bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2023–12–17
sixty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.
  2. Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
  3. Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.
  4. Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.
  5. Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML.
  6. Frontline treatment options for higher-risk MDS: can we move past azacitidine?
  7. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.
  8. The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy.
  9. Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group.
  10. Osimertinib covalently binds to CD34 and eliminates myeloid leukemia stem/progenitor cells.
  11. Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression.
  12. Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia.
  13. Mechanisms of resistance to hypomethylating agents and BCL-2 inhibitors.
  14. When to use which molecular prognostic scoring system in the management of patients with MDS?
  15. Clonal hematopoiesis in frequent whole blood donors.
  16. Novel immunotherapies in the treatment of AML: is there hope?
  17. Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations.
  18. PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.
  19. Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein.
  20. TP53 variant allele frequency and therapy-related setting independently predict survival in myelodysplastic syndromes with del(5q).
  21. Clonal evolution in inherited marrow failure syndromes predicts disease progression.
  22. Expansion of human hematopoietic stem cells by inhibiting translation.
  23. Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
  24. The approach of HMA plus VEN with or without BMT for all patients with AML.
  25. How to classify risk based on clinical and molecular modeling: integrating molecular markers in the risk assessment of myelodysplastic syndrome.
  26. Nardilysin determines hematopoietic stem cell fitness by regulating protein synthesis.
  27. Profound sympathetic neuropathy in the bone marrow of patients with acute myeloid leukemia.
  28. Long-term follow-up of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation after primary induction failure.
  29. Understanding differential technologies for detection of MRD and how to incorporate into clinical practice.
  30. Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors.
  31. Next-generation therapy for lower-risk MDS.
  32. Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy.
  33. Clinical forecasting of acute myeloid leukemia using ex vivo drug-sensitivity profiling.
  34. Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations.
  35. Identification and surveillance of rare relapse-initiating stem cells during complete remission post-transplantation.
  36. PPM1D inhibition may allow us to WIP leukemia.
  37. SON is an essential m6A target for hematopoietic stem cell fate.
  38. Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.
  39. Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia.
  40. WHO, what, when, where, and why: New classification systems for acute myeloid leukemia and their impact on clinical practice.
  41. Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.
  42. AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells.
  43. Novel therapies upon failure of HMA plus venetoclax.
  44. Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia.
  45. A defined serum-free culture system for human long-term haematopoietic stem cells.
  46. Menin Inhibitors Trigger Leukemia Remissions.
  47. Phenotypic profiling of solute carriers characterizes serine transport in cancer.
  48. Ex vivo Hematopoietic Stem Cell Expansion Technologies: Recent Progress, Applications, and Open Questions.
  49. Atypical CML: diagnosis and treatment.
  50. Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome.
  51. Generation of transgene-free hematopoietic stem cells from human induced pluripotent stem cells.
  52. SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.
  53. A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response.
  54. Telehealth Serious Illness Care Program for Older Adults with Hematologic Malignancies: A single-arm pilot study.
  55. Comparing malignant monocytosis across the updated WHO and ICC classifications of 2022.
  56. Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders.
  57. Accelerated-phase CML: de novo and transformed.
  58. Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.
  59. Clinical characteristics and prognostic factors analysis of core binding factor acute myeloid leukemia in real world.
  60. Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?
  61. Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD.
  62. Evidence creation for myelofibrosis: Challenges and opportunities.
  1. Blood Cancer Discov. 2023 Dec 13.
    IDH1-mutant preleukemic hematopoietic stem cells can be eliminated by inhibition of oxidative phosphorylation.
    Niklas Landberg, Thomas Köhnke, Yang Feng, Yusuke Nakauchi, Amy C Fan, Miles H Linde, Daiki Karigane, Kelly Lim, Rahul Sinha, Luca Malcovati, Daniel Thomas, Ravindra Majeti.
      Rare preleukemic hematopoietic stem cells (pHSCs) harboring only the initiating mutations can be detected at the time of AML diagnosis. pHSCs are the origin of leukemia and a potential reservoir for relapse. Using primary human samples and gene-editing to model isocitrate dehydrogenase 1 (IDH1) mutant pHSCs, we show epigenetic, transcriptional, and metabolic differences between pHSCs and healthy hematopoietic stem cells (HSCs). We confirm that IDH1 driven clonal hematopoiesis is associated with cytopenia, suggesting an inherent defect to fully reconstitute hematopoiesis. Despite giving rise to multilineage engraftment, IDH1-mutant pHSCs exhibited reduced proliferation, blocked differentiation, downregulation of MHC Class II genes, and reprogramming of oxidative phosphorylation metabolism. Critically, inhibition of oxidative phosphorylation resulted in complete eradication of IDH1-mutant pHSCs but not IDH2-mutant pHSCs or wildtype HSCs. Our results indicate that IDH1-mutant preleukemic clones can be targeted with complex I inhibitors, offering a potential strategy to prevent development and relapse of leukemia.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-23-0195
  2. Nat Commun. 2023 Dec 07. 14(1): 8102
    Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells.
    J McClatchy, R Strogantsev, E Wolfe, H Y Lin, M Mohammadhosseini, B A Davis, C Eden, D Goldman, W H Fleming, P Conley, G Wu, L Cimmino, H Mohammed, A Agarwal.
      Clonal hematopoiesis (CH) is defined as a single hematopoietic stem/progenitor cell (HSPC) gaining selective advantage over a broader range of HSPCs. When linked to somatic mutations in myeloid malignancy-associated genes, such as TET2-mediated clonal hematopoiesis of indeterminate potential or CHIP, it represents increased risk for hematological malignancies and cardiovascular disease. IL1β is elevated in patients with CHIP, however, its effect is not well understood. Here we show that IL1β promotes expansion of pro-inflammatory monocytes/macrophages, coinciding with a failure in the demethylation of lymphoid and erythroid lineage associated enhancers and transcription factor binding sites, in a mouse model of CHIP with hematopoietic-cell-specific deletion of Tet2. DNA-methylation is significantly lost in wild type HSPCs upon IL1β administration, which is resisted by Tet2-deficient HSPCs, and thus IL1β enhances the self-renewing ability of Tet2-deficient HSPCs by upregulating genes associated with self-renewal and by resisting demethylation of transcription factor binding sites related to terminal differentiation. Using aged mouse models and human progenitors, we demonstrate that targeting IL1 signaling could represent an early intervention strategy in preleukemic disorders. In summary, our results show that Tet2 is an important mediator of an IL1β-promoted epigenetic program to maintain the fine balance between self-renewal and lineage differentiation during hematopoiesis.
    DOI:  https://doi.org/10.1038/s41467-023-43697-y
  3. Am J Hematol. 2023 Dec 10.
    Venetoclax and hypomethylating agent combination therapy in newly diagnosed acute myeloid leukemia: Genotype signatures for response and survival among 301 consecutive patients.
    Naseema Gangat, Omer Karrar, Moazah Iftikhar, Kristen McCullough, Isla M Johnson, Maymona Abdelmagid, Mostafa Abdallah, Aref Al-Kali, Hassan B Alkhateeb, Kebede H Begna, Abhishek Mangaonkar, Antoine N Saliba, Mehrdad Hefazi Torghabeh, Mark R Litzow, William Hogan, Mithun Shah, Mrinal M Patnaik, Animesh Pardanani, Talha Badar, Hemant Murthy, James Foran, Jeanne Palmer, Lisa Sproat, Nandita Khera, Cecilia Arana Yi, Ayalew Tefferi.
      Venetoclax + hypomethylating agent (Ven-HMA) is currently the standard frontline therapy for older/unfit patients with newly diagnosed acute myeloid leukemia (ND-AML). Our objective in the current retrospective study of 301 adult patients (median age 73 years; 62% de novo) with ND-AML was to identify molecular predictors of treatment response to Ven-HMA and survival; European LeukemiaNet (ELN) genetic risk assignment was favorable 15%, intermediate 16%, and adverse 69%. Complete remission, with (CR) or without (CRi), count recovery, was documented in 182 (60%) patients. In multivariable analysis, inclusive of mutations only, "favorable" predictors of CR/CRi were NPM1 (86% vs. 56%), IDH2 (80% vs. 58%), and DDX41 (100% vs. 58%) and "unfavorable" TP53 (40% vs. 67%), FLT3-ITD (36% vs. 63%), and RUNX1 (44% vs. 64%) mutations; significance was sustained for each mutation after adjustment for age, karyotype, and therapy-related qualification. CR/CRi rates ranged from 36%, in the presence of unfavorable and absence of favorable mutation, to 91%, in the presence of favorable and absence of unfavorable mutation. At median follow-up of 8.5 months, 174 deaths and 41 allogeneic stem cell transplants (ASCT) were recorded. In multivariable analysis, risk factors for inferior survival included failure to achieve CR/CRi (HR 3.4, 95% CI 2.5-4.8), adverse karyotype (1.6, 1.1-2.6), TP53 mutation (1.6, 1.0-2.4), and absence of IDH2 mutation (2.2, 1.0-4.7); these risk factors were subsequently applied to construct an HR-weighted risk model that performed better than the ELN genetic risk model (AIC 1661 vs. 1750): low (n = 130; median survival 28.9 months), intermediate (n = 105; median 9.6 months), and high (n = 66; median 3.1 months; p < .001); survival in each risk category was significantly upgraded by ASCT. The current study identifies genotype signatures for predicting response and proposes a 3-tiered, CR/CRi-based, and genetics-enhanced survival model for AML patients receiving upfront therapy with Ven-HMA.
    DOI:  https://doi.org/10.1002/ajh.27138
  4. Biochem Pharmacol. 2023 Dec 09. pii: S0006-2952(23)00574-9. [Epub ahead of print] 115981
    Enhancing anti-AML activity of venetoclax by isoflavone ME-344 through suppression of OXPHOS and/or purine biosynthesis in vitro.
    Katie H Hurrish, Yongwei Su, Shraddha Patel, Cassandra L Ramage, Jianlei Zhao, Brianna R Temby, Jenna L Carter, Holly Edwards, Steven A Buck, Sandra E Wiley, Maik Hüttemann, Lisa Polin, Juiwanna Kushner, Sijana H Dzinic, Kathryn White, Xun Bao, Jing Li, Jay Yang, Julie Boerner, Zhanjun Hou, Gheath Al-Atrash, Sergej N Konoplev, Jonathan Busquets, Stefano Tiziani, Larry H Matherly, Jeffrey W Taub, Marina Konopleva, Yubin Ge, Natalia Baran.
      Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis.
    Keywords:  Acute myeloid leukemia; ME-344; Oxidative phosphorylation; Purine biosynthesis; Venetoclax
    DOI:  https://doi.org/10.1016/j.bcp.2023.115981
  5. Blood. 2023 Dec 14. pii: blood.2023021105. [Epub ahead of print]
    Mezigdomide is effective alone and in combination with Menin inhibition in pre-clinical models of KMT2A-r and NPM1c AML.
    Wallace Bourgeois, Jevon A Cutler, Brandon J Aubrey, Daniela Wenge, Florian Perner, Cynthia Martucci, Jill A Henrich, Kelly Klega, Radoslaw P Nowak, Katherine Aleisha Donovan, Meaghan Boileau, Yanhe Wen, Charles Hatton, Athina A Apazidis, Sarah N Olsen, Nadia Kirmani, Yana Pikman, Jessica A Pollard, Jennifer A Perry, Adam S Sperling, Benjamin L Ebert, Gerard M McGeehan, Brian D Crompton, Eric S Fischer, Scott A Armstrong.
      Small molecules that target the MENIN-KMT2A protein-protein interaction (Menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A, MLL1) rearranged (KMT2A-r) and nucleophosmin mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with Menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with Menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared to lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in five patient derived xenograft (PDX) models of KMT2A-r and one NPM1c AML. The combination of mezigdomide with the Menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving Menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single-agent or in combination with Menin inhibitors.
    DOI:  https://doi.org/10.1182/blood.2023021105
  6. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 65-72
    Frontline treatment options for higher-risk MDS: can we move past azacitidine?
    David A Sallman, Zhuoer Xie.
