patients in the luspatercept group reached the primary endpoint (110 [60%] vs 63 [35%]; common risk difference on response rate 25·4% [95% CI 15·8-35·0]; p<0·0001). Median follow-up for safety analyses was 21·4 months (IQR 14·2-32·4) for the luspatercept group and 20·3 months (12·7-30·9) for the epoetin alfa group. Common grade 3-4 treatment-emergent adverse events occurring among luspatercept recipients (n=182) were hypertension (19 [10%] patients), anaemia (18 [10%]), pneumonia (ten [5%]), syncope (ten [5%]), neutropenia (nine [5%]), thrombocytopenia (eight [4%]), dyspnoea (eight [4%]), and myelodysplastic syndromes (six [3%]); and among epoetin alfa recipients (n=179) were anaemia (14 [8%]), pneumonia (14 [8%]), neutropenia (11 [6%]), myelodysplastic syndromes (ten [6%]), hypertension (eight [4%]), iron overload (seven [4%]), and COVID-19 pneumonia (six [3%]). The most common serious treatment-emergent adverse events in both groups were pneumonia (nine [5%] luspatercept recipients and 13 [7%] epoetin alfa recipients) and COVID-19 (eight [4%] luspatercept recipients and ten [6%] epoetin alfa recipients). One death (due to acute myeloid leukaemia) considered to be luspatercept-related was reported at the interim analysis., Interpretation: Luspatercept represents a new standard of care for ESA-naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes. Significantly more patients had red blood cell transfusion independence and haematological improvement with luspatercept than with epoetin alfa, with benefits observed across patient subgroups., Funding: Celgene and Acceleron Pharma., Competing Interests: Declaration of interests Editorial and medical writing support were funded by Bristol Myers Squibb. MGDP reports receiving honoraria from and advisory or data safety monitoring board fees from Bristol Myers Squibb. GG-M reports receiving consulting fees from Bristol Myers Squibb; research support from AbbVie, Astex, Bristol Myers Squibb, Chordia, Curis, Genentech, Novartis, Rigel Pharmaceuticals, and Zentalis; and honoraria from Astex and Curis. VS reports receiving honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Jazz Pharmaceuticals; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Curis, Geron, Gilead, Keros, Menarini, Novartis, Servier, and Syros. AMZ reports receiving grant support from AbbVie, Amgen, Astex, Bristol Myers Squibb, Celgene, Geron, Kura, Novartis, Otsuka, Shattuck Labs, and Syros; and consulting fees and honoraria from AbbVie, Agios, Akeso Pharma, ALX Oncology, Amgen, Astellas Pharma, BeiGene, BioCryst, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Chiesi, Daiichi Sankyo, Epizyme, Faron, Genentech, Geron, Gilead, Glycomimetics, Hikma, Janssen, Karyopharma, Keros, Kura, Kyowa Kirin, Lava Therapeutics, Medus, Notable, Novartis, Orum, Otsuka, Pfizer, Regeneron, Rigel Pharmaceuticals, Schrodinger, Servier, Sumitomo Pharma, Syndax, Syros, Taiho, Takeda, Treadwell, Vincerx, and Zentalis. RSK reports receiving grant support from Bristol Myers Squibb; consulting fees from Geron, Janssen, and Sumitomo Pharma; speakers bureau fees from AbbVie, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, and Sobi; and advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, DSI, Jazz Pharmaceuticals, Pharma Essentia, Rigel Pharmaceuticals, Servio, Sobi, and Sumitomo Pharma. JS reports receiving grant support from Amgen Australia, Astex Pharmaceuticals, and Bristol Myers Squibb; consulting fees paid to himself from Astellas Pharma, Mundipharma, Novartis, Otsuka, and Pfizer; speakers bureau fees paid to himself and his institution from Mundipharma and Novartis; support for meeting attendance from AstraZeneca (no payment to healthcare provider); being a named investigator on patent PCT/AU2021/050562 assigned to his institution; trial steering committee fees paid to his institution from Bristol Myers Squibb; and serving an unpaid appointment on the Australasia Leukaemia and Lymphoma Group Scientific Advisory Committee. DV reports receiving consulting fees from Amgen, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Sanofi, and Sobi; honoraria from Agios, Amgen, Astellas Pharma, Bristol Myers Squibb, Gebro, Grifols, Janssen, Jazz Pharmaceuticals, Kite Pharma, Merck Sharp & Dohme, Novartis, Pfizer, Sanofi, and Sobi; travel support from Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Sanofi, and Sobi; and advisory or data safety monitoring board fees from Amgen, Bristol Myers Squibb, Grifols, Jazz