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Russell Lewis, Jan Philipp Bewersdorf, Amer M Zeidan Department of Medicine, Section of Hematology, Yale University, New Haven, CT, USACorrespondence: Amer M ZeidanDepartment of Medicine, Section of Hematology, Smilow Cancer Center at Yale New Haven Hospital, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028, USAEmail amer.zeidan@yale.eduAbstract: For the majority of patients with lower-risk myelodysplastic syndrome (LR-MDS), one of the primary clinical goals is to alleviate the symptoms associated with the resultant cytopenias and to minimize the transfusion burden. While supportive red blood cell (RBC) transfusions and erythropoiesis-stimulating agents (ESAs) may lead to clinical improvement, frequent transfusions are often complicated by iron overload and decreased quality of life; furthermore, most patients either do not respond to ESAs or will eventually develop resistance. As such, there is a great need for further therapeutic options in the management of anemia related to MDS. Several additional therapeutics are now available in select patients with LR-MDS and symptomatic anemia including luspatercept, lenalidomide, and immunosuppressive therapy. Furthermore, several novel agents are currently in development to address this area of clinical need such as imetelstat and roxadustat. In this article, we review the currently available therapeutic options for symptomatic anemia in LR-MDS as well as review the therapeutic agents in development.Keywords: myelodysplastic syndrome, erythropoiesis-stimulating agents, novel agents, clinical trials

Jan Philipp Bewersdorf,1 Sara Mohamed Jaszczur,2 Salma Afifi,2 Jennifer C Zhao,2 Amer M Zeidan1,3 1Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT, USA; 2Department of Pharmacy, Yale New Haven Hospital, New Haven, CT, USA; 3Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale University, New Haven, CT, USACorrespondence: Amer M ZeidanSection of Hematology, Department of Internal Medicine, Yale University, 37 College Street, PO Box 208028, New Haven, CT 06520-8028, USATel +1 203-737-7103Fax +1 203-785-7232Email amer.zeidan@yale.eduAbstract: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal proliferation of differentiated myeloid cells leading to bone marrow fibrosis, cytopenias and extramedullary hematopoiesis. In late 2019, the FDA approved the highly selective JAK2 inhibitor, fedratinib, for intermediate-2 or high-risk primary or secondary MF, making it the second drug approved for MF after ruxolitinib, a JAK1/2 inhibitor, which was approved for MF in 2011. The approval of fedratinib was based on phase II trials and the phase III JAKARTA trial, in which the drug significantly reduced splenomegaly and symptom burden compared to placebo, including some patients previously treated with ruxolitinib. The main side effects of fedratinib include anemia, gastrointestinal symptoms, and elevations in liver transaminases. Fedratinib also has ablack box warning for encephalopathy, although this occurred only in about 1% of the treated patients, most of which were ultimately felt not to represent Wernicke’s encephalopathy. Nonetheless, monitoring of thiamine levels and supplementation are recommended especially in high-risk patients. This concern has led to a prolonged clinical hold and delayed the drug approval by several years during which the drug exchanged manufacturers, highlighting the need for meticulous investigation and adjudication of serious, but rare, adverse events in drug development that could end up preventing drugs with favorable risk/benefit ratio from being approved. In this review, we discuss the pharmacokinetic data and efficacy, as well as the toxicity results of clinical trials of fedratinib. We also review ongoing trials of JAK inhibitors in MF and explore future treatment options for MF patients who are refractory to ruxolitinib.Keywords: fedratinib, ruxolitinib, myelofibrosis, MF, JAK2

The WHO and International Consensus Classification 2022 classifications of myelodysplastic syndromes enhance diagnostic precision and refine decision-making processes in these diseases. However, some discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. We adopted a data-driven approach to provide a harmonisation between these two classification systems. We investigated the importance of genomic features and their effect on the cluster assignment process to define harmonised entity labels. A panel of expert haematologists, haematopathologists, and data scientists who are members of the International Consortium for Myelodysplastic Syndromes was formed and a modified Delphi consensus process was adopted to harmonise morphologically defined categories without a distinct genomic profile. The panel held regular online meetings and participated in a two-round survey using an online voting tool. We identified nine clusters with distinct genomic features. The cluster of highest hierarchical importance was characterised by biallelic TP53 inactivation. Cluster assignment was irrespective of blast count. Individuals with monoallelic TP53 inactivation were assigned to other clusters. Hierarchically, the second most important group included myelodysplastic syndromes with del(5q). Isolated del(5q) and less than 5% of blast cells in the bone marrow were the most relevant label-defining features. The third most important cluster included myelodysplastic syndromes with mutated SF3B1. The absence of isolated del(5q), del(7q)/-7, abn3q26.2, complex karyotype, RUNX1 mutations, or biallelic TP53 were the basis for a harmonised label of this category. Morphologically defined myelodysplastic syndrome entities showed large genomic heterogeneity that was not efficiently captured by single-lineage versus multilineage dysplasia, marrow blasts, hypocellularity, or fibrosis. We investigated the biological continuum between myelodysplastic syndromes with more than 10% bone marrow blasts and acute myeloid leukaemia, and found only a partial overlap in genetic features. After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting., Competing Interests: Declaration of interests UG reports speaker honoraria from Novartis, AbbVie, and BMS; and institutional research support from BMS, AbbVie, and Jazz Pharmaceuticals. FE reports consultancy or advisory roles for AbbVie, Incyte, Syros, Novartis, and Jazz Pharmaceuticals. SH reports research support from STORM Therapeutics and AstraZeneca. EAG reports honoraria from AAMDS, MedscapeLIVE!, MediCom Worldwide, MJH Life Sciences, ASH, MDS International Foundation, and Physicians’ Education Resource; consulting fees from AbbVie, Alexion, Apellis, Takeda Oncology, Astex/Taiho Oncology, Alexion/AstraZeneca Rare Disease, Celgene/BMS, CTI BioPharma, Novartis, Partner Therapeutics, Picnic Health, and Servier; and research funding from Alexion, Apellis, Astex /Otsuka/Taiho Oncology, Blueprint Medicines, Celldex Therapeutics, Genentech, and NextCure. MAS reports participation on advisory boards for BMS, Kurome, Schrödinger, and Karyopharm. MD-C reports participation on a data safety monitoring board or advisory board for BMS, Novartis, Blueprint Medicines, GSK, Agios, Hemavan, Syros, Keros, Curis, and Astex/Otsuka; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events for BMS, Novartis, and Keros. UP reports research support and honoraria from BMS, Geron, Curis, AbbVie, and Janssen. RBe reports employment or equity from Aptose Biosciences; participation on advisory boards for BMS, Servier, NeoGenomics, and Geron; being Data Monitoring Committee Chair for Gilead, Ipsen, and Keros; and consultancy for TenSixteen. YM reports honoraria from Nippon Shinyaku, BMS, Novartis, Sumitomo Pharma, Kyowa Kirin, AbbVie, Daiichi Sankyo, Takeda, Janssen, Astellas, Pfizer, Eisai, and Otsuka; and research funding from Chugai. AED reports participation on advisory boards, consultancy, or honoraria from Celgene/BMS, Agios, Novartis, Astellas, and Gilead; and participation on clinical trial committees or data safety monitoring boards for Novartis, AbbVie, Kura, Geron, Servier, Keros, and Celgene/BMS. DPS reports employment by Ajax Therapeutics; former employment by Novartis; and minor equity in Arrowhead and Bluebird. TKK reports consultancy for Agenus and ImmunoBiome. AK reports research support from Novartis and BMS; consulting fees from Alexion, Novartis, Amgen, Agios, Pfizer, Samsung, Celgene, F Hoffmann-La Roche, and Sobi; honoraria from Alexion, Novartis, Pfizer, Amgen, Samsung, Celgene, F Hoffmann-La Roche, BMS, Sobi, and Silence Therapeutics; and speakers fees from Alexion, Novartis, Amgen, Pfizer, Celgene, F Hoffmann-La Roche, and Sobi. 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.)

