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BackgroundT-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive disease. In this study, we report our experience from 119 patients with T-PLL.Patients and methodsWe reviewed the clinico-pathologic records of 119 consecutive patients with T-PLL, who presented to our institution between 1990 and 2016.ResultsOne hundred and nineteen patients with T-PLL were analysed. Complex karyotype and aberrations in chromosome 14 were seen in 65% and 52% patients, respectively. Seventy-five patients (63%) were previously untreated and 43 (37%) were initially treated outside our institution. Sixty-three previously untreated patients (84%) received frontline therapies. Overall, 95 patients (80%) have died. Median overall survival (OS) from diagnosis was 19 months [95% confidence interval (CI) 16-26 months]. Using recursive partitioning (RP), we found that patients with hemoglobin

B Introduction: b We investigated the efficacy and safety of ibrutinib, rituximab (IR) and venetoclax (IRV) followed by risk-stratified short course R-HCVAD/MTX-ARA-C as consolidation and IRV maintenance in previously untreated young patients (pts) (<=65 yrs) with MCL (mantle cell lymphoma). We anticipated that using a triplet chemotherapy-free induction would minimize chemotherapy exposure. IBRUTINIB-RITUXIMAB AND VENETOCLAX (IRV) FOLLOWED BY RISK-STRATIFIED R-HYPERCVAD/MTX IN YOUNG PATIENTS WITH UNTREATED MANTLE CELL LYMPHOMA - PHASE-II WINDOW-2 TRIAL. [Extracted from the article]

We conducted whole exome sequencing (WES; I n i = 41) and RNA-seq ( I n i = 41) from MCL tissue biopsies from patients treated with BTKi (ibrutinib, acalabrutinib or zanubrutinib) in combination with the analysis of a published MCL cohort ( I n i = 122). Immune depleted TME subtype in MCL is a biomarker to predict BTKi resistance and poor outcomes in MCL patients. B Introduction: b An understanding of the tumor microenvironment (TME) and its cellular and analyte composition plays a critical role in promoting mantle cell lymphoma (MCL) cell growth, proliferation. [Extracted from the article]

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.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

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Introduction: NPM1-mutated (NPM1 mut ) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1 mut MNs<20) are uncommon, and their classification remains inconsistent., Methods: The clinicopathologic features of 54 patients with NPM1 mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1 mut MNs≥20, respectively., Results: NPM1 mut 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 NPM1 mut 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 NPM1 mut MNs <20 had marrow blast progression to ≥20%., Conclusions: Overall, NPM1 mut MNs define a unique entity independent of BM blast percentage., (© 2024 American Cancer Society.)

RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Here, using single-cell, multi-omics technologies, we seek to dissect the biological mechanisms underlying the initiation and progression of RAS pathway-mutated CMML. We identify that RAS pathway mutations induce transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs) and downstream monocytic populations in response to cell-intrinsic and -extrinsic inflammatory signaling that also impair the functions of immune cells. HSPCs expand at disease progression after therapy with HMA or the BCL2 inhibitor venetoclax and rely on the NF-κB pathway effector MCL1 to maintain survival. Our study has implications for the development of therapies to improve the survival of patients with RAS pathway-mutated CMML., Competing Interests: Declaration of interests G.M.-B. declares research support from Rigel Pharmaceuticals, IFM Therapeutics, and Takeda Oncology. K.T. declares support from Symbio Pharmaceuticals, Novartis, Celgene/BMS, and GSK, and honoraria from Mission Bio and Illumina. H.K. declares research support from and an advisory role at Actinium and research support from AbbVie, Agio, Amgen, Ariad, Astex, Bristol Myers Squibb, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. G.G-M. declares research support from and an advisory role at Bristol Myers Squibb, Astex, and Helsinn, and research support from Amphivena, Novartis, AbbVie, H3 Biomedicine, Onconova, and Merck. S.C. declares research support from Amgen., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Therapy-related myeloid neoplasms (t-MNs) arise after exposure to cytotoxic therapies and are associated with high-risk genetic features and poor outcomes. We analyzed a cohort of patients with therapy-related chronic myelomonocytic leukemia (tCMML; n = 71) and compared its features to that of de novo CMML (dnCMML; n = 461). Median time from cytotoxic therapy to tCMML diagnosis was 6.5 years. Compared with dnCMML, chromosome-7 abnormalities (4% vs 13%; P = .005) but not complex karyotype (3% vs 7%; P = .15), were more frequent in tCMML. tCMML was characterized by higher TP53 mutation frequency (4% vs 12%; P = .04) and lower NRAS (6% vs 22%, P = .007) and CBL (4% vs 12%, P = .04) mutation frequency. Prior therapy with antimetabolites (odd ratio [OR], 1.22; 95% confidence interval [CI], 1.05-1.42; P = .01) and mitotic inhibitors (OR, 1.24; 95% CI, 1.06-1.44; P = .009) was associated with NF1 and SETBP1 mutations whereas prior mitotic inhibitor therapy was associated with lower TET2 mutation frequency (OR, 0.71; 95% CI, 0.55-0.92; P = .01). Although no differences in median overall survival (OS) were observed among tCMML and dnCMML (34.7 months vs 35.9 months, P = .26), multivariate analysis for OS revealed that prior chemotherapy was associated with increased risk of death (hazard ratio, 1.76; 95% CI, 1.07-2.89; P = .026). Compared with a cohort of therapy-related myelodysplastic syndrome, tCMML had lower TP53 mutation frequency (12% vs 44.4%, P < .001) and less unfavorable outcomes. In summary, tCMML does not exhibit the high-risk features and poor outcomes of t-MNs., (© 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.)

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.)

Optical Genome Mapping (OGM) is rapidly emerging as an exciting cytogenomic technology both for research and clinical purposes. In the last 2 years alone, multiple studies have demonstrated that OGM not only matches the diagnostic scope of conventional standard of care cytogenomic clinical testing but it also adds significant new information in certain cases. Since OGM consolidates the diagnostic benefits of multiple costly and laborious tests (e.g., karyotyping, fluorescence in situ hybridization, and chromosomal microarrays) in a single cost-effective assay, many clinical laboratories have started to consider utilizing OGM. In 2021, an international working group of early adopters of OGM who are experienced with routine clinical cytogenomic testing in patients with hematological neoplasms formed a consortium (International Consortium for OGM in Hematologic Malignancies, henceforth "the Consortium") to create a consensus framework for implementation of OGM in a clinical setting. The focus of the Consortium is to provide guidance for laboratories implementing OGM in three specific areas: validation, quality control and analysis and interpretation of variants. Since OGM is a complex technology with many variables, we felt that by consolidating our collective experience, we could provide a practical and useful tool for uniform implementation of OGM in hematologic malignancies with the ultimate goal of achieving globally accepted standards., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

The molecular mechanisms of venetoclax-based therapy failure in patients with acute myeloid leukemia were recently clarified, but the mechanisms by which patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show an expansion of MDS hematopoietic stem cells (HSCs) with a granulo-monocytic-biased transcriptional differentiation state in MDS patients who initially responded to venetoclax but eventually relapsed. While MDS HSCs in an undifferentiated cellular state are sensitive to venetoclax treatment, differentiation towards a granulo-monocytic-biased transcriptional state, through the acquisition or expansion of clones with STAG2 or RUNX1 mutations, affects HSCs' survival dependence from BCL2-mediated anti-apoptotic pathways to TNFα-induced pro-survival NF-κB signaling and drives resistance to venetoclax-mediated cytotoxicity. Our findings reveal how hematopoietic stem and progenitor cell (HSPC) can eventually overcome therapy-induced depletion and underscore the importance of using close molecular monitoring to prevent HSPC hierarchical change in MDS patients enrolled in clinical trials of venetoclax., (© 2024. The Author(s).)