      Although remarkable international efforts have been ongoing for over 17 years to improve upon azacitidine, representing the standard of care therapy for higher-risk myelodysplastic neoplasms (MDS), there still has not been a positive randomized trial in comparison to azacitidine. Real-world data from numerous trials have shown similar results with a median overall survival of 14-18 months, a 40%-50% overall response rate, and a complete remission rate close to 20%. Despite these outcomes, 6 randomized controlled trials have failed to improve outcomes in this patient population, although relevant issues in some of these studies included improper dose adjustments of the hypomethylating agent, lack of placebo- controlled studies, and lack of overall survival (OS) as a primary endpoint, among others. Critical updates in MDS management include the development of molecular prognostication models (eg, the molecular international prognostic scoring system), updates in classification systems highlighting significant overlap in patients with MDS-increased blasts and acute myeloid leukemia (most relevant to TP53 mutations), and refinement of response criteria. Although these paradigm-shifting studies have had great impact in MDS management, the current ongoing randomized phase 3 trials were initiated prior, and prognostic stratification remains via the revised international prognostic scoring system) and with bone marrow blast counts of <20%. Notably, azacitidine + venetoclax, azacitidine + sabatolimab, and azacitidine + magrolimab have shown exciting results in large, single-arm studies and have completed accrual in placebo-controlled, double-blind studies with OS as a primary endpoint. We all eagerly await the results of these studies.
    DOI:  https://doi.org/10.1182/hematology.2023000421
  7. Bone Marrow Transplant. 2023 Dec 13.
    Allogeneic hematopoietic cell transplantation for acute myeloid leukemia with hyperdiploid complex karyotype.
    Xavier Poiré, Myriam Labopin, Emmanuelle Polge, Arnold Ganser, Gérard Socié, Tobias Gedde-Dahl, Edouard Forcade, Jürgen Finke, Yves Chalandon, Claude-Eric Bulabois, Ibrahim Yakoub-Agha, Mahmoud Aljurf, Nicolaus Kröger, Igor Wolfgang Blau, Arnon Nagler, Jordi Esteve, Mohamad Mohty.
      Allogeneic hematopoietic cell transplantation (allo-HCT) remains the best consolidation strategy for acute myeloid leukemia (AML) with complex karyotype (CK). However, CK is a heterogenous and highly diverse entity. Numerical abnormalities have been associated with a controversial prognosis and AML with only multiple numerical abnormalities known as pure hyperdiploid karyotype (HDK) may have a distinct prognosis after allo-HCT compared to non-pure HDK CK AML. A total of 236 patients were identified within the EBMT registry as having HDK comprising 95 pure (pHDK) and 141 with other cytogenetic abnormalities (HDK+). The 2-year probability of leukemia-free survival (LFS) was 50% for pHDK and 31% for HDK+ (p = 0.003). The 2-year probability of overall survival (OS) was 57% for pHDK and 36% for HDK+ (p = 0.007). The 2-year cumulative incidence of relapse (RI) was 22% for pHDK and 44% for HDK+ (p = 0.001). The 2-year probability of graft-versus-host disease (GvHD)-free and relapse-free survival (GRFS) was 36% for pHDK and 21% for HDK+ (p = 0.01). On multivariate analysis, pHDK remained associated with significantly better LFS, OS and GRFS and lower RI (all p-values <0.004). pHDK AML constitutes probably a distinct cytogenetic entity from HDK+ or other non-hyperdiploid CK AML with better outcomes after allo-HCT.
    DOI:  https://doi.org/10.1038/s41409-023-02167-1
  8. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 192-197
    The future paradigm of HMA + VEN or targeted inhibitor approaches: sequencing or triplet combinations in AML therapy.
    Sangeetha Venugopal, Justin Watts.
      The routine use of next-generation sequencing methods has underscored the genetic and clonal heterogeneity of acute myeloid leukemia (AML), subsequently ushering in an era of precision medicine-based targeted therapies exemplified by the small-molecule inhibitors of FLT3, IDH1/IDH2, and BCL2. This advent of targeted drugs in AML has broadened the spectrum of antileukemic therapies, and the approval of venetoclax in combination with a hypomethylating agent has been a welcome addition to our AML patients unable to tolerate intensive chemotherapy. Mounting evidence demonstrates that molecularly targeted agents combined with epigenetic therapies exhibit synergistic augmented leukemic cell kill compared to single-agent therapy. With such great power comes greater responsibility in determining the appropriate frontline AML treatment regimen in a molecularly defined subset and identifying safe and effective combination therapies with different mechanisms of action to outmaneuver primary and secondary resistance mechanisms in AML.
    DOI:  https://doi.org/10.1182/hematology.2023000429
  9. Lancet Haematol. 2023 Dec 04. pii: S2352-3026(23)00305-8. [Epub ahead of print]
    Indication and management of allogeneic haematopoietic stem-cell transplantation in myelofibrosis: updated recommendations by the EBMT/ELN International Working Group.
    Nicolaus Kröger, Andrea Bacigalupo, Tiziano Barbui, Markus Ditschkowski, Nico Gagelmann, Martin Griesshammer, Vikas Gupta, Nada Hamad, Claire Harrison, Juan Carlos Hernandez-Boluda, Steffen Koschmieder, Tania Jain, John Mascarenhas, Ruben Mesa, Uday R Popat, Francesco Passamonti, Nicola Polverelli, Alessandro Rambaldi, Marie Robin, Rachel B Salit, Thomas Schroeder, Bart L Scott, Roni Tamari, Ayalew Tefferi, Alessandro M Vannucchi, Donal P McLornan, Giovanni Barosi.
      New options for medical therapy and risk scoring systems containing molecular data are leading to increased complexity in the management of patients with myelofibrosis. To inform patients' optimal care, we updated the 2015 guidelines on indications for and management of allogeneic haematopoietic stem-cell transplantation (HSCT) with the support of the European Society for Blood and Marrow Transplantation (EBMT) and European LeukemiaNet (ELN). New recommendations were produced using a consensus-building methodology after a comprehensive review of articles released from January, 2015 to December, 2022. Seven domains and 18 key questions were selected through a series of questionnaires using a Delphi process. Key recommendations in this update include: patients with primary myelofibrosis and an intermediate-2 or high-risk Dynamic International Prognostic Scoring System score, or a high-risk Mutation-Enhanced International Prognostic Score Systems (MIPSS70 or MIPSS70-plus) score, or a low-risk or intermediate-risk Myelofibrosis Transplant Scoring System score should be considered candidates for allogeneic HSCT. All patients who are candidates for allogeneic HSCT with splenomegaly greater than 5 cm below the left costal margin or splenomegaly-related symptoms should receive a spleen-directed treatment, ideally with a JAK-inhibitor; HLA-matched sibling donors remain the preferred donor source to date. Reduced intensity conditioning and myeloablative conditioning are both valid options for patients with myelofibrosis. Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion. In a disease where evidence-based guidance is scarce, these recommendations might help clinicians and patients in shared decision making.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00305-8
  10. Cancer Res. 2023 Dec 14.
    Osimertinib covalently binds to CD34 and eliminates myeloid leukemia stem/progenitor cells.
    Li Xia, Jie-Yang Liu, Meng-Ying Yang, Xue-Hong Zhang, Yue Jiang, Qian-Qian Yin, Chen-Hui Luo, Hong-Chen Liu, Zhi-Jie Kang, Cheng-Tao Zhang, Bei-Bei Gao, Ai-Wu Zhou, Hai-Yan Cai, Edmund K Waller, Jin-Song Yan, Ying Lu.
      Osimertinib is a third-generation covalent epidermal growth factor receptor (EGFR) inhibitor that is used in treating non-small cell lung cancer. First-generation EGFR inhibitors were found to elicit pro-differentiation effect on acute myeloid leukemia (AML) cells in preclinical studies, but clinical trials yielded mostly negative results. Here, we report that osimertinib selectively induced apoptosis of CD34+ leukemia stem/progenitor cells but not CD34- cells in EGFR-negative acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). Covalent binding of osimertinib to CD34 at cysteines 199 and 177 and suppression of Src family kinases (SFK) and downstream STAT3 activation contributed to osimertinib-induced cell death. SFK and STAT3 inhibition induced synthetic lethality with osimertinib in primary CD34+ cells. CD34 expression was elevated in AML cells compared to their normal counterparts. Genomic, transcriptomic, and proteomic profiling identified mutation and gene expression signatures of AML patients with high CD34 expression, and univariate and multivariate analyses indicated the adverse prognostic significance of high expression of CD34. Osimertinib treatment induced responses in AML patient-derived xenograft models that correlated with CD34 expression while sparing normal CD34+ cells. Clinical responses were observed in two CD34high AML patients who were treated with osimertinib on a compassionate-use basis. These findings reveal the therapeutic potential of osimertinib for treating CD34high AML and CML and describe an EGFR-independent mechanism of osimertinib-induced cell death in myeloid leukemia.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1632
  11. Leukemia. 2023 Dec 12.
    Preclinical efficacy of targeting epigenetic mechanisms in AML with 3q26 lesions and EVI1 overexpression.
    Christine E Birdwell, Warren Fiskus, Tapan M Kadia, Christopher P Mill, Koji Sasaki, Naval Daver, Courtney D DiNardo, Naveen Pemmaraju, Gautam Borthakur, John A Davis, Kaberi Das, Sunil Sharma, Stephen Horrigan, Xinjia Ruan, Xiaoping Su, Joseph D Khoury, Hagop Kantarjian, Kapil N Bhalla.
      AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions.
    DOI:  https://doi.org/10.1038/s41375-023-02108-3
  12. Leukemia. 2023 Dec 12.
    Panel-based RNA fusion sequencing improves diagnostics of pediatric acute myeloid leukemia.
    Lina Marie Hoffmeister, Julia Suttorp, Christiane Walter, Evangelia Antoniou, Yvonne Lisa Behrens, Gudrun Göhring, Amani Awada, Nils von Neuhoff, Dirk Reinhardt, Markus Schneider.
      New methods like panel-based RNA fusion sequencing (RNA-FS) promise improved diagnostics in various malignancies. We here analyzed the impact of RNA-FS on the initial diagnostics of 241 cases with pediatric acute myeloid leukemia (AML). We show that, compared to classical cytogenetics (CCG), RNA-FS reliably detected risk-relevant fusion genes in pediatric AML. In addition, RNA-FS strongly improved the detection of cryptic fusion genes like NUP98::NSD1, KMT2A::MLLT10 and CBFA2T3::GLIS2 and thereby resulted in an improved risk stratification in 25 patients (10.4%). Validation of additionally detected non-risk-relevant high confidence fusion calls identified PIM3::BRD1, C22orf34::BRD1, PSPC1::ZMYM2 and ARHGAP26::NR3C1 as common genetic variants and MYB::GATA1 as recurrent aberration, which we here describe in AML subtypes M0 and M7 for the first time. However, it failed to detect rare cytogenetically confirmed fusion events like MNX1::ETV6 and other chromosome 12p-abnormalities. As add-on benefit, the proportion of patients for whom measurable residual disease (MRD) monitoring became possible was increased by RNA-FS from 44.4 to 75.5% as the information on the fusion transcripts' sequence allowed the design of new MRD assays.
    DOI:  https://doi.org/10.1038/s41375-023-02102-9
  13. Best Pract Res Clin Haematol. 2023 Dec;pii: S1521-6926(23)00082-8. [Epub ahead of print]36(4): 101521
    Mechanisms of resistance to hypomethylating agents and BCL-2 inhibitors.
    Sudhamsh Reddy Desai, Samarpana Chakraborty, Aditi Shastri.
      Myeloid malignancies such as myelodysplastic syndrome (MDS) & acute myeloid leukemia (AML) are clonal diseases that emerge and progress due to the expansion of disease-initiating aberrant hematopoietic stem cells, that are not eliminated by conventional cytotoxic therapies. Hypomethylating agents(HMA), azacytidine and decitabine are the first line agents for treatment of MDS and a combination with BCL-2 inhibitor, venetoclax, is approved for AML induction in patients above 75 years and is also actively being investigated for use in high risk MDS. Resistance to these drugs has become a significant clinical challenge in treatment of myeloid malignancies. In this review, we discuss molecular mechanisms underlying the development of resistance to HMA and venetoclax. Insights into these mechanisms can help identify potential biomarkers for resistance prediction, aid in the development of combination therapies and strategies to prevent resistance and advance the field of cancer therapeutics.
    Keywords:  AML; Azacytidine; Decitabine; Therapy resistance; Venetoclax
    DOI:  https://doi.org/10.1016/j.beha.2023.101521
  14. Best Pract Res Clin Haematol. 2023 Dec;pii: S1521-6926(23)00078-6. [Epub ahead of print]36(4): 101517
    When to use which molecular prognostic scoring system in the management of patients with MDS?