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 duration 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.

Abstract: Although intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remission among older patients with nucleophosmin 1 (NPM1) mutations. Whether IC or HMA/VEN is superior in patients aged ≥60 years with NPM1-mutant AML is unknown. We performed an international, multicenter retrospective cohort study of 221 patients (147 IC and 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR) (defined as CR + CR with incomplete count recovery) rate was similar for IC and HMA/VEN (cCR, 85% vs 74%; P = .067). Although overall survival (OS) was favorable with IC in unselected patients compared with HMA/VEN (24-month OS, 59% [95% confidence interval (CI), 52-69%] vs 38% [95% CI, 27-55%]; P = .013), it was not statistically different among patients aged 60-75 years (60% [95% CI, 52-70%] vs 44% [95% CI, 29-66%]; P = .069) and patients who received an allogeneic stem cell transplant (70% [95% CI, 58-85%] vs 66% [95% CI, 44-100%]; P = .56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS, 65% [95% CI, 56-74%] with IC vs 40% [95% CI, 26-60%] with HMA/VEN; P = .009) and without FLT3 internal tandem duplication mutations might benefit from IC compared with HMA/VEN (24-month OS, 68% [95% CI, 59-79%] vs 43% [95% CI, 29-63%]; P = .008). In multivariable analysis, OS was not statistically different between patients treated with IC and HMA/VEN (hazard ratio for death with HMA/VEN vs IC, 0.71; 95% CI, 0.40-1.27; P = .25)., (© 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.)

Myelodysplastic neoplasms/syndromes (MDS) are a heterogeneous group of biologically distinct entities characterized by variable degrees of ineffective hematopoiesis. Recently, two classification systems (the 5th edition of the WHO Classification and the International Consensus Classification) further sub-characterized MDS into morphologic and genetically defined groups. Accurate diagnosis and subclassification of MDS require a multistep systemic approach. The International Consortium for MDS (icMDS) summarizes a contemporary, practical, and multimodal approach to MDS diagnosis and classification., (Copyright © 2024. Published by Elsevier Inc.)

Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms., Competing Interests: Declaration of competing interest RMS had a consultancy with Bristol Myers Squibb, Curio Science, Gilead Sciences, Kura Oncology, Servier, and Rigel and served in Steering Committees for Servier. MS served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, Rigel, BMS, Sobi and Syndax; consulted for Boston Consulting and Dedham group and participated in CME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options. AMZ reports receiving grant support from AbbVie, ADC Therapeutics, Amgen, Aprea, Astex, AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Bristol Myers Squibb, Incyte, Medimmune, Novartis, Otsuka, Pfizer, Takeda, and Trovagene; consulting fees from AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas Pharma, BeyondSpring, Bristol Myers Squibb, Boehringer-Ingelheim, Cardiff Oncology, Cardinal Health, Daiichi Sankyo, Epizyme, Geron, Gilead, Incyte, Ionis, Janssen, Jazz Pharmaceuticals, Kura, Novartis, Otsuka, Pfizer, Seattle Genetics, Syndax, Taiho, Takeda, Trovagene, and Tyme; travel support from Cardiff Oncology, Novartis, and Pfizer; and serving on clinical trial committees of AbbVie, Bristol Myers Squibb, Geron, Gilead, Kura, and Novartis, (Copyright © 2024 Elsevier Inc. All rights reserved.)

The FLT3 inhibitor quizartinib has been shown to improve overall survival when added to intensive induction chemotherapy ("7 + 3") in patients 18-75 years old with newly diagnosed AML harboring a FLT3- ITD mutation. However, the health economic implications of this approval are unknown. We evaluated the cost-effectiveness of quizartinib using a partitioned survival analysis model. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, the addition of quizartinib to 7 + 3 resulted in incremental costs of $289,932 compared with 7 + 3 alone. With an incremental gain of 0.84 quality-adjusted life years (QALYs) with quizartinib + 7 + 3 induction vs. 7 + 3 alone, the incremental cost-effectiveness ratio for the addition of quizartinib to standard 7 + 3 was $344,039/QALY. Only an 87% reduction in the average wholesale price of quizartinib or omitting quizartinib continuation therapy after completion of consolidation therapy and allogeneic hematopoietic cell transplant would make quizartinib a cost-effective option.

Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 CCUS patients investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count <100×109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the Clonal Cytopenia Risk Score (CCRS), which stratified patients into low- (score <2.5 points), intermediate- (score 2.5-<5), and high-risk (score ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high- (37.2%) risk groups, respectively, by Gray's test (P <.0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P =.005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs., (Copyright © 2024 American Society of Hematology.)

Acute myeloid leukemia (AML) is a complex hematological malignancy characterized by diverse genetic alterations, each with distinct clinical implications. Chromosome 3 inversion (inv(3)) is a rare genetic anomaly found in approximately 1.4-1.6% of AML cases, which profoundly affects prognosis. This review explores the pathophysiology of inv(3) AML, focusing on fusion genes like GATA2::EVI1 or GATA2::MECOM . These genetic rearrangements disrupt critical cellular processes and lead to leukemia development. Current treatment modalities, including intensive chemotherapy (IC), hypomethylating agents (HMAs) combined with venetoclax, and allogeneic stem cell transplantation are discussed, highlighting outcomes achieved and their limitations. The review also addresses subgroups of inv(3) AML, describing additional mutations and their impact on treatment response. The poor prognosis associated with inv(3) AML underscores the urgent need to develop more potent therapies for this AML subtype. This comprehensive overview aims to contribute to a deeper understanding of inv(3) AML and guide future research and treatment strategies.

Background: TP53 mutations are associated with an adverse prognosis in acute myeloid leukemia (AML) and higher-risk myelodysplastic syndromes (HR-MDS). However, the integrated genetic, epigenetic, and immunologic landscape of TP53 -mutated AML/HR-MDS is not well defined., Objectives: To define the genetic, epigenetic, and immunologic landscape of TP53- mutant and TP53 wild-type AML and HR-MDS patients., Design: Post hoc analysis of TP53- mutant and TP53 wild-type patients treated on the randomized FUSION trial with azacitidine ± the anti-PD-L1 antibody durvalumab., Methods: We performed extensive molecular, epigenetic, and immunologic assays on a well-annotated clinical trial dataset of 61 patients with TP53- mutated disease (37 AML, 24 MDS) and 144 TP53 wild-type (89 AML, 55 MDS) patients, all of whom received azacitidine-based therapy. A 38 gene-targeted myeloid mutation analysis from screening bone marrow (BM) was performed. DNA methylation arrays, immunophenotyping and immune checkpoint expression by flow cytometry, and gene expression profiles by bulk RNA sequencing were assessed at baseline and serially during the trial., Results: Global DNA methylation from peripheral blood was independent of TP53 mutation and allelic status. AZA therapy led to a statistically significant decrease in global DNA methylation scores independent of TP53 mutation status. In BM from TP53- mutant patients, we found both a higher T-cell population and upregulation of inhibitory immune checkpoint proteins such as PD-L1 compared to TP53 wild-type. RNA sequencing analyses revealed higher expression of the myeloid immune checkpoint gene LILRB3 in TP53- mutant samples suggesting a novel therapeutic target., Conclusion: This integrated analysis of the genetic, epigenetic, and immunophenotypic landscape of TP53 mutant AML/HR-MDS suggests that differences in the immune landscape resulting in an immunosuppressive microenvironment rather than epigenetic differences contribute to the poor prognosis of TP53- mutant AML/HR-MDS with mono- or multihit TP53 mutation status., Trial Registration: FUSION trial (NCT02775903)., Competing Interests: AMZ received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron, and Celgene/BMS. RMS participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc.; divested equity interest in Curis Oncology. IB, ET, DLM, BF, VH, and SR are employees of Celgene, a Bristol Myers Squibb company, and may be shareholders. SH has received research funding received honoraria from FORMA Therapeutics. TH is the owner of Munich Leukemia Laboratory. All other authors have no relevant conflicts of interest to declare., (© The Author(s), 2024.)

