bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2024‒10‒13
24 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
  2. Data-driven, harmonised classification system for myelodysplastic syndromes: a consensus paper from the International Consortium for Myelodysplastic Syndromes.
  3. Measurable Residual Disease as Predictor of Post-Day +100 Relapses Following Allografting in Adult AML.
  4. How I use Maintenance Therapy in Acute Myeloid Leukemia.
  5. CHIP shot: aiming at therapy-induced clonal hematopoiesis.
  6. Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia.
  7. Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signalling and Oxidative Phosphorylation Killing Acute Myeloid Leukemia Cells.
  8. AML typical mutations (CEBPA, FLT3, and NPM1) identify a high-risk CMML independent of CPSS-Mol classification.
  9. Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia.
  10. Beyond HMAs: Novel Targets and Therapeutic Approaches.
  11. The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
  12. Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.
  13. Splicing the Difference: Harnessing the complexity of the transcriptome in hematopoiesis.
  14. Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.
  15. Anti-CLL1 liposome loaded with miR-497-5p and venetoclax as a novel therapeutic strategy in acute myeloid leukemia.
  16. Offering patients a second chance: what is the minimum cure rate needed to justify allogeneic hematopoietic cell transplantation?
  17. Outcomes of Haploidentical Transplants with PT-CY versus 10/10 MUD Transplants with ATG in Germany.
  18. A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.
  19. How I treat Blastic Plasmacytoid Dendritic Cell Neoplasm.
  20. Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia (AML).
  21. CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network.
  22. Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.
  23. Neutrophil/lymphocyte ratio identifies low-risk polycythaemia vera patients for early Ropeginterferon alfa-2b therapy.
  24. The role of corticosteroids in the current treatment paradigm for myelofibrosis.
  1. Blood Adv. 2024 Oct 07. pii: bloodadvances.2024014046. [Epub ahead of print]
    Maintenance of hematopoietic stem cells by tyrosine-unphosphorylated STAT5 and JAK inhibition.
    Matthew J Williams, Xiaonan Wang, Hugo P Bastos, Gabriela Grondys-Kotarba, Qin Wu, Shucheng Jin, Carys S Johnson, Nicole Mende, Emily Francesca Calderbank, Michelle Wantoch, Hyun Jung Park, Giovanna Mantica, Rebecca Louise Hannah, Nicola K Wilson, Dean C Pask, Tina L Hamilton, Sarah J Kinston, Ryan Asby, Rachel Sneade, E Joanna Baxter, Peter J Campbell, George S Vassiliou, Elisa Laurenti, Juan Li, Berthold Gottgens, Anthony R Green.
      Adult haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood and immune cells, a process regulated by extracellular cues including cytokines. Many cytokines signal through the conserved JAK/STAT pathway, in which tyrosine-phosphorylated STATs (pSTATs) function as transcription factors. STAT5 is a pivotal downstream mediator of several cytokines known to regulate haematopoiesis but its function in the HSC compartment remains poorly understood. Here, we show that STAT5-deficient HSCs exhibit an unusual phenotype: reduced multi-lineage repopulation and self-renewal, combined with reduced exit from quiescence and increased differentiation. This was driven not only by loss of canonical pSTAT5 signalling, but also by loss of distinct transcriptional functions mediated by STAT5 lacking canonical tyrosine phosphorylation (uSTAT5). Consistent with this concept, expression of an unphosphorylatable STAT5 mutant constrained wild-type HSC differentiation, promoted their maintenance and upregulated transcriptional programs associated with quiescence and stemness. The JAK1/2 inhibitor, ruxolitinib, which increased the uSTAT5:pSTAT5 ratio, had similar effects on murine HSC function: it constrained HSC differentiation and proliferation, promoted HSC maintenance and upregulated transcriptional programs associated with stemness. Ruxolitinib also enhanced serial replating of normal human HSPCs, CALR-mutant murine HSCs and HSPCs obtained from patients with myelofibrosis. Our results therefore reveal a previously unrecognized interplay between pSTAT5 and uSTAT5 in the control of HSC function and highlight JAK inhibition as a potential strategy for enhancing HSC function during ex vivo culture. Increased levels of uSTAT5 may also contribute to the failure of JAK inhibitors to eradicate myeloproliferative neoplasms.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014046
  2. Lancet Haematol. 2024 Oct 08. pii: S2352-3026(24)00251-5. [Epub ahead of print]
    Data-driven, harmonised classification system for myelodysplastic syndromes: a consensus paper from the International Consortium for Myelodysplastic Syndromes.