Pharmaceuticals, Novartis, Servier, and Sobi. AJ reports receiving support for study materials from Bristol Myers Squibb; consulting fees from Bristol Myers Squibb; honoraria from AbbVie, Bristol Myers Squibb, and Novartis; travel support from AbbVie and Novartis; advisory or data safety monitoring board fees from AbbVie, Bristol Myers Squibb, GSK, and Novartis; and a leadership or fiduciary role as the head of the Czech MDS Group. JL, RP, SK, KLK, TP, and YL are employed by and own stock in Bristol Myers Squibb. JZ is employed by Bristol Myers Squibb. VP is employed by and owns stock in Bristol Myers Squibb and owns stock in Merck. SR is employed by, owns stock in, and has received travel support from Bristol Myers Squibb and owns stock in Celgene. AD reports receiving honoraria from Bristol Myers Squibb; travel support from Johnson & Johnson; and advisory or data safety monitoring board fees from Swixx BioPharma. TC reports receiving consulting fees from AbbVie, Agios, BluePrint, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, and Servier; honoraria from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda; travel support from AbbVie, Bristol Myers Squibb/Celgene, Gilead, Novartis, Pfizer, and Servier; and advisory or data safety monitoring board fees from Astellas, Bristol Myers Squibb/Celgene, Incyte, Jazz Pharmaceuticals, Novartis, Servier, and Takeda. PF reports receiving grant support from AbbVie, Agios, Bristol Myers Squibb, and Novartis; and honoraria from AbbVie, Agios, Bristol Myers Squibb, and Novartis. UP reports receiving grant support paid to GWT-TUD, from Amgen and Janssen; grant support, paid to University of Leipzig, from Bristol Myers Squibb, Merck, and Novartis; consulting fees from AbbVie, Bristol Myers Squibb, Curis, Geron, Janssen, and Novartis; honoraria from Bristol Myers Squibb and Novartis; and fees for serving on a steering committee and travel support from Bristol Myers Squibb. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1 K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS., (© 2024. The Author(s).)

Higher-risk myelodysplastic syndromes (HR-MDS) are clonal myeloid neoplasms that cause life-limiting complications from severe cytopenias and leukemic transformation. Efforts to better classify, prognosticate, and assess therapeutic responses in HR-MDS have resulted in publication of new clinical tools in the last several years. Given limited current treatment options and suboptimal outcomes, HR-MDS stands to benefit from the study of investigational agents.Higher-risk myelodysplastic syndromes (HR-MDS) are a heterogenous group of clonal myeloid-lineage malignancies often characterized by high-risk genetic lesions, increased blood transfusion needs, constitutional symptoms, elevated risk of progression to acute myeloid leukemia (AML), and therapeutic need for allogeneic bone marrow transplantation. Use of blast percentage and other morphologic features to define myelodysplastic neoplasm subtypes is rapidly shifting to incorporate genetics, resulting in a subset of former HR-MDS patients now being considered as AML in presence of leukemia-defining genetic alterations. A proliferation of prognostic tools has further focused use of genetic features to drive decision making in clinical management. Recently, criteria to assess response of HR-MDS to therapy were revised to incorporate more clinically meaningful endpoints and better match AML response criteria. Basic science investigations have resulted in improved understanding of the relationship between MDS genetic lesions, bone marrow stromal changes, germline predispositions, and disease phenotype. However, therapeutic advances have been more limited. There has been import of the IDH1 inhibitor ivosidenib, initially approved for AML; the Bcl-2 inhibitor venetoclax and liposomal daunorubicin/cytarabine (CPX-351) are under active investigation as well. Unfortunately, effective treatment of TP53-mutated disease remains elusive, though preliminary evidence suggests improved outcomes with oral decitabine/cedazuridine over parenteral hypomethylating agent monotherapy. Investigational agents with novel mechanisms of action may help expand the repertoire of treatment options for HR-MDS and trials continue to offer a hopeful therapeutic avenue for suitable patients., Competing Interests: Disclosure M.J.H. has no conflicts of interest. A.E.D. has received consulting fees from or served on advisory boards for Novartis, Geron, Keros, AbbVie, Apellis, Bristo-Myers