bims-tremyl 2024-12-01 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2024–12–01
29 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Relevance of blast counts for genetic subclassification in MDS.
Genotype-immunophenotype relationships in NPM1 -mutant AML clonal evolution uncovered by single cell multiomic analysis.
Azacitidine and venetoclax with or without pevonedistat in patients with newly diagnosed acute myeloid leukemia.
Methotrexate Versus Mycophenolate Mofetil Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Malignancies: A Retrospective Analysis on Behalf of the Chronic Malignancies Working Party of the EBMT.
RSK1 dependency in FLT3-ITD acute myeloid leukemia.
Prospective feasibility of a minimal BH3 profiling assay in acute myeloid leukemia.
Targeting chromatin modifying complexes in acute myeloid leukemia.
Unraveling lipid metabolism for acute myeloid leukemia therapy.
Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse.
Long-term follow-up of a phase 2 study of all-trans retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin in acute promyelocytic leukemia.
Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.
Pacritinib prevents inflammation-driven myelofibrosis-like phenotype in a miR-146a-/- murine model.
Central nervous system relapse after allogeneic HCT in FLT3-mutated AML.
Evaluation of Gemtuzumab Ozogamicin and Anthracycline Dosing for Favorable Risk Acute Myeloid Leukemia.
Genocopy of EVI1-AML with paraneoplastic diabetes insipidus: PRDM16 overexpression by t(1;2)(p36;p21) and enhancer hijacking.
Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.
When, which and how to switch: Navigating JAK inhibitors in myelofibrosis.
Implications for metabolic disturbances in myelodysplastic syndromes.
Myeloproliferative Neoplasms: Challenging Dogma.
Successful Treatment-Free Remission After Ponatinib Discontinuation in Pretreated Patients with Chronic Myeloid Leukemia in Chronic Phase.
Preclinical activity of resazurin in acute myeloid leukaemia.
Oral azacitidine maintenance after intensive chemotherapy versus venetoclax and azacitidine: real world outcomes in newly diagnosed acute myeloid leukemia.
Salvage monotherapy with venetoclax after failure from a single course of standard induction chemotherapy for acute myeloid leukaemia.
Decoding Acute Myeloid Leukemia: A Clinician's Guide to Functional Profiling.
Relationship Between Age, Conditioning Intensity, and Outcome After Allografting in Adults Age ≥60 Years with AML.
Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing.
Real-world impact of luspatercept on red blood cell transfusions among patients with myelodysplastic syndromes: A United States healthcare claims database study.
Spatial transcriptomic approaches for characterising the bone marrow landscape: pitfalls and potential.
Molecular landscape and clinical outcome of SRSF2/TET2 Co-mutated myeloid neoplasms.

Leukemia. 2024 Nov 27.

Relevance of blast counts for genetic subclassification in MDS.

Sandra Huber, Torsten Haferlach, Stephan Hutter, Gregor Hoermann, Wolfgang Kern, Claudia Haferlach.

DOI: https://doi.org/10.1038/s41375-024-02484-4
bioRxiv. 2024 Nov 12. pii: 2024.11.11.623033. [Epub ahead of print]

Genotype-immunophenotype relationships in NPM1 -mutant AML clonal evolution uncovered by single cell multiomic analysis.

Morgan Drucker, Darren Lee, Xuan Zhang, Bailee Kain, Michael Bowman, Deedra Nicolet, Zhe Wang, Richard M Stone, Krzysztof Mrózek, Andrew J Carroll, Daniel T Starczynowski, Ross L Levine, John C Byrd, Ann-Kathrin Eisfeld, Nathan Salomonis, H Leighton Grimes, Robert L Bowman, Linde A Miles.

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1 -mutant AML patients at different stages of disease. Here we show that diagnosis and relapsed AML samples display similar clonal architecture patterns, but signaling mutations can drive increased clonal diversity specifically at relapse. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on therapy identified dynamic clonal, transcriptomic, and immunophenotypic changes. Our studies provide resolved understanding of leukemic clonal evolution and the relationships between genotype and cell state in leukemia biology.

DOI: https://doi.org/10.1101/2024.11.11.623033
Leuk Lymphoma. 2024 Nov 28. 1-11

Azacitidine and venetoclax with or without pevonedistat in patients with newly diagnosed acute myeloid leukemia.

Nicholas J Short, Agnieszka Wierzbowska, Thomas Cluzeau, Kamel Laribi, Christian Recher, Jaroslaw Czyz, Bogdan Ochrem, Lionel Ades, Maria Pilar Gallego-Hernanz, Mael Heiblig, Ernesta Audisio, Ewa Zarzycka, Shuli Li, Nicholas Ferenc, Tammie Yeh, Douglas V Faller, Farhad Sedarati, Cristina Papayannidis.

  This phase 2 study investigated pevonedistat + azacitidine + venetoclax (n = 83) versus azacitidine + venetoclax (n = 81) in patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy. The study was stopped early following negative results from PANTHER, which evaluated pevonedistat in higher-risk myelodysplastic syndromes/chronic myelomonocytic leukemia or low-blast AML. Outcomes were analyzed up to the datacut. For pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax, the median follow-up was 8.44 versus 7.95 months; the complete remission (CR) rate was 45% versus 49%; composite CR (CCR; CR+CR with incomplete blood count recovery) was 77% versus 72%. There were no differences in event-free survival (primary endpoint; hazard ratio [HR]: 0.99; 95% confidence interval [CI]: 0.61-1.60; p = 0.477) or overall survival (HR: 1.42; 95% CI: 0.82-2.49; p = 0.896). In exploratory analyses in IDH-mutated AML, CCR rates were higher with pevonedistat + azacitidine + venetoclax versus azacitidine + venetoclax. Safety was similar between treatment arms. Efficacy/safety with azacitidine + venetoclax was consistent with the phase 3 VIALE-A study.
TRIAL REGISTRATION: NCT04266795.

Keywords:  Acute myeloid leukemia; azacitidine; pevonedistat; phase 2; venetoclax

DOI:  https://doi.org/10.1080/10428194.2024.2431878
Am J Hematol. 2024 Nov 28.

Methotrexate Versus Mycophenolate Mofetil Prophylaxis in Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Malignancies: A Retrospective Analysis on Behalf of the Chronic Malignancies Working Party of the EBMT.

