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

Myelodysplastic syndrome, or myelodysplastic neoplasms, are a rare finding in pediatric, adolescent, and young adult (AYA) patients. More literature is needed to highlight trends of survival or treatment resistance in subpopulations to improve treatment. Here we report a single center retrospective analysis of pediatric and AYA patients from 2000 to 2022 including molecular and cytogenetic data. Using the IPSS-R and IPSS-M, which have been reported exclusively in adults, and excluding patients with bone marrow failure syndromes, we analyzed 119 pediatric and AYA patients with myelodysplastic neoplasms. Therapy-related myelodysplastic neoplasms were present in 36 % of patients, and 31 % of patients developed acute myeloid leukemia. The 5-year overall survival (OS) rate for the entire cohort was 45 %. Contrary to young adults and older adults, mutations were not common in pediatrics. Those who underwent stem cell transplant (SCT)(at any time) had significantly longer median OS. Although SCT at any time improved OS in the de novo myelodysplastic neoplasm group, the choice of the initial treatment with intensive chemotherapy, hypomethylating agents, or SCT did not significantly alter OS. Median OS was shorter in the pediatric group (<18 years old) and longer for those with isolated deletion of 5q or TET2 mutation, but these were not significant findings. Median OS was significantly shorter in those with monosomy 7 or 7q deletion and those with therapy-related myelodysplastic neoplasms. These findings build on previously reported findings and encourage the use of SCT along with molecular and cytogenetic analysis., Competing Interests: Declaration of Competing Interest The authors have no competing financial interests or other conflicts of interests to declare for this study. Declarations of interest: none, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood., Experimental Design: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes., Results: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes., Conclusions: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax., (©2024 American Association for Cancer Research.)