Squibb, and Astellas., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Imetelstat (RYTELO™), an oligonucleotide telomerase inhibitor, is being developed by Geron Corporation for the treatment of myeloid hematologic malignancies. In June 2024, imetelstat was approved in the USA for use in adult patients with low- to intermediate-1 risk myelodysplastic syndromes (MDS) with transfusion-dependent anemia requiring 4 or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents (ESA). This article summarizes the milestones in the development of imetelstat leading to this first approval for the treatment of adult patients with low- to intermediate-1 risk MDS with transfusion-dependent anemia., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The clinical application of the therapeutic approach in myelodysplastic syndromes (MDS) remains an insurmountable challenge for the high propensity for progressing to acute myeloid leukemia and predominantly affecting elderly individuals. Thus, the discovery of molecular mechanisms underlying the regulatory network of different programmed cell death holds great promise for the identification of therapeutic targets and provides insights into new therapeutic avenues. Herein, we found that disulfiram/copper (DSF/Cu) significantly repressed the cell viability, increased reactive oxygen species (ROS) accumulation, destroyed mitochondrial morphology, and altered oxygen consumption rate. Further studies verified that DSF/Cu induces cuproptosis, as evidenced by the depletion of glutathione (GSH), aggregation of lipoylated DLAT, and induced loss of Fe-S cluster-containing proteins, which could be rescued by tetrathiomolybdate and knockdown of ferredoxin 1 (FDX1). Additionally, GSH contributed to the tolerance of DSF/Cu-mediated cuproptosis, while pharmacological chelation of GSH triggered ROS accumulation and sensitized cell death. The xCT-GSH-GPX4 axis is the ideal downstream component of ferroptosis that exerts a powerful protective mechanism. Notably, classical xCT inhibitors were capable of leading to the catastrophic accumulation of ROS and exerting synergistic cell death, while xCT overexpression restored these phenomena. Simvastatin, an inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, has beneficial effects in repurposing for inhibiting GPX4. Similarly, the combination treatment of DSF/Cu and simvastatin dramatically decreased the expression of GPX4 and Fe-S proteins, ultimately accelerating cell death. Moreover, we identified that the combination treatment of DSF/Cu and simvastatin also had a synergistic antitumor effect in the MDS mouse model, with the reduced GPX4, increased COX-2 and accumulated lipid peroxides. Overall, our study provided insight into developing a novel synergistic strategy to sensitize MDS therapy by targeting ferroptosis and cuproptosis., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States., Patients and Methods: This retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©)., Results: A total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure., Conclusion: Our results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments., Competing Interests: Disclosure Guillermo Garcia-Manero received research support from Bristol Myers Squibb. Rayna K. Matsuno, Hina Mohammed, Danny Idryo, Ronda Broome, Autumn Herriman, Tiffany Johnson, Kristiana Wilkinson, Andrew Schrag, and Monika Izano are employees of Syapse. Rayna K. Matsuno, Hina Mohammed, Ronda Broome, Kristiana Wilkinson, and Monika Izano report divested equity in a private or publicly traded company in the past 24 months at Syapse. Rayna K. Matsuno, Hina Mohammed, Tiffany Johnson, and Colden Johanson also report research funding from Bristol Myers Squibb. Ali McBride and Adeola Makinde are employees of Bristol Myers Squibb. Sudipto Mukherjee participated in advisory boards for AbbVie, Blueprint Medicines, Bristol Myers Squibb, Celgene/Acceleron, EUSA Pharma, Genentech, and Novartis; received honoraria from the Aplastic Anemia and MDS International Foundation, Bristol Myers Squibb, Celgene, McGraw Hill Hematology Oncology Board Review, Partnership for Health Analytic Research, and EUSA Pharma; reports consultancy from BioPharm, Bristol Myers Squibb, Celgene, EUSA Pharma, and Novartis; and research funding to the institution from Celgene, Jazz Pharmaceuticals, and Novartis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent., Methods: This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete., Findings: Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified., Interpretation: An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes., Funding: Bristol Myers Squibb., Competing Interests: Declaration of interests MD-C reports receiving consulting fees from BMS, Novartis, Blueprint Medicines, GlaxoSmithKline, Agios Pharmaceuticals, Hemavan, Syros Pharmaceuticals, Keros Therapeutics, and Curis; honoraria for lectures, presentations, speaking bureaus, manuscript writing, or educational events from BMS, Novartis, and Keros Therapeutics. RCJ reports receiving support for attending meetings or travel from Novartis, AbbVie, and AstraZeneca and her participation on a data safety monitoring board or an advisory board for AstraZeneca and Novartis. J-ÁH-R reports grants or contracts from Janssen and Sanofi; consulting fees from Janssen, AbbVie, AstraZeneca, BeiGene, Lilly, and Menarini Stemline; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Roche, AbbVie, BeiGene, BMS and Celgene, Amgen, Takeda, AstraZeneca, Sanofi, and Lilly; support for attending meetings or travel from Janssen, AbbVie, Amgen, AstraZeneca, BeiGene, and Novartis; participating on a data safety monitoring board or an advisory Board for Janssen, Roche, AbbVie, BeiGene, BMS and Celgene, Amgen, Takeda, AstraZeneca, Sanofi and Lilly. JB reports receiving payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and Celgene; support for attending meetings or travel from BMS and Celgene; and participation on an advisory board for BMS and Celgene. UP reports grants or contracts from Amgen paid to GWT-TUD and the University of Leipzig; grants or contracts from Janssen paid to GWT-TUD; consulting fees from BMS, Novartis, AbbVie, Geron, and Curis; and support for attending meetings or travel from BMS. KSG reports grants or contracts from BMS; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from BMS and AbbVie; participation on a data safety monitoring board or an advisory board for BMS, AbbVie, and Jazz Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Myelodysplastic syndromes (MDS) patients with DEAD-box helicase 41 ( DDX41 ) mutations have been reported to be treated effectively with lenalidomide; however, there are no randomized studies to prove it. Venetoclax and azacitidine are safe and effective in high-risk MDS/AML. In this study, we evaluated the efficacy of venetoclax and azacitidine combination therapy in eight consecutive MDS patients with DDX41 mutations at our centre from March 2021 to November 2023. We retrospectively analyzed the genetic features and clinical characteristics of these patients. Our findings suggest that MDS patients with DDX41 mutation may benefit from the therapy, for six subjects received this regimen as initial therapy and five of the six subjects achieved complete remission.

Purpose: To explore the potential of testosterone therapy in managing cytopenias in myelodysplastic neoplasm and investigate the link between hypogonadism and hematologic malignancies., Methods: A case of a patient with intermediate-risk myelodysplastic neoplasm and hypogonadism treated with testosterone replacement therapy is presented. Testosterone, prostate specific antigen, and erythropoietin levels were checked prior to therapy initiation and 3 months after. Blood counts were monitored over time. This is followed by a literature review of testosterone use in myelodysplastic neoplasm and the prevalence of hypogonadism in hematologic malignancies., Results: The patient showed sustained improvement in anemia with testosterone therapy and reported subjective improvement in his weakness and fatigue. This improvement occurred even in the setting of an undetectable follow up erythropoietin level. His repeat prostate specific antigen levels remained low, while testosterone levels showed marked improvement. The literature review demonstrated positive response rates for testosterone in treating myelodysplastic neoplasm-related cytopenias, and showed a higher incidence of hypogonadism in hematologic malignancies., Conclusion: Our review suggests that the use of testosterone in low and intermediate-risk myelodysplastic neoplasm is underexplored and poses to have significant potential as a future therapeutic agent, after careful consideration of risks and benefits. In addition, the incidence of hypogonadism in myelodysplastic neoplasm and its potential impact on exacerbating cytopenias in myelodysplastic neoplasm warrants further investigation., (© 2024. The Author(s).)