Thomas Luft, Luuk Gras, Linda Koster, Nicolaus Kröger, Thomas Schröder, Uwe Platzbecker, Katja Sockel, Régis Peffault de Latour, Matthias Stelljes, Henrik Sengeloev, Matthias Eder, Igor Wolfgang Blau, Peter Dreger, Ibrahim Yakoub-Agha, Johan Maertens, Urpu Salmenniemi, Wolfgang Bethge, Stephan Mielke, Guido Kobbe, Anastasia Pouli, Liesbeth C de Wreede, Kavita Raj, Joanna Drozd-Sokolowska, Donal P McLornan, Marie Robin.

  Prophylaxis strategies for Graft versus host disease (GVHD) in allogeneic hematopoietic cell transplantation (allo-HCT) frequently encompass a combination of a calcineurin inhibitor (CNI) with either methotrexate (MTX) or mycophenolate mofetil (MMF). The aim of this retrospective, EBMT registry-based study was to determine outcome differences for chronic myeloid malignancies and secondary acute myeloid leukemia (sAML) between MTX- and MMF-based prophylaxis regimens while taking potential heterogeneity between subgroups into consideration. Eligible were patients transplanted between 2007 and 2017 who received either MTX- or MMF prophylaxis in combination with a CNI. Endpoints after allo-HCT were overall survival, relapse-free survival (RFS), relapse incidence, non-relapse mortality (NRM), and Grades 2-4 acute GVHD (aGvHD). Overall, 13 699 patients from 321 centers were included. Median follow-up was 42.8 months (IQR 19.8-74.5 months). MTX prophylaxis was associated with reduced overall mortality (HR 0.87, 95% CI 0.81-0.95, p = 0.001) and NRM (HR 0.86, 95% CI 0.78-0.96, p = 0.006) compared with MMF in multivariable Cox regression models in the whole cohort without significant interaction between prophylaxis and subgroups. In contrast, there was no significant association of prophylaxis with risk of relapse (HR 1.03 MTX vs. MMF, 95% CI 0.94-1.14, p = 0.53) or RFS (HR 0.95, 95% CI 0.88-1.01, p = 0.12). There was a reduced risk of Grades 2-4 acute GVHD and reduced mortality after acute GVHD with MTX prophylaxis but no association with outcome in a landmark analysis in patients without aGvHD at 3 months after allo-HCT. In conclusion, MTX-complemented CNI prophylaxis was associated with favorable survival, and with favorable survival after aGVHD compared with MMF.

Keywords:  acute GVHD; allogeneic stem cell transplantation; methotrexate (MTX); mycophenolate mofetil (MMF); survival

DOI:  https://doi.org/10.1002/ajh.27531
Blood Cancer J. 2024 Nov 26. 14(1): 207

RSK1 dependency in FLT3-ITD acute myeloid leukemia.

Tim Kong, Angelo B A Laranjeira, Christopher T Letson, LaYow Yu, Fan He, Aarthi Jayanthan, Gerrit Los, Sandra E Dunn, Grant A Challen, Stephen T Oh.

Internal tandem duplications (ITD) in fms-like tyrosine kinase 3 (FLT3) represent the most common genetic alteration in de novo acute myeloid leukemia (AML). Here, we identify ribosomal protein s6 kinase a1 (RSK1) as a core dependency in FLT3-ITD AML and unveil the existence of crucial bi-directional regulation. RSK1 perturbation resulted in marked apoptosis and abrogated phosphorylation of FLT3 and associated downstream signaling cascades in FLT3-ITD AML cell lines. Using cycloheximide, MG-132, and ubiquitination assays, we further demonstrate mechanistically that RSK1 regulates FLT3-ITD activity, and protein stability through deubiqutinase USP1, which we identify as a second dependency. Importantly, multivariate analysis revealed heightened expression of RPS6KA1 and USP1 to be associated with poor patient prognosis, and these effectors may serve as biomarkers predictive of patient survival and therapeutic response to FLT3-ITD inhibitors. Lastly, RSK1 inhibition utilizing a first-in-class RSK inhibitor, PMD-026, that is currently undergoing Phase 2 development for breast cancer, diminished leukemic disease burden in MV4-11 xenograft and syngeneic Flt3ITDTet2KO leukemia models. These findings illustrate an unconventional and promising therapeutic strategy targeting FLT3-ITD leukemia.

DOI: https://doi.org/10.1038/s41408-024-01187-4
Cytometry B Clin Cytom. 2024 Nov 27.

Prospective feasibility of a minimal BH3 profiling assay in acute myeloid leukemia.

Kim Pacchiardi, Victoire de Marcellus, Tony Huynh, Sofiane Fodil, Rathana Kim, Reinaldo Dal Bello, Morgane Fontaine, Catherine Lonchamp, Laureen Chat, Lorea Aguinaga, Etienne Lengliné, Marie Sébert, Emmanuel Raffoux, Lionel Adès, Hervé Dombret, Emmanuelle Clappier, Alexandre Puissant, Stéphanie Mathis, Clémentine Chauvel, Raphael Itzykson.

  BH3 profiling can assess global mitochondrial priming and dependence of leukemic cells on specific BH3 anti-apoptotic proteins such as BCL-2. In acute myeloid leukemia (AML), proof-of-concept prognostic studies have been performed on archived samples variably accounting for molecular genetics. We undertook a single-center feasibility study of a simplified flow-based assay to determine the absolute mitochondrial priming and BCL-2 dependence in consecutive AML patients. When possible, results on the leukemic fraction were normalized to the cognate lymphocyte population (relative priming and BCL-2 dependence). Samples from 97 (89.8%) of the 108 referred patients were successfully processed. Relative priming and BCL-2 dependence could be determined in 62 (67.4%) and 67 (62.0%) samples, respectively. Absolute mitochondrial priming was lower in patients having previously failed intensive chemotherapy compared to chemotherapy-naïve patients (p = 0.01), but its prognostic impact was limited. Conversely, relative BCL-2 independence tended to predict worse EFS (HR = 2.51, p = 0.07) and OS (HR = 2.79, p = 0.10) independently of adverse genetic risk. Our results show that simplified BH3 profiling can be prospectively assessed in AML patients but that its prognostic use may require internal normalization. Future studies should compare its relevance with other functional assays such as ex vivo drug testing or BH3 protein expression.

Keywords:  BH3 profiling; acute myeloid leukemia; mitochondrial priming; prognosis

DOI:  https://doi.org/10.1002/cyto.b.22217
Stem Cells Transl Med. 2024 Nov 28. pii: szae089. [Epub ahead of print]

Targeting chromatin modifying complexes in acute myeloid leukemia.