Background: Hypomethylating agents are approved in higher-riskmyelodysplastic syndromes. The combination of a hypomethylating agent with venetoclax is standard of care in acute myeloid leukaemia. We investigated the safety and activity of the first totally oral combination of decitabine plus cedazuridine and venetoclax in patients with higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia., Methods: We did a single-centre, dose-escalation and dose-expansion, phase 1/2, clinical trial. Patients with treatment-naive higher-risk-myelodysplastic syndromes or chronic myelomonocytic leukaemia (risk level categorised as intermediate-2 or higher by the International Prognostic Scoring System) with excess blasts (>5%). Treatment consisted of oral decitabine 35 mg plus cedazuridine 100 mg on days 1-5 and venetoclax (variable doses of 100-400 mg, day 1 to 14, 28-day cycle). The primary outcomes were safety for the phase 1 part and the overall response for the phase 2 part of the study. The trial is ongoing and this analysis was not prespecified. This study is registered with ClinicalTrials.gov, NCT04655755, and is currently enrolling participants., Findings: Between Jan 21, 2021, and Jan 20, 2023, we enrolled 39 patients (nine in phase 1 and 30 in phase 2). The median age was 71 years (range 27-94), 28 (72%) patients were male, and 11 (28%) were female. The maximum tolerated dose was not reached, and the recommended phase 2 dose was established as oral decitabine 35 mg plus cedazuridine 100 mg for 5 days and venetoclax (400 mg) for 14 days. The most common grade 3-4 adverse events were thrombocytopenia (33 [85%] of 39), neutropenia (29 [74%]), and febrile neutropenia (eight [21%]). Four non-treatment-related deaths occurred on the study drugs due to sepsis (n=2), lung infection (n=1), and undetermined cause (n=1). The median follow-up time was 10·8 months (IQR 5·6-16·4). The overall response rate was 95% (95% CI 83-99; 37/39). 19 (49%) patients proceeded to hematopoietic stem-cell transplantation., Interpretation: This early analysis suggests that the combination of oral decitabine plus cedazuridine with venetoclax for higher-risk-myelodysplastic syndromes and chronic myelomonocytic leukaemia is safe in most patients, with encouraging activity. Longer follow-up will be needed to confirm these data., Funding: MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech/AbbVie, and Astex Pharmaceuticals., Competing Interests: Declaration of interests GM-B declares research support from Takeda, Rigel, and IFN Therapeutics. KSC declares research funding from Amgen and consultancy fees from AbbVie. JI declares funding from the US National Institutes of Health, the Leukemia Research Foundation, and the US Department of Defense, and honoraria from AstraZeneca. KS declares consultancy fees from Novartis and honoraria from Otsuka Pharmaceuticals and Amgen. NS declares grants from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and Nexcure; consultancy fees from Pfizer, GSK, NKARTA, and Sanofi; and honoraria from Adaptive Biotechologies, Novartis, Amgen, Takeda, Pfizer, Astellas Pharma, Sanofi, and BeiGene. GCI declares consultancy fees from Novartis, Kura Oncology, and Nuprobe; and research funding from Celgene, Kura Oncology, Syndax, Merck, Cullinan, and Novartis. ND declares grants from Daiichi-Sankyo, Bristol Myers Squibb (BMS), Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Hanmi, Trovagene, FATE Therapeutics, Novimmune, Glycomimetics, and KITE; and consultancy fees from Daiichi-Sankyo, BMS, Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Arog, Novartis, Jazz Pharmaceuticals, Celgene, Syndax, Shattuck Labs, Agios, KITE, and Stemline/Menarini. TMK declares grants from BMS, Abbvie, Amgen, Ascentage Pharma Group, Astellas Pharma, DrenBio, Astex, AstraZeneca, Celgene, Incyte, Cellenkos, Cyclacel, Delta-Fly Pharma, Genentech, Genfleet, Glycomimetics, Iterion, Janssen, Jazz Pharmaceuticals, Pfizer, Pulmotect, Regeneron, and SELLAS; consultancy fees from AbbVie, Agios, Daiichi Sankyo, Genentech, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Pukmotect, Sanofi-Aventis, Servier; and honoraria from AbbVie, Agios, Daiichi Sankyo, DAVA Oncology, Delta-Fly, DrenBio, Genentech, Genfleet, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, Rigel, Sanofi-Aventis, SELLAS, and Servier. FR declares research funding from ASTEX and TAIHO. EJ received research grants from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, BMS, Genentech, Incyte, Novartis, Pfizer, and Takeda. HMK declares research funding from Abbvie, Amgen, Ascentage, BMS, Daiichi Sankyo, Immunogen, Jazz Pharmaceuticals, and Novartis; and honoraria from Abbvie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Precision Biosciences, Shenzhen Target Rx, Stemline, and Takeda. GG-M declares research funding from Astex Pharmaceuticals, Novartis, Abbvie, BMS, Genentech, Aprea Therapeutics, Curis, and Gilead Sciences; consultancy fees from Astex Pharmaceuticals, Acceleron Pharma, and BMS; and honoraria from Astex Pharmaceuticals, Acceleron Pharma, Abbvie, Novartis, Gilead Sciences, Curis, Genentech, and BMS. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Early mortality is a historical measure of the quality of care incorporated into many quality measure algorithms that mostly account for patient comorbidities but do not incorporate disease characteristics and treatment status which independently increase early mortality. This is particularly significant in leukemia, especially in the refractory and salvage settings., Study Aim: To define the independent adverse effect of leukemia salvage vs. frontline therapy on early mortality in acute myeloid leukemia (AML) after accounting for the pretreatment independent adverse effects associated with early mortality., Patients and Methods: A total of 4151 patients with AML were analyzed, 2893 newly diagnosed and 1258 in salvage. Univariate and multivariate analyses (MVA) were conducted to determine the independent adverse effects associated with 8-week mortality., Results: The 8-week mortality was 13% in frontline therapy and 18% in salvage therapy. By MVA, older age; therapy-related AML; prior history of myelodysplastic syndrome; poorer performance status; high white blood cell count; lower platelet count; higher percent of peripheral blasts; lower albumin levels; higher bilirubin, creatinine, and lactate dehydrogenase levels; and adverse cytogenetic risk groups were independently associated with a higher 8-week mortality rate. Adding treatment status after accounting for the independent adverse variables still selected salvage status as significantly adverse for 8-week mortality (hazard ratio 1.954; P-value < .001)., Conclusions: Quality measure algorithms should incorporate a risk mortality index related to leukemia vs. other tumors and benign conditions and a risk mortality index related to the treatment status of leukemia (salvage vs. frontline therapy)., Competing Interests: Disclosures The authors have stated that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies., Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy., Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1-9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders., Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit., (©2023 American Association for Cancer Research.)