    International Consortium on Myelodysplastic Syndromes
      The WHO and International Consensus Classification 2022 classifications of myelodysplastic syndromes enhance diagnostic precision and refine decision-making processes in these diseases. However, some discrepancies still exist and potentially cause inconsistency in their adoption in a clinical setting. We adopted a data-driven approach to provide a harmonisation between these two classification systems. We investigated the importance of genomic features and their effect on the cluster assignment process to define harmonised entity labels. A panel of expert haematologists, haematopathologists, and data scientists who are members of the International Consortium for Myelodysplastic Syndromes was formed and a modified Delphi consensus process was adopted to harmonise morphologically defined categories without a distinct genomic profile. The panel held regular online meetings and participated in a two-round survey using an online voting tool. We identified nine clusters with distinct genomic features. The cluster of highest hierarchical importance was characterised by biallelic TP53 inactivation. Cluster assignment was irrespective of blast count. Individuals with monoallelic TP53 inactivation were assigned to other clusters. Hierarchically, the second most important group included myelodysplastic syndromes with del(5q). Isolated del(5q) and less than 5% of blast cells in the bone marrow were the most relevant label-defining features. The third most important cluster included myelodysplastic syndromes with mutated SF3B1. The absence of isolated del(5q), del(7q)/-7, abn3q26.2, complex karyotype, RUNX1 mutations, or biallelic TP53 were the basis for a harmonised label of this category. Morphologically defined myelodysplastic syndrome entities showed large genomic heterogeneity that was not efficiently captured by single-lineage versus multilineage dysplasia, marrow blasts, hypocellularity, or fibrosis. We investigated the biological continuum between myelodysplastic syndromes with more than 10% bone marrow blasts and acute myeloid leukaemia, and found only a partial overlap in genetic features. After the survey, myelodysplastic syndromes with low blasts (ie, less than 5%) and myelodysplastic syndromes with increased blasts (ie, 5% or more) were recognised as disease entities. Our data-driven approach can efficiently harmonise current classifications of myelodysplastic syndromes and provide a reference for patient management in a real-world setting.
    DOI:  https://doi.org/10.1016/S2352-3026(24)00251-5
  3. Blood Adv. 2024 Oct 07. pii: bloodadvances.2024013214. [Epub ahead of print]
    Measurable Residual Disease as Predictor of Post-Day +100 Relapses Following Allografting in Adult AML.
    Naveed Ali, Megan Othus, Eduardo Rodríguez-Arbolí, Corentin Orvain, Filippo Milano, Brenda M Sandmaier, Chris Davis, Ryan Basom, Fred R Appelbaum, Roland B Walter.
      Measurable residual disease (MRD) by multiparametric flow cytometry (MFC) before allogeneic hematopoietic cell transplantation (HCT) identifies patients at high risk of acute myeloid leukemia (AML) relapse, often occurring early after allografting. To examine the role of MFC MRD testing for the prediction of later relapses, we examined 935 adults with AML or myelodysplastic neoplasm (MDS)/AML transplanted in first or second morphologic remission who underwent bone marrow restaging studies between day 70 and 100 post-HCT and were alive and without relapse by day +100. Of these 136 (15%) had MRD before HCT, whereas only 11 (1%) had MRD at day +70-100. In day +100 landmark analyses, pre-HCT and day +70-100 MFC MRD were both associated with relapse (both P<0.001), relapse-free survival (RFS; both P<0.001) overall survival (OS; both P<0.001), and, for post-HCT MRD, non-relapse mortality (P=0.001) after multivariable adjustment. Importantly, while 126 of the 136 patients (92%) with MRD before HCT tested negative for MRD at day +70-100, their outcomes were inferior to those without MRD before HCT and at day +70-100, with 3-year relapse risk of 40% vs. 15% (P<0.001), 3-year RFS of 50% vs. 72% (P<0.001), and 3-year OS of 56% vs. 76% (P<0.001), whereas 3-year NRM estimates were similar (P=0.53). Thus, despite high MRD conversion rates, outcomes for MRDpos/MRDneg patients are inferior to MRDneg/MRDneg patients, suggesting all patients with pre-HCT MRD should be considered for pre-emptive therapeutic strategies after allografting.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013214
  4. Blood. 2024 Oct 07. pii: blood.2024024010. [Epub ahead of print]
    How I use Maintenance Therapy in Acute Myeloid Leukemia.
    Gail J Roboz, Jonathan Canaani.
      Outcomes for acute myeloid leukemia have improved significantly in the last decade with the approval of novel therapeutics targeting diverse vulnerabilities of leukemic cells, expanded access to stem cell transplantation, and improved safety of transplantation. While attainment of initial remission is now an expected outcome in most AML patients receiving intensive or non-intensive induction regimens, maintaining long-term remission and decreasing the risk of relapse remain critical challenges. Maintenance approaches employing assorted agents have yielded variable success and only recently have been integrated to the standard of care. We present four commonly encountered clinical scenarios that highlight challenges facing physicians as they care for AML patients in remission and contemplate using post-remission maintenance. Using published studies and emerging clinical data, we discuss our approach to maintenance treatment in AML, emphasizing that selection of a specific strategy is an individualized decision based on leukemia biology and risk stratification, presence of targetable mutations, initial treatment approach, performance status, and feasibility of allogeneic stem cell transplantation.