Alexandra Schurer, Shira G Glushakow-Smith, Kira Gritsman.

  Acute myeloid leukemia (AML) is a devastating hematologic malignancy with high rates of relapse, which can, in part, be attributed to the dysregulation of chromatin modifications. These epigenetic modifications can affect the capacity of hematopoietic cells to self-renew or differentiate, which can lead to transformation. Aberrant histone modifications contribute to the derepression of self-renewal genes such as HOXA/B and MEIS1 in committed hematopoietic progenitors, which is considered a key mechanism of leukemogenesis in MLL-rearranged (MLL-r) and NPM1-mutated AML. As regulators of some of the key histone modifications in this disease, the menin-KMT2A and polycomb repressive (PRC1/2) complexes have been identified as promising targets for the treatment of AML. This review explores recent discoveries of how leukemic cells hijack these complexes and their interactions with other chromatin regulators to promote disease progression. We also discuss inhibitors targeting these complexes that have demonstrated therapeutic efficacy in preclinical and clinical studies and propose novel therapeutic combinations targeting the KMT2A and PRC1/2 broader interacting networks to overcome issues of resistance to existing monotherapies.

Keywords:   HOXA/B ; MEIS1 ; KMT2A; KMT2A-rearrangement; NPM1c; PRC1; PRC2; acute myeloid leukemia; chromatin; histones; menin inhibition

DOI:  https://doi.org/10.1093/stcltm/szae089
Curr Opin Hematol. 2024 Nov 19.

Unraveling lipid metabolism for acute myeloid leukemia therapy.

Cristiana O'Brien, Courtney L Jones.

PURPOSE OF REVIEW: The aim of this review is to highlight the importance of lipids' intricate and interwoven role in mediating diverse acute myeloid leukemia (AML) processes, as well as potentially novel lipid targeting strategies. This review will focus on new studies of lipid metabolism in human leukemia, particularly highlighting work in leukemic stem cells (LSCs), where lipids were assessed directly as a metabolite.
RECENT FINDINGS: Lipid metabolism is essential to support LSC function and AML survival through diverse mechanisms including supporting energy production, membrane composition, signaling pathways, and ferroptosis. Recent work has highlighted the role of lipid rewiring in metabolic plasticity which can underlie therapy response, the impact of cellular and genetic heterogeneity in AML on lipid metabolism, and the discovery of noncanonical roles of lipid related proteins in AML.
SUMMARY: Recent findings around lipid metabolism clearly demonstrates their importance to our understanding and therapeutic targeting of AML. We have only begun to unravel the regulation and utilization of lipids in this disease. Further, understanding the layered dynamics of lipid homeostasis could provide novel opportunities to target lipid metabolism in AML and LSCs with the potential of improving outcomes for patients with AML.

DOI: https://doi.org/10.1097/MOH.0000000000000853
bioRxiv. 2024 Nov 11. pii: 2024.11.09.622796. [Epub ahead of print]

Targeting IL-1/IRAK1/4 signaling in Acute Myeloid Leukemia Stem Cells Following Treatment and Relapse.

Tzu-Chieh Ho, Mark W LaMere, Hiroki Kawano, Daniel K Byun, Elizabeth A LaMere, Yu-Chiao Chiu, Chunmo Chen, Jian Wang, Nikolay V Dokholyan, Laura M Calvi, Jane L Liesveld, Craig T Jordan, Reuben Kapur, Rakesh K Singh, Michael W Becker.

Therapies for acute myeloid leukemia (AML) face formidable challenges due to relapse, often driven by leukemia stem cells (LSCs). Strategies targeting LSCs hold promise for enhancing outcomes, yet paired comparisons of functionally defined LSCs at diagnosis and relapse remain underexplored. We present transcriptome analyses of functionally defined LSC populations at diagnosis and relapse, revealing significant alterations in IL-1 signaling. Interleukin-1 receptor type I (IL1R1) and interleukin-1 receptor accessory protein (IL1RAP) were notably upregulated in leukemia stem and progenitor cells at both diagnosis and relapse. Knockdown of IL1R1 and IL1RAP reduced the clonogenicity and/or engraftment of primary human AML cells. In leukemic MLL-AF9 mice, Il1r1 knockout reduced LSC frequency and extended survival. To target IL-1 signaling at both diagnosis and relapse, we developed UR241-2, a novel interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4) inhibitor. UR241-2 robustly suppressed IL-1/IRAK1/4 signaling, including NF-κB activation and phosphorylation of p65 and p38, following IL-1 stimulation. UR241-2 selectively inhibited LSC clonogenicity in primary human AML cells at both diagnosis and relapse, while sparing normal hematopoietic stem and progenitor cells. It also reduced AML engraftment in leukemic mice. Our findings highlight the therapeutic potential of UR241-2 in targeting IL-1/IRAK1/4 signaling to eradicate LSCs and improve AML outcomes.

DOI: https://doi.org/10.1101/2024.11.09.622796
Cancer. 2024 Nov 25.

Long-term follow-up of a phase 2 study of all-trans retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin in acute promyelocytic leukemia.

Wei-Ying Jen, Jennifer Marvin-Peek, Hagop M Kantarjian, Yesid Alvarado, Gautam Borthakur, Elias Jabbour, William Wierda, Tapan M Kadia, Naval G Daver, Courtney D DiNardo, Nicholas J Short, Nitin Jain, Alessandra Ferrajoli, Steven Kornblau, Musa Yilmaz, Maro Ohanian, David McCue, Jan Burger, Danielle Hammond, Keyur Patel, Ghayas C Issa, Naveen Pemmaraju, Koji Sasaki, Abhishek Maiti, Hussein A Abbas, Kelly Chien, Koichi Takahashi, Fadi Haddad, Prithviraj Bose, Lucia Masarova, Guillermo Montalban-Bravo, Mahesh Swaminathan, Mark Brandt, Sherry Pierce, Guillermo Garcia-Manero, Farhad Ravandi.