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ∼5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%), and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients (8%; grades 3 and 4), and IDH-inhibitor-associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) was 74%, including 70% composite CR (CRc: CR + mCR). Median time to best response was 1 month (range, 1-4), and a median of 4 cycles was received (1-32). The median overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range, 1-29), and the median OS was 20 months (range, 11 to not reached). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as #NCT03383575., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The aim of this study was to develop a prognostic model for survival in older/unfit patients with newly diagnosed acute myeloid leukemia (AML) who were treated with lower-intensity chemotherapy regimens., Methods: The authors reviewed all older/unfit patients with newly diagnosed AML who received lower-intensity chemotherapy from 2000 until 2020 at their institution. A total of 1462 patients were included. They were divided (3:1 basis) into a training (n = 1088) and a validation group (n = 374)., Results: In the training cohort of 1088 patients (median age, 72 years), the multivariate analysis identified 11 consistent independent adverse factors associated with survival: older age, therapy-related myeloid neoplasm, existence of previous myelodysplastic syndrome or myeloproliferative neoplasms, poor performance status, pulmonary comorbidity, anemia, thrombocytopenia, elevated lactate dehydrogenase, cytogenetic abnormalities, and the presence of infection at diagnosis, and therapy not containing venetoclax. The 3-year survival rates were 52%, 24%, 10%, and 1% in favorable, intermediate, poor, and very poor risk, respectively. This survival model was validated in an independent cohort. In a subset of patients in whom molecular mutation profiles were performed in more recent times, adding the mutation profiles after accounting for the effects of previous factors identified IDH2 (favorable), NPM1 (favorable), and TP53 (unfavorable) mutations as molecular prognostic factors., Conclusion: The proposed survival model with lower-intensity chemotherapy in older/unfit patients with newly diagnosed AML may help to advise patients on their expected outcome, to propose different strategies in first complete remission, and to compare the results of different existing or future investigational therapies., Plain Language Summary: Lower intensity therapy can be considered for older patients to avoid severe toxicities and adverse events. However, survival prediction in AML was commonly developed in patients who received intensive chemotherapy. In this study, we have proposed a survival model to guide therapeutic approach in older patients who received lower-intensity therapy., (© 2023 American Cancer Society.)

Hypomethylating agents (HMAs) are the standard of care for myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). HMA treatment failure is a major clinical problem and its mechanisms are poorly characterized. We performed RNA sequencing in CD34 + bone marrow stem hematopoietic stem and progenitor cells (BM-HSPCs) from 51 patients with CMML and MDS before HMA treatment and compared transcriptomic signatures between responders and nonresponders. We observed very few genes with significant differential expression in HMA non-responders versus responders, and the commonly altered genes in non-responders to both azacitidine (AZA) and decitabine (DAC) treatments were immunoglobulin genes. Gene set analysis identified 78 biological pathways commonly altered in non-responders to both treatments. Among these, we determined that the γ-aminobutyric acid (GABA) receptor signaling significantly affected hematopoiesis in both human BM-HSPCs and mice, indicating that the transcriptomic signatures identified here could serve as candidate biomarkers and therapeutic targets for HMA failure in MDS and CMML., Competing Interests: Conflict of Interest Disclosure The authors declare no competing interests., (Published by Elsevier Inc.)