Purpose of Review: Myelodysplastic syndromes/neoplasms (MDS) represent a diverse group of pathologically distinct diseases with varying prognoses and risks of leukemia progression. This review aims to discuss current treatment options for elderly patients with MDS, focusing on patients ineligible for intensive chemotherapy or allogenic hematopoietic stem cell transplantation (HSCT). The challenges associated with treatment in this population and emerging therapeutic prospects are also explored., Recent Findings: Recent advancements in molecular diagnostics have enhanced risk stratification by incorporating genetic mutations, notably through the molecular International Prognostic Scoring System (IPSS-M). Lower-risk MDS (LR-MDS) treatment ranges from observation to supportive measures and erythropoiesis-stimulating agents (ESAs), with emerging therapies like luspatercept showing promise. High-risk MDS (HR-MDS) is treated with hypomethylating agents (HMAs) or allogenic HSCT, but outcomes remain poor. Elderly MDS patients, often diagnosed after 70, pose challenges in treatment decision-making. The IPSS-M aids risk stratification, guiding therapeutic choices. For LR-MDS, supportive care, ESAs, and novel agents like luspatercept are considered. Treatment of HR-MDS involves HMAs or allogenic HSCT. Emerging treatments, including oral HMAs and novel agents targeting FLT3, and IDH 1/2 mutations, show promise. Future research should refine treatment strategies for this elderly population focusing on quality-of-life improvement., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.

Notable treatment advances have been made in recent years for patients with myelodysplastic syndromes/neoplasms (MDS), and several new drugs are under development. For example, the emerging availability of oral MDS therapies holds the promise of improving patients' health-related quality of life (HRQoL). Within this rapidly evolving landscape, the inclusion of HRQoL and other patient-reported outcomes (PROs) is critical to inform the benefit/risk assessment of new therapies or to assess whether patients live longer and better, for what will likely remain a largely incurable disease. We provide practical considerations to support investigators in generating high-quality PRO data in future MDS trials. We first describe several challenges that are to be thoughtfully considered when designing an MDS-focused clinical trial with a PRO endpoint. We then discuss aspects related to the design of the study, including PRO assessment strategies. We also discuss statistical approaches illustrating the potential value of time-to-event analyses and their implications within the estimand framework. Finally, based on a literature review of MDS randomized controlled trials with a PRO endpoint, we note the PRO items that deserve special attention when reporting future MDS trial results. We hope these practical considerations will facilitate the generation of rigorous PRO data that can robustly inform MDS patient care and support treatment decision-making for this patient population., Competing Interests: Fabio Efficace had consultancy or advisory role for AbbVie, Incyte, Syros, Novartis, and JAZZ Pharmaceuticals outside the submitted work. Rena Buckstein: Research funding and honoraria for advisory boards and speaking engagements from BMS, TAIHO, and Abbvie. Gregory A. Abel has consulted for Novartis and Geron outside the submitted work. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen; and had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Andrew M. Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead; and has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Rafael Bejar owns equity in and is employed by Aptose Biosciences; he has served as an advisor to BMS, Servier, Gilead, and Ipsen; he is on the SAB for NeoGenomics. Amy E DeZern participated in advisory boards, and/or had a consultancy with and received honoraria from Celgene/BMS, Agios, Regenergon, Sobi, Novartis, Astellas, and Gilead. Amy E. DeZern served on clinical trial committees for Novartis, Abbvie, Kura, Geron, and Celgene/BMS. Gail J. Roboz: Consultancy: Abbvie, Amgen, Astra Zeneca, Bristol‐Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, Genoptix, Geron, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Oncoverity, OncoPrecision, Rigel, Roche, Syndax, Takeda (IRC Chair), Telix Pharma; and research support: Janssen. Michael R. Savona: Membership on a board or advisory committee: Bristol Myers Squibb, CTI, Forma, Geron, GSK, Karyopharm, Rigel Ryvu, Taiho, Takeda, Treadwell; patents and royalties: Boehringer Ingelheim, Empath Biosciences; research funding: ALX Oncology, Astex, Incyte, Takeda, TG Therapeutics; equity ownership: Empath Biosciences, Karyopharm, Ryvu; consultancy: Forma, Geron, Karyopharm, Ryvu. Rami Komrokji: Abbvie: Speaker Bureau, Advisory board; BMS: Research grant, Advisory board; DSI: Advisory board; Geron: Consultancy; Janssen: Consultancy; Jazz: Speaker Bureau, Advisory board; Pharma Essentia: Speaker Bureau, Advisory board; Rigel: Speaker Bureau, Advisory board; Servio: Speaker Bureau, Advisory board; Sobi: Speaker Bureau, Advisory board; Sumitomo Pharma: consultancy, Advisory board. David A. Sallman served on the advisory board or panel for Agios, Avencell, BlueBird Bio, BMS, Dark Blue, Jasper Therapeutics, Kite, Magenta Therapeutics, NKARTA, Novartis, Rigel Shattuck Labs, Servier, Syndax, Syros; and had a consultancy with AbbBie, Gilead, Molecular Partners AG, Takeda. Guillermo Sanz received honoraria, advisory board membership, or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Hetty E. Carraway: Consultancy: Abbvie, Amgen, Bristol‐Myers Squibb, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Rigel, Syndax, Servier; and research support: Celgene. Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera, GSK, Rigel, and Sierra Oncology; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media, and Clinical care options (CCO). Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/Astra Zeneca, Boehringer‐Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. He participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer‐Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. He served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron, and Celgene/BMS. Fabio Efficace, Rena Buckstein, and Gregory A. Abel report being involved in the development and validation of the QUALMS, one of the PROs discussed in this paper. The QUALMS is copyrighted by Dana‐Farber Cancer Institute (DFCI) and the Children's Hospital of Eastern Ontario (CHEO). The remaining authors declare no conflict of interest., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Molecularly defined secondary acute myeloid leukemia is associated with a prior myeloid neoplasm and confers a worse prognosis. We compared outcomes of molecularly defined secondary AML patients (n = 395) treated with daunorubicin and cytarabine (7 + 3, n = 167), liposomal daunorubicin and cytarabine (CPX-351, n = 66) or hypomethylating agents (HMA) + venetoclax (VEN) (n = 162). Median overall survival (OS) was comparable between treatment groups among patients aged >60 years. In a multivariable model HMA + VEN vs. 7 + 3 was associated with better OS (hazard ratio [HR] 0.64 [95% confidence interval (CI) 0.42-0.98, p = 0.041]), whereas CPX-351 vs. 7 + 3 was not (HR 0.79 [CI 95% 0.50-1.25, p = 0.31]). Allogeneic hematopoietic stem cell transplantation, BCOR and IDH mutations were associated with improved OS; older age, prior myeloid disease, NRAS/KRAS mutations, EZH2 mutation, and monosomal karyotype were associated with worse OS. When analyzed in each treatment separately, the IDH co-mutations benefit was seen with 7 + 3 and the detrimental effect of NRAS/KRAS co-mutations with HMA + VEN and CPX-351. In pairwise comparisons adjusted for age, HMA + VEN was associated with improved OS vs. 7 + 3 in patients with SF3B1 mutation and improved OS vs. CPX-351 in those with RNA splicing factor mutations. In molecularly defined secondary AML treatment with HMA + VEN might be preferred but could further be guided by co-mutations., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: There is an overlap in the cerebrospinal fluid (CSF) characteristics of patients presenting with different etiologies of CSF pleocytosis. Here, we characterized patients with CSF pleocytosis treated in a large hospital., Methods: A retrospective cohort study of 1150 patients with an elevated CSF leukocyte count > 5 cells/µl treated at a university hospital in Germany from January 2015 to December 2017 was performed. Information on clinical presentation, laboratory parameters, diagnosis and outcome was collected. Clinical and laboratory features were tested for their potential to differentiate between bacterial meningitis (BM) and other causes of CSF pleocytosis., Results: The most common etiologies of CSF pleocytosis were CNS infections (34%: 20% with detected pathogen, 14% without), autoimmune (21%) and neoplastic diseases (16%). CSF cell count was higher in CNS infections with detected pathogen (median 82 cells/µl) compared to autoimmune (11 cells/µl, p = 0.001), neoplastic diseases (19 cells/µl, p = 0.01) and other causes (11 cells/µl, p < 0.001). The CHANCE score was developed to differentiate BM from other causes of CSF pleocytosis: Multivariate regression revealed that CSF cell count > 100 cells/µl, CSF protein > 100 mg/dl, CRP > 5 mg/dl, elevated white blood cell count, abnormal mental status and nuchal rigidity are important indicators. The CHANCE score identified patients with BM with high sensitivity (92.1%) and specificity (90.9%) (derivation cohort: AUC: 0.955, validation cohort: AUC: 0.956)., Conclusion: Overall, the most common causes for CSF pleocytosis include infectious, neoplastic or autoimmune CNS diseases in ~ 70% of patients. The CHANCE score could be of help to identify patients with high likelihood of BM and support clinical decision making., (© 2023. The Author(s).)