   BACKGROUND: All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) combinations have produced excellent outcomes in patients with standard-risk acute promyelocytic leukemia (APL). Herein, the authors update their long-term results with the regimen of ATO-ATRA and gemtuzumab ozogamicin (GO) in standard-risk and high-risk APL.
METHODS: This was a phase 2 trial of patients with newly diagnosed APL. Induction comprised ATRA 45 mg/m2 and ATO 0.15 mg/kg daily. GO 6-9 mg/m2 was added for high-risk patients and for standard-risk patients who developed leukocytosis >10 × 109/L. Consolidation consisted of four courses of ATO-ATRA, with GO for patients who had PML::RARA persistence.
RESULTS: One hundred forty-six patients (median age, 53.0 years; range, 19.3-83.9 years) were treated, including 106 patients (72.6%) with standard-risk APL and 40 (27.4%) with high-risk APL. GO was administered to 68 standard-risk patients (64.2%) for leukocytosis. The complete remission rate was 93.8% (95% confidence interval [CI], 92.2%-98.5%). Negative measurable residual disease status was achieved in 97.1% of patients who attained complete remission. At a median follow-up of 61.8 months (95% CI, 4.7-128.4 months), the 5-year event-free survival, disease-free survival, and overall survival rates were 92.4% (95% CI, 87.9%-97.1%), 93.6% (95% CI, 89.5%-97.8%), and 93.1% (95% CI, 88.9%-97.7%), respectively. Induction mortality was 2.7%. The most common severe adverse events were elevated transaminases in 41.0% of patients and infection in 13.7%. There were no cases of veno-occlusive disease.
CONCLUSIONS: The combination of ATO-ATRA and GO was curative in 94% of patients who had APL with a favorable safety profile (ClinicalTrials.gov identifier NCT01409161).

Keywords:  acute promyelocytic leukemia (APL); all‐trans retinoic acid (ATRA); arsenic trioxide (ATO); clinical trial; gemtuzumab ozogamicin (GO)

DOI:  https://doi.org/10.1002/cncr.35662
Nat Genet. 2024 Nov 25.

Single-cell multiomics analysis reveals dynamic clonal evolution and targetable phenotypes in acute myeloid leukemia with complex karyotype.

Aino-Maija Leppä, Karen Grimes, Hyobin Jeong, Frank Y Huang, Alvaro Andrades, Alexander Waclawiczek, Tobias Boch, Anna Jauch, Simon Renders, Patrick Stelmach, Carsten Müller-Tidow, Darja Karpova, Markus Sohn, Florian Grünschläger, Patrick Hasenfeld, Eva Benito Garagorri, Vera Thiel, Anna Dolnik, Bernardo Rodriguez-Martin, Lars Bullinger, Krzysztof Mrózek, Ann-Kathrin Eisfeld, Alwin Krämer, Ashley D Sanders, Jan O Korbel, Andreas Trumpp.

Chromosomal instability is a major driver of intratumoral heterogeneity (ITH), promoting tumor progression. In the present study, we combined structural variant discovery and nucleosome occupancy profiling with transcriptomic and immunophenotypic changes in single cells to study ITH in complex karyotype acute myeloid leukemia (CK-AML). We observed complex structural variant landscapes within individual cells of patients with CK-AML characterized by linear and circular breakage-fusion-bridge cycles and chromothripsis. We identified three clonal evolution patterns in diagnosis or salvage CK-AML (monoclonal, linear and branched polyclonal), with 75% harboring multiple subclones that frequently displayed ongoing karyotype remodeling. Using patient-derived xenografts, we demonstrated varied clonal evolution of leukemic stem cells (LSCs) and further dissected subclone-specific drug-response profiles to identify LSC-targeting therapies, including BCL-xL inhibition. In paired longitudinal patient samples, we further revealed genetic evolution and cell-type plasticity as mechanisms of disease progression. By dissecting dynamic genomic, phenotypic and functional complexity of CK-AML, our findings offer clinically relevant avenues for characterizing and targeting disease-driving LSCs.

DOI: https://doi.org/10.1038/s41588-024-01999-x
Biomed Pharmacother. 2024 Nov 26. pii: S0753-3322(24)01598-1. [Epub ahead of print]181 117712

Pacritinib prevents inflammation-driven myelofibrosis-like phenotype in a miR-146a-/- murine model.

Ernesto José Cuenca-Zamora, Constantino Martínez, María Luz Morales, Pedro Jesús Guijarro-Carrillo, María José López-Poveda, Carlos Alcolea-Guardiola, Natalia Vidal-Garrido, María Luisa Lozano, Rocío Gonzalez-Conejero, Raúl Teruel-Montoya, Francisca Ferrer-Marín.

  Chronic proinflammatory signaling is a characteristic trait in myeloproliferative neoplasms (MPN), particularly myelofibrosis (MF). Aberrant inflammatory signaling, particularly from NF-κB pathway, exacerbates the progression of MPN. Previously, we identified a critical role of miR-146a, a negative regulator of the TLR/NF-κB axis, in MF development. MPN patients carrying the miR-146a rs2431697-TT genotype, associated with lower miR-146a expression levels, have a higher risk of progression to overt-MF from chronic-phase disease. Using miR-146a-/- (KO) mice, a MF-like model lacking MPN driver mutations, we here investigate whether pacritinib, a dual JAK/NF-κB pathways inhibitor (via JAK2/IRAK1, respectively), prevents the age-associated myelofibrotic phenotype of these mice. Young miR-146a-/- mice were treated either with or without pacritinib, for 3 or 6 months. Notably, pacritinib prevented the splenomegaly, reticulin fibrosis and osteosclerosis observed in untreated KO mice. Pacritinib also avoided the myeloproliferation, loss of splenic architecture, and extramedullary hematopoiesis observed in age-matched untreated KO mice. Pharmacological targeting of IRAK1/JAK2 attenuated the pro-inflammatory environment, preventing the increase of inflammatory cytokines, particularly CXCL1 and TNF-α, without inducing cytopenias but rather the opposite. Compared to age-matched untreated KO mice, treated mice showed higher platelet counts irrespective of treatment duration, and higher erythrocyte counts with the longer treatment. Additionally, pacritinib preventive treatment reduced COL1A1 production in an in vitro model mimicking JAK2-driven fibrosis. These findings highlight that dual inhibition of JAK2/IRAK1 with pacritinib, by delaying or attenuating the myelofibrotic progression, could be a potential modifier of the natural course of MPN.

Keywords:  IRAK1; Inflammation; Myelofibrosis; Myeloproliferative neoplasms; Pacritinib; miR-146a

DOI:  https://doi.org/10.1016/j.biopha.2024.117712
Ann Hematol. 2024 Nov 26.

Central nervous system relapse after allogeneic HCT in FLT3-mutated AML.

Khouloud Kouidri, Fabian Acker, Rosa Toenges, Saskia Pfaff, Sarah Lindner, Julia Riemann, Marek Werth, Salem Ajib, Fabian Lang, Björn Steffen, Thomas Oellerich, Hubert Serve, Anjali Cremer, Gesine Bug.