Background: The occurrence of somatic mutations in patients with no evidence of hematological disorders is called clonal hematopoiesis (CH). CH, whose subtypes include CH of indeterminate potential and clonal cytopenia of undetermined significance, has been associated with both hematologic cancers and systemic comorbidities. However, CH's effect on patients, especially those with concomitant malignancies, is not fully understood., Methods: We performed a retrospective evaluation of all patients with CH at a tertiary cancer center. Patient characteristics, mutational data, and outcomes were collected and analyzed., Results: Of 78 individuals included, 59 (76%) had a history of cancer and 60 (77%) had moderate to severe comorbidity burdens. DNMT3A, TET2, TP53, and ASXL1 were the most common mutations. For the entire cohort, the 2-year overall survival rate was 79% (95% CI: 70, 90), while the median survival was not reached. Of 20 observed deaths, most were related to primary malignancies (n = 7, 35%), comorbidities (n = 4, 20%), or myeloid neoplasms (n = 4, 20%). Twelve patients (15%) experienced transformation to a myeloid neoplasm. According to the clonal hematopoiesis risk score, the 3-year transformation rate was 0% in low-risk, 15% in intermediate-risk (p = 0.098), and 28% in high-risk (p = 0.05) patients. By multivariate analysis, transformation was associated with variant allele frequency ≥0.2 and hemoglobin <10 g/dL., Conclusions: In a population including mostly cancer patients, CH was associated with comorbidities and myeloid transformation in patients with higher mutational burdens and anemia. Nevertheless, such patients were less likely to die of their myeloid neoplasm than of primary malignancy or comorbidities., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.)

DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover mechanisms through which MM cells overcome DNA damage, we investigate how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting Interleukin enhancer binding factor 2 (ILF2), a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo adaptive metabolic rewiring to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identify the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage. Our study reveals a mechanism of vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation., (© 2024. The Author(s).)

In this manuscript, we review myeloid neoplasms in the fifth edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5), focusing on changes from the revised fourth edition (WHO-HEM4R). Disease types and subtypes have expanded compared with WHO-HEM4R, mainly because of the expansion in genomic knowledge of these diseases. The revised classification is based on a multidisciplinary approach including input from a large body of pathologists, clinicians, and geneticists. The revised classification follows a hierarchical structure allowing usage of family (class)-level definitions where the defining diagnostic criteria are partially met or a complete investigational workup has not been possible. Overall, the WHO-HEM5 revisions to the classification of myeloid neoplasms include major updates and revisions with increased emphasis on genetic and molecular drivers of disease. The most notable changes have been applied to the sections of acute myeloid leukemia and myelodysplastic neoplasms (previously referred to as myelodysplastic syndrome) with incorporation of novel, disease-defining genetic changes. In this review we focus on highlighting the updates in the classification of myeloid neoplasms, providing a comparison with WHO-HEM4R, and offering guidance on how the new classification can be applied to the diagnosis of myeloid neoplasms in routine practice., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Patients with multiple myeloma (MM) who undergo high-dose chemotherapy and autologous hematopoietic cell transplantation (Auto-HCT) have an increased risk of developing therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). We retrospectively reviewed the medical records of all MM patients who underwent an Auto-HCT at our institution between 1 January and 31 December 2018 and later developed t-MDS/AML. Among the 2982 patients who underwent at least 1 Auto-HCT, 55 (2%) developed t-MDS/AML (MDS, n = 52; AML, n = 3). The median age at t-MDS/AML diagnosis was 66 years (range 43-83 years), and the median time from Auto-HCT to t-MDS/AML diagnosis was 58.5 months (range 6-206 months). At diagnosis, all 3 patients with tAML and 65% of those with therapy-related myelodysplastic syndrome (tMDS) had high-risk disease, per 2022 European LeukemiaNet and R-IPSS, respectively, and 62% had TP53 gene mutations. Patients who developed tMDS/AML were older at MM diagnosis (median 61 versus 59 years; P = .06), more often were male (73% versus 58%; P = .029), received more than 2 years of lenalidomide maintenance (57% versus 39%; P = .014), and experienced complete remission more frequently after Auto-HCT compared to those who did not develop t-MDS/AML (56% versus 40%; P = .012). In a multivariable model, male gender, advanced age at MM diagnosis, experiencing complete remission after Auto-HCT, and lenalidomide maintenance were independent predictors of developing t-MDS/AML. Among the patients who developed t-MDS/AML, 14 (25%) underwent allogeneic hematopoietic stem transplantation (Allo-HCT). After a median follow-up of 9.9 months from t-MDS/AML diagnosis, the median overall survival (OS) after t-MDS/AML diagnosis was 11.8 months for all patients, and 18.2 months versus 11.1 months for Allo-HCT recipients versus nonrecipients, respectively (P = .25). On univariate analysis, receiving an alkylator as induction for MM (hazard ratio [95% confidence interval]: 2.9 [1.3-6.3]; P = .009), age > 60 years (3.1 [1.2-8.2]; P = .025), and higher-risk R-IPSS (2.7 [1.3-6.0]; P=0.011) predicted worse OS after t-MDS/AML diagnosis. None of these retained significance in the multivariable analysis. T-MDS/AML after Auto-HCT for MM is associated with aggressive disease characteristics, including high-risk cytogenetics and TP53 mutations. The outcomes of patients remain poor, even with Allo-HCT. A better understanding of disease biology and novel therapeutic approaches is warranted., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond.

Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy., (Copyright © 2023. Published by Elsevier Inc.)

Hematological malignancies with underlying germline predisposition disorders have been recognized by the World Health Organization 5th edition and International Consensus Classification (ICC) classification systems. The list of genes and the associated phenotypes are expanding and involve both pediatric and adult populations. While the clinical presentation and underlying molecular pathogenesis are relatively well described, the knowledge regarding the bone marrow morphologic features, the landscape of somatic aberrations associated with progression to hematological malignancies is limited. These pose challenges in the diagnosis of low-grade myelodysplastic syndrome (MDS) to hematopathologists which carries direct implication for various aspects of clinical management of the patient, donor selection for transplantation, and family members. Here in, we provide a focused review on the diagnostic work-up of hematological malignancies with underlying germline predisposition disorders with emphasis on the spectrum of hematological malignancies associated with each entity, and characteristic bone marrow morphologic, somatic cytogenetic and molecular alterations at the time of diagnosis of hematological malignancies. We also review the key clinical, morphologic, and molecular features, that should initiate screening for these entities., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This manuscript has not been previously published and is not under consideration for publication elsewhere., (Copyright © 2023. Published by Elsevier Inc.)

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival., (© 2023 Wiley Periodicals LLC.)

Patients with chronic myeloid leukemia (CML) and T315I mutation generally have a poor prognosis. Their outcome in the post-ponatinib era remains unclear. We reviewed patients with CML in chronic (CP) or accelerated phase (AP) who developed a T315I mutation between March 15, 2004, and July 26, 2022. Patients were divided into CP, AP, or blastic phase (BP) at the time of mutation detection. Overall survival (OS) was defined from the time of mutation detection to the date of death or last follow-up. We identified a total of 107 patients: 54 (51%) in CP, 14 (13%) in AP, and 39 (36%) in BP. One hundred and two patients received subsequent therapy after the T315I mutation was detected. At a median follow-up of 75 months (95% CI, 41-110), the median OS was 49 months (95% CI, 26-73) and the 5-year OS rate was 44%. Patients who were in CML-CP at the time of mutation detection had better survival compared with those in AP or BP, with a median OS of 132, 31, and 6 months, and 5-year OS rates of 70%, 37%, and 10%, respectively (p < .001). Patients with CML-CP treated with ponatinib and/or asciminib had a 5-year OS of 77% compared with 50% in those who received other treatments (chemotherapy, second-generation tyrosine kinase inhibitors, homoharringtonine, and investigational drugs) (p = .14). In summary, patients with CML-CP at the time of T315I mutation detection may have a relatively indolent disease course with a long-term OS of 70%. Treatment with third-generation tyrosine kinase inhibitors seemed to improve survival in patients with CML-CP., (© 2023 Wiley Periodicals LLC.)