    Tariq Kewan, Jan Philipp Bewersdorf, Carmelo Gurnari, Zhuoer Xie, Maximilian Stahl, Amer M Zeidan.
      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.
    Keywords:  MDS; Molecular markers; Prognosis; Scoring system
    DOI:  https://doi.org/10.1016/j.beha.2023.101517
  15. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 299-304
    Clonal hematopoiesis in frequent whole blood donors.
    Darja Karpova.
      Healthy volunteer donors are committed to contributing key medical resources. Repeated, regular donation of whole blood represents a specific trigger of hematopoietic stress. Hematopoietic stem cells (HSCs) are known to respond to environmental triggers by altering their differentiation and/or proliferative behavior. This can manifest in long-term changes in the clonal dynamics of HSCs, such as the age-associated expansion of HSCs carrying somatic mutations in genes associated with hematologic cancers-that is, clonal hematopoiesis (CH). A recent study revealed a higher prevalence of CH in frequent donors driven by low-risk mutations in genes encoding for epigenetic modifiers, with DNMT3A and TET2 being the most common. No difference in the prevalence of known preleukemic driver mutations was detected between the cohorts, underscoring the safety of repetitive blood donations. Functional analyses suggest a link between the presence of selected DNMT3A mutations found in the frequent donor group and the responsiveness of the cells to the molecular mediator of bleeding stress, erythropoietin (EPO), but not inflammation. These findings define EPO as one of the environmental factors that provide a fitness advantage to specific mutant HSCs. Analyzing CH prevalence and characteristics in other donor cohorts will be important to comprehensively assess the health risks associated with the different types of donation.
    DOI:  https://doi.org/10.1182/hematology.2023000483
  16. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 691-701
    Novel immunotherapies in the treatment of AML: is there hope?
    Marion Subklewe, Veit Bücklein, David Sallman, Naval Daver.
      The success of allogeneic stem cell transplantation has demonstrated the potential for immunotherapy to treat acute myeloid leukemia (AML). Although alternative T-cell-based immunotherapies have shown efficacy, they also pose the risk of on-target off-leukemia hematotoxicity. So far, adoptive autologous or allogeneic chimeric antigen receptor (CAR) T/natural killer cell therapy is almost exclusively employed as a bridge-to-transplant strategy in the context of clinical trials. For now, clinical trials predominantly target lineage-restricted antigens, but emerging approaches focus on leukemia-associated/specific intracellular target antigens, including dual and split targeting strategies. Adapter CAR T cells and T-cell-recruiting bispecific antibodies offer transient exposure with enhanced safety and multitargeting potential against antigen-escape variants. However, these have yet to demonstrate sustained responses and should be used earlier to treat low leukemia burden, preferably if measurable residual disease is present. To address immune dysregulation and enhance T-cell fitness, novel CAR T and bispecific designs, along with combinatorial strategies, might prove essential. Furthermore, genetic associations with inflammatory bone marrow signatures suggest the need for tailored platforms in defined AML subtypes. The eagerly anticipated results of trials investigating magrolimab, an anti-CD47 antibody targeting the "do not eat me" signal in p53-mutated AML, should shed further light on the potential of these evolving immunotherapeutic approaches.
    DOI:  https://doi.org/10.1182/hematology.2023000455
  17. Exp Hematol. 2023 Dec 08. pii: S0301-472X(23)01773-3. [Epub ahead of print]
    Epigenetic vulnerabilities of leukemia harboring inactivating EZH2 mutations.
    Mona A Alqazzaz, Genna M Luciani, Victoria Vu, Raquel Martinez Machado, Magdalena M Szewczyk, Ella C Adamson, Sehyun Cheon, Fengling Li, Cheryl H Arrowsmith, Mark D Minden, Dalia Barsyte-Lovejoy.
      Epigenetic regulators such as the polycomb repressive complex 2 (PRC2) play a critical role in both normal development and carcinogenesis. Mutations and functional dysregulation of PRC2 complex components such as EZH2 are implicated in various forms of cancer and associated with poor prognosis. This study investigated the epigenetic vulnerabilities of acute myeloid leukemia (AML) and myelodysplastic/myeloproliferative disorders (MDS/MPN) by performing a chemical probe screen in patient cells. Paradoxically, we observed increased sensitivity to EZH2 and EED inhibitors in AML and MDS/MPN patient cells harboring EZH2 mutations. Expression analysis indicated that EZH2 inhibition elicited upregulation of pathways responsible for cell death and growth arrest, specifically in patient cells with mutant EZH2. The identified EZH2 mutations had drastically reduced catalytic activity, resulting in lower cellular H3K27me3 levels and were associated with decreased EZH2 and PRC2 component EED protein levels. Overall, this study provides an important understanding of the role of EZH2 dysregulation in blood cancers and may indicate disease etiology for these poor prognosis AML and MDS/MPN cases.
    Keywords:  Acute myeloid leukemia; EZH2; Epigenetics; Histone methylation
    DOI:  https://doi.org/10.1016/j.exphem.2023.11.009
  18. J Clin Invest. 2023 Dec 07. pii: e164325. [Epub ahead of print]
    PD-1H/VISTA mediates immune evasion in acute myeloid leukemia.
    Tae Kon Kim, Xue Han, Qianni Hu, Esten N Vandsemb, Carly M Fielder, Junshik Hong, Kwang Woon Kim, Emily F Mason, R Skipper Plowman, Jun Wang, Qi Wang, Jian-Ping Zhang, Ti Badri, Miguel F Sanmamed, Linghua Zheng, Tianxiang Zhang, Jude Alawa, Sang Won Lee, Amer M Zeidan, Stephanie Halene, Manoj M Pillai, Namrata S Chandhok, Jun Lu, Mina L Xu, Steven D Gore, Lieping Chen.
      Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics such as targeted therapy and immunotherapy, including anti-PD therapy. We demonstrate that Programmed Death-1 Homolog (PD-1H), an immune co-inhibitory molecule is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells have the expression of PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell-mediated immune responses. Importantly, ablation of AML cell surface PD-1H by antibody blockade or genetic targeting significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression as well and the combination of PD-1H blockade with PD-1 blockade conferred a synergistic anti-leukemia effect. Our findings provide the basis for PD-1H as an attractive therapeutic target to treat human AML.
    Keywords:  Cancer immunotherapy; Costimulation; Immunology; Leukemias; Oncology
    DOI:  https://doi.org/10.1172/JCI164325
  19. J Clin Invest. 2023 Dec 07. pii: e176311. [Epub ahead of print]
    Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia-initiating CBFB::MYH11 oncofusion protein.
    Ryan B Day, Julia A Hickman, Ziheng Xu, Casey Ds Katerndahl, Francesca Ferraro, Sai Mukund Ramakrishnan, Petra Erdmann-Gilmore, Robert W Sprung, Yiling Mi, R Reid Townsend, Christopher A Miller, Timothy J Ley.
      Several canonical translocations produce oncofusion genes that can initiate Acute Myeloid Leukemia (AML). Although each translocation is associated with unique features, the mechanisms responsible remain unclear. While proteins interacting with each oncofusion are known to be relevant for how they act, these interactions have not yet been systematically defined. To address this issue in an unbiased fashion, we fused a promiscuous biotin ligase ("TurboID") in-frame with three favorable-risk acute myeloid leukemia (AML) oncofusion cDNAs (PML::RARA, RUNX1::RUNX1T1, and CBFB::MYH11), and identified their interacting proteins in primary murine hematopoietic cells. The PML::RARA- and RUNX1::RUNX1T1-TurboID fusion proteins labeled common and unique nuclear repressor complexes, implying their nuclear localization. However, CBFB::MYH11-TurboID interacting proteins were largely cytoplasmic, probably due to an interaction of the MYH11 domain with several cytoplasmic myosin-related proteins. Using a variety of methods, we showed that the CBFB domain of CBFB::MYH11 sequesters RUNX1 in cytoplasmic aggregates; these findings were confirmed in primary human AML cells. Paradoxically, CBFB::MYH11 expression was associated with increased RUNX1/2 expression, suggesting the presence of a sensor for reduced functional RUNX1 protein, and a feedback loop that that may attempt to compensate by increasing RUNX1/2 transcription. These findings may have broad implications for AML pathogenesis.
    Keywords:  Epigenetics; Leukemias; Oncology; Proteomics
    DOI:  https://doi.org/10.1172/JCI176311
  20. Br J Haematol. 2023 Dec 11.
    TP53 variant allele frequency and therapy-related setting independently predict survival in myelodysplastic syndromes with del(5q).
    Ayalew Tefferi, Farah Fleti, Onyee Chan, Najla H Al Ali, Aref Al-Kali, Kebede H Begna, James M Foran, Talha Badar, Nandita Khera, Mithun Shah, Devendra Hiwase, Eric Padron, David A Sallman, Animesh Pardanani, Daniel A Arber, Attilio Orazi, Kaaren K Reichard, Rong He, Rhett P Ketterling, Naseema Gangat, Rami Komrokji.
      Among 210 patients with myelodysplastic syndromes (MDSs) with del(5q), molecular information was available at diagnosis or at least 3 months before leukaemic transformation in 146 cases. Multivariate analysis identified therapy-related setting (p = 0.02; HR 2.3) and TP53 variant allele frequency (VAF) ≥22% (p < 0.01; HR 2.8), but not SF3B1 mutation (p = 0.65), as independent risk factors for survival. Median survival was 11.7 versus 4 years (5/10-year survival 73%/52% vs. 42%/14%) in the absence (N = 112) versus presence (N = 34) of ≥1 risk factors; leukaemia-free survival was affected by TP53 VAF ≥22% (p < 0.01). Such information might inform treatment decision-making in MDS-del(5q) regarding allogeneic stem cell transplant.
    Keywords:   SF3B1 ; cytogenetics; mutation; prognosis; survival
    DOI:  https://doi.org/10.1111/bjh.19247
  21. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 125-134
    Clonal evolution in inherited marrow failure syndromes predicts disease progression.
    Kristen E Schratz.
      Progression to myelodysplastic syndromes (MDS) and acute myeloid leukemia is one of the most serious complications of the inherited bone marrow failure and MDS-predisposition syndromes. Given the lack of predictive markers, this risk can also be a source of great uncertainty and anxiety to patients and their providers alike. Recent data show that some acquired mutations may provide a window into this risk. While maladaptive mechanisms, such as monosomy 7, are associated with a high risk of leukemogenesis, mutations that offset the inherited defect (known as somatic genetic rescue) may attenuate this risk. Somatic mutations that are shared with age-acquired clonal hematopoiesis mutations also show syndrome-specific patterns that may provide additional data as to disease risk. This review focuses on recent progress in this area with an emphasis on the biological underpinnings and interpretation of these patterns for patient care decisions.
    DOI:  https://doi.org/10.1182/hematology.2023000469
  22. bioRxiv. 2023 Nov 29. pii: 2023.11.28.568925. [Epub ahead of print]
    Expansion of human hematopoietic stem cells by inhibiting translation.
    Chenchen Li, Hanna Shin, Dheeraj Bhavanasi, Mai Liu, Xiang Yu, Scott A Peslak, Xiaolei Liu, Juan R Alvarez-Dominguez, Gerd A Blobel, Brian D Gregory, Jian Huang, Peter S Klein.
      Hematopoietic stem cell (HSC) transplantation using umbilical cord blood (UCB) is a potentially life-saving treatment for leukemia and bone marrow failure but is limited by the low number of HSCs in UCB. The loss of HSCs after ex vivo manipulation is also a major obstacle to gene editing for inherited blood disorders. HSCs require a low rate of translation to maintain their capacity for self-renewal, but hematopoietic cytokines used to expand HSCs stimulate protein synthesis and impair long-term self-renewal. We previously described cytokine-free conditions that maintain but do not expand human and mouse HSCs ex vivo. Here we performed a high throughput screen and identified translation inhibitors that allow ex vivo expansion of human HSCs while minimizing cytokine exposure. Transplantation assays show a ∼5-fold expansion of long-term HSCs from UCB after one week of culture in low cytokine conditions. Single cell transcriptomic analysis demonstrates maintenance of HSCs expressing mediators of the unfolded protein stress response, further supporting the importance of regulated proteostasis in HSC maintenance and expansion. This expansion method maintains and expands human HSCs after CRISPR/Cas9 editing of the BCL11A+58 enhancer, overcoming a major obstacle to ex vivo gene correction for human hemoglobinopathies.