Patients with myelodysplastic syndromes/neoplasms (MDS) or acute myeloid leukemia (AML) with hypomethylating agent failure have a poor prognosis. Myeloid-derived suppressor cells (MDSCs) can contribute to MDS progression and mediate resistance to anti-PD1 therapy. As histone deacetylase inhibitors (HDACi) decrease MDSCs in preclinical models, we conducted an investigator-initiated, NCI-Cancer Therapy Evaluation Program-sponsored, multicenter, dose escalation, and expansion phase Ib trial (NCT02936752) of the HDACi entinostat and the anti-PD1 antibody pembrolizumab. Twenty-eight patients (25 MDS and 3 AML) were enrolled. During dose escalation (n=13 patients), there was one dose-limiting toxicity (DLT) on dose level (DL) 1 (G5 pneumonia/bronchoalveolar hemorrhage) and two DLTs at DL 2 (G3 pharyngeal mucositis and G3 anorexia). Per the 3 + 3 dose escalation design, DL 1 (entinostat 8 mg PO days 1 and 15 + pembrolizumab 200 mg IV day 1 every 21 days) was expanded and another 15 patients were enrolled. Hematologic adverse events (AEs) were common. The most common non-hematologic ≥G3 AEs were infection (32%), hypoxia/respiratory failure (11%), and dyspnea (11%). There were no protocol-defined responses among the 28 patients enrolled. Two patients achieved a marrow complete remission (mCR). Using a systems immunology approach with mass cytometry and machine learning analysis, mCR patients had increased classical monocytes and macrophages but there was no significant change of MDSCs. In conclusion, combining entinostat with pembrolizumab in patients with advanced MDS and AML was associated with limited clinical efficacy and substantial toxicity. Absence of an effect on MDSCs could be a potential explanation for the limited efficacy of this combination. ClinicalTrial.gov Identifier: NCT02936752., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematopoietic cancers characterized by recurrent molecular alterations driving the disease pathogenesis with a variable propensity for progression to acute myeloid leukemia (AML). Clinical decision making for MDS relies on appropriate risk stratification at diagnosis, with higher-risk patients requiring more intensive therapy. The conventional clinical prognostic systems including the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) have dominated the risk stratification of MDS from 1997 until 2022. Concurrently, the use of next-generation sequencing has revolutionized the field by revealing multiple recurrent genetic mutations, which correlate with phenotype and prognosis. Significant efforts have been made to formally incorporate molecular data into prognostic tools to improve proper risk identification and personalize treatment strategies. In this review, we will critically compare the available molecular scoring systems for MDS focusing on areas of progress and potential limitations that can be improved in subsequent revisions of these tools., Competing Interests: Declaration of competing interest Amer Zeidan is a Leukemia and Lymphoma Society Scholar in Clinical Research. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Kura, Medimmune/AstraZeneca, Boehringer-Ingelheim, Incyte, Takeda, Novartis, Shattuck Labs, Geron, Foran, and Aprea. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Servier, Boehringer-Ingelheim, Novartis, Astellas, Daiichi Sankyo, Geron, Taiho, Seattle Genetics, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Zentalis, Schrodinger, Regeneron, Syros, Schrodinger, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, Syros, BioCryst, Abbvie, ALX Oncology, Kura, Geron and Celgene/BMS. Maximilian Stahl served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, and Rigel; consulted for Boston Consulting and Dedham group and participated in GME activity for Novartis, Curis Oncology, Haymarket Media, and Clinical Care Options. The other authors declare no competing financial interests., (Copyright © 2023. Published by Elsevier Ltd.)

Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease., (© 2023 by The American Society of Hematology.)