BACKGROUND: The hypomethylating agents are part of the standard of care in the treatment of myelodysplastic syndromes (MDS), but their role in patients with lower-risk disease is unclear. METHODS: We randomly assigned patients with previously untreated MDS with low/intermediate-1 risk by the International Prognostic Scoring System with a Bayesian response-adaptive design to receive either 20 mg/m2 decitabine daily or 75 mg/m2 azacitidine daily on days 1 to 3 every 28-day cycle. RESULTS: A total of 113 patients were treated: 73 (65%) with decitabine and 40 (35%) with azacitidine. The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) reached transfusion independence (decitabine, 16 of 39 [41%]; azacitidine, 3 of 20 [15%]; P=0.039). Of the 19 patients who reached transfusion independence, the median duration of transfusion independency was 22 months. Among 54 patients who were transfusion independent at baseline, 5 patients (9%) became transfusion dependent after therapy. No early death was observed. With a median follow-up of 68 months, the median overall event-free survival and overall survival were 17 months and 33 months, respectively. CONCLUSIONS: Attenuated dose treatment of hypomethylating agents in patients with lower-risk MDS can improve outcomes without dose-limiting side effects in a high-risk cohort as defined by the Lower-Risk Prognostic Scoring System. (Funded in part by The University of Texas MD Anderson Cancer Center and others; ClinicalTrials.gov number, NCT01720225.)

EZH2 coding mutation (EZH2 MUT ), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2 MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2 MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2 MUT MDS showed frequent loss-of-expression compared to EZH2 WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2 WT MDS also showed loss-of-expression. EZH2 MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2 MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Chromosome banding analysis (CBA) remains the standard-of-care for structural variant (SV) assessment in MDS. Optical genome mapping (OGM) is a novel, non-sequencing-based technique for high-resolution genome-wide SV profiling (SVP). We explored the clinical value of SVP by OGM in 101 consecutive, newly diagnosed MDS patients from a single-center, who underwent standard-of-care cytogenetic and targeted NGS studies. OGM detected 383 clinically significant, recurrent and novel SVs. Of these, 224 (51%) SVs, seen across 34% of patients, were cryptic by CBA (included rearrangements involving MECOM, NUP98::PRRX2, KMT2A partial tandem duplications among others). SVP decreased the proportion of normal karyotype by 16%, identified complex genomes (17%), chromothripsis (6%) and generated informative results in both patients with insufficient metaphases. Precise gene/exon-level mapping allowed assessment of clinically relevant biomarkers (TP53 allele status, KMT2A-PTD) without additional testing. SV data was complementary to NGS. When applied in retrospect, OGM results changed the comprehensive cytogenetic scoring system (CCSS) and R-IPSS risk-groups in 21% and 17% patients respectively with an improved prediction of prognosis. By multivariate analysis, CCSS by OGM only (not CBA), TP53 mutation and BM blasts independently predicted survival. This is the first and largest study reporting the value of combined SVP and NGS for MDS prognostication., (© 2022. The Author(s).)

Background: SF3B1 mutations (SF3B1 mut ) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1 mut is uncertain., Methods: The authors analyzed the clinicopathological features and outcomes of a single-institution series of 94 treatment-naive SF3B1 mut MDS patients (18%) and 415 treatment-naive SF3B1 wt MDS patients and explored the differences between K700E and non-K700E SF3B1 mut MDS., Results: Fifty-five patients (59%) carried K700E. Recurrent non-K700E mutations (39 [41%]) included R625, H662, and K666. Compared with SF3B1 mut K700E patients, non-K700E patients had a lower median absolute neutrophil count (1.8 vs 2.4; P = .005) and were frequently "high" according to the Revised International Prognostic Scoring System (19% vs 4%; P = .031). Non-K700E MDS was associated frequently with RUNX1 (26% vs 7%; P = .012) and exclusively with BCOR, IDH2, and SRSF2 mutations. A splicing analysis showed the differential distribution of alternatively spliced events and gene expression profiles between K700 and non-K700E MDS patients. The majority (at least 80%) of SF3B1 mut K700E, SF3B1 mut non-K700E, and SF3B1 wt patients were treated with hypomethylating agents. Over a median follow-up of 16 months, SF3B1 mut had superior overall survival (OS) in comparison with SF3B1 wt in all MDS patients (not reached vs 25.2 months; P = .0003), in patients with low-grade MDS, and in patients with myelodysplastic syndromes with ring sideroblasts (MDS-RS). Compared with SF3B1 wt , SF3B1 mut K700E had superior outcomes in all MDS (median OS, 25 months vs not reached; P = .0001), in low-grade MDS (median OS, 41.3 months vs not reached; P = .0015), and in MDS-RS (median OS, 22.3 months vs not reached; P = .0001), but no significant difference was seen between non-K700E and SF3B1 wt MDS. By multivariable analysis, the absence of SF3B1 mut K700E mutations was independently associated with the prognosis., Conclusions: This study highlights the importance of the SF3B1 mutation subtype in MDS risk assessment., Lay Summary: Myelodysplastic syndromes (MDS) with SF3B1 mutations are regarded as having a favorable prognosis by both the World Health Organization and the International Working Group for the Prognosis of Myelodysplastic Syndromes. However, this article shows that only MDS patients with SF3B1 K700E mutations have a favorable prognosis (and not MDS patients with SF3B1 mutations involving other codons). This has important implications for refining future MDS subclassification and risk assessment criteria., (© 2021 American Cancer Society.)