    DOI:  https://doi.org/10.1101/2023.11.28.568925
  23. J Clin Invest. 2023 Dec 07. pii: e172256. [Epub ahead of print]
    Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms.
    Fan He, Angelo B A Laranjeira, Tim Kong, Shuyang Lin, Katrina J Ashworth, Alice Liu, Nina M Lasky, Daniel Ac Fisher, Maggie J Cox, Mary C Fulbright, Lilian A Antunes Heck, LaYow C Yu, Molly Brakhane, Bei Gao, Stephen M Sykes, Angelo D'Alessandro, Jorge A Di Paola, Stephen T Oh.
      Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR and oxidative phosphorylation (OXPHOS) in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation, accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid (TCA) cycle, but lower alpha-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F mice with α-KG significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte and platelet counts. Finally, α-KG incubation significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling, contributing to platelet hyperreactivity in MPN patients.
    Keywords:  Hematology; Platelets
    DOI:  https://doi.org/10.1172/JCI172256
  24. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 186-191
    The approach of HMA plus VEN with or without BMT for all patients with AML.
    Heather J Male, Tara L Lin.
      Treatment options for acute myeloid leukemia (AML) have expanded over the last 5 years. New regimens are increasing the options for patients who previously may not have been offered any antineoplastic therapy. The use of the hypomethylating agent (HMA) decitabine or azacitidine combined with the BCL2 inhibitor venetoclax (HMA-VEN) has improved overall survival in an older and unfit population compared to HMA therapy alone. Delivering these regimens outside academic centers allows more patients with AML to be treated, though support and collaboration with allogeneic stem cell transplant (SCT) centers should still be considered to determine eligibility and promptly initiate a donor search for potential transplant candidates. Expanding the use of HMA-VEN to younger and fit patients who are also candidates for intensive chemotherapy (IC) is being studied prospectively and is not recommended at this time outside of a clinical trial. Retrospective studies suggest populations that may benefit from HMA-VEN over IC, but this is not yet confirmed prospectively. Utilizing HMA-VEN prior to allogeneic SCT is also under investigation, and some retrospective data show feasibility and the ability to achieve measurable residual disease negativity pretransplant. Upcoming prospective randomized clinical trials aim to answer the comparability or superiority of HMA-VEN vs IC in fit populations and its potential use as a standard pretransplant induction regimen.
    DOI:  https://doi.org/10.1182/hematology.2023000428
  25. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 51-58
    How to classify risk based on clinical and molecular modeling: integrating molecular markers in the risk assessment of myelodysplastic syndrome.
    Rena R Xian.
      Myelodysplastic syndrome (MDS), also known as "myelodysplastic neoplasm," is a heterogeneous group of clonal myeloid neoplasms that typically affects older adults. The clinical phenotype, symptoms, and complications relate to the depth of cytopenia and progression to acute myeloid leukemia (AML). The diagnosis of MDS relies on morphologic criteria, such as evidence of dysplasia, disordered maturation, and increasing blast counts, which separate the disease into histologic subtypes with different probabilities for progression to AML. The treatment of MDS is often risk-adapted depending on the prognostic profile of each patient's disease. There has been a coevolution of diagnostic and prognostic systems for MDS developed over the past 40 years, both of which have now incorporated molecular markers. The new International Prognostic Scoring System-Molecular (IPSS-M) improves partitioning of patients compared to prior versions with resultant upgrading of 34% of patients into higher-risk groups due to the presence of mutations. The new IPSS-M also more accurately distinguishes intermediate-risk patients separating them into two tiers. The two new diagnostic classifications include MDS defined by mutations in SF3B1 and TP53, though there are differences in diagnostic criteria. Future efforts to refine MDS prognostication could investigate the interface between MDS and clonal cytopenia of undetermined significance, expand access to genomic testing, obtain results in a less invasive manner, and develop treatment-response predictors and dynamic risk models.
    DOI:  https://doi.org/10.1182/hematology.2023000420
  26. Biochem Biophys Res Commun. 2023 Dec 06. pii: S0006-291X(23)01449-3. [Epub ahead of print]693 149355
    Nardilysin determines hematopoietic stem cell fitness by regulating protein synthesis.
    Shinichiro Oshima, Rahul Sinha, Mikiko Ohno, Kiyoto Nishi, Koji Eto, Akifumi Takaori-Kondo, Eiichiro Nishi, Ryo Yamamoto.
      Nardilysin (NRDC) is a multifunctional protein required for maintaining homeostasis in various cellular and tissue contexts. However, its role in hematopoietic stem cells (HSCs) remains unclear. Here, through the conditional deletion of NRDC in hematopoietic cells, we demonstrate that NRDC is required for HSCs expansion in vitro and the reconstitution of hematopoiesis in vivo after transplantation. We found NRDC-deficient HSCs lose their self-renewal ability and display a preferential bias to myeloid differentiation in response to replication stress. Transcriptome data analysis revealed the upregulation of heat shock response-related genes in NRDC-deficient HSCs. Additionally, we observed increased protein synthesis in cultured NRDC-deficient HSCs. Thus, loss of NRDC may cause the inability to control protein synthesis in response to replication induced protein stress, leading to the impaired HSC self-renewal ability. This highlights a novel model of action of NRDC specifically in HSCs.
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149355
  27. Leukemia. 2023 Dec 08.
    Profound sympathetic neuropathy in the bone marrow of patients with acute myeloid leukemia.
    Iryna Kovtun, Malte von Bonin, Liliia Ibneeva, Julia Frimmel, Jan Moritz Middeke, Desiree Kunadt, Lisa Heberling, Manja Wobus, Martin Bornhäuser, Tatyana Grinenko.
      
    DOI:  https://doi.org/10.1038/s41375-023-02104-7
  28. Blood Cancer J. 2023 Dec 10. 13(1): 179
    Long-term follow-up of patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation after primary induction failure.
    Miriam Mozaffari Jovein, Gabriele Ihorst, Jesús Duque-Afonso, Ralph Wäsch, Hartmut Bertz, Claudia Wehr, Justus Duyster, Robert Zeiser, Jürgen Finke, Florian Scherer.
      Primary induction failure (PIF) in acute myeloid leukemia (AML) patients is associated with poor outcome, with allogeneic hematopoietic stem cell transplantation (HCT) being the sole curative therapeutic option. Here, we retrospectively evaluated long-term outcomes of 220 AML patients undergoing allogeneic HCT after PIF who never achieved remission, and identified clinical and molecular risk factors associated with treatment response and ultimate prognosis. In this high-risk population, disease-free survival was 25.2% after 5 years and 18.7% after 10 years, while overall survival rates were 29.8% and 21.6% after 5 and 10 years of HCT, respectively. 10-year non-relapse mortality was 32.5%, and 48.8% of patients showed disease relapse within 10 years after allogeneic HCT. Adverse molecular risk features determined at initial diagnosis, poor performance status at the time of allogeneic HCT, and long diagnosis-to-HCT intervals were associated with unfavorable prognosis. Collectively, our data suggests that immediate allogeneic HCT after PIF offers long-term survival and cure in a substantial subset of cases and that high-risk AML patients who never achieved complete response during induction might benefit from early donor search.
    DOI:  https://doi.org/10.1038/s41408-023-00953-0
  29. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 682-690
    Understanding differential technologies for detection of MRD and how to incorporate into clinical practice.
    Jacqueline Cloos, Lok Lam Ngai, Michael Heuser.
      Patient- and leukemia-specific factors assessed at diagnosis classify patients with acute myeloid leukemia (AML) in risk categories that are prognostic for outcome. The induction phase with intensive chemotherapy in fit patients aims to reach a complete remission (CR) of less than 5% blasts in bone marrow by morphology. To deepen and sustain the response, induction is followed by consolidation treatment. This postremission treatment of patients with AML is graduated in intensity based on this favorable, intermediate, or adverse risk group classification as defined in the European Leukemia Network (ELN) 2022 recommendations. The increment of evidence that measurable residual disease (MRD) after induction can be superimposed on risk group at diagnosis is instrumental in tailoring further treatment accordingly. Several techniques are applied to detect MRD such as multiparameter flow cytometry (MFC), quantitative (digital) polymerase chain reaction (PCR), and next-generation sequencing. The clinical implementation of MRD and the technique used differ among institutes, leading to the accumulation of a wide range of data, and therefore harmonization is warranted. Currently, evidence for MRD guidance is limited to the time point after induction using MFC or quantitative PCR for NPM1 and core binding factor abnormalities in intermediate-risk patients. The role of MRD in targeted or nonintensive therapies needs to be clarified, although some data show improved survival in patients achieving CR-MRD negativity. Potential application of MRD for selection of conditioning before stem cell transplantation, monitoring after consolidation, and use as an intermediate end point in clinical trials need further evaluation.
    DOI:  https://doi.org/10.1182/hematology.2023000454
  30. Br J Haematol. 2023 Dec 10.
    Durable responses in acute lymphoblastic leukaemia with the use of FLT3 and IDH inhibitors.
    Rafael Madero-Marroquin, Adam S DuVall, Caner Saygin, Peng Wang, Sandeep Gurbuxani, Richard A Larson, Wendy Stock, Anand Ashwin Patel.
      Data regarding the use of FMS-like tyrosine kinase 3 (FLT3) and isocitrate dehydrogenase 1/2 (IDH1/2) inhibitors in acute lymphoblastic leukaemia (ALL) are lacking. We identified 14 patients with FLT3- or IDH1/2-mutated ALL. Three early T-cell precursor-ALL patients received FLT3 or IDH2 inhibitors. Patient 1 maintains a complete remission (CR) with enasidenib after intolerance to chemotherapy. Patient 2 maintained a CR for 27 months after treatment with enasidenib for relapsed disease. Patient 3 was treated with venetoclax and gilteritinib at the time of relapse and maintained a CR with gilteritinib for 8 months. These cases suggest that FLT3 and IDH inhibitors could represent a viable therapeutic option for ALL patients with these mutations.
    Keywords:  ALL; FLT3; IDH1; IDH2; targeted
    DOI:  https://doi.org/10.1111/bjh.19250
  31. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 59-64
    Next-generation therapy for lower-risk MDS.
    Marie Sébert.
      Myelodysplastic syndromes (MDS) are malignant myeloid neoplasms characterized by ineffective clonal hematopoiesis leading to peripheral blood cytopenia and a variable risk of transformation to acute myeloid leukemia. In lower-risk (LR) MDS, as defined by prognostic scoring systems recently updated with the addition of a mutation profile, therapeutic options aim to reduce cytopenia, mainly anemia. Although options for reducing the transfusion burden have recently been improved, erythropoiesis-stimulating agents (ESAs), lenalidomide, hypomethylating agents, and, more recently, luspatercept have shown efficacy in rarely more than 50% of patients with a duration of response often far inferior to the patient's life expectancy. Nevertheless, several new therapies are currently under investigation aiming at improving cytopenia in patients with LR-MDS, mostly by targeting different biological pathways. Targeting ligands of the transforming growth factor β pathway has led to the approval of luspatercept in LR-MDS with ring sideroblasts or SF3B1 mutation, potentially replacing first-line ESAs in this population. Here, we also discuss the evolving standard of care for the treatment of LR-MDS and explore some of the most promising next-generation agents under investigation.
    DOI:  https://doi.org/10.1182/hematology.2023000520
  32. Sci Rep. 2023 Dec 09. 13(1): 21809
    Metabolomic profile of acute myeloid leukaemia parallels of prognosis and response to therapy.
    Lukasz Bolkun, Tomasz Pienkowski, Julia Sieminska, Joanna Godzien, Karolina Pietrowska, Janusz Kłoczko, Agnieszka Wierzbowska, Marcin Moniuszko, Mariusz Ratajczak, Adam Kretowski, Michal Ciborowski.