Background: Brain pericytes participate in the regulation of cerebral blood flow and the maintenance of blood-brain barrier integrity. Because of their perivascular localization, their receptor repertoire, and their potential ability to respond to inflammatory and infectious stimuli by producing various cytokines and chemokines, these cells are also thought to play an active role in the immune response to brain infections. This assumption is mainly supported by in vitro studies, investigations in in vivo disease models are largely missing. Here, we analysed the role of brain pericytes in pneumococcal meningitis, in vitro and in vivo in two animal models of pneumococcal meningitis., Methods: Primary murine and human pericytes were stimulated with increasing concentrations of different serotypes of Streptococcus pneumoniae in the presence or absence of Toll-like receptor inhibitors and their cell viability and cytokine production were monitored. To gain insight into the role of pericytes in brain infection in vivo, we performed studies in a zebrafish embryo model of pneumococcal meningitis in which pericytes were pharmacologically depleted. Furthermore, we analyzed the impact of genetically induced pericyte ablation on disease progression, intracranial complications, and brain inflammation in an adult mouse model of this disease., Results: Both murine and human pericytes reacted to pneumococcal exposure with the release of selected cytokines. This cytokine release is pneumolysin-dependent, TLR-dependent in murine (but not human) pericytes and can be significantly increased by macrophage-derived IL-1b. Pharmacological depletion of pericytes in zebrafish embryos resulted in increased cerebral edema and mortality due to pneumococcal meningitis. Correspondingly, in an adult mouse meningitis model, a more pronounced blood-brain barrier disruption and leukocyte infiltration, resulting in an unfavorable disease course, was observed following genetic pericyte ablation. The degree of leukocyte infiltration positively correlated with an upregulation of chemokine expression in the brains of pericyte-depleted mice., Conclusions: Our findings show that pericytes play a protective role in pneumococcal meningitis by impeding leukocyte migration and preventing blood-brain barrier breaching. Thus, preserving the integrity of the pericyte population has the potential as a new therapeutic strategy in pneumococcal meningitis., (© 2023. The Author(s).)