Hypomethylating agents (HMAs) are frontline therapies for Myelodysplastic Neoplasms (MDS) and Acute Myeloid Leukemia (AML). However, acquired resistance and treatment failure are commonplace. To address this, we perform a genome-wide CRISPR-Cas9 screen in a human MDS-derived cell line, MDS-L, and identify TOPORS as a loss-of-function target that synergizes with HMAs, reducing leukemic burden and improving survival in xenograft models. We demonstrate that depletion of TOPORS mediates sensitivity to HMAs by predisposing leukemic blasts to an impaired DNA damage response (DDR) accompanied by an accumulation of SUMOylated DNMT1 in HMA-treated TOPORS-depleted cells. The combination of HMAs with targeting of TOPORS does not impair healthy hematopoiesis. While inhibitors of TOPORS are unavailable, we show that inhibition of protein SUMOylation with TAK-981 partially phenocopies HMA-sensitivity and DDR impairment. Overall, our data suggest that the combination of HMAs with inhibition of SUMOylation or TOPORS is a rational treatment option for High-Risk MDS (HR-MDS) or AML., (© 2024. The Author(s).)

Objective: To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) . Methods: A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results: Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype ( P =0.02, OR =0.39, 95% CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation ( P =0.02, OR =0.22, 95% CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95% CI 21.14-30.19) months. HMA response ( P =0.036, HR =0.47, 95% CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype ( P =0.024, HR =2.14, 95% CI 1.10-4.15) , leukemia transformation ( P <0.001, HR =2.839, 95% CI 1.64-4.92) , and TP53 mutation ( P =0.012, HR =2.19, 95% CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P =0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion: Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Abstract: Ivosidenib is a first-in-class mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor with efficacy and tolerability in patients with advanced mIDH1 hematologic malignancies, leading to approval in frontline and relapsed/refractory (R/R) mIDH1 acute myeloid leukemia. We report final data from a phase 1 single-arm substudy of once-daily ivosidenib in patients with R/R mIDH1 myelodysplastic syndrome (MDS) after failure of standard-of-care therapies. Primary objectives were to determine safety, tolerability, and clinical activity. The primary efficacy end point was the complete remission (CR) + partial remission (PR) rate. Nineteen patients were enrolled; 18 were included in the efficacy analysis. Treatment-related adverse events occurred in 8 (42.1%) patients, including a grade 1 QT interval prolongation in 1 (5.3%) patient and grade 2 differentiation syndrome in 2 (10.5%) patients. Rates of CR + PR and objective response (CR + PR + marrow CR) were 38.9% (95% confidence interval [CI], 17.3-64.3) and 83.3% (95% CI, 58.6-96.4), respectively. Kaplan-Meier estimates showed a 68.6% probability of patients in CR achieving a remission duration of ≥5 years, and a median overall survival of 35.7 months. Of note, 71.4% and 75.0% baseline red blood cell (RBC)- and platelet-transfusion-dependent patients, respectively, became transfusion independent (TI; no transfusion for ≥56 days); 81.8% and 100% of baseline RBC and platelet TI patients, respectively, remained TI. One (5.3%) patient proceeded to a hematopoietic stem cell transplant. In conclusion, ivosidenib is clinically active, with durable remissions and a manageable safety profile observed in these patients. This trial was registered at www.ClinicalTrials.gov as #NCT02074839., (© 2024 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.)