      The heterogeneity of acute myeloid leukemia (AML), a complex hematological malignancy, is caused by mutations in myeloid cells affecting their differentiation and proliferation. Thus, various cytogenetic alterations in AML cells may be characterized by a unique metabolome and require different treatment approaches. In this study, we performed untargeted metabolomics to assess metabolomics differences between AML patients and healthy controls, AML patients with different treatment outcomes, AML patients in different risk groups based on the 2017 European LeukemiaNet (ELN) recommendations for the diagnosis and management of AML, AML patients with and without FLT3-ITD mutation, and a comparison between patients with FLT3-ITD, CBF-AML (Core binding factor acute myelogenous leukemia), and MLL AML (mixed-lineage leukemia gene) in comparison to control subjects. Analyses were performed in serum samples using liquid chromatography coupled with mass spectrometry (LC-MS). The obtained metabolomics profiles exhibited many alterations in glycerophospholipid and sphingolipid metabolism and allowed us to propose biomarkers based on each of the above assessments as an aid for diagnosis and eventual classification, allowing physicians to choose the best-suited treatment approach. These results highlight the application of LC-MS-based metabolomics of serum samples as an aid in diagnostics and a potential minimally invasive prognostic tool for identifying various cytogenetic and treatment outcomes of AML.
    DOI:  https://doi.org/10.1038/s41598-023-48970-0
  33. Cell Rep Methods. 2023 Dec 05. pii: S2667-2375(23)00325-9. [Epub ahead of print] 100654
    Clinical forecasting of acute myeloid leukemia using ex vivo drug-sensitivity profiling.
    Aram N Andersen, Andrea M Brodersen, Pilar Ayuda-Durán, Laure Piechaczyk, Dagim Shiferaw Tadele, Lizet Baken, Julia Fredriksen, Mia Stoksflod, Andrea Lenartova, Yngvar Fløisand, Sigrid S Skånland, Jorrit M Enserink.
      Current treatment selection for acute myeloid leukemia (AML) patients depends on risk stratification based on cytogenetic and genomic markers. However, the forecasting accuracy of treatment response remains modest, with most patients receiving intensive chemotherapy. Recently, ex vivo drug screening has gained traction in personalized treatment selection and as a tool for mapping patient groups based on relevant cancer dependencies. Here, we systematically evaluated the use of drug sensitivity profiling for predicting patient survival and clinical response to chemotherapy in a cohort of AML patients. We compared computational methodologies for scoring drug efficacy and characterized tools to counter noise and batch-related confounders pervasive in high-throughput drug testing. We show that ex vivo drug sensitivity profiling is a robust and versatile approach to patient prognostics that comprehensively maps functional signatures of treatment response and disease progression. In conclusion, ex vivo drug profiling can assess risk for individual AML patients and may guide clinical decision-making.
    Keywords:  CP: Cancer biology
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100654
  34. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 667-675
    Evolving landscape of JAK inhibition in myelofibrosis: monotherapy and combinations.
    Harinder Gill, Garret M K Leung, Yok-Lam Kwong.
      Myeloproliferative neoplasms (MPNs) are characterized by clonal myeloproliferation in 1 or more of the hematopoietic stem cell lineages. Primary myelofibrosis (MF), post-polycythemia vera MF, and post-essential thrombocythemia MF have the worst prognosis and are characterized by the presence of cytokine-mediated symptom complex, splenomegaly, progressive marrow failure, and clonal instability, leading to leukemic transformation. The key therapeutic aims encompass the management of symptoms, splenomegaly, and anemia and the improvement of survivals. These therapeutic aims have evolved with the availability of Jak inhibitors and novel agents, making disease modification potentially achievable. Novel agents may potentially target MPN stem cells, epigenetic alterations, signaling pathways, and apoptotic pathways. In this case-based review, we outline our approach to the management of MF and discuss the therapeutic landscape of MF, highlighting the utility of Jak inhibitors and novel Jak inhibitor-based combinations.
    DOI:  https://doi.org/10.1182/hematology.2023000452
  35. Blood. 2023 Dec 14. pii: blood.2023022851. [Epub ahead of print]
    Identification and surveillance of rare relapse-initiating stem cells during complete remission post-transplantation.
    Marios Dimitriou, Teresa Mortera-Blanco, Magnus Tobiasson, Stefania Mazzi, Madeleine Lehander, Kari Högstrand, Mohsen Karimi, Gunilla Walldin, Monika Jansson, Sofie Vonlanthen, Per Ljungman, Saskia M C Langemeijer, Tetsuichi Yoshizato, Eva S Hellstrom-Lindberg, Petter S Woll, Sten Eirik W Jacobsen.
      Relapse following complete remission (CR) remains the main cause of mortality after allogeneic stem cell transplantation for hematological malignancies and therefore improved biomarkers for early prediction of relapse remains a critical goal towards development and assessment of preemptive relapse treatment. Since the significance of cancer stem cells as a source of relapses remains unclear, we investigated whether mutational screening for persistence of rare cancer stem cells would enhance measurable residual disease (MRD) and early relapse-prediction post-transplantation. In a retrospective study of relapse patients and continuous-CR patients with myelodysplastic syndromes and related myeloid malignancies, combined flow cytometric cell sorting and mutational screening for persistence of rare relapse-initiating stem cells was performed in bone marrow at multiple CR time points post-transplantation. In 25 CR samples from 15 patients that later relapsed, only 9 samples were MRD-positive in mononuclear cells (MNCs) whereas flowcytometric sorted hematopoietic stem and progenitor cells (HSPCs) were MRD-positive in all samples, and always with a higher variant allele frequency than in MNCs (mean 97-fold). MRD-positivity in HSPCs preceded MNCs in multiple sequential samples, in some cases preceding relapse by more than 2 years. In distinction, in 13 patients in long-term continuous-CR, HSPCs remained MRD-negative. Enhanced MRD-sensitivity was also observed in total CD34+ cells, but HSPCs were always more clonally involved (mean 8-fold).In conclusion, identification of relapse-initiating cancer stem cells and mutational MRD-screening for their persistence consistently enhances MRD-sensitivity and earlier prediction of relapse after allogeneic stem cell transplantation.
    DOI:  https://doi.org/10.1182/blood.2023022851
  36. Blood. 2023 Dec 14. 142(24): 2040-2042
    PPM1D inhibition may allow us to WIP leukemia.
    Bridget K Marcellino.
      
    DOI:  https://doi.org/10.1182/blood.2023021943
  37. Cell Stem Cell. 2023 Dec 07. pii: S1934-5909(23)00398-3. [Epub ahead of print]30(12): 1658-1673.e10
    SON is an essential m6A target for hematopoietic stem cell fate.
    Hanzhi Luo, Mariela Cortés-López, Cyrus L Tam, Michael Xiao, Isaac Wakiro, Karen L Chu, Aspen Pierson, Mandy Chan, Kathryn Chang, Xuejing Yang, Daniel Fecko, Grace Han, Eun-Young Erin Ahn, Quaid D Morris, Dan A Landau, Michael G Kharas.
      Stem cells regulate their self-renewal and differentiation fate outcomes through both symmetric and asymmetric divisions. m6A RNA methylation controls symmetric commitment and inflammation of hematopoietic stem cells (HSCs) through unknown mechanisms. Here, we demonstrate that the nuclear speckle protein SON is an essential m6A target required for murine HSC self-renewal, symmetric commitment, and inflammation control. Global profiling of m6A identified that m6A mRNA methylation of Son increases during HSC commitment. Upon m6A depletion, Son mRNA increases, but its protein is depleted. Reintroduction of SON rescues defects in HSC symmetric commitment divisions and engraftment. Conversely, Son deletion results in a loss of HSC fitness, while overexpression of SON improves mouse and human HSC engraftment potential by increasing quiescence. Mechanistically, we found that SON rescues MYC and suppresses the METTL3-HSC inflammatory gene expression program, including CCL5, through transcriptional regulation. Thus, our findings define a m6A-SON-CCL5 axis that controls inflammation and HSC fate.
    Keywords:  RNA binding proteins; RNA methylation; RNA modifications; SON; cell fate; differentiation; hematopoietic stem cells; inflammation; nuclear speckles; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2023.11.006
  38. Int J Mol Sci. 2023 Nov 24. pii: 16720. [Epub ahead of print]24(23):
    Folate-Appended Hydroxypropyl-β-Cyclodextrin Induces Autophagic Cell Death in Acute Myeloid Leukemia Cells.
    Yasushi Kubota, Toshimi Hoshiko, Taishi Higashi, Keiichi Motoyama, Seiji Okada, Shinya Kimura.
      Acute myeloid leukemia (AML) is a heterogenous myeloid neoplasm that remains challenging to treat. Because intensive conventional chemotherapy reduces survival rates in elderly patients, drugs with lower toxicity and fewer side effects are needed urgently. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CyD) is used clinically as a pharmaceutical excipient for poorly water-soluble drugs. Previously, we showed that HP-β-CyD exerts antitumor activity by disrupting cholesterol homeostasis. Recently, we developed folate-conjugated HP-β-CyD (FA-HP-β-CyD) and demonstrated its potential as a new antitumor agent that induces not only apoptosis, but also autophagic cell death; however, we do not know whether FA-HP-β-CyD exerts these effects against AML. Here, we investigated the effects of FA-HP-β-CyD on folate receptor (FR)-expressing AML cells. We found that the cytotoxic activity of FA-HP-β-CyD against AML cells was stronger than that of HP-β-CyD. Also, FA-HP-CyD induced the formation of autophagosomes in AML cell lines. FA-HP-β-CyD increased the inhibitory effects of cytarabine and a BCL-2-selective inhibitor, Venetoclax, which are commonly used treat elderly AML patients. Notably, FA-HP-β-CyD suppressed the proliferation of AML cells in BALB/c nude recombinase-activating gene-2 (Rag-2)/Janus kinase 3 (Jak3) double-deficient mice with AML. These results suggest that FA-HP-β-CyD acts as a potent anticancer agent for AML chemotherapy by regulating autophagy.
    Keywords:  2-hydroxypropyl-β-cyclodextrin; Venetoclax; acute myeloid leukemia; autophagy; cholesterol; folate receptor; folic acid; metabolism; mitochondria; molecular targeting
    DOI:  https://doi.org/10.3390/ijms242316720
  39. Hematology. 2024 Dec;29(1): 2293512
    Reduced duration and dosage of venetoclax is efficient in newly diagnosed patients with acute myeloid leukemia.
    Jingying Cui, Xuexing Chen, Chunfang Li, Qiong Yan, Guolin Yuan.
       OBJECTIVES: The combination of Venetoclax (VEN) and Azacitidine (AZA) increases survival outcomes and yields excellent responses in patients with acute myeloid leukemia (AML). However, dose reduction (or discontinuation) is commonly encountered due to therapy-related toxicity. Thus, this study aimed to investigate the efficiency and safety of a lower dosage of venetoclax for the treatment of AML.
    METHODS: This observational study analyzed the characteristics and outcomes of newly diagnosed AML patients who received 100 mg VEN combined with AZA for 14 days at our institution.
    RESULTS: A total of 36 patients were enrolled, and the median age at diagnosis was 64 years. After a median follow-up of 15 (range 4-29) months, the median overall survival (OS) and progression-free survival (PFS) for the whole cohort were 17 (4-29) months and 12 (1-28) months, respectively. Meanwhile, the overall response rate (ORR) was 69.4%, and the CRc rate was 66.7% in the whole cohort. Subgroup analysis revealed that NPM1 mutations and FAB-M5 subtype were associated with higher response rates, whereas the adverse ELN risk group was predictive of an inferior response. Moreover, ASXL1, NPM1, and IDH1/2 mutations negatively impacted PFS.
    DISCUSSION: Our study optimized the administration of venetoclax plus azacytidine for the treatment of AML patients. Response rates were favorable, with median survival in agreement with the findings of earlier reports, offering valuable insights for optimizing VEN-based regimens.
    CONCLUSION: In summary, the VEN combination regimen is effective for the treatment of newly diagnosed AML patients in the real world despite VEN dose reductions .
    Keywords:  Newly diagnosed; Venetoclax; acute myeloid leukemia; azacytidine; dose and duration optimization; efficiency and safety; myelosuppression management; retrospective study
    DOI:  https://doi.org/10.1080/16078454.2023.2293512
  40. Best Pract Res Clin Haematol. 2023 Dec;pii: S1521-6926(23)00079-8. [Epub ahead of print]36(4): 101518
    WHO, what, when, where, and why: New classification systems for acute myeloid leukemia and their impact on clinical practice.
    Frederick R Appelbaum.