The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera, GSK, Rigel, Sierra Oncology; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on several patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. Gail Roboz: Consultancy: Abbvie, Amgen, Argenx, Astra Zeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Rigel, Roche, Syndax, Takeda (IRC Chair), Telix Pharma Research support: Janssen. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Fabio Efficace had a consultancy or advisory role for AbbVie, Incyte, Janssen, and Syros, outside the submitted work. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H. Wei receives such a financial benefit. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In recent years, the therapeutic landscape of myeloid malignancies has been completely revolutionized by the introduction of several new drugs, targeting molecular alterations or pathways crucial for leukemia cells survival. Particularly, many agents targeting apoptosis have been investigated in both pre-clinical and clinical studies. For instance, venetoclax, a pro-apoptotic agent active on BCL-2 signaling, has been successfully used in the treatment of acute myeloid leukemia (AML). The impressive results achieved in this context have made the apoptotic pathway an attractive target also in other myeloid neoplasms, translating the experience of AML. Therefore, several drugs are now under investigation either as single or in combination strategies, due to their synergistic efficacy and capacity to overcome resistance. In this paper, we will review the mechanisms of apoptosis and the specific drugs currently used and under investigation for the treatment of myeloid neoplasia, identifying critical research necessities for the upcoming years., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised., Competing Interests: Declaration of interests RMS has served in a consulting or advisory role for Bristol Myers Squibb, Curio Science, Gilead Sciences, and Sciences, Servier, and Rigel. ND has received research funding from Daiichi Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi Sankyo, AbbVie, Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen. ND has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. JKA has received institutional research funding from AbbVie, Agios, ALX Oncology, Amgen, Amphivena, Aprea AB, Aptose Biosciences, Astellas Pharma, BioSight, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cyclacel, Fujifilm, Immunogen, Kartos Therapeutics, Kura Oncology, Loxo, Pfizer, and Telios; has served in a consulting or advisory role for AbbVie, Astellas Pharma, BioSight, Bluebird Bio, Curio, Gilead, Kura Oncology, Kymera, Stemline Therapeutics, and Syros; and has served on a data monitoring committee for GlycoMimetics. DAP has served as a consultant or advisor for AbbVie, Novartis, Karyopharm, Syndax, Jazz, Syros, Bristol Myers Squibb, BeiGene, Bergen Bio, Arcellx, Genentech, Immunogen, AstraZeneca, Kura, Ryvu, Magenta, Qihan, Zentalis, Medivir, Hibercell, Link, Daiichi Sankyo, Schrodinger, Aptevo, Rigel, Sumitomo, Adicet, Gilead, and Oncoverity; he has received research funding from AbbVie, Karyopharm, Teva, and Bristol Myers Squibb. TB has served as a consultant or advisor for Pfizer and Takeda. VRB reports participating in safety monitoring committee for protagonist. VRB receives consulting fees from Imugene, research funding from AbbVie, Pfizer, Incyte, Jazz Pharmaceuticals, and National Marrow Donor Program, and provided drug from Chimerix for a trial. AdlFB received research funding from Janssen-Cilag, Novartis, BTG Pharmaceuticals, and AbbVie; has served on advisory boards for Abbvie, Astellas, Bristol Meyers Squibb, Curis, Daiichi Sankyo, Incyte, Immunogen, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. AdlFB has received speakers' fees from Abbvie, Astellas, Celgene-BMS, Daiichi Sankyo, Incyte, Janssen Cilag, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. HEC received research funding from Celgene and has served as a consultant or advisor for Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Daiichi, Genentech and Stemline. She has received speakers fees from Jazz, Novartis, BMS and Stemline; she has been on Data Safety Monitoring Board Committees for AbbVie, ASTEX, Syndax, and Takeda. FEC has received institutional research funding from Celgene, Bristol Myers Squib, Amgen, Fibrogen, Sumitomo Pharma Oncology, and AbbVie, and is a consultant for the Association of Community Cancer Centers. ATF has received research funding from Celgene, AbbVie, and Servier, and has served in a consulting or advisory role for Genentech, Celgene, Foghorn, Kite, Morphosys, AbbVie, Takeda, Ipsen, Forma, Amgen, Novartis, Astellas, Immunogen, Mablytics, EnClear, Orum, PureTech, Pfizer, Daiichi Sankyo, Minovia, Rigel, and Servier. IG has received research funding from Merck, Amgen, Gilead, Incyte, and Genentech, and has served as a consultant and advisor for Immunogen, Bristol Meyer Squibb, Amgen, ClearView, Curio, and Nkarta. MRG has stock ownership in Medtronic, received research support from Incyte and Jannsen, and received consulting fees from AbbVie, Amgen, Astellas, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, CTI BioPharma, Daiichi Sankyo, Gamida Cell, Genentech, Gilead, GSK, Sierra Oncology, Incyte, Invitae, Jazz, Karius, Novartis, Ono Pharmaceutical, Pfizer, Pharmacosmos, Premier, Servier, and Stemline Therapeutics. BAJ has served as a consultant and advisor for AbbVie, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Jazz, Kymera, Pfizer, Rigel, Servier, and Takeda; was on the protocol steering committee for GlycoMimetics, data monitoring committee for Gilead; and received travel reimbursement and [ support from AbbVie and Rigel; BAJ received institutional research funding from AbbVie, Amgen, Aptose, AROG, Bristol Meyers Squibb, Celgene, Daiichi Sankyo, F Hoffmann-La Roche, Forma, Forty Seven, Genentech, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. GNM has received research funding from Bristol Meyers Squibb, Celgene, Glycomimetics, Forty Seven, Jazz, Astex, Syndax, Immune Onc, and Immunogen; has served as a consultant and advisor for AbbVie, Agios, Macrogenics and Pfizer, and has served on a scientific advisory committee for Abbvie, Agios, Astellas, Bristol Myers Squibb, Forty Seven, Genentech, and Stemline. JM has received institutional research funding from Incyte, Novartis, Bristol Meyers Squibb, CTI Bio, Geron, AbbVie, Kartos, and PharmaEssentia, and has received consulting fees from Bristol Meyers Squibb Incyte, Novartis, Roche, CTI Bio, Geron, Kartos, GSK, MorphoSys, PharmaEssentia, Imago, and Galecto. LCM has received institutional research funding from Jazz Pharmaceuticals, has served in a consulting or advisory role for AbbVie, Curio Science, Celgene Corp, Sierra Oncology, and Nkarta; has received honoraria from the American Society of Hematology, the American Board of Internal Medicine, and the Society of Hematologic Oncology; received royalties from Wintrobe's Publishing; and has served as an expert witness for Incyte Corporation. ASM has served in a consulting or advisory role for AbbVie, Servier, Syndax Pharmaceuticals, Bristol Meyers Squibb, Astellas, Rigel, Zentalis, and Ryvu Therapeutics; has served on a data monitoring safety committee for Jazz Pharmaceuticals, Daiichi Sankyo, and Foghorn Therapeutics; and has served as a medical monitor for the Leukemia and Lymphoma Society Beat AML Study. OP has served in a consulting or advisory role for Scopio Labs, Sysmex America, and F Hoffman-La Roche. KWP Research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; was an advisory board member for AbbVie, Astellas, AstraZeneca, Boston BioMedical, Bristol Myers Squibb, Celgene, Novartis, Roche, Jazz Pharmaceuticals, and Servier. MAS has served on advisory boards for Bristol Meyers Squibb, Novartis, Kurome, and Gilead. CCS has received research funding from AbbVie, Bristol Myers Squibb, Erasca, Revolution Medicines, and Zentalis, and has served on a board of advisory committee for Astellas Pharma, Daichi Sanyko, and Genentech. MSt served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, and Rigel; consulted for Boston Consulting and Dedham group and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options. MSu receives industry research support from Amgen, Bristol Myers Squibb, Gilead, Janssen, Miltenyi Biotec, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda; serves as a consultant and advisor to AvenCell, CDR-Life, Ichnos Sciences, Incyte Biosciences, Janssen, Molecular Partners, and Takeda; and serves on the speakers' bureau at Amgen, AstraZeneca, Bristol Meyers Squibb, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. GLU served in a consulting role for Novartis and Jazz. MTV received compensation for being a speakers from AbbVie, Bristol Myers Squibb, Astellas, Jazz, Novartis, and Servier; has served in a consulting or advisory role for Jazz and Syros Pharmaceuticals. RBW received laboratory research grants and clinical trial support from Amgen, Aptevo, Celgene, ImmunoGen, Janssen, Jazz Pharmaceuticals, Kura, MacroGenics, and Pfizer; has ownership interests in Amphivena; and served in a consulting role to AbbVie, Adicet, Amphivena, BerGenBio, Bristol Myers Squibb, GlaxoSmithKline, ImmunoGen, Kura, and Orum. ESW has served in a consulting and advisory role for AbbVie, Astellas, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlaxoSmithKline, Janssen, Jazz, Kite, Kura, Novartis, NuProbe, Pfizer, Rigel, Sellas, and Sumitomo Pharma; has received speaking fees from AbbVie, Astellas, Dava Oncology, Kura Oncology, Novartis, and Pfizer; has served on a data monitoring committee for Abbvie and Gilead; and has served on a research committee for Gilead. JFZ has received honoraria from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Gilead, Immunogen, Servier, and Shattuck Labs; has served as a consultant for AbbVie, Foghorn, Gilead and Servier; and has received research funding from AbbVie, Arog, Astex, Gilead, Jazz, Merck, Shattuck Labs, Stemline, Sumitomo Dainippon Pharma, and Takeda. AZ has served in a consulting or advisory role for AbbVie, Astellas, Jannsen, Novartis, and Pfizer, and received honoraria from AbbVie, Astellas, Jannsen, Novartis, and Takeda. AMZ has served in a consulting or advisory role for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, AstraZeneca, BeyondSpring, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Daiichi Sankyo, Epizyme, Genentech, Gilead, Kura, Incyte, Ionis, Loxo Oncology, Janssen, Novartis; served on clinical trial committees for AbbVie, BioCryst, Bristol Meyers Squibb, Geron, Gilead, Kura, Loxo Oncology, Novartis; has received research funding from AbbVie, Acceleron, ADC Therapeutics, Amgen, Aprea, Astex, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Incyte, Jasper, Jazz, Novartis, and Pfizer. JPB, RSK, SdB, PD, RD, ND, SDF, MK, TLL, PM, and ACS declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H.Wei receives such a financial benefit. Valeria Santini served in advisory boards from Abbvie, BMS, Geron, Gilead,Menarini, Novartis, Servier, Syros, ad received research support from BMS. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Approval of new agents to treat higher risk (HR) myelodysplastic syndrome (MDS) has stalled since the approval of DNA methyltransferase inhibitors (DNMTi). In addition, the options for patients with lower risk (LR) MDS who have high transfusion needs and do not harbor ring sideroblasts or 5q- syndrome are limited. Here, we review the current treatment landscape in MDS and identify areas of unmet need, such as treatment after failure of erythropoiesis-stimulating agents or DNMTis, TP53-mutated disease, and MDS with potentially targetable mutations. We discuss how our understanding of MDS pathogenesis can inform therapy development, including treating HR-MDS similarly to AML and pursuing therapies to address splicing factor mutations and dysregulated inflammation. We then bring a critical lens to current methodology of MDS studies and propose solutions to improve the efficiency and yield of these clinical trials, including using the most meaningful response metrics and expanding enrollment., Competing Interests: Declaration of Competing Interest M.S. has consulted for Curis Oncology and Boston Consulting and is a member of the advisory boards for Novartis, Kymera, GSK and Sierra Oncology. R.M.S. reports support from AbbVie, AbbVie/Genentech, Actinium, Aprea, Arog, AvenCell, BerGenBio, BMS, Boston Pharmaceuticals, CTI Pharma, Elevate Bio, Foghorn Therapeutics, Gemoab, GSK, Innate, Janssen, Jazz, Kura Onc, Novartis, and Syros (Advisory Boards) and from Aptevo, Syntrix/ACI Clinical, Epizyme and Takeda (DSMB). D.J.D. has received funding/grant support from AbbVie, Blueprint Medicines, GlycoMimetics, and Novartis and honoraria or consulting fees from Amgen, Astella, Bristol-Myers Squibb, Blueprint Medicines, Gilead, Incyte, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. A.M.Z. is a Leukemia and Lymphoma Society Scholar in Clinical Research. A.M.Z. received research funding (institutional) from Celgene/BMS, AbbVie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. A.M.Z. served on clinical trial committees for Novartis, AbbVie, Gilead, BioCryst, ALX Oncology, Geron and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Abstract: Myelodysplastic syndromes/neoplasms (MDSs) constitute a heterogeneous group of clonal disorders that are clinically characterized by dysplastic changes in multiple hematopoietic lineages, cytopenias, and a variable risk of progression to acute myeloid leukemia. Patients with MDS are classified as either lower- or higher-risk based on risk stratification tools such as the International Prognostic Scoring System and its revised version, which continue to be the basis for prognosis and treatment selection. Although anemic patients with lower-risk MDS are currently treated with an erythropoiesis-stimulating agent, luspatercept, and transfusions, the telomerase inhibitor imetelstat and the hypoxia-inducible factor α inhibitor roxadustat have shown encouraging early results and are now in phase III clinical trials. For higher-risk MDS patients, hypomethylating agent monotherapy continues to be the standard of care. However, with various novel hypomethylating agent-based combination therapies in advanced clinical testing and an increased emphasis on individualized biomarker-driven treatment decisions, the standard therapy paradigms might change in the future., Competing Interests: Conflicts of Interest and Source of Funding: A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Foran, Syros, and Tyme. A.M.Z. served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron, and Celgene/BMS. J.P.B. and Z.X. do not report any conflicts of interest. A.M.Z. is a Leukemia and Lymphoma Society scholar in clinical research. All figures were created with BioRender.com., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Myelodysplastic syndromes/neoplasms (MDS) are heterogeneous, clonal myeloid neoplasms characterized by ineffective hematopoiesis, progressive cytopenias, and an increased risk of progression to acute myeloid leukemia. The diversity in disease severity, morphology, and genetic landscape challenges not only novel drug development but also therapeutic response assessment. The MDS International Working Group (IWG) response criteria were first published in the year 2000 focusing on measures of blast burden reduction and hematologic recovery. Despite revision of the IWG criteria in 2006, correlation between IWG-defined responses and patient-focused outcomes, including long-term benefits, remains limited and has potentially contributed to failures of several phase III clinical trials. Several IWG 2006 criteria also lacked clear definitions leading to problems in practical applications and interobserver and intraobserver consistency of response reporting. Although the 2018 revision addressed lower-risk MDS, the most recent update in 2023 redefined responses for higher-risk MDS and has set out to provide clear definitions to enhance consistency while focusing on clinically meaningful outcomes and patient-centered responses. In this review, we analyze the evolution of the MDS response criteria, limitations, and areas of improvement., Competing Interests: Conflicts of Interest and Source of Funding: M.S. consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media, and Clinical Care Options (CCO). A.M.Z. is a Leukemia and Lymphoma Society Scholar in Clinical Research. A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff Oncology, Incyte, Takeda, Novartis, Shattuck Labs, Geron, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Servier, Boehringer-Ingelheim, Novartis, Astellas, Daiichi Sankyo, Geron, Taiho, Seattle Genetics, BeyondSpring, Takeda, Ionis, Amgen, Janssen, Genentech, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, Mendus, Foran, Syros, and Tyme. A.M.Z. served on clinical trial committees for Novartis, Abbvie, Gilead, Syros, BioCryst, Abbvie, ALX Oncology, Geron, and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. For the remaining authors, none were declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action., (© 2023 by The American Society of Hematology.)