  Central nervous system (CNS) relapse in acute myeloid leukemia (AML) is rare, but prognostically extremely unfavorable and associated with very high mortality rates. Aim of our single-center study was to define risk factors for CNS relapse in patients with FLT3-mutated AML after allogeneic hematopoietic cell transplantation (HCT) and to determine the impact of pre-emptive or salvage therapy with FLT3-inhibitors (FLT3i) on occurrence of CNS relapse and overall prognosis. We analyzed 39 FLT3-mutated AML patients who were treated with intensive induction therapy and consecutively underwent HCT at our institution. We observed that the remission status before HCT was strongly associated with relapse probability. Notably, FLT3-mutated AML showed a high propensity for CNS relapse with a cumulative incidence of 50% (95% confidence interval [CI], 16-77) at 2 years in non-responders pre-HCT compared to 0% in responders (cause-specific hazard ratio, 24.5, 95% CI, 2.9-206.2; p = 0.003). This was not abrogated by pre-emptive or salvage therapy with FLT3i in first relapse. Targeted therapies prior to transplant, use of intrathecal chemoprophylaxis or closer monitoring may be considered in patients with FLT3-mutated AML with active disease prior to HCT in order to prevent CNS relapse.

Keywords:  AML; CNS; FLT3; HCT; Real-World Data; Relapse; Retrospective

DOI:  https://doi.org/10.1007/s00277-024-06106-y
Eur J Haematol. 2024 Nov 27.

Evaluation of Gemtuzumab Ozogamicin and Anthracycline Dosing for Favorable Risk Acute Myeloid Leukemia.

Joseph F Mort, David Brighton, Samantha DiBenedetto, Leah Wells, Stephen M Clark, Justin Reid, Imari Patel, Clayton Jackson, Bradley Yelvington, Ryan Miller, Matthew Perciavalle, Katherine Walsh, Heather Wolfe, Susan C Locke, Joshua F Zeidner, Vu H Duong, Daniel R Reed, Bhagirathbhai Dholaria, Thomas W LeBlanc, Michael Keng, Bethany Horton, Firas El Chaer.

  Gemtuzumab ozogamicin (GO) is a CD33-targeting antibody-drug conjugate approved for the treatment of CD33-positive de novo and relapsed and refractory acute myeloid leukemia (AML). Subset analyses have demonstrated improved clinical outcomes in patients with favorable-risk disease. It is unclear whether the addition of GO to cytarabine and anthracycline chemotherapy (7+3) improves clinical outcomes compared with other conventional regimens for AML. We evaluated the real-world experience with GO added to 7+3 chemotherapy for patients with favorable risk AML. This retrospective analysis included 174 patients with de novo favorable risk AML undergoing induction chemotherapy between 2010 and 2020. The primary outcome was overall survival (OS) and secondary outcomes included rates of remission, measurable residual disease (MRD), and toxicity. Eighteen patients received GO, 37 received a high-dose (HD) anthracycline, and 119 received an intermediate-dose anthracycline. Composite complete remission was achieved in 162 patients (93.1%). Among the 54 patients who were assessed for MRD at remission, 66.7% were undetectable. An improvement in OS was seen for patients who received GO and those treated with HD anthracycline, which was better explained by differences in patient performance status and comorbidities. Patients who received GO did not show increased toxicity.

Keywords:  anthracycline; favorable risk acute myeloid leukemia; gemtuzumab ozogamicin; overall survival; relapse‐free survival

DOI:  https://doi.org/10.1111/ejh.14354
Br J Haematol. 2024 Nov 26.

Genocopy of EVI1-AML with paraneoplastic diabetes insipidus: PRDM16 overexpression by t(1;2)(p36;p21) and enhancer hijacking.

Julian List, Etienne Sollier, Fiona Brown-Burke, Katherine Kelly, Dietmar Pfeifer, Valeria Shlyakhto, Kristina Maas-Bauer, Milena Pantic, Christoph Plass, Michael Lübbert.

  Diabetes insipidus (DI) in patients with acute myeloid leukaemia (AML) and chromosome 3q alterations (EVI1/PRDM3/MECOM overexpression) constitutes a poorly understood paraneoplasia. A 44-year-old patient presented with clinical and morphological features of this syndrome but, surprisingly, disclosed the rare translocation t(1;2)(p36;p21), with massive PRDM16 overexpression. WGS and RNA sequencing suggest enhancer hijacking of the ZFP36L2 enhancer region as underlying mechanism. Methylome alterations were similar to those in EVI1/PRDM3/MECOM AML, indicating converging pathways. The patient was successfully allografted, she is in complete remission 14 months later. We conclude that t(1;2)(p36;p21), with massive PRDM16 overexpression, can result in a faithful genocopy of EVI1/PRDM3/MECOM AML, including DI.

Keywords:  AML; genes rearrangement; malignant haematology

DOI:  https://doi.org/10.1111/bjh.19922
Nat Commun. 2024 Nov 26. 15(1): 10268

Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life.

Jesse Kreger, Jazlyn A Mooney, Darryl Shibata, Adam L MacLean.

Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared prenatal circulation of monozygotic twins, that weak selection conferred by stem cell variation created before birth can reliably yield clonal hematopoiesis later in life. Theory indicates weak selection will lead to dominance given enough time and large enough population sizes. Human hematopoiesis satisfies both these conditions. Stochastic loss of weakly selected variants is naturally prevented by the expansion of stem cell lineages during development. The dominance of stem cell clones created before birth is supported by blood fluctuating CpG methylation patterns that exhibit low correlation between unrelated individuals but are highly correlated between many elderly monozygotic twins. Therefore, clonal hematopoiesis driven by weak selection in later life appears to reflect variation created before birth.

DOI: https://doi.org/10.1038/s41467-024-54711-2
Br J Haematol. 2024 Nov 27.

When, which and how to switch: Navigating JAK inhibitors in myelofibrosis.

Jennifer O'Sullivan, Imran Omerdeen, Bethan Psaila.

  Navigating choice of JAK inhibitor (JAKi) therapy for patients with myelofibrosis who are JAKi-naïve and for those who have previously been treated with a JAKi.

Keywords:  clinical haematology; megakaryocytes; myelofibrosis; myeloproliferative disorder; therapy

DOI:  https://doi.org/10.1111/bjh.19929
Semin Hematol. 2024 Nov 22. pii: S0037-1963(24)00130-6. [Epub ahead of print]

Implications for metabolic disturbances in myelodysplastic syndromes.