    DOI:  https://doi.org/10.1182/blood.2024024010
  5. Blood Adv. 2024 Oct 08. 8(19): 5213-5214
    CHIP shot: aiming at therapy-induced clonal hematopoiesis.
    Leo Y Luo, Alexander G Bick.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2024013724
  6. Blood Adv. 2024 Oct 07. pii: bloodadvances.2024014446. [Epub ahead of print]
    Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia.
    Fiona C Brown, Xin Wang, Richard W Birkinshaw, Chong Chyn Chua, Thomas David Morley, Sila Kasapgil, Giovanna Pomilio, Piers Blombery, David Ching Siang Huang, Peter E Czabotar, Salvatore F Priore, Guang Yang, Martin P Carroll, Andrew H Wei, Alexander E Perl.
      We report and characterize three venetoclax-resistant BCL2 variants arising during venetoclax/azacitidine therapy in acute myeloid leukemia (AML). Our results indicate the potential for on-target venetoclax resistance in patients with AML at relapse.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014446
  7. Mol Cancer Ther. 2024 Oct 09.
    Zelenirstat Inhibits N-Myristoyltransferases to Disrupt Src Family Kinase Signalling and Oxidative Phosphorylation Killing Acute Myeloid Leukemia Cells.
    Jay M Gamma, Qiang Liu, Erwan Beauchamp, Aishwarya Iyer, Megan C Yap, Zoulika Zak, Cassidy Ekstrom, Rony Pain, Morris A Kostiuk, John R Mackey, Joseph Brandwein, Jean Cy Wang, Luc G Berthiaume.
      Acute myeloid leukemia (AML) is a hematological malignancy with limited treatment options and a high likelihood of recurrence after chemotherapy. We studied N-myristoylation, the myristate modification of proteins linked to survival signaling and metabolism, as a potential therapeutic target for AML. N-myristoylation is catalyzed by two N-myristoyltransferases (NMTs), NMT1 and NMT2, with varying expressions in AML cell lines and patient samples. We identified NMT2 expression as a marker for AML patient survival, and low NMT2 expression was associated with poor outcomes. We used the first-in-class pan-NMT inhibitor, zelenirstat, to investigate the role of N-myristoylation in AML. Zelenirstat effectively inhibits myristoylation in AML cell lines and patient samples, leading to degradation of Src family kinases (SFKs), induction of endoplasmic reticulum (ER) stress, apoptosis, and cell death. Zelenirstat was well tolerated in vivo and reduced the leukemic burden in an ectopic AML cell line and in multiple orthotopic AML patient-derived xenograft models. The leukemia stem cell (LSC)-enriched fractions of the hierarchical OCI-AML22 model were highly sensitive to myristoylation inhibition. Zelenirstat also impairs mitochondrial complex I and oxidative phosphorylation, which are critical for LSC survival. These findings suggest that targeting N-myristoylation with zelenirstat represents a novel therapeutic approach for AML, with promise in patients with currently poor outcomes.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-24-0307
  8. Blood Adv. 2024 Oct 10. pii: bloodadvances.2024013648. [Epub ahead of print]
    AML typical mutations (CEBPA, FLT3, and NPM1) identify a high-risk CMML independent of CPSS-Mol classification.
    Sandra Castaño-Díez, Mònica López-Guerra, Inés Zugasti, Xavier Calvo, Felicitas Isabel Schulz, Alejandro Avendaño, Elvira Mora, Jose Francisco Falantes-González, Gemma Azaceta, Mariam Ibañez, Tzu-Hua Chen-Liang, Cristina Notario Mc Donnell, Neus Amer-Salas, Laura Palomo, Helena Pomares, Jordi Vila, Teresa Bernal Del Castillo, Carlos Jiménez-Vicente, Daniel Esteban, Francesca Guijarro, José Ramón Álamo Moreno, Albert Cortés-Bullich, Víctor Torrecillas-Mayayo, Ana Triguero, Lucía Mont-de Torres, Ester Carcelero, Aina Cardús, Ulrich Germing, Beate Betz, Maria Rozman, Leonor Arenillas, Lurdes Zamora, María Díez-Campelo, Blanca Xicoy, Jordi Esteve, Marina Díaz-Beyá.
      Mutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2 and NPM1 are rarely found in chronic myelomonocytic leukemia (CMML) and their prognostic significance in CMML has not been clearly identified. In 127 CMML patients, we have retrospectively analyzed next-generation sequencing and PCR data from analyses of bone marrow samples performed at diagnosis of CMML. Seven patients harbored CEBPA mutations, eight FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations and 11 NPM1 mutations. CMML patients harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN)were more frequently associated with the myeloproliferative subtype (MP-CMML) , a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CPSS-Mol classification, mutCFN CMML patients had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN CMML patients closely resembled that of AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible, and consider certain targeted therapies approved for use in AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013648
  9. Blood. 2024 Oct 07. pii: blood.2024025800. [Epub ahead of print]
    Asciminib plus dasatinib and prednisone for Philadelphia chromosome-positive acute leukemia.