LILRB4 is expressed in AML M4/M5 cells and negatively regulates immune cell activation via T-cell suppression. Its expression and role in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS) are unknown. We investigated LILRB4 expression in 19 CMML and 27 MDS patients and correlated it with response to subsequent hypomethylating agent (HMA) therapy. LILRB4 RNA expression was increased in CMML patients when compared to MDS patients and healthy controls ( q  < 0.1) and slightly increased in patients who responded to HMAs ( q  > 0.1). Pathway analysis revealed upregulation of PD-1 signaling, CTLA-4 signaling, and inflammatory response, and gene correlates were positively associated with CTLA-4 expression. Given current modest results with immunotherapy in myeloid malignancies, further investigation of LILRB4 as an immune checkpoint inhibitor target is needed. With the positive correlation between LILRB4 and CTLA-4 expression, combining anti-LILRB4 and anti-CTLA-4 agents may be a novel therapeutic approach in myeloid malignancies that warrants larger studies.

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. We evaluated 415 patients with AML-MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML-MRC, therapy type and mutation profile. Criteria for AML-MRC included: cytogenetic abnormalities (AML-MRC-C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML-MRC-H) and 28 (7%) with previously treated MDS (AML-MRC-TS), and 97 (23%) with multilineage dysplasia (AML-MRC-M). Median age was 70 years (range 18-94). Among 95 evaluable patients, a total of 37 (39%) had secondary-type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML-MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML-MRC-M (HR 0.56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions., (© 2020 Wiley Periodicals, Inc.)

Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis and cytopenias due to uncontrolled programmed cell death. The presence of pro-inflammatory cytokines and constitutive activation of innate immunity signals in MDS cells suggest inflammatory cell death, such as necroptosis, may be responsible for disease phenotype. We evaluated 64 bone marrow samples from 55 patients with MDS or chronic myelomonocytic leukemia (CMML) obtained prior to (n = 46) or after (n = 18) therapy with hypomethylating agents (HMAs). RNA from sorted bone marrow CD34+ cells was isolated and subject to amplification and RNA-Seq. Compared with healthy controls, expression levels of MLKL (CMML: 2.09 log2FC, p = 0.0013; MDS: 1.89 log2FC, p = 0.003), but not RIPK1 or RIPK3, were significantly upregulated. Higher expression levels of MLKL were associated with lower hemoglobin levels at diagnosis (-0.19 log2FC per 1 g/dL increase of Hgb, p = 0.03). Significant reduction in MLKL levels was observed after HMA therapy (-1.06 log2FC, p = 0.05) particularly among nonresponders (-2.89 log2FC, p = 0.06). Higher RIPK1 expression was associated with shorter survival (HR 1.92, 95% CI 1.00-3.67, p = 0.049 by Cox proportional hazards). This data provides further support for a role of necroptosis in MDS, and potentially response to HMAs and prognosis. This data also indicate that RIPK1/RIPK3/MLKL are potential therapeutic targets in MDS.

TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors., (© 2020 by The American Society of Hematology.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS., Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities., Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3α (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival., Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS., (© 2019 American Cancer Society.)

The outcome of patients with myelodysplastic syndromes (MDSs) after failure of hypomethylating agents (HMAs) failure is poor with a median overall survival (OS) of only 4-6 months. Omacetaxine mepesuccinate (OM) is safe and effective in myeloid malignancies but has not been studied in MDS with HMA failure. We conducted a phase II study of OM in patients with MDS or chronic myelomonocytic leukemia (CMML) who had previously failed or been intolerant to HMAs. Patients received OM at a dose of 1.25 mg/m 2 subcutaneously every 12 hours for 3 consecutive days on a 4- to 7-week schedule. The primary endpoints were the overall response rate (ORR) and OS. A total of 42 patients were enrolled with a median age of 76 years. The ORR was 33%. Patients with diploid cytogenetics were more likely to respond to OM than were those with cytogenetic abnormalities (58% vs 23%, respectively; P = .03). Overall, the median OS was 7.5 months and 1-year OS rate was 25%. Patients with diploid cytogenetics had superior OS to those with cytogenetic abnormalities (median OS 14.8 vs 6.8 months, respectively; P = .01). Two patients had ongoing response to OM of 2 years or longer (both MDS with diploid cytogenetics and RUNX1 mutation). The most common grade ≥ 3 adverse events were infections in 11 patients (26%), febrile neutropenia in 4 (10%), and hemorrhage in 3 (7%). Overall, OM was safe and active in patients with MDS or CMML who experienced HMA failure. These results support the further development of OM in this setting., (© 2018 Wiley Periodicals, Inc.)

Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m 2 intravenously/subcutaneously daily or decitabine 20 mg/m 2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% ( P = .03) for patients treated with decitabine and azacitidine, respectively. Thirty-two percent of patients treated with decitabine became transfusion independent compared with 16% of patients treated with azacitidine ( P = .2). Cytogenetic response rates were 61% and 25% ( P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with decitabine and azacitidine, respectively ( P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225)., (© 2017 by The American Society of Hematology.)

Behçet disease (BD) is rarely seen in children. Its clinical manifestations are believed to differ between pediatric and adult patients. The characteristics of BD complicated by myelodysplastic syndrome (MDS) are well established for adult patients; however, because only a few cases of pediatric-onset BD complicated by MDS have been reported, its clinical characteristics remain unknown. We here retrospectively review pediatric-onset BD complicated by myeloid malignancies in Japan, having identified five such patients. All patients were female and had gastrointestinal involvements, but lacked both major features of BD, i.e., uveitis and association with HLA-B51. All patients had advanced MDS or acute myeloid leukemia and received chemotherapy followed by hematopoietic stem cell transplantation. These five cases suggest that intestinal BD and myeloid malignancies have one or more pathophysiological mechanisms in common.