Kathy L McGraw, Daniel R Larson.

  The Myelodysplastic Syndromes (MDS) are heterogeneous stem cell malignancies clinically characterized by bone marrow dysplasia, peripheral blood cytopenias, and a high risk for transformation to acute myeloid leukemia. In early stages of disease, differentiation defects and maturation blocks result in deficient hematopoiesis. In higher risk disease, unrestricted proliferation of immature blast cells leads to leukemogenesis. Disease pathogenesis can be attributed to many factors including chronic inflammation that is driven in part by commonly found somatic gene mutations (SGM) fostering expansion of malignant clones while suppressing normal hematopoiesis. Cellular metabolism that both directly and indirectly regulates hematopoietic stem cell (HSC) fate, is intimately connected to the immune system, is altered by MDS somatic gene mutations and is likely is a major contributor to disease pathophysiology. Despite this likely role in pathobiology, there is an underwhelming depth of literature on the subject and the precise metabolic dysregulations in these myeloid malignancies have yet to be fully delineated. In this review, we will provide a general overview of several major metabolic processes and how each directs HSC fate, provide a summary of metabolic studies in MDS, discuss how common SGM and inflammation influence metabolic pathways to drive bone marrow failure, and end with a discussion of standards of care and how these should be carefully considered in the context of metabolic dysregulation.

Keywords:  Glycolysis; Inflammation; Metabolism; Mitochondria; Somatic Gene Mutation

DOI:  https://doi.org/10.1053/j.seminhematol.2024.11.004
J Clin Med. 2024 Nov 19. pii: 6957. [Epub ahead of print]13(22):

Myeloproliferative Neoplasms: Challenging Dogma.

Jerry L Spivak.

  Myeloproliferative neoplasms, polycythemia vera, essential thrombocytosis, and primary myelofibrosis are a unique group of clonal hematopoietic stem cell neoplasms that share somatic, gain-in-function driver mutations in JAK2, CALR, and MPL. As a consequence, these disorders exhibit similar phenotypic features, the most common of which are the ceaseless production of normal erythrocytes, myeloid cells, platelets alone or in combination, extramedullary hematopoiesis, myelofibrosis, and a potential for leukemic transformation. In the case of polycythemia vera and essential thrombocytosis, however, prolonged survival is possible. With an incidence value in the range of 0.5-2.0/100,000, myeloproliferative neoplasms are rare disorders, but they are not new disorders, and after a century of scrutiny, their clinical features and natural histories are well-defined, though their individual management continues to be controversial. With respect to polycythemia vera, there has been a long-standing dispute between those who believe that the suppression of red blood cell production by chemotherapy is superior to phlebotomy to prevent thrombosis, and those who do not. With respect to essential thrombocytosis, there is a similar dispute about the role of platelets in veinous thrombosis, and the role of chemotherapy in preventing thrombosis by suppressing platelet production. Linked to these disputes is another: whether therapy with hydroxyurea promotes acute leukemia in disorders with a substantial possibility of longevity. The 21st century revealed new insights into myeloproliferative neoplasms with the discovery of their three somatic, gain-of-function driver mutations. Almost immediately, this triggered changes in the diagnostic criteria for myeloproliferative neoplasms and their therapy. Most of these changes, however, conflicted with prior well-validated, phenotypically driven diagnostic criteria and the management of these disorders. The aim of this review is to examine these conflicts and demonstrate how genomic discoveries in myeloproliferative neoplasms can be used to effectively complement the known phenotypic features of these disorders for their diagnosis and management.

Keywords:  ARCH; CHIP; MPN driver mutations; acute leukemia; blood volume; diagnostic criteria; hematopoietic stem cells; hydroxyurea; myelofibrosis; natural history; phlebotomy

DOI:  https://doi.org/10.3390/jcm13226957
Clin Lymphoma Myeloma Leuk. 2024 Nov 07. pii: S2152-2650(24)02403-0. [Epub ahead of print]

Successful Treatment-Free Remission After Ponatinib Discontinuation in Pretreated Patients with Chronic Myeloid Leukemia in Chronic Phase.

Fadi G Haddad, Koji Sasaki, Jayastu Senapati, Shimin Hu, Sara Dellasala, Ghayas C Issa, Elias Jabbour, Hagop Kantarjian.

   INTRODUCTION: The discontinuation of third-generation BCR::ABL1 tyrosine kinase inhibitors (TKIs) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is not well understood. We aim to evaluate treatment-free remission in patients with CML-CP who discontinue ponatinib.
METHODS: We retrospectively reviewed 361 patients who attempted TKI discontinuation between November 2005 and February 2024 and identified those receiving ponatinib at the time of discontinuation. Molecular relapse-free survival (MRFS) was calculated from the time of ponatinib discontinuation to the date of loss of major molecular response (MMR) or last follow-up.
RESULTS: Eleven patients discontinued ponatinib. Before ponatinib discontinuation, patients were on TKI therapy for a median of 146.6 months and on ponatinib for a median of 67.5 months. The median number of TKIs prior to starting ponatinib was 2 (range, 1-3). The median durations of sustained MR4 and MR4.5 before ponatinib discontinuation were 32.8 and 29.4 months, respectively. After a median follow-up of 60.3 months, the 60-month MRFS rate was 53%. Five patients lost MMR; their median MR4.5 duration was 5 months before ponatinib discontinuation.
CONCLUSION: Ponatinib discontinuation is feasible in patients with CML-CP failing prior TKIs. Patients who achieve sustained MR4.5 for at least 2 years have the highest likelihood of remaining in treatment-free remission following ponatinib discontinuation.

Keywords:  Cessation; Intolerance; Resistance; TFR; Tyrosine kinase inhibitor

DOI:  https://doi.org/10.1016/j.clml.2024.11.003
Br J Haematol. 2024 Nov 24.

Preclinical activity of resazurin in acute myeloid leukaemia.

Trung Quang Ha, Vibeke Andresen, Bjarte Skoe Erikstein, Mihaela Popa, Stein-Erik Gullaksen, Håkon Reikvam, Emmet McCormack, Bjørn Tore Gjertsen.