    Marlise R Luskin, Mark Alan Murakami, Julia H Keating, Yael Flamand, Eric S Winer, Jacqueline S Garcia, Maximilian Stahl, Richard M Stone, Martha Wadleigh, Stella Louise Jaeckle, Ella Hagopian, David M Weinstock, Jessica Liegel, Malgorzata McMasters, Eunice S Wang, Wendy Stock, Daniel J DeAngelo.
      Dasatinib is effective treatment for Philadelphia chromosome-positive (Ph+) acute leukemia but some patients develop resistance. Combination treatment with dasatinib and asciminib, an allosteric inhibitor of BCR::ABL1, may deepen responses and prevent the emergence of dasatinib-resistant clones. In this phase 1 study (NCT03595017), 24 adults with Ph+ acute lymphoblastic leukemia (ALL, n=22; p190, n=16; p210, n=6) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC, n=2) were treated with escalating daily doses of asciminib in combination with dasatinib 140 mg daily plus prednisone 60 mg/m2 daily to determine the maximum tolerated dose (MTD). After a 28-day induction, dasatinib and asciminib continued indefinitely or until hematopoietic stem cell transplant. The median age was 64.5 years (range, 33-85; 50% ³65). The recommended phase 2 dose of asciminib was 80 mg daily in combination with dasatinib and prednisone. The dose limiting toxicity at 160 mg daily was asymptomatic grade 3 pancreatic enzyme elevation without symptomatic pancreatitis. There were no vaso-occlusive events. Among patients with de novo ALL, the complete hematologic remission rate at day 28 and 84 was 84% and 100%, respectively. At day 84, 100% of patients achieved complete cytogenetic remission, 89% achieved measurable residual disease negativity (<0.01%) by multicolor flow cytometry, and 74% and 26% achieved BCR::ABL1 RT-PCR <0.1% and <0.01%. Dual BCR::ABL1 inhibition with dasatinib and asciminib is safe with encouraging activity in patients with de novo Ph+ ALL. ClinicalTrials.gov NCT02081378.
    DOI:  https://doi.org/10.1182/blood.2024025800
  10. Semin Hematol. 2024 Aug 30. pii: S0037-1963(24)00087-8. [Epub ahead of print]
    Beyond HMAs: Novel Targets and Therapeutic Approaches.
    Ted M Getz, Jan P Bewersdorf, Tariq Kewan, Jessica M Stempel, Aram Bidikian, Rory M Shallis, Maximilian Stahl, Amer M Zeidan.
      Myelodysplastic syndromes/neoplasms (MDS) constitute a heterogeneous group of clonal hematopoietic disorders with extremely variable clinical features and outcomes. Management of MDS is largely based on risk stratification of patients into either lower-risk or higher-risk categories using the International Prognostic Scoring System-Revised and, more recently, on the Molecular International Prognostic Scoring System. Lower-risk MDS is often managed with the goal of ameliorating cytopenias and improving quality of life, while higher-risk MDS is treated with therapies aimed at extending survival and delaying progression to acute myeloid leukemia (AML). Therapeutic strategies in lower-risk MDS patients may consist of erythropoiesis stimulating agents, luspatercept, and lenalidomide for selected patients. Furthermore, imetelstat has recently been added to the FDA-approved therapeutic armamentarium for lower-risk MDS. In higher-risk MDS, monotherapy with hypomethylating agents continues to be the standard of care. While several novel hypomethylating agent combinations have and are being studied in large randomized phase 3 clinical trials, including the combination of azacitidine and venetoclax, no combination to date have improved overall survival to azacitidine monotherapy. Moreover, biomarker-directed therapies as well as immonotherapeutic approaches are currently being evaluated in early phase trials. Despite recent advancements, the lack of therapeutic agents, particularly after the failure of first line therapy in higher risk MDS, continues to be a major hurdle in the management of MDS. In this review, we discuss the current treatment landscape of MDS and provide an overview of novel agents currently in clinical development that have the potential to alter our current treatment paradigms.
    Keywords:  Hypomethylating Agents; MDS; Myelodysplastic Syndrome; Novel Therapies
    DOI:  https://doi.org/10.1053/j.seminhematol.2024.08.001
  11. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614781. [Epub ahead of print]
    The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.
    Kentson Lam, Yoon Joon Kim, Carlo M Ong, Andrea Z Liu, Fanny J Zhou, Mary Jean Sunshine, Bernadette A Chua, Silvia Vicenzi, Pierce W Ford, Jie-Hua Zhou, Yuning Hong, Eric J Bennett, Leslie A Crews, Edward D Ball, Robert A J Signer.
      Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo . Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.
    DOI:  https://doi.org/10.1101/2024.09.24.614781
  12. Haematologica. 2024 Oct 10.
    Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.