Hypomethylating agents (HMA) such as azacitidine and decitabine are a mainstay in the current management of patients with myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML) as either single agents or in multidrug combinations. Resistance to HMA is not uncommon, and it can result due to several tumor cellular adaptations. Several clinical and genomic factors have been identified as predictors of HMA resistance. However, the management of MDS/AML patients after the failure of HMA remains challenging in the absence of standardized guidelines. Indeed, this is an area of active research with several potential therapeutic agents currently under development, some of which have demonstrated therapeutic potential in early clinical trials, especially in cases with particular mutational characteristics. Here, we review the latest findings and give a rational approach for such a challenging scenario.

Acute myeloid leukemia (AML) is the most common acute leukemia in adults in the United States and has seen the approval of several novel agents over the past decade. Similar to treatments for other hematologic and solid malignancies, these novel agents are costly. In the setting of finite financial resources in the healthcare system, the concept of cost-effectiveness analyses has been developed to compare the estimated costs and associated benefits expected with different interventions (eg, drugs, diagnostic tests, procedures). Although drug approvals in the United States are not based on budgetary considerations, cost-effectiveness analyses can inform health policy decisions, resource allocation, and societal debates. However, such analyses are only capturing parts of the costs and benefits to the healthcare system, payers, and consumers, and are based on modeling assumptions with inherent limitations. In addition, cost-effectiveness analyses for several of the novel agents approved for treatment of AML are limited and have reported conflicting results. This review uses cost-effectiveness analyses of azacitidine/venetoclax and liposomal cytarabine/daunorubicin as examples to review considerations and best practices when conducting and interpreting such studies. To ensure adequate interpretability of cost-effectiveness studies, transparency in the model inputs/assumptions, data sources, and funding is of great importance, as evidenced by the discrepant conclusions across studies. Furthermore, the perspective and the healthcare system from which a cost-effectiveness analysis is conducted are important to consider because practice patterns and drug prices between countries can be variable. However, with advances in health economic modeling techniques, adherence to best practices, and increasing public interest in these types of studies, cost-effectiveness analyses can become an important tool to inform various stakeholders in the healthcare system to allocate limited resources most efficiently.

We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33-75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24-18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10-0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09-0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15-0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML., Methods: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients., Results: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant., Conclusions: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations., (© 2022 American Cancer Society.)

Background/objectives: Severe acute pancreatitis is associated with significant morbidity and mortality. Identifying factors that affect the risk of developing severe disease could influence management. Plasma levels of renalase, an anti-inflammatory secretory protein, dramatically decrease in a murine acute pancreatitis model. We assessed this response in hospitalized acute pancreatitis patients to determine if reduced plasma renalase levels occur in humans., Methods: Plasma samples were prospectively and sequentially collected from patients hospitalized for acute pancreatitis. Two forms of plasma renalase, native (no acid) and acidified, were measured by ELISA and RNLS levels were compared between healthy controls and patients with mild and severe disease (defined as APACHE-II score ≥7) using nonparametric statistical analysis., Results: Control (33) and acute pancreatitis (mild, 230 (76.7%) and severe, 70 (23.3%) patients were studied. Acidified RNLS levels were lower in pancreatitis patients: Control: 10.1 μg/ml, Mild 5.1 μg/ml, Severe 6.0 μg/ml; p < 0.001. Native RNLS levels were increased in AP: Control: 0.4 μg/ml, Mild 0.9 μg g/ml, Severe 1.2 μg/ml p < 0.001; those with severe AP trended to have higher native RNLS levels than those with mild disease (p = 0.056). In patients with severe AP, higher APACHE-II scores at 24 h after admission correlated with lower acid-sensitive RNLS levels on admission (r = -0.31, p = 0.023)., Conclusion: Low plasma acidified RNLS levels, and increased native RNLS levels are associated with AP. Additional studies should assess the clinical correlation between plasma RNLS levels and AP severity and outcomes., (Copyright © 2023 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Ivosidenib + azacitidine (IVO/AZA) is approved in the United States for newly diagnosed, older or intensive chemotherapy-ineligible patients with IDH1 -mutated acute myeloid leukemia. We created a partitioned survival analysis model to evaluate the health economic implications of this approval. Model outputs were used to calculate the incremental cost-effectiveness ratio (ICER) of IVO/AZA versus AZA. One-way and probabilistic sensitivity analyses were conducted. In the base case scenario, IVO/AZA and AZA resulted in life-time costs of $403,062 and $161,887, respectively. With an incremental gain of 0.95 QALYs, the ICER of IVO/AZA was $252,782/QALY. In sensitivity analyses, only a reduction in the price of IVO by 59.3% lowered the ICER to below $150,000/QALY and 99.95% of model calculations yielded ICERs of >$150,000/QALY. In a model in which all patients received IVO monotherapy after progression on AZA monotherapy, the ICER was $155,453/QALY and various model inputs that would make IVO/AZA cost-effective were identified.