Objective: To analyze the efficacy and safety of low-dose azacitidine in the treatment of senile myelodysplastic syndromes (MDS)., Methods: A total of 92 elderly MDS patients who were initially diagnosed in the Huaibei Miners General Hospital and the Affiliated Hospital of Xuzhou Medical University from January 2018 to June 2022 were randomly divided into the observation group and the control group with 46 patients in each group. The observation group received a low dose of azacitidine 100 mg/d, d1-7, 28 days as a course of treatment, 6 courses in total, and the control group received a standard dose of azacitidine 75 mg(m 2 ·d), d1-7, 28 days as a course of treatment, a total of 6 courses of treatment. The clinical efficacy, overall survival (OS) and adverse reactions of the two groups of patients were observed., Results: There was no statistically significant difference in the clinical data between the two groups ( P >0.05). After treatment, the hemoglobin and platelet levels of the two groups of patients were significantly higher than before treatment in each group ( P < 0.05). There was no statistically significant difference in leukocyte, hemoglobin and platelet levels between patients in the observation group and control group ( P >0.05). The number of cases with complete remission, partial remission, hematological remission, disease stabilization and disease progression in the observation group were 4, 10, 22, 6 and 4, respectively, with a total effective rate of 78.26%. The numbers of cases with complete remission, partial remission, hematological remission, disease stabilization and disease progression in control group were 8, 12, 18, 4 and 4, respectively, with a total effective rate of 82.61%. The total effective rate of patients in the observation group was slightly lower than that of the control group(χ 2 =0.457, P =0.254). There was no significant difference between the two treatment schemes in the treatment of patients with blood transfusion dependence and patients with low risk, medium risk and high risk ( P >0.05). It takes 4 and 6 courses of treatment to achieve the best treatment response in the control group and observation group respectively. There was no significant difference in OS between the two groups ( P >0.05). In the observation group, there were 4, 6 and 2 cases of infection, III-IV degree myelosuppression and gastrointestinal reaction, respectively, with the incidence rate of adverse events being 26.09%. In the control group, there were 6, 16 and 6 cases of infection, III-IV degree myelosuppression and gastrointestinal reaction, respectively, with the adverse event rate was 60.87%. The incidence of adverse events in the control group was significantly higher than that in the observation group (χ 2 =7.095, P =0.036)., Conclusion: Elderly patients with MDS have poor tolerance to chemotherapy. Reducing azacitidine in the treatment of elderly MDS patients shows good efficacy and safety.

As a selective and potent inhibitor targeting the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib obtained approval from the US Food and Drug Administration (FDA) in 2017 for adult patients with acute myeloid leukemia (AML) with an IDH2 mutation. In vitro investigations demonstrated that enasidenib affects various drug metabolic enzymes and transporters. This current investigation aimed to assess enasidenib on the pharmacokinetics (PKs) of CYP substrates, including dextromethorphan (CYP2D6 probe drug), flurbiprofen (CYP2C9 probe drug), midazolam (CYP3A4 probe drug), omeprazole (CYP2C19 probe drug), and pioglitazone (CYP2C8 probe drug), in patients with AML or myelodysplastic syndrome. Results showed that following the co-administration of enasidenib (100 mg, once daily) for 28 days, the PK parameters AUC (0-∞) and C max of dextromethorphan increased by 1.37 (90% confidence interval (CI): 0.96, 1.96) and 1.24 (90% CI: 0.94, 1.65)-fold, respectively, compared to dextromethorphan alone. For flurbiprofen, these parameters increased by 1.14 (90%CI: 1.01, 1.29) and 0.97 (90% CI 0.86, 1.08)-fold, respectively, when compared to flurbiprofen alone. Conversely, midazolam exhibited decreases to 0.57 (90% CI 0.34, 0.97) and 0.77 (90% CI 0.39, 1.53)-fold, respectively, in comparison to midazolam alone. The parameters for omeprazole increased by 1.86 (90% CI: 1.33, 2.60) and 1.47 (0.93, 2.31)-fold, respectively, compared to omeprazole alone, while those for pioglitazone decreased to 0.80 (90% CI: 0.62, 1.03) and 0.87 (90% CI: 0.65, 1.16)-fold, respectively, in comparison to pioglitazone alone. These findings provide valuable insights into dose recommendations concerning drugs acting as substrates of CYP2D6, CYP2C9, CYP3A4, CYP2C19, and CYP2C8 when administered concurrently with enasidenib., (© 2024, The American College of Clinical Pharmacology.)