    Federico Mosna, Erika Borlenghi, Mark Litzow, John C Byrd, Cristina Papayannidis, Cristina Tecchio, Felicetto Ferrara, Guido Marcucci, Roberto Cairoli, Elizabeth A Morgan, Carmela Gurrieri, Cecilia C S Yeung, H Joachim Deeg, Debora Capelli, Anna Candoni, Jason R Gotlib, Monia Lunghi, Sheeja Pullarkat, Francesco Lanza, Sara Galimberti, Fabio Forghieri, Adriano Venditti, Moreno Festuccia, Ernesta Audisio, Denise Marvalle, Gian Matteo Rigolin, Giovanni Roti, Eros DiBona, Giuseppe Visani, Francesco Albano, Ann-Kathrin Eisfeld, Peter Valent, Gerwin Huls, Gautam Borthakur, Mauro Krampera, Giovanni Martinelli, Nicolaus Kröger, Alessandra Sperotto, Michele Gottardi.
      Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.
    DOI:  https://doi.org/10.3324/haematol.2024.285448
  13. Exp Hematol. 2024 Oct 09. pii: S0301-472X(24)00520-4. [Epub ahead of print] 104655
    Splicing the Difference: Harnessing the complexity of the transcriptome in hematopoiesis.
    Hannah M Maul-Newby, Stephanie Halene.
      Alternative splicing has long been recognized as a powerful tool to expand the diversity of the transcriptome and the proteome. The study of hematopoiesis, from hematopoietic stem cell maintenance and differentiation into committed progenitors to maturation into functional blood cells, has led the field of stem cell research and cellular differentiation for decades. The importance of aberrant splicing due to mutations in cis has been exemplified in thalassemias, resulting from aberrant expression of beta-globin. The simultaneous development of increasingly sophisticated technologies, in particular the combination of multi-color flowcytometric cell sorting with bulk and single cell sequencing, has provided sophisticated insights into the complex regulation of the blood system. The recognition that mutations in key splicing factors drive myeloid malignancies, in particular myelodysplastic syndromes, has galvanized research into alternative splicing in hematopoiesis and its diseases. In this review, we will update the audience on the exciting novel technologies, highlight alternative splicing events and their regulators with essential functions in hematopoiesis, and provide a high-level overview how splicing factor mutations contribute to hematologic malignancies.
    DOI:  https://doi.org/10.1016/j.exphem.2024.104655
  14. Haematologica. 2024 Oct 10.
    Expression levels of genes implicated in the working mechanism of lenalidomide predict treatment response in lower risk myelodysplastic syndrome patients.
    Florentien E M In 't Hout, Thessa N Scheele, Theresia M Westers, Canan Alhan, Carolien Duetz, Eline M P Cremers, Heleen A Visser-Wisselaar, Annelies Verbrugge, Dana A Chitu, Bert A Van der Reijden, Aniek O De Graaf, Arjan A Van de Loosdrecht, Joop H Jansen.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2024.286157
  15. Mol Ther. 2024 Oct 04. pii: S1525-0016(24)00659-2. [Epub ahead of print]
    Anti-CLL1 liposome loaded with miR-497-5p and venetoclax as a novel therapeutic strategy in acute myeloid leukemia.
    Qiaoyu Pan, Xiaofei Xin, Sohan Mahto, Yuxiang Dong, Virender Kumar, R Katherine Hyde, Neha Gupta, Vijaya R Bhatt, Ram I Mahato.
      Acute myeloid leukemia (AML) is a lethal hematologic malignancy. Chemotherapy resistance results in a dismal survival of 1-2 years in older adults with AML. Therefore, novel therapies are urgently required. In this context, microRNA (miRNA)-based treatments remain an untapped strategy in AML. Using patient-derived specimens, we found increased inflammatory cytokines including IL-6 in serum of older adults with AML, and decreased miR-497-5p in CD34+ leukemic blasts. Target prediction revealed that miR-497-5p could directly target mitogen-activated protein kinase-1 (MAP2K1) mRNA, to indirectly target cytokines and JAK/STAT signaling pathway through p38-MAPK signaling pathway, potentially inhibiting leukemic growth, and overcoming chemoresistance from venetoclax. To improve miRNA delivery and minimize off-target effects, which represent key barriers to clinical translation, we developed liposomes for co-delivery of miR-497-5p and venetoclax. We decorated our liposomes with a peptide targeting CLL1, which is present on 92% leukemia blasts while being absent in normal hematopoietic cells. This targeted approach demonstrated high efficacy in inhibiting AML growth in mice with minimal toxicity, as well as reduced exposure to chemoresistance. Our findings suggested that anti-CLL1-decorated, miR-497-5p and venetoclax-loaded liposomes represent a promising novel miRNA-based therapeutic, which should be further investigated as a strategy to reduce venetoclax resistance in AML.
    DOI:  https://doi.org/10.1016/j.ymthe.2024.09.036
  16. Leukemia. 2024 Oct 09.
    Offering patients a second chance: what is the minimum cure rate needed to justify allogeneic hematopoietic cell transplantation?