Background: The outcome of patients with higher-risk myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor. This study evaluated the safety and activity of a combination of low-dose clofarabine and cytarabine for these patients., Methods: Seventy patients with higher-risk MDS who had no response, progressed, or relapsed after at least 4 cycles of HMA therapy were treated., Results: The median age was 72 years. Thirty-nine percent of the patients had high-risk disease according to the International Prognostic Scoring System, and 50% of the patients had poor-risk cytogenetics. Twenty-three percent of the patients had therapy-related MDS. The median number of prior cycles of HMA was 6 (range, 4-45). The overall response rate was 44%. The 6-week mortality rate was 9%. Grade 3 and higher nonhematologic toxicities were rare, but infections occurred in 52% of the patients, and fever of unknown origin occurred in 33%. The median overall survival (OS) was 10 months (95% confidence interval, 1-37 months). Thirteen percent of the patients underwent allogeneic stem cell transplantation. The responding patients had a median OS of 22 months, whereas the nonresponding patients had a median OS of 4 months. A complex karyotype was associated with worse response rates and OS., Conclusions: The combination of low-dose clofarabine and cytarabine is clinically active in these patients with few treatment options. Cancer 2017;123:629-637. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Purpose: To learn whether an antecedent hematologic disorder (AHD) is associated with additional risk in patients with therapy-related acute myeloid leukemia (t-AML)., Patients and Methods: We reviewed data of 301 patients with newly diagnosed t-AML who sought care from January 2000 to January 2014 (183 t-AML without AHD, 118 t-AML with AHD). Overall, median follow-up was 44 months., Results: The primary malignancy was non-Hodgkin lymphoma in 92 (31%), breast cancer in 80 (27%), and prostate cancer in 49 (16%). Median relapse-free survival (RFS) in t-AML without or with AHD was 10 months and 29 months, respectively (P = .032); median overall survival (OS) was 8 months and 8 months, respectively (P = .53). Multivariate analysis for OS identified older age, poor performance status, thrombocytopenia, nonfavorable cytogenetics, and lack of response as adverse factors., Conclusion: The favorable-risk cohort had better RFS and OS compared to the outcomes of patients in the intermediate- and adverse-risk cohorts; the RFS and OS did not differ between intermediate- and adverse-risk cohorts. The presence of AHD did not affect OS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: NPM1‐mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. Methods: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild‐type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. Results: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p =.023) and FLT3 (70% vs 11%, p <.001) frequency in patients with ≥20% BM blasts. Thirty‐three (61%) patients with NPM1mut MNs <20 received low‐intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p =.006) and median overall survival (mOS) (not reached vs 30.4 months, p =.06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p =.025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%–19%, and ≥20% blasts, p =.700) regardless of treatment modality (LIC: p =.900; IC: p =.360). Twenty‐three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. Conclusions: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage. NPM1 mutations define a unique leukemia entity regardless of bone marrow blast percentage. Patients with NPM1‐mutated myeloid neoplasms benefit from intensive chemotherapy approaches even in the setting of low bone marrow blast percentage. [ABSTRACT FROM AUTHOR]

This letter to the editor discusses the prevalence and characteristics of TP53 Y220C mutations in patients with myeloid malignancies. The study found that these mutations were detected in 4.8% of patients with TP53 mutated myeloid neoplasms, most of whom had myelodysplastic syndromes or acute myeloid leukemia. The study also identified other co-occurring mutations. The authors suggest that targeted therapies may hold promise in improving outcomes for patients with this mutation, but further research is needed to address other TP53 mutations. [Extracted from the article]

The understanding of the molecular pathobiology of acute myeloid leukemia (AML) has spurred the identification of therapeutic targets and the development of corresponding novel targeted therapies. Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor). Other targeted therapies (menin inhibitors, CD123 antibody-drug conjugates) are showing promising results. To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions. [ABSTRACT FROM AUTHOR]

Simple Summary: The DEAD-box RNA helicase 41, DDX41, is one of the most frequently identified mutations in myeloid neoplasms with germline predispositions, which represents 2% of the entire MDS/AML population. DDX41 is located at 5q35.3, and its mutation has unique features of male predominance and long-term cytopenia before the development of myeloid neoplasms. So far, mechanism studies revealed that DDX41 mutations, affected by both germline and somatic mutations, can be pathogenic by impairments in the normal function of genes involving RNA splicing and processing, ribosomal biogenesis, metabolism, cycle progression, and innate immunity. We are gaining a better understanding of disease from more studies coming out with larger cohorts. The survival impact of the mutation remains unclear, although recent larger studies suggest a better treatment response and survival in higher risk MDS/AML. Several studies showed a good response to lenalidomide in certain patients with MDS with DDX41 mutations. Early identification of stem-cell transplant donors in the family for patients with DDX41 mutations is crucial to avoid donor-derived leukemia from germline carriers. In this article, we reviewed the current understanding of DDX41 mutations in AML/MDS, including its pathogenesis and clinical characteristics, outcome, and treatment. The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene's normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications. [ABSTRACT FROM AUTHOR]