Myeloid sarcoma (MS) occurs in patients with acute myeloid leukemia (AML). In rare cases, MS can represent a form of blast transformation in patients with myeloproliferative neoplasms (MPN), myelodysplastic neoplasms (MDS), or MDS/MPN. The most frequent chromosomal alterations in MS are t(8;21) or inv(16), with other alterations being reported. Cases of MS in Janus kinase 2 (JAK2)-positive MDS with fibrosis are exceedingly rare. Here, we describe such a case. To the best of our knowledge, this is the first report of a JAK2 V617F mutation-positive MDS case occurring concurrently with MS involving the posterior aspect of the left seventh rib. No clear association has been previously demonstrated between the intramedullary AML cytogenetics and extramedullary disease occurrence. Interestingly, samples from the intramedullary MDS and extramedullary mass in this patient presented the same JAK2 V617F mutation. Following a treatment regimen of azacitidine and venetoclax, the patient achieved complete remission. The chest CT scan showed that the seventh posterior rib mass disappeared. This case provides valuable information for the potential future treatment of this disease., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors., (©2024 American Association for Cancer Research.)

Rational: Patients with gastric cancer show a relatively low incidence of developing secondary myelodysplastic syndrome (MDS)., Patient Concerns: A 60-year-old man was admitted because of pain and discomfort in the upper abdomen and intermittent abdominal pain., Diagnoses: Ulcerative moderately poorly differentiated adenocarcinoma (pT2N2M0G3, stage IIB) and MDS., Interventions: The patient underwent chemotherapy with oxaliplatin (OXP, intravenously guttae on day 1) plus capecitabine (CAP, bis in die orally on day 1-14). The patient developed degree III myelosuppression after OXP plus CAP chemotherapy and MDS was subsequently confirmed by diagnosis of the bone marrow biopsy. Temporary but significant hematological improvements were observed after the patient received corresponding treatment, which helped achieve remission and improve pancytopenia., Outcomes: The patient presented partial remission after corresponding treatment and no other complications have been recorded., Lessons: Acute MDS is an unusual adverse effect induced by OXP plus CAP chemotherapy. It is urgent to suggest implementing a supplementary assessment or examination for patients receiving these therapies in future cases., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: Venetoclax selectively inhibits B-cell lymphoma 2 (BCL-2) and restores apoptotic signaling of hematologic malignant cells. Venetoclax, in combination with hypomethylating and low-dose cytotoxic agents, has revolutionized the management of older patients affected by acute myeloid leukemia (AML) and that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed or refractory AML, the combination of venetoclax and intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax, when combined with hypomethylating agents and cytotoxic drugs, seems to be a safe and efficacious bridge to transplant. The promising results on the use of venetoclax combinations in advanced myelodysplastic syndromes (MDS) and therapy-related MDS/AML have also been reported in small case series. This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms and discusses the possible integration of BCL-2 inhibition in the current treatment algorithm of these children. It also focuses on specific genetic subgroups potentially associated with response in preclinical and clinical studies., (© 2024 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.)

Objective: Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC)., Methods: All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs., Results: Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months., Conclusions: Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis., (© 2024 Japan Society of Obstetrics and Gynecology.)