    Frederick R Appelbaum.
      
    DOI:  https://doi.org/10.1038/s41375-024-02384-7
  17. Blood Adv. 2024 Oct 05. pii: bloodadvances.2024013719. [Epub ahead of print]
    Outcomes of Haploidentical Transplants with PT-CY versus 10/10 MUD Transplants with ATG in Germany.
    Aysenur Arslan, Svenja Labuhn, Elisa Sala, Mark Ringhoffer, Johannes Schetelig, Thomas Schroeder, Gesine Bug, Georg-Nikolaus Franke, Matthias Stelljes, Peter Dreger, Robert Zeiser, Daniel Teschner, Wolfgang Andreas Bethge, Matthias Eder, Matthias Edinger, Elisa Maria Amann, Christine Neuchel, Amelie Schmid-Möglich, Sandra Schmeller, Jan Beyersmann, Hubert Schrezenmeier, Joannis Mytilineos, Nicolaus Kröger, Daniel Fuerst.
      Allogeneic stem cell transplantation (alloHSCT) is the best curative treatment modality for many malignant haematological disorders. In the absence of a matched related donor (MRD), matched unrelated donors (MUD) and haploidentical donors (Haplo-Tx) are the most important sources of stem cells. However, multicenter real-life data which compare 10/10 MUD transplantations with Haplo-Tx is still limited. In this registry based retrospective study, we compared the outcomes of alloHSCTs from 10/10 MUD with anti-thymocyte globulin (ATG) based regimens (n=7050) versus Haplo-Tx using post-transplant cyclophosphamide (PT-CY Haplo) (n=487) in adult patients with haematological malignancies between 2010 and 2020. Cox proportional hazard models and competing risks regression models were formed to compare the outcomes of the groups. OS, DFS and GRFS were superior for 10/10 MUD (OS: HR 1.27, CI 1.10- 1.47, p=0.001, DFS: HR 1.17, CI 1.02-1.34, p=0.022, GRFS: HR 1.34, CI 1.19-1.50, p<0.001). Risk for aGVHD grade II-IV, aGVHD grade III-IV and cGVHD was higher in the PT-CY Haplo group compared to the 10/10 MUD group (aGVHD grade II-IV: HR 1.46, CI 1.25- 1.71, p<0.001; aGVHD grade III-IV: HR 1.74, CI 1.37- 2.20, p<0.001 and cGVHD: HR 1.30, CI 1.11-1.51, p=0.001). A lower incidence of relapse was observed in the PT-CY Haplo group (relapse: HR 0.83, CI 0.69-0.99, p=0.038). Unrelated 10/10 matched transplantation with ATG treatment leads to lower GvHD rates and improved survival rates when compared to PT-CY Haplo transplantation in Germany.
    DOI:  https://doi.org/10.1182/bloodadvances.2024013719
  18. Sci Transl Med. 2024 Oct 09. 16(768): eadj7552
    A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis.
    Rong Li, Michela Colombo, Guanlin Wang, Antonio Rodriguez-Romera, Camelia Benlabiod, Natalie J Jooss, Jennifer O'Sullivan, Charlotte K Brierley, Sally-Ann Clark, Juan M Pérez Sáez, Pedro Aragón Fernández, Erwin M Schoof, Bo Porse, Yiran Meng, Abdullah O Khan, Sean Wen, Pengwei Dong, Wenjiang Zhou, Nikolaos Sousos, Lauren Murphy, Matthew Clarke, Aude-Anais Olijnik, Zoë C Wong, Christina Simoglou Karali, Korsuk Sirinukunwattana, Hosuk Ryou, Ruggiero Norfo, Qian Cheng, Joana Carrelha, Zemin Ren, Supat Thongjuea, Vijay A Rathinam, Anandi Krishnan, Daniel Royston, Gabriel A Rabinovich, Adam J Mead, Bethan Psaila.
      Myeloproliferative neoplasms are stem cell-driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a "quartet" of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside-binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell-niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis.
    DOI:  https://doi.org/10.1126/scitranslmed.adj7552
  19. Blood. 2024 Oct 07. pii: blood.2024024262. [Epub ahead of print]
    How I treat Blastic Plasmacytoid Dendritic Cell Neoplasm.
    Mohamed A Kharfan-Dabaja, Andrew A Lane, Naveen Pemmaraju.