  Resazurin, a phenoxazine used in cell viability assays, acts in vitro as an anti-leukaemic compound through the production of cellular reactive oxygen species (ROS) resulting in mitochondrial dysfunction and cell death. However, the in vivo tolerance and efficacy of resazurin in cancer are unknown. In this study, we investigated the in vitro and in vivo effects of resazurin in acute myeloid leukaemia (AML). Resazurininduced cell death in a dose-dependent manner in AML cell lines and reduced proliferation and colony formation in ex vivo treated patient-derived AML cells. Cells treated with a reduced dose of resazurin for 72 h acquired a more mature immunophenotype suggesting cell differentiation as a mechanism contributing to the anti-leukaemic effect. In vivo optical imaging in healthy mice demonstrated a reduction of resazurin to resorufin within 30 min and non-detectable after 2 h, supporting dosing twice daily as optimal. In subcutaneous and orthotopic models of MV4-11 AML in NOD/SCID IL2rγnull mice, anti-tumour effects and an increased survival were found at a dose level of 75 mg/kg twice daily without observed toxicity. Our results suggest that resazurin represents a novel experimental therapeutic for the treatment of AML.

Keywords:  AML; optical imaging; preclinical; resazurin; therapy

DOI:  https://doi.org/10.1111/bjh.19872
Leuk Lymphoma. 2024 Nov 28. 1-9

Oral azacitidine maintenance after intensive chemotherapy versus venetoclax and azacitidine: real world outcomes in newly diagnosed acute myeloid leukemia.

Alice Mims, Zhuoer Xie, Ravi Potluri, David Rotter, Manoj Chevli, Thomas Prebet, Lona Gaugler, Maria Strocchia, Alberto Vasconcelos, Jan Sieluk.

  Oral azacitidine (Oral-AZA) is recommended as maintenance therapy for patients with newly diagnosed acute myeloid leukemia (ND AML) achieving remission with intensive chemotherapy (IC) but not transplant candidates; venetoclax plus injectable azacitidine (VEN-AZA) is recommended for patients ineligible for IC. Some patients may be considered candidates for either regimen. This retrospective study used Flatiron Health's database to compare treatment patterns and clinical outcomes with Oral-AZA maintenance after IC (IC🡪Oral-AZA) versus frontline VEN-AZA. Relapse-free survival (RFS) and overall survival (OS) were analyzed at 4 different time points, including from Oral-AZA initiation (IC🡪Oral-AZA cohort) or from remission (VEN-AZA cohort) in the Core Analysis. Median RFS was 14.9 and 8.1 months for IC🡪Oral-AZA and VEN-AZA propensity score-matched cohorts, in the Core Analysis (n = 32 in each; p = 0.027); median OS was 18.7 and 15.2 months (p = 0.034). In patients with AML, IC🡪Oral-AZA significantly improved RFS and OS compared with VEN-AZA.

Keywords:  Acute myeloid leukemia; health outcomes research; oral azacitidine; real-world evidence

DOI:  https://doi.org/10.1080/10428194.2024.2425792
Br J Haematol. 2024 Nov 26.

Salvage monotherapy with venetoclax after failure from a single course of standard induction chemotherapy for acute myeloid leukaemia.

Pierre-Yves Sansen, Carlos Graux, Anne Sonet, Marc André, Chantal Doyen, Elodie Collinge, Hélène Vellemans, Wivine Bernard, Gilles Crochet, Julien Devreux, Julien Depaus, Bérangère Devalet, Florence Desquesnes, Marie Pouplard, François Dachy.

DOI: https://doi.org/10.1111/bjh.19906
Diagnostics (Basel). 2024 Nov 14. pii: 2560. [Epub ahead of print]14(22):

Decoding Acute Myeloid Leukemia: A Clinician's Guide to Functional Profiling.

Prasad Iyer, Shaista Shabbir Jasdanwala, Yuhan Wang, Karanpreet Bhatia, Shruti Bhatt.

  Acute myeloid leukemia (AML) is a complex clonal disorder characterized by clinical, genetic, metabolomic, and epigenetic heterogeneity resulting in the uncontrolled proliferation of aberrant blood-forming precursor cells. Despite advancements in the understanding of the genetic, metabolic, and epigenetic landscape of AML, it remains a significant therapeutic challenge. Functional profiling techniques, such as BH3 profiling (BP), gene expression profiling (GEP), proteomics, metabolomics, drug sensitivity/resistance testing (DSRT), CRISPR/Cas9, and RNAi screens offer valuable insights into the functional behavior of leukemia cells. BP evaluates the mitochondrial response to pro-apoptotic BH3 peptides, determining a cell's apoptotic threshold and its reliance on specific anti-apoptotic proteins. This knowledge can pinpoint vulnerabilities in the mitochondria-mediated apoptotic pathway in leukemia cells, potentially informing treatment strategies and predicting therapeutic responses. GEP, particularly RNA sequencing, evaluates the transcriptomic landscape and identifies gene expression alterations specific to AML subtypes. Proteomics and metabolomics, utilizing mass spectrometry and nuclear magnetic resonance (NMR), provide a detailed view of the active proteins and metabolic pathways in leukemia cells. DSRT involves exposing leukemia cells to a panel of chemotherapeutic and targeted agents to assess their sensitivity or resistance profiles and potentially guide personalized treatment strategies. CRISPR/Cas9 and RNAi screens enable systematic disruption of genes to ascertain their roles in leukemia cell survival and proliferation. These techniques facilitate precise disease subtyping, uncover novel biomarkers and therapeutic targets, and provide a deeper understanding of drug-resistance mechanisms. Recent studies utilizing functional profiling have identified specific mutations and gene signatures associated with aggressive AML subtypes, aberrant signaling pathways, and potential opportunities for drug repurposing. The integration of multi-omics approaches, advances in single-cell sequencing, and artificial intelligence is expected to refine the precision of functional profiling and ultimately improve patient outcomes in AML. This review highlights the diverse landscape of functional profiling methods and emphasizes their respective advantages and limitations. It highlights select successes in how these methods have further advanced our understanding of AML biology, identifies druggable targets that have improved outcomes, delineates challenges associated with these techniques, and provides a prospective view of the future where these techniques are likely to be increasingly incorporated into the routine care of patients with AML.

Keywords:  BH3 profiling; acute myeloid leukemia; drug sensitivity/resistance testing; functional profiling; gene expression profiling; metabolomics; proteomics

DOI:  https://doi.org/10.3390/diagnostics14222560
Res Sq. 2024 Nov 15. pii: rs.3.rs-5220097. [Epub ahead of print]

Relationship Between Age, Conditioning Intensity, and Outcome After Allografting in Adults Age ≥60 Years with AML.

Phuong Vo, Brenda Sandmaier, Megan Othus, Naveed Ali, Eduardo Rodríguez-Arbolí, Corentin Orvain, Chris Davis, Ryan Basom, Rainer Storb, Roland Walter.

Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥ 70 (n = 122) who underwent allogeneic HCT for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥ 70 years had a higher risk of non-relapse mortality (NRM) than those aged ≥ 60-64 ( P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter ( P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Age ≥ 70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no association was found with nonmyeloablative conditioning. Conversely, patients aged 60-64 and 65-69, not those aged ≥ 70, had a significantly lower risk of relapse with RIC, but NRM risk increased with age. Our findings support allogeneic HCT for adults with AML in remission even if aged beyond 70, especially with nonmyeloablative conditioning.

DOI: https://doi.org/10.21203/rs.3.rs-5220097/v1
bioRxiv. 2024 Nov 18. pii: 2024.11.18.624191. [Epub ahead of print]

Cancer-associated SF3B1 mutation K700E causes widespread changes in U2/branchpoint recognition without altering splicing.

Andrey Damianov, Chia-Ho Lin, Jian Zhang, James L Manley, Douglas L Black.

Myelodysplastic syndromes and other cancers are often associated with mutations in the U2 snRNP protein SF3B1. Common SF3B1 mutations, including K700E, disrupt SF3B1 interaction with the protein SUGP1 and induce aberrant activation of cryptic 3' splice sites (ss), presumably resulting from aberrant U2/branch site (BS) recognition by the mutant spliceosome. Here, we apply the new method of U2 IP-seq to profile BS binding across the transcriptome of K562 leukemia cells carrying the SF3B1 K700E mutation. For cryptic 3' ss activated by K700E, we identify their associated BSs and show that they are indeed shifted from the WT sites. Unexpectedly, we also identify thousands of additional changes in BS binding in the mutant cells that do not alter 3' ss choice. These new BS are usually very close to the natural sites, occur upstream or downstream, and either exhibit stronger base-pairing potential with U2 snRNA or are adjacent to stronger polypyrimidine tracts than the WT sites. The widespread imprecision in BS recognition induced by K700E with limited changes in 3' ss selection supports a positive role for SUGP1 in early BS choice and expands the physiological consequences of this oncogenic mutation.

DOI: https://doi.org/10.1101/2024.11.18.624191
Leuk Res. 2024 Nov 17. pii: S0145-2126(24)00190-5. [Epub ahead of print]148 107624

Real-world impact of luspatercept on red blood cell transfusions among patients with myelodysplastic syndromes: A United States healthcare claims database study.

Leslie A Andritsos, Ali McBride, Derek Tang, Victoria Barghout, Enrico Zanardo, Rui Song, Lynn Huynh, Mihran Yenikomshian, Adeola Y Makinde, Christina Hughes, Kirollos S Hanna, Kashyap Patel.

  Myelodysplastic syndromes (MDS) are associated with anemia and the need for blood transfusions. In clinical trials, luspatercept reduced transfusion dependency among patients with lower-risk MDS. This United States (US) study describes real-world clinical outcomes pre- and post-luspatercept initiation among patients with MDS. Symphony Health Integrated Dataverse claims data (August 1, 2010-December 29, 2022) were used to identify patients with MDS treated with luspatercept (first luspatercept claim = index date). Transfusion-dependent (TD) or non-TD (NTD) patients at baseline were described as 8-week transfusion-independent (TI) or as maintaining NTD, respectively, if they had no transfusion for 8 weeks in the 6 months post-index (similarly for 12, 16, and 24 weeks). Transfusion status was measured overall and among patients who were baseline NTD, TD, TD and exposed to erythropoiesis-stimulating agents (ESA) (TD+ESA-exposed), MDS with ring sideroblasts (RS) (MDS-RS), and MDS-non-RS. MDS-related treatments were measured pre- and post-index. Among the 871 patients who received luspatercept (mean age: 74.7 years), 87.4 % achieved 8-week TI/maintained NTD within 6 months post-index, 64.9 % of patients did not receive additional MDS-related treatments post-luspatercept initiation (median follow-up: 14.8 months), 98.5 % of baseline NTD patients maintained 8-week NTD 6 months post-luspatercept initiation, and 88.6 % did not receive a transfusion for 24 weeks. Baseline TD (64.2 %) and TD+ESA-exposed (64.2 %) patients achieved 8-week TI 6 months post-luspatercept initiation. Eight-week TI proportions were similar between MDS-RS (89.8 %) and MDS-non-RS (84.8 %) subgroups. These findings corroborate clinical trial data by showing the high effectiveness of luspatercept among real-world patients with MDS in the US.

Keywords:  Lower-risk myelodysplastic syndromes; Real-world clinical outcomes; Red blood cell transfusions; Transfusion dependence

DOI:  https://doi.org/10.1016/j.leukres.2024.107624
Leukemia. 2024 Nov 28.

Spatial transcriptomic approaches for characterising the bone marrow landscape: pitfalls and potential.

Rosalin A Cooper, Emily Thomas, Anna M Sozanska, Carlo Pescia, Daniel J Royston.

DOI: https://doi.org/10.1038/s41375-024-02480-8
Leuk Lymphoma. 2024 Nov 29. 1-10

Molecular landscape and clinical outcome of SRSF2/TET2 Co-mutated myeloid neoplasms.

Samuel G Cockey, Hailing Zhang, Mohammed Hussaini, Ling Zhang, Lynn Moscinski, Ethan Yang, Julie Li, Le Wang, Jinming Song.

  The mutations in SRSF2 and TET2 genes are frequently present in various myeloid neoplasms. The potential impact of SRSF2/TET2 co-mutations on patient survival is incompletely understood. We identified 412 patients with SRSF2/TET2 co-mutations from our NextGen sequencing database of around 8000 patients and reported likely the largest cohort study. Our study demonstrated the presence of these co-mutations in a spectrum of myeloid neoplasms, which show different genetic and molecular characteristics. Most of the patients with these co-mutations had normal karyotype. Interestingly, our study provided insights into the prevalence of additional mutations such as ASXL1, RUNX1, and KRAS with this co-mutation and their potential impact on patients' prognosis. We found that ASXL1, RUNX1, and KRAS can negatively impact these patients' survival with different impacts in different morphological diagnosis categories, suggesting a complex interaction between these genes. This study underscores the need for personalized approaches in the treatment of myeloid neoplasms.

Keywords:  Myelodysplastic syndrome; chronic myelomonocytic leukemia; myeloproliferative neoplasm

DOI:  https://doi.org/10.1080/10428194.2024.2432581