      The goal of a disease classification system is (or should be) to provide a tool for researchers and clinicians to study and treat the disease. The last decade has seen a markedly improved understanding of the pathophysiology of acute myeloid leukemia (AML), the development of new methods to measure the disease, and approval by the Food and Drug Administration (FDA) of at least ten new therapies targeted to its treatment. In response, in 2022 one updated and one new AML classification system were published. In the same year, the European LeukemiaNet updated their recommendations about how to incorporate the advances in diagnosis and treatment into the risk stratification of AML and its treatment. The following discussion summarizes the highlights of these changes and offers an opinion of how well these changes meet the goal of aiding researchers and clinicians in the study and treatment of AML.
    Keywords:  Acute myeloid leukemia; Classification of myeloid neoplasms; Myelodysplasia
    DOI:  https://doi.org/10.1016/j.beha.2023.101518
  41. Lancet Haematol. 2023 Dec 05. pii: S2352-3026(23)00333-2. [Epub ahead of print]
    Sabatolimab plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes (STIMULUS-MDS1): a randomised, double-blind, placebo-controlled, phase 2 trial.
    Amer M Zeidan, Kiyoshi Ando, Odile Rauzy, Mehmet Turgut, Ming-Chung Wang, Roberto Cairoli, Hsin-An Hou, Yok-Lam Kwong, Montserrat Arnan, Stef Meers, Vinod Pullarkat, Valeria Santini, Kamel Malek, Flavia Kiertsman, Julie Niolat, Pedro Marques Ramos, Hans D Menssen, Pierre Fenaux, Yasushi Miyazaki, Uwe Platzbecker.
       BACKGROUND: Sabatolimab is an immunotherapy targeting T-cell immunoglobulin domain and mucin domain-3 (TIM-3), an immuno-myeloid regulator expressed on immune cells and leukaemic stem cells. In this trial, we compared the efficacy and safety of sabatolimab plus hypomethylating agent with placebo plus hypomethylating agents in previously untreated patients with higher-risk myelodysplastic syndromes.
    METHODS: STIMULUS-MDS1 was a multicentre, randomised, double-blind, placebo-controlled, phase 2 study done at 54 investigational sites in 17 countries. Adult patients (aged ≥18 years) with intermediate-risk, high-risk, and very high-risk myelodysplastic syndromes (according to Revised International Prognostic Scoring System criteria) who had not received previous treatment were included. Patients were randomly assigned (1:1) to intravenous sabatolimab (400 mg on day 8 and 22) or placebo plus a hypomethylating agent (intravenous decitabine 20 mg/m2 on day 1-5 or intravenous or subcutaneous azacitidine 75 mg/m2 on day 1-7 or day 1-5 and day 8 and 9) every 28 days until treatment discontinuation. The two primary endpoints were complete response rate and progression-free survival, assessed in the full analysis set, which included all randomly assigned patients. Complete response was analysed, as prespecified, 7 months after the last patient was randomly assigned. All other analyses presented, including progression-free survival, were done at the final data cutoff prespecified via a protocol amendment on Sept 2, 2021. Safety was assessed in in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03946670, and is ongoing.
    FINDINGS: Between July 29, 2019, and Aug 10, 2020, 127 patients were randomly assigned to sabatolimab plus a hypomethylating agent group (sabatolimab group; n=65) or placebo plus a hypomethylating agent (placebo group; n=62). The median age of participants was 73 years (IQR 69-77), of whom 86 (68%) of 127 patients were male and 77 (61%) were White. The primary endpoints were not met. Complete response (cutoff date of March 10, 2021) was achieved in 14 (22%; 95% CI 12·3-33·5) of 65 patients in the sabatolimab group vs 11 (18%; 9·2-29·5) of 62 patients in the placebo group (p=0·77). At the cutoff date of the final analysis (March 1, 2022), median follow-up for progression-free survival was 17·8 months (IQR 16·6-19·4) in the sabatolimab group and 19·2 months (17·7-22·3) in the placebo group, and the median progression-free survival was 11·1 months (95% CI 7·6-17·6) in the sabatolimab group vs 8·5 months (6·9-11·3) in the placebo group (hazard ratio 0·75 [95% CI 0·48-1·17]; p=0·1022). The most common adverse events of any grade were neutropenia (35 [56%] of 62 patients in the sabatolimab group vs 43 [68%] of 63 patients in the placebo group), thrombocytopenia (30 [48%] vs 32 [51%]), constipation (29 [47%] vs 24 [38%]), diarrhoea (27 [44%] vs 14 [22%]), anaemia (22 [35%] vs 34 [54%]), febrile neutropenia (22 [35%] vs 15 [24%]), and leukopenia (15 [24%] vs 20 [32%]). One patient developed a serious potential treatment-related immune-mediated adverse event in the sabatolimab group. There was one treatment-related death in the sabatolimab group due to pneumonitis.
    INTERPRETATION: The addition of sabatolimab to hypomethylating agents in this study did not result in a significant improvement in complete response rates or progression-free survival. Sabatolimab had a manageable safety in most patients with higher-risk myelodysplastic syndromes. A randomised phase 3 trial is ongoing to assess the potential benefit of sabatolimab plus azacitidine on overall survival in this setting.
    FUNDING: Novartis Pharmaceuticals.
    DOI:  https://doi.org/10.1016/S2352-3026(23)00333-2
  42. Cell Rep Methods. 2023 Dec 06. pii: S2667-2375(23)00340-5. [Epub ahead of print] 100663
    AA2P-mediated DNA demethylation synergizes with stem cell agonists to promote expansion of hematopoietic stem cells.
    Javed K Manesia, Harinad B Maganti, Sakhar Almoflehi, Suria Jahan, Tanvir Hasan, Roya Pasha, Chelsea McGregor, Nellie Dumont, Josée Laganière, Julie Audet, Nicolas Pineault.
      Small molecules have enabled expansion of hematopoietic stem and progenitor cells (HSPCs), but limited knowledge is available on whether these agonists can act synergistically. In this work, we identify a stem cell agonist in AA2P and optimize a series of stem cell agonist cocktails (SCACs) to help promote robust expansion of human HSPCs. We find that SCACs provide strong growth-promoting activities while promoting retention and function of immature HSPC. We show that AA2P-mediated HSPC expansion is driven through DNA demethylation leading to enhanced expression of AXL and GAS6. Further, we demonstrate that GAS6 enhances the serial engraftment activity of HSPCs and show that the GAS6/AXL pathway is critical for robust HSPC expansion.
    Keywords:  AXL; CP: Stem cell; DNA demethylation; GAS6; engraftment; epigenetic modulators; hematopoietic stem cells; stem cell agonists; stem cell expansion; umbilical cord blood
    DOI:  https://doi.org/10.1016/j.crmeth.2023.100663
  43. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 702-708
    Novel therapies upon failure of HMA plus venetoclax.
    Onyee Chan, Alison R Walker.
      The efficacy and tolerability of the combination of hypomethylating agents with venetoclax (HMA-VEN) in patients with newly diagnosed acute myeloid leukemia has been a practice-changing milestone in the field. However, treatment failure and relapse remain major barriers to prolonged survival. TP53 mutation is a predictor of primary induction failure and portends especially poor outcomes. Prelinical data suggest that VEN resistance stems from these genetic changes, which lead to increases in antiapoptotic proteins such as MCL-1 and BCLXL. For patients who discontinue HMA-VEN for reasons other than disease progression, such as post allotransplantation, infection, and personal preference, rechallenge with HMA-VEN at the time of relapse may be considered. For those who progress on HMA-VEN, clinical trials with novel agents or rational drug combinations are preferred if available. If no trial option is available, fit patients may benefit from intensive chemotherapy. Emerging therapies aim to overcome venetoclax resistance, target interactions that promote leukemogenesis, and harness the immune system to irradicate leukemic blasts and stem cells.
    DOI:  https://doi.org/10.1182/hematology.2023000456
  44. Int J Mol Sci. 2023 Nov 29. pii: 16899. [Epub ahead of print]24(23):
    Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia.
    Keli Lima, Maria Fernanda Lopes Carvalho, Diego Antonio Pereira-Martins, Frederico Lisboa Nogueira, Lívia Bassani Lins de Miranda, Mariane Cristina do Nascimento, Rita de Cássia Cavaglieri, Jan Jacob Schuringa, João Agostinho Machado-Neto, Eduardo Magalhães Rego.
      Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.
    Keywords:  THZ-P1-2; acute myeloid leukemia; phosphatidylinositol-5-phosphate 4-kinase type 2; venetoclax
    DOI:  https://doi.org/10.3390/ijms242316899
  45. Br J Haematol. 2023 Dec 08.
    A defined serum-free culture system for human long-term haematopoietic stem cells.
    Yichao Dong, Ruikun Cai, Mingxia Fang, Yuqi Chen, Peng Li, Changlong Guo, Xu Ma.
      Long-term repopulating haematopoietic stem cells (LT-HSCs) have the ability to reconstitute the entire haematopoietic system following transplantation permanently. Despite great achievements in HSC transplantation, the limited transplantable HSC number, especially LT-HSCs, remains critical for successful transplantation and broader applications. In this study, we established a defined serum-free culture system for in vitro expansion of LT-HSCs. This culture system (E1) expanded LT-HSCs from umbilical cord blood, human mobilization peripheral blood and bone marrow. These E1-expanded HSCs reconstituted the haematopoietic and immune systems in primary and secondary transplanted mice in a short time. Better haematopoietic reconstitution was observed in secondary xenografted mice. Moreover, we obtained the comprehensive expression profile and cellular components of LT-HSCs from umbilical cord blood. Our study provides a valuable tool for LT-HSC research and may improve clinical applications of HSCs.
    Keywords:  HSC expansion; haematopoietic stem cell transplantation; long-term haematopoietic stem cell; umbilical cord blood
    DOI:  https://doi.org/10.1111/bjh.19204
  46. Cancer Discov. 2023 Dec 14. OF1
    Menin Inhibitors Trigger Leukemia Remissions.
      Menin inhibitors have proven effective in patients with acute leukemias. A phase II study of revumenib yielded a response rate of 63% in patients with relapsed or refractory disease and KMT2A rearrangements; a phase I trial combining the drug with three chemotherapies also yielded complete remissions in patients with acute myeloid leukemia. A phase I study of a different menin inhibitor detected responses in 63% of patients with acute leukemia and certain gene alterations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-ND2023-0019
  47. Nat Metab. 2023 Dec 08.
    Phenotypic profiling of solute carriers characterizes serine transport in cancer.
    Vasileios Papalazarou, Alice C Newman, Alejandro Huerta-Uribe, Nathalie M Legrave, Mattia Falcone, Tong Zhang, Lynn McGarry, Dimitris Athineos, Emma Shanks, Karen Blyth, Karen H Vousden, Oliver D K Maddocks.
      Serine is a vital amino acid in tumorigenesis. While cells can perform de novo serine synthesis, most transformed cells rely on serine uptake to meet their increased biosynthetic requirements. Solute carriers (SLCs), a family of transmembrane nutrient transport proteins, are the gatekeepers of amino acid acquisition and exchange in mammalian cells and are emerging as anticancer therapeutic targets; however, the SLCs that mediate serine transport in cancer cells remain unknown. Here we perform an arrayed RNAi screen of SLC-encoding genes while monitoring amino acid consumption and cell proliferation in colorectal cancer cells using metabolomics and high-throughput imaging. We identify SLC6A14 and SLC25A15 as major cytoplasmic and mitochondrial serine transporters, respectively. We also observe that SLC12A4 facilitates serine uptake. Dual targeting of SLC6A14 and either SLC25A15 or SLC12A4 diminishes serine uptake and growth of colorectal cancer cells in vitro and in vivo, particularly in cells with compromised de novo serine biosynthesis. Our results provide insight into the mechanisms that contribute to serine uptake and intracellular handling.
    DOI:  https://doi.org/10.1038/s42255-023-00936-2
  48. Exp Hematol. 2023 Dec 08. pii: S0301-472X(23)01774-5. [Epub ahead of print]
    Ex vivo Hematopoietic Stem Cell Expansion Technologies: Recent Progress, Applications, and Open Questions.
    Grace A Meaker, Adam C Wilkinson.