      Historically, treatment options for blastic plasmacytoid dendritic cell neoplasm (BPDCN) were limited to conventional chemotherapy, adopted from regimens used to treat acute myeloid or acute lymphoblastic leukemias, or lymphomas. Nowadays, a novel therapy targeting CD123 is available to treat BPDCN. Yet, regardless of treatment choice, achieving a first complete remission (CR1) represents the main goal of therapy, because it represents the best opportunity to prolong survival in BPDCN, if offered an allogeneic hematopoietic cell transplant (allo-HCT) as consolidative therapy. Although no specific conditioning regimen is considered standard-of-care in allo-HCT eligible patients, recent data from two large registries reported a survival advantage when offering total body irradiation-based myeloablative conditioning (MAC) regimens. Unfortunately, applicability of MAC regimens is not feasible in older/unfit patients, which represents a considerable proportion of patients presenting worldwide. In such cases, reduced intensity conditioning regimens represent the next best option. Auto-HCT could be considered in older/unfit patients who did not have BM involvement at initial presentation and at time of the procedure, albeit data supporting this option is less abundant. Future research is needed to decipher the interplay between clinical, genetic, and molecular features of the disease to personalize treatment accordingly, by enhancing efficacy and avoiding unnecessary toxicities.
    DOI:  https://doi.org/10.1182/blood.2024024262
  20. Blood Adv. 2024 Oct 05. pii: bloodadvances.2024014291. [Epub ahead of print]
    Identification of factors predicting low-risk febrile neutropenia admissions in adults with acute myeloid leukemia (AML).
    Khusboo V Pal, Megan Othus, Zahra Ali, Kathryn Russell, Carole Shaw, Mary-Elizabeth M Percival, Paul C Hendrie, Jacob S Appelbaum, Roland B Walter, Anna B Halpern.
      Febrile neutropenia (FN) is the most common reason for hospital readmission following chemotherapy for AML and is a major driver of healthcare resource utilization. While FN risk models exist, these have largely been developed and validated in solid tumors. We therefore examined whether baseline characteristics could predict which AML patients with FN have a lower risk of progression to severe illness. We identified adults with high-grade myeloid neoplasm (³10% blasts in blood/marrow) who received intensive chemotherapy and were admitted for FN from 2016-2023. We collected baseline clinical and disease variables. Outcomes were: infections identified, hospital length of stay (LOS), intensive care unit (ICU) admission, and survival. A "lower-risk [LR]" outcome was defined as LOS <72hrs without ICU admission or inpatient death. Univariate and multivariable (MV) logistic regression models were used to assess covariate associations with outcomes. We identified 397 FN admissions in 248 patients (median age 61 [range: 29-77] years). The median hospital LOS was 6 (range: 1-56) days; 10% required ICU admission and 3.5% died inpatient. Only 15% of admissions were LR. Infection was identified in 59% of admissions. Physiologic parameters including heart rate, blood pressure and fever height were the best predictors of LR admission and infection. We developed MV models to predict LR admission and infection with AUCs of 0.82 and AUC 0.72, respectively. Established FN and critical illness models were not predictive of outcomes in AML, where we could not identify a lower risk group; thus an AML-specific FN risk model requires further development and validation.
    DOI:  https://doi.org/10.1182/bloodadvances.2024014291
  21. Nat Commun. 2024 Oct 09. 15(1): 8747
    CBFA2T3-GLIS2 mediates transcriptional regulation of developmental pathways through a gene regulatory network.
    Elizabeth A R Garfinkle, Pratima Nallagatla, Binay Sahoo, Jinjun Dang, Mohammad Balood, Anitria Cotton, Camryn Franke, Sharnise Mitchell, Taylor Wilson, Tanja A Gruber.
      CBFA2T3-GLIS2 is a fusion oncogene found in pediatric acute megakaryoblastic leukemia that is associated with a poor prognosis. We establish a model of CBFA2T3-GLIS2 driven acute megakaryoblastic leukemia that allows the distinction of fusion specific changes from those that reflect the megakaryoblast lineage of this leukemia. Using this model, we map fusion genome wide binding that in turn imparts the characteristic transcriptional signature. A network of transcription factor genes bound and upregulated by the fusion are found to have downstream effects that result in dysregulated signaling of developmental pathways including NOTCH, Hedgehog, TGFβ, and WNT. Transcriptional regulation is mediated by homo-dimerization and binding of the ETO transcription factor through the nervy homology region 2. Loss of nerve homology region 2 abrogated the development of leukemia, leading to downregulation of JAK/STAT, Hedgehog, and NOTCH transcriptional signatures. These data contribute to the understanding of CBFA2T3-GLIS2 mediated leukemogenesis and identify potential therapeutic vulnerabilities for future studies.
    DOI:  https://doi.org/10.1038/s41467-024-53158-9
  22. Science. 2024 Oct 11. 386(6718): eadl4492
    Epigenetic regulators of clonal hematopoiesis control CD8 T cell stemness during immunotherapy.
    Tae Gun Kang, Xin Lan, Tian Mi, Hongfeng Chen, Shanta Alli, Song-Eun Lim, Sheetal Bhatara, Anoop Babu Vasandan, Grace Ward, Sofia Bentivegna, Josh Jang, Marianne L Spatz, Jin-Hwan Han, Balthasar Clemens Schlotmann, Jakob Schmidt Jespersen, Christopher Derenzo, Peter Vogel, Jiyang Yu, Stephen Baylin, Peter Jones, Casey O'Connell, Kirsten Grønbæk, Ben Youngblood, Caitlin C Zebley.