Thrombopoietin receptor agonists (TPO-RAs) induce trilineage hematopoiesis under conditions with acquired hematopoietic failure. We evaluated safety, tolerability, and preliminary efficacy of a TPO-RA, romiplostim (Nplate), with or without standard-of-care immunosuppressive therapy (±IST) for children (ages < 21 y) with newly diagnosed and relapsed/refractory severe aplastic anemia (SAA) and myelodysplastic syndrome (MDS). Data were collected from an observational study and a single arm interventional pilot study. The safety outcome was treatment-related adverse events (AEs). Efficacy was evaluated by complete hematopoietic response (CHR) at week 24. Romiplostim was commenced at 5 µg/kg/week, with dose escalation of 2.5 µg/kg/week (maximum, 20 µg/kg/dose) based on platelet response. Romiplostim was continued until CHR was observed. Ten subjects (SAA, 9 [IST, 4; without IST, 5]; MDS, 1) completed the study (median age: 9.2 y). Median romiplostim dose was 10 µg/kg/week (range: 5 to 17.5 µg/kg/week). The cumulative incidence of CHR was 70.4% (95% CI, 20.2%-92.6%). Among 21 AEs (Grade 1 to 3), 3 were attributed to romiplostim. At a median posttherapy follow-up of 10.9 months (range: 0.7 to 77.5), no clonal evolution, bone marrow fibrosis or mortality was reported. This proof-of-concept study provides data about short-term safety, tolerability, and preliminary efficacy of romiplostim (±IST) for treatment of pediatric SAA/MDS., Competing Interests: A.S. received funding from Amgen, Inc, to conduct this pilot study under investigator sponsored study category. Funding agency has no role in study design, data analyses and publication of the manuscript. M.B. is founder and chief executive officer of LSF Medical Solutions whose work does not overlap topically with this work. The other authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP) enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field., (© 2024, The American College of Clinical Pharmacology.)

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Mouse double minute-2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes., Methods: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high-risk myelodysplastic syndromes., Results: Seventy-four patients (monotherapy, n = 57; milademetan-AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14-21 days of 28-day cycles as monotherapy and on Days 5-14 in combination with AZA. Dose-limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment-emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre-existing below standard detection frequency by droplet digital polymerase chain reaction., Interpretation: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Splicing factors are frequently mutated in patients with myelodysplastic syndromes and acute myeloid leukaemia. Recent studies have revealed convergent molecular defects caused by splicing factor mutations, among which R-loop dysregulation and resultant genome instability are suggested as contributing factors to disease progression. On the other hand, understanding how mutant cells survive upon aberrant R-loop formation and genome instability is essential for developing novel therapeutics., Methods: The immunoprecipitation was performed to identify R-loops in association with PARP1/poly-ADP-ribosylation. The western blot, immunofluorescence, and flow cytometry assays were used to test the cell viability, cell cycle arrest, apoptosis, and ATM activation in mutant cells following the treatment of the PARP inhibitor. The Srsf2(P95H) knock-in murine hematopoietic cells and MLL-AF9 transformed leukaemia model were generated to investigate the potential of the PARP inhibitor as a therapy for haematological malignancies., Results: The disease-causing mutations in SRSF2 activate PARP and elevate the overall poly-ADP-ribosylation levels of proteins in response to R-loop dysregulation. In accordance, mutant cells are more vulnerable to the PARP inhibitors in comparison to the wild-type counterpart. Notably, the synthetic lethality was further validated in the Srsf2(P95H) knock-in murine hematopoietic cell and MLL-AF9 leukaemia model., Conclusions: Our findings suggest that mutant cells antagonise the genome threat caused by R-loop disruption by PARP activation, thus making PARP targeting a promising therapeutic strategy for myeloid cancers with mutations in SRSF2., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0-38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138., Competing Interests: Declaration of Competing Interest GMB declares grant/research support from Takeda, Rigel and IFM Therapeutics. M.K. declares consulting and honoraria from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji; research funding and/or clinical trial support from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and Astra Zeneca; and stock options/royalties from Reata Pharmaceutical. H.K. declares research support from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer, honoraria from AbbVie, Actinium, Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda, and an advisory role with Actinium. G.G-M. declares support from and an advisory role with Celgene Corporation, Astex, and Amphivena, and grant/research support 15 from Helsinn, Novartis, AbbVie, Onconova, H3 Biomedicine, and Merck. S.L grant/research support from Amgen and Astellas and consulting and honoraria from Guidepoint, Qual World, Gerson Lehman Group, Caris, Blueprint Medicines Corporation, Daiichi Sankyo, Recordati, Abbvie, and Arima and owns Abbvie stocks. The rest of authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests. All co-author shave seen and approved this version of the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)