Therapy resistance is a major challenge in the treatment of cancer. Here, we performed CRISPR-Cas9 screens across a broad range of therapies used in acute myeloid leukemia to identify genomic determinants of drug response. Our screens uncover a selective dependency on RNA splicing factors whose loss preferentially enhances response to the BCL2 inhibitor venetoclax. Loss of the splicing factor RBM10 augments response to venetoclax in leukemia yet is completely dispensable for normal hematopoiesis. Combined RBM10 and BCL2 inhibition leads to mis-splicing and inactivation of the inhibitor of apoptosis XIAP and downregulation of BCL2A1, an anti-apoptotic protein implicated in venetoclax resistance. Inhibition of splicing kinase families CLKs (CDC-like kinases) and DYRKs (dual-specificity tyrosine-regulated kinases) leads to aberrant splicing of key splicing and apoptotic factors that synergize with venetoclax, and overcomes resistance to BCL2 inhibition. Our findings underscore the importance of splicing in modulating response to therapies and provide a strategy to improve venetoclax-based treatments., Competing Interests: Declaration of interests E.M., E.C., M.J., C.B., C.-C.M., and D.M.B. are employees of Biosplice Therapeutics. O.A.-W. has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder. O.A.-W. has received prior research funding from H3B Biomedicine, Nurix Therapeutics, and LOXO Oncology unrelated to the current manuscript. The remaining authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

FLT3, IDH1 and IDH2 inhibitors as well as venetoclax in combination with hypomethylating agents or low-dose cytarabine have expanded treatment options for patients with acute myeloid leukemia (AML). However, little data exist on the efficacy of venetoclax-based therapies in AML patients previously treated with FLT3 or IDH1/2 inhibitors. In this multicenter, retrospective cohort study, we included 44 patients who received venetoclax-based therapy after FLT3, IDH1 or IDH2 inhibitors. The overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 56.8% (18.2% CR) and a median overall survival of 9.2 months. While 6 out of 7 patients with IDH1 mutations who had previously been treated with ivosidenib responded to venetoclax-based therapy, FLT3- ITD mutations were associated with a lower response rate. Our data suggest that venetoclax can be an effective salvage therapy in patients previously treated with IDH1/2 or FLT3 inhibitors.

Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered., (© 2022 Wiley Periodicals LLC.)

The BCR-ABL-negative myeloproliferative neoplasms (MPNs) have a variable risk of progressing to accelerated- or blast-phase MPN (MPN-AP/MPN-BP), defined by the presence of 10% to 19% and more than or equal to 20% myeloid blasts in the peripheral blood or bone marrow, respectively. The molecular processes underlying the progression to MPN-AP/MPN-BP are becoming increasingly understood with the acquisition of additional mutations in epigenetic modifiers (eg, ASXL1, EZH2, TET2), TP53, the Ras pathway, or splicing factors (eg, SRSF2, U2AF1), having been described as important steps in this evolutionary process. At least partially driven by the enrichment of these high-risk molecular features, the prognosis of patients with MPN-BP remains inferior to other patients with acute myeloid leukemia, with a median overall survival of 3 to 6 months. Allogeneic hematopoietic cell transplantation remains the only potentially curative therapeutic modality, but only a minority of patients are eligible. In the absence of curative intent, therapeutic strategies or palliative treatment with hypomethylating agents as monotherapy or in combination with ruxolitinib or venetoclax can be considered. Several novel agents are in various stages of clinical development but are not available for routine use at this point, highlighting the need for ongoing research and the prioritization of clinical trial enrollment when feasible., (Copyright © 2022 by The American Society of Hematology.)

Small molecule inhibitors targeting mutant FLT3, IDH1, and IDH2 as well as venetoclax-based combination therapies have expanded treatment options for patients with acute myeloid leukemia (AML). As the landmark trials leading to the approval of FLT3, IDH1, and IDH2 inhibitors in R/R-AML were conducted prior to the widespread use of venetoclax, it is unclear how these results apply in the current era of venetoclax based therapy frequently being used in the frontline treatment of AML. In this multicenter, retrospective cohort study, we included 53 patients who received FLT3, IDH1 or IDH2 inhibitors after disease progression on venetoclax-based therapy. Among patients treated with targeted agents after venetoclax, the overall response rate (ORR; composite of complete remission [CR]/CR with incomplete count recovery, partial remission, and morphologic leukemia free state) was 17.7 % (n = 9 patients) and median OS of 4.2 months. Eight of 9 patients responding to targeted agents after venetoclax received gilteritinib. None of the patients with RAS pathway mutations responded to targeted agents after venetoclax. Additionally, mutations in TP53 and KRAS were associated with shorter OS among patients treated targeted agents. Our data suggest that response rates to targeted therapies after venetoclax are low and novel therapeutic strategies are warranted., Competing Interests: Conflict of Interest R.M.S. participated in advisory boards, and/or had a consultancy with and received honoraria from Bristol Myers Squibb and Gilead Sciences, Inc; divested equity interest in Curis Oncology. A.D.G. received research funding from Celularity, ADC Therapeutics, Aprea, AROG, Pfizer, Prelude, and Trillium; received research funding from and served as a consultant for Aptose and Daiichi Sankyo; served as a consultant and member of advisory committees for Astellas, Celgene, and Genentech; received research funding from, served as a consultant for, and was a member of advisory committees for AbbVie; and received honoraria from Dava Oncology. A.M.Z. received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Trovagene/Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. A.M.Z. participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, and Tyme. A.M.Z. served on clinical trial committees for Novartis, Abbvie, Geron and Celgene/BMS. A.M.Z. received travel support for meetings from Pfizer, Novartis, and Cardiff Oncology. E.M.S. received research funding from Bayer; was a consultant for Amgen, AbbVie, Seattle Genetics, and Biotheryx; served as a consultant and received research funding from Syndax; was a member of the Board of Directors or advisory committee for PTC Therapeutics and Syros; served as a consultant and was member of the Board of Directors or advisory committee for Astellas Pharmaceutical, Agios Pharmaceuticals, and Genentech; served as a consultant, received research funding, and was a member of the Board of Directors or advisory committee for Daiichi-Sankyo, Celgene Pharmaceuticals, and Novartis; and is a current equity holder in privately held Auron Therapeutics. G.M. received research funding from Merck, served on the scientific board for BMS, and Abbvie, and participated as a speaker for Abbvie. A.S. served on the speakers bureau for Amgen. D.J.D. had a consultancy with Abbvie Amgen, Autolus, Blueprint, Forty-Seven, Glycomimetrics, Inctye, Jazz, Kite, Novartis, Pfizer, Servier, and Takeda. D.J.D. received grant/research funding Abbvie, Novartis, Blueprint, Glycomimetrics. R.M.S. received personal fees from Abbvie, Actinium, Agios, Astellas, Biolinerx, Celgene, Daiichi-Sankyo, Elevate, Gemoab, Janssen, Jazz, Macrogenics, Novartis, OncoNova, Syndax, Syntrix, Syros, Takeda, Trovagene, BerGenBio, Foghorn Therapeutics, GlaxoSmith Kline, Aprea, Innate, Amgen, BMS, Boston Pharmaceuticals, Kura Oncology, and Epizyme. R.M.S. received grant funding from Abbvie, Agios, Arog, and Novartis. IA serves on advisory boards for Amgen, Kite pharmaceuticals, AbbVie, JAZZ and Agios Pharmaceuticals, and is a consultant for Pfizer, Autolus Therapeutics and Amgen, and received research support by MacroGenics and Abbvie. B.J.B. served on the advisory board for Oncovalent. MS is a member of the advisory board for Novartis and is consulting for Curis Oncology, Haymarket Media and Boston Consulting., (Copyright © 2022 Elsevier Ltd. All rights reserved.)