      Hematopoietic stem cells (HSCs) are a rare but potent cell type that support life-long hematopoiesis and will stably regenerate the entire blood and immune system following transplantation. HSC transplantation represents a mainstay treatment for various diseases of the blood and immune systems. The ex vivo expansion and manipulation of HSCs therefore represents an important approach to ask biological questions in experimental hematology and to help improve clinical HSC transplantation therapies. However, it has remained challenging to expand transplantable HSCs ex vivo. This review summarizes recent progress in ex vivo HSC expansion technologies and their applications to biological and clinical problems, and discusses current questions in the field.
    Keywords:  CRISPR; Hematopoietic stem cell; ex vivo; expansion; gene therapy; self-renewal; stem cell transplantation
    DOI:  https://doi.org/10.1016/j.exphem.2023.12.001
  49. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 476-482
    Atypical CML: diagnosis and treatment.
    Massimo Breccia.
      Atypical chronic myeloid leukemia (aCML) is included in the group of myelodysplastic/myeloproliferative neoplasms by the International Consensus Classification and has been renamed as MDS/MPN with neutrophilia by the fifth edition of World Health Organization classification. It is always characterized by morphologic identification of granulocytic dysplasia with >10% circulating immature myeloid cells, 2 distinguished features that differentiate this disease among the others. Somatic mutations may help to diagnose but are not specifically pathognomonic of the disease, with the most detected including ASXL1, SETBP1, NRAS, KRAS, SRSF2, and TET2 and with low-frequency CBL, CSF3R, JAK2, and ETNK1. The genomic landscape of aCML has been recently unravelling, revealing that SETBP1 and ETNK1 are usually not ancestral but secondary events associated with disease progression. Unfortunately, until now, no consensus on risk stratification and treatment has been developed: Mayo Clinic prognostic score identified as adverse events age >67 years, hemoglobin level <10  g/dL, and TET2 mutations. Although some possible genetic markers have been identified, allogeneic transplant remains the only curative strategy.
    DOI:  https://doi.org/10.1182/hematology.2023000448
  50. Blood Adv. 2023 Dec 26. 7(24): 7445-7456
    Sensitivity to targeted UBA1 inhibition in a myeloid cell line model of VEXAS syndrome.
    Adriana Chiaramida, Sandra G Obwar, Anja E H Nordstrom, Maria Ericsson, Aisha Saldanha, Elena V Ivanova, Gabriel K Griffin, Dilshad H Khan, Roger Belizaire.
      Somatic UBA1 mutations in hematopoietic cells are a hallmark of Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) syndrome, which is a late-onset inflammatory disease associated with bone marrow failure and high mortality. The majority of UBA1 mutations in VEXAS syndrome comprise hemizygous mutations affecting methionine-41 (M41), leading to the expression of UBA1M41T, UBA1M41V, or UBA1M41L and globally reduced protein polyubiquitination. Here, we used CRISPR-Cas9 to engineer isogenic 32D mouse myeloid cell lines expressing hemizygous Uba1WT or Uba1M41L from the endogenous locus. Consistent with prior analyses of patients with VEXAS syndrome samples, hemizygous Uba1M41L expression was associated with loss of the UBA1b protein isoform, gain of the UBA1c protein isoform, reduced polyubiquitination, abnormal cytoplasmic vacuoles, and increased production of interleukin-1β and inflammatory chemokines. Vacuoles in Uba1M41L cells contained a variety of endolysosomal membranes, including small vesicles, multivesicular bodies, and multilamellar lysosomes. Uba1M41L cells were more sensitive to the UBA1 inhibitor TAK243. TAK243 treatment promoted apoptosis in Uba1M41L cells and led to preferential loss of Uba1M41L cells in competition assays with Uba1WT cells. Knock-in of a TAK243-binding mutation, Uba1A580S, conferred TAK243 resistance. In addition, overexpression of catalytically active UBA1b in Uba1M41L cells restored polyubiquitination and increased TAK243 resistance. Altogether, these data indicate that loss of UBA1b underlies a key biochemical phenotype associated with VEXAS syndrome and renders cells with reduced UBA1 activity vulnerable to targeted UBA1 inhibition. Our Uba1M41L knock-in cell line is a useful model of VEXAS syndrome that will aid in the study of disease pathogenesis and the development of effective therapies.
    DOI:  https://doi.org/10.1182/bloodadvances.2023010531
  51. Cell Stem Cell. 2023 Dec 07. pii: S1934-5909(23)00394-6. [Epub ahead of print]30(12): 1610-1623.e7
    Generation of transgene-free hematopoietic stem cells from human induced pluripotent stem cells.
    Olivier Piau, Mathias Brunet-Manquat, Bruno L'Homme, Laurence Petit, Brigitte Birebent, Christine Linard, Laetitia Moeckes, Thomas Zuliani, Hélène Lapillonne, Marc Benderitter, Luc Douay, Alain Chapel, Laurence Guyonneau-Harmand, Thierry Jaffredo.
      Hematopoietic stem cells (HSCs) are the rare cells responsible for the lifelong curative effects of hematopoietic cell (HC) transplantation. The demand for clinical-grade HSCs has increased significantly in recent decades, leading to major difficulties in treating patients. A promising but not yet achieved goal is the generation of HSCs from pluripotent stem cells. Here, we have obtained vector- and stroma-free transplantable HSCs by differentiating human induced pluripotent stem cells (hiPSCs) using an original one-step culture system. After injection into immunocompromised mice, cells derived from hiPSCs settle in the bone marrow and form a robust multilineage hematopoietic population that can be serially transplanted. Single-cell RNA sequencing shows that this repopulating activity is due to a hematopoietic population that is transcriptionally similar to human embryonic aorta-derived HSCs. Overall, our results demonstrate the generation of HSCs from hiPSCs and will help identify key regulators of HSC production during human ontogeny.
    Keywords:  hematopoietic grafts; hematopoietic stem cell signature; hematopoietic stem cells; human induced pluripotent stem cells; regenerative medicine; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.stem.2023.11.002
  52. Mol Cell. 2023 Dec 07. pii: S1097-2765(23)00919-X. [Epub ahead of print]83(23): 4239-4254.e10
    SRSF2 plays an unexpected role as reader of m5C on mRNA, linking epitranscriptomics to cancer.
    Hai-Li Ma, Martin Bizet, Christelle Soares Da Costa, Frédéric Murisier, Eric James de Bony, Meng-Ke Wang, Akihide Yoshimi, Kuan-Ting Lin, Kristin M Riching, Xing Wang, John I Beckman, Shailee Arya, Nathalie Droin, Emilie Calonne, Bouchra Hassabi, Qing-Yang Zhang, Ang Li, Pascale Putmans, Lionel Malbec, Céline Hubert, Jie Lan, Frédérique Mies, Ying Yang, Eric Solary, Danette L Daniels, Yogesh K Gupta, Rachel Deplus, Omar Abdel-Wahab, Yun-Gui Yang, François Fuks.
      A common mRNA modification is 5-methylcytosine (m5C), whose role in gene-transcript processing and cancer remains unclear. Here, we identify serine/arginine-rich splicing factor 2 (SRSF2) as a reader of m5C and impaired SRSF2 m5C binding as a potential contributor to leukemogenesis. Structurally, we identify residues involved in m5C recognition and the impact of the prevalent leukemia-associated mutation SRSF2P95H. We show that SRSF2 binding and m5C colocalize within transcripts. Furthermore, knocking down the m5C writer NSUN2 decreases mRNA m5C, reduces SRSF2 binding, and alters RNA splicing. We also show that the SRSF2P95H mutation impairs the ability of the protein to read m5C-marked mRNA, notably reducing its binding to key leukemia-related transcripts in leukemic cells. In leukemia patients, low NSUN2 expression leads to mRNA m5C hypomethylation and, combined with SRSF2P95H, predicts poor outcomes. Altogether, we highlight an unrecognized mechanistic link between epitranscriptomics and a key oncogenesis driver.
    Keywords:  NSUN2; RNA methylation; RNA modification; RNA splicing; SRSF2; SRSF2(P95H); cancer; epitranscriptomics; leukemia; m(5)C
    DOI:  https://doi.org/10.1016/j.molcel.2023.11.003
  53. Blood. 2023 Dec 14. pii: blood.2023021581. [Epub ahead of print]
    A p53 score derived from TP53 CRISPR/Cas9 HMCLs predicts survival and reveals major role of BAX in BH3 mimetics response.
    Romane Durand, Geraldine Descamps, Christelle Dousset, Celine Bellanger, Sophie Maïga, Jean-Baptiste Alberge, Jennifer Derrien, Jonathan Cruard, Stephane Minvielle, Nicoletta Libera Lilli, Catherine Godon, Yannick Le Bris, Benoit Tessoulin, Martine Amiot, Patricia Gomez-Bougie, Cyrille Touzeau, Philippe Moreau, David Chiron, Agnes Moreau-Aubry, Catherine Pellat-Deceunynck.
      To establish a strict p53-dependent gene expression profile, TP53-/- clones were derived from TP53+/+ and TP53-/mut t(4;14) human myeloma cell lines (HMCLs) using CRISPR/Cas9 technology. From the 17 dysregulated genes shared between the TP53-/- clones from TP53+/+ HMCLs, we established a functional p53 score, involving 13 genes specifically downregulated upon p53 silencing. This functional score segregated clones and myeloma cell lines, as well as other cancer cell lines according to their TP53 status. The score was efficient to identify myeloma patient samples with biallelic TP53 inactivation and was predictive of overall survival in MMRF-coMMpass and CASSIOPEA cohorts. At the functional level, we showed that among the 13 genes, p53-regulated BAX expression correlated to, and directly impacted, the MCL1 BH3 mimetic S63845 sensitivity of myeloma cells by decreasing MCL1-BAX complexes. However, resistance to S63845 was overcome by combining MCL1 and BCL2 BH3 mimetics which displayed synergistic efficacy. BH3 mimetics combination was efficient in 97% of patient samples with or without del17p. Nevertheless, scRNAseq analysis showed that myeloma cells surviving to the combination had lower p53 score, showing that myeloma cells with higher p53 score were more sensitive to BH3 mimetics. Taken together, we established a functional p53 score that identifies myeloma cells with biallelic TP53 invalidation, demonstrated that p53-regulated BAX is critical for optimal cell response to BH3 mimetics, and showed that MCL1 and BCL2 BH3 mimetics combination may be of interest for patients with biallelic TP53 invalidation, for whom there is still an unmet medical need.
    DOI:  https://doi.org/10.1182/blood.2023021581
  54. Blood Adv. 2023 Dec 13. pii: bloodadvances.2023011046. [Epub ahead of print]
    Telehealth Serious Illness Care Program for Older Adults with Hematologic Malignancies: A single-arm pilot study.
    Marissa Locastro, Soroush Mortaz Hedjri, Ying Wang, Jason H Mendler, Sally A Norton, Rachelle Bernacki, Thomas Carroll, Heidi D Klepin, Jane L Liesveld, Eric J Huselton, Benzi Kluger, Kah Poh Loh.
      Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) feel shocked and bewildered when diagnosed. Serious illness conversations (SICs) may increase disease understanding and preparations for the future. However, SICs often happen late, due in part clinician-perceived patient discomfort. Telehealth may promote patient comfort by allowing SICs to take place at home. This study assesses the feasibility and usability of a telehealth-delivered Serious Illness Care Program (SICP) for older adults with AML and MDS. We conducted a single-arm pilot including 20 older adults with AML and MDS. Feasibility was measured using retention rate: >80% considered feasible. Usability was measured using telehealth usability questionnaire (TUQ, range 1-7): >5 considered usable. We collected other outcomes including acceptability and disease understanding and conducted post-visit qualitative interviews to elicit feedback. Hypothesis testing was performed at α=0.10 due to the pilot nature and small sample size. Retention rate was 95% (19/20); mean TUQ scores were 5.9 (SD 0.9) and 5.9 (SD 1.1) for patients and caregivers, respectively. We found the SICP to be acceptable. The majority of patients found the SICP to be very or extremely worthwhile (88.2%, 15/17) and it increased closeness with their clinician (75.0%, 12/16). After their visit, patient estimates of curability and overall life expectancy aligned more closely with those of their clinicians. In qualitative interviews, most patients said they would recommend this program to others (89.5%, 17/19). This study demonstrated that delivery of the telehealth SICP to older patients with AML and MDS is feasible, usable, and acceptable. This trial is registered at www.clinicaltrials.gov as NCT04745676.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011046
  55. Blood. 2023 Dec 08. pii: blood.2023021199. [Epub ahead of print]
    Comparing malignant monocytosis across the updated WHO and ICC classifications of 2022.