      Epigenetic reinforcement of T cell exhaustion is known to be a major barrier limiting T cell responses during immunotherapy. However, the core epigenetic regulators restricting antitumor immunity during prolonged antigen exposure are not clear. We investigated three commonly mutated epigenetic regulators that promote clonal hematopoiesis to determine whether they affect T cell stemness and response to checkpoint blockade immunotherapy. CD8 T cells lacking Dnmt3a, Tet2, or Asxl1 preserved a progenitor-exhausted (Tpex) population for more than 1 year during chronic antigen exposure without undergoing malignant transformation. Asxl1 controlled the self-renewal capacity of T cells and reduced CD8 T cell differentiation through H2AK119 ubiquitination and epigenetic modification of the polycomb group-repressive deubiquitinase pathway. Asxl1-deficient T cells synergized with anti-PD-L1 immunotherapy to improve tumor control in experimental models and conferred a survival advantage to mutated T cells from treated patients.
    DOI:  https://doi.org/10.1126/science.adl4492
  23. Br J Haematol. 2024 Oct 07.
    Neutrophil/lymphocyte ratio identifies low-risk polycythaemia vera patients for early Ropeginterferon alfa-2b therapy.
    Tiziano Barbui, Alessandra Carobbio, Paola Guglielmelli, Arianna Ghirardi, Francesca Fenili, Giuseppe Gaetano Loscocco, Valerio De Stefano, Francesco Ramundo, Maria Chiara Finazzi, Alessandro Rambaldi, Alessandro M Vannucchi.
      We investigated the effect of Ropeginterferon alfa-2b (Ropeg) versus phlebotomy-only (Phl-O) on the neutrophil-to-lymphocyte ratio (NLR) in 126 patients randomized in the low-polycythaemia vera (PV) phase II trial. Patients with a baseline NLR ≥3.5 vs. <3.5 had a longer history of PV, were more likely to have splenomegaly, higher JAK2V617F variant allele frequency (VAF) (56% vs. 20% p = 0.001) and more proliferative disease. Ropeg was superior to Phl-O in reducing NLR (p = 0.008), and the reduction was strongly influenced by the reduction in neutrophils and less by a change in lymphocytes (-59% and -14% respectively). This effect was associated with the achievement of the low-PV primary end-point (p = 0.021), symptom reduction and reduction in JAK2 VAF. Interestingly, the reduction in JAK2 VAF from baseline was linearly associated with the reduction in NLR. Patients who failed Phl-O at 12 months had characteristics that distinguished them from responders, including very high NLR and resistance to cross-over to 100 μg Ropeg every 2 weeks suggesting higher escalated doses of Ropeg. In conclusion, the study provides evidence that NLR can serve as a valuable biomarker to assess and guide treatment with Ropeg in the early stage of low-risk PV patients.
    Keywords:   JAK2 VAF ; Ropeginterferon; neutrophil/lymphocyte ratio; quality of life; treatment response
    DOI:  https://doi.org/10.1111/bjh.19813
  24. Expert Opin Pharmacother. 2024 Oct 11. 1-8
    The role of corticosteroids in the current treatment paradigm for myelofibrosis.
    Antonella Bruzzese, Enrica Antonia Martino, Caterina Labanca, Francesco Mendicino, Eugenio Lucia, Virginia Olivito, Teresa Rossi, Antonino Neri, Fortunato Morabito, Ernesto Vigna, Massimo Gentile.
      INTRODUCTION: Myelofibrosis (MF) is a clonal hematological disorder characterized by bone marrow fibrosis, splenomegaly, and inflammatory cytokine dysregulation. While the role of steroids in MF is not fully defined, their anti-inflammatory properties may offer therapeutic benefits, particularly in managing anemia and other cytopenias. Steroids exert their effects by suppressing pro-inflammatory cytokines such as IL1, IL6, and TNF, and by enhancing anti-inflammatory cytokines like IL4 and IL10. Elevated levels of IL6 and other cytokines in MF are associated with anemia and poor prognosis, suggesting that steroid therapy could mitigate these effects.AREAS COVERED: In this manuscript, we review clinical studies which evaluated the safety and efficacy of steroids in MF patients. Moreover, we examine clinical data of the combination of steroids with immunomodulatory agents and JAK inhibitors. Our literature search consisted of an extensive review of PubMed and clinicaltrials.gov.
    EXPERT OPINION: The role of steroids in the management of MF remains poorly defined, though emerging evidence suggests a potential therapeutic benefit, particularly in managing anemia and other cytopenias. The combination with IMIDs has also yielded positive outcomes as demonstrated in several studies. Steroids may also play a crucial role in managing cytopenias in MF patients receiving JAKi.
    Keywords:  JAKi; MFI; Steroids; myeloproliferative disorder; therapy
    DOI:  https://doi.org/10.1080/14656566.2024.2415710
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