    Francis Baumgartner, Constance Baer, Stefanos A Bamopoulos, Edward Ayoub, Marietta Truger, Manja Meggendorfer, Miriam Lenk, Gregor Hoermann, Stephan Hutter, Heiko Müller, Wencke Walter, Martha-Lena Mueller, Niroshan Nadarajah, Piers Blombery, Ulrich Keller, Wolfgang Kern, Claudia Haferlach, Torsten Haferlach.
      The World Health Organization Classification of Hematolymphoid Tumors (WHO) and the International Consensus Classification (ICC) of 2022 introduced major changes to the definition of CMML. To assess qualitative and quantitative implications for patient care, we started with 3,311 established CMML cases (according to WHO 2017 criteria) and included also 2,130 oligomonocytosis cases fulfilling the new CMML diagnostic criteria. Applying both classification systems from 2022, 356 and 241 of oligomonocytosis cases were newly classified as myelodysplastic (MD)-CMML (WHO and ICC 2022, respectively), most of which were diagnosed as MDS according to WHO 2017. Importantly, 1.5 times more oligomonocytosis cases were classified as CMML according to WHO 2022 than based on ICC, due to different diagnostic criteria. Genetic analyses of the newly classified CMML cases showed a distinct mutational profile with strong enrichment of MDS-typical alterations, resulting in a transcriptional subgroup separated from established MD- and myeloproliferative (MP)-CMML. Despite a different cytogenetic, molecular, immunophenotypic, and transcriptional landscape, no differences in overall survival were found between newly classified and established MD-CMML cases. To the best of our knowledge, this study represents the most comprehensive analysis of routine CMML cases to date, both in terms of clinical characterization and transcriptomic analysis, placing newly classified CMML cases on a disease continuum between MDS and previously established CMML.
    DOI:  https://doi.org/10.1182/blood.2023021199
  56. Curr Hematol Malig Rep. 2023 Dec 14.
    Adaptive and Maladaptive Clonal Hematopoiesis in Telomere Biology Disorders.
    Terra Lasho, Mrinal M Patnaik.
       PURPOSE OF REVIEW: Telomere biology disorders (TBDs) are germline-inherited conditions characterized by reduction in telomerase function, accelerated shortening of telomeres, predisposition to organ-failure syndromes, and increased risk of neoplasms, especially myeloid malignancies. In normal cells, critically short telomeres trigger apoptosis and/or cellular senescence. However, the evolutionary mechanism by which TBD-related telomerase-deficient cells can overcome this fitness constraint remains elusive.
    RECENT FINDINGS: Preliminary data suggests the existence of adaptive somatic mosaic states characterized by variants in TBD-related genes and maladaptive somatic mosaic states that attempt to overcome hematopoietic fitness constraints by alternative methods leading to clonal hematopoiesis. TBDs are both rare and highly heterogeneous in presentation, and the association of TBD with malignant transformation is unclear. Understanding the clonal complexity and mechanisms behind TBD-associated molecular signatures that lead to somatic adaptation in the setting of defective hematopoiesis will help inform therapy and treatment for this set of diseases.
    Keywords:  Clonal hematopoiesis; Somatic rescue; Telomere biology disorder
    DOI:  https://doi.org/10.1007/s11899-023-00719-2
  57. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 459-468
    Accelerated-phase CML: de novo and transformed.
    Naranie Shanmuganathan, Timothy P Hughes.
      Despite the dramatic improvements in outcomes for the majority of chronic myeloid leukemia (CML) patients over the past 2 decades, a similar improvement has not been observed in the more advanced stages of the disease. Blast phase CML (BP-CML), although infrequent, remains poorly understood and inadequately treated. Consequently, the key initial goal of therapy in a newly diagnosed patient with chronic phase CML continues to be prevention of disease progression. Advances in genomic investigation in CML, specifically related to BP-CML, clearly demonstrate we have only scratched the surface in our understanding of the disease biology, a prerequisite to devising more targeted and effective therapeutic approaches to prevention and treatment. Importantly, the introduction of the concept of "CML-like" acute lymphoblastic leukemia (ALL) has the potential to simplify the differentiation between BCR::ABL1-positive ALL from de novo lymphoid BP-CML, optimizing monitoring and therapeutics. The development of novel treatment strategies such as the MATCHPOINT approach for BP-CML, utilizing combination chemotherapy with fludarabine, cytarabine, and idarubicin in addition to dose-modified ponatinib, may also be an important step in improving treatment outcomes. However, identifying patients who are high risk of transformation remains a challenge, and the recent 2022 updates to the international guidelines may add further confusion to this area. Further work is required to clarify the identification and treatment strategy for the patients who require a more aggressive approach than standard chronic phase CML management.
    DOI:  https://doi.org/10.1182/hematology.2023000446
  58. Sci Adv. 2023 Dec 15. 9(50): eadj4407
    Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.
    Akira Nishimura, Kazuaki Yokoyama, Takuya Naruto, Chika Yamagishi, Toshihiko Imamura, Hiroto Nakazono, Shunsuke Kimura, Mieko Ito, Maiko Sagisaka, Yukie Tanaka, Jinhua Piao, Yui Namikawa, Masakatsu Yanagimachi, Takeshi Isoda, Akinori Kanai, Hirotaka Matsui, Tomoya Isobe, Aiko Sato-Otsubo, Naoko Higuchi, Akiko Takada, Haruna Okuno, Shoji Saito, Shuhei Karakawa, Shogo Kobayashi, Daisuke Hasegawa, Hiroyuki Fujisaki, Daiichiro Hasegawa, Kazutoshi Koike, Takashi Koike, Shinya Rai, Katsutsugu Umeda, Hideki Sano, Yujin Sekinaka, Atsushi Ogawa, Akitoshi Kinoshita, Norio Shiba, Mizuka Miki, Fumihiko Kimura, Hideki Nakayama, Yozo Nakazawa, Takashi Taga, Tomohiko Taki, Souichi Adachi, Atsushi Manabe, Katsuyoshi Koh, Yasushi Ishida, Junko Takita, Fumihiko Ishikawa, Hiroaki Goto, Tomohiro Morio, Shuki Mizutani, Arinobu Tojo, Masatoshi Takagi.
      Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.
    DOI:  https://doi.org/10.1126/sciadv.adj4407
  59. Cancer Med. 2023 Dec 07.
    Clinical characteristics and prognostic factors analysis of core binding factor acute myeloid leukemia in real world.
    Yamei Zhai, Qingya Wang, Li Ji, Hanyun Ren, Yujun Dong, Fan Yang, Yue Yin, Zeyin Liang, Qian Wang, Wei Liu, Yan Mei, Lu Zhang, Yuan Li.
       BACKGROUND: Chromosomal translocations involving core binding factor (CBF) genes account for 15% of adult acute myeloid leukemia (AML) cases in China. Despite being classified as favorable-risk by European Leukemia Net (ELN), CBF-AML patients have a 40% relapse rate. This study aims to analyze clinical characteristics and prognosis of CBF-AML, compare its subtypes (inv(16) and t(8;21)), and validate prognostic factors.
    METHODS: Retrospective analysis of 149 AML patients (75 CBF-AML, 74 non-CBF) at Peking University First Hospital (March 2012-March 2022).
    RESULTS: CBF-AML patients have significantly lower disease-free survival (DFS) (p = 0.005) and higher non-relapse mortality (NRM) (p = 0.028) compared to non-CBF AML. inv (16) and t(8;21) show distinct co-occurring gene mutation patterns, with inv(16) being prone to central nervous system (CNS) leukemia. Multivariate analysis identifies age as a risk factor for overall survival (OS) and disease free survival (DFS), kinase mutation as a risk factor for DFS and Recurrence, while WT1 mutation as a risk factor for OS and non relapse mortality (NRM) risk in t(8;21) AML. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) improves prognosis in low-risk t(8;21).
    CONCLUSION: Prognosis of CBF-AML is poorer than ELN guidelines suggest. inv(16) and (8;21) are separate entities with relatively poor prognoses, requiring rational risk stratification strategies. Allo-HSCT may benefit low-risk t(8;21), but further research is needed for conclusive evidence.
    Keywords:  acute myeloid leukemia; core binding factor; hematopoietic stem cell transplantation; prognostic; risk stratifocation strategy
    DOI:  https://doi.org/10.1002/cam4.6693
  60. Hematology Am Soc Hematol Educ Program. 2023 Dec 08. 2023(1): 141-148
    Posttransplant complications in patients with marrow failure syndromes: are we improving long-term outcomes?
    Zahra Hudda, Kasiani C Myers.
      Inherited bone marrow failure syndromes (IBMFS) encompass a group of rare genetic disorders characterized by bone marrow failure, non-hematologic multisystemic comorbidities, disease defining congenital anomalies, and a susceptibility to myelodysplastic syndrome, acute myeloid leukemia, and in some instances solid tumors. The most common IBMFS include Fanconi anemia, Shwachman-Diamond syndrome, Diamond-Blackfan anemia, and telomere biology disorders/ dyskeratosis congenita. Allogeneic hematopoietic stem cell transplant (HCT) is a well-established curative treatment to correct the hematological manifestations but does not halt or reverse the nonhematological complications and may hasten them. With advances in HCT and in our ability to care for patients with IBMFS, an increasing number of survivors are making it imperative to not only diagnose but also treat late effects from the pre-, peri-, and post-HCT course and complications relating to the natural history of the syndrome. As the field of HCT evolves to allow for the incorporation of alternate graft sources, for expansion of donor options to include unrelated and mismatched donors, and for use of reduced-intensity conditioning or reduced toxicity myeloablative regimens, we have yet to determine if these advances modify the disease-specific course. While long-term outcomes of these patients are often included under one umbrella, this article seeks to address disease-specific post-HCT outcomes within IBMFS.
    DOI:  https://doi.org/10.1182/hematology.2023000471
  61. Blood Adv. 2023 Dec 13. pii: bloodadvances.2023011625. [Epub ahead of print]
    Single Center Randomized Trial of T-reg graft alone versus T-reg graft Plus Tacrolimus for the Prevention of Acute GVHD.
    Cameron S Bader, Anna Pavlova, Robert Lowsky, Lori Muffly, Parveen Shiraz, Sally Arai, Laura J Johnston, Andrew R Rezvani, Wen-Kai Weng, David B Miklos, Matthew J Frank, John S Tamaresis, Vaibhav Agrawal, Sushma Bharadwaj, Surbhi Sidana, Judith A Shizuru, Nathaniel B Fernhoff, Amy Putnam, Scott Killian, Bryan J Xie, Robert S Negrin, Everett Meyer.
      Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10 matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n=12) or T-reg graft plus single-agent GVHD prophylaxis (n=12) to determine if T-reg graft alone was non-inferior in preventing acute GVHD. All patients developed full donor myeloid chimerism. Patients with T-reg graft alone versus with prophylaxis had an incidence of grade II-IV acute GVHD of 58% versus 8% (p=0.005) and grade III-IV of 17% versus 0% (p=0.149), respectively. The incidence of moderate to severe chronic GVHD was 28% in the T-reg graft alone arm versus 0% with prophylaxis (p=0.056). Among patients with T-reg graft and prophylaxis, CD4+ T cell:Treg ratios were reduced after transplantation, gene-expression profiles showed reduced CD4+ proliferation, and the achievement of full donor T cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred to T-reg graft alone for the prevention of acute GVHD. Clinical Trial #: NCT01660607.
    DOI:  https://doi.org/10.1182/bloodadvances.2023011625
  62. Br J Haematol. 2023 Dec 11.
    Evidence creation for myelofibrosis: Challenges and opportunities.
    Vikas Gupta.
      Evidence-based guidelines for rare diseases, such as myelofibrosis (MF), continue to prove challenging to develop, and decision-making for MF is complex. The British Society for Haematology (BSH) has created a pragmatic symptom-guided risk-adapted framework on all aspects of management of MF and shared best practices on the use of JAK inhibitors, transplantation and other conventional therapies in the management of myelofibrosis. Commentary on: McLornan et al. The management of myelofibrosis: A British Society for Haematology Guideline. Br J Haematol 2023 (Online ahead of print). doi: 10.1111/bjh.19186.
    Keywords:  JAK inhibitors; myelofibrosis; transplantation
    DOI:  https://doi.org/10.1111/bjh.19257
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