bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–07–13
twenty-six papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.
  2. Landscape and clinicopathologic features of RAS pathway mutations in chronic myelomonocytic leukemia.
  3. The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia.
  4. ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications.
  5. CSF3R mutations and variants in myeloid neoplasms: associated phenotypes, co-mutations, and survival trends.
  6. Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.
  7. VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML.
  8. An isoform-specific RUNX1C-BTG2 axis governs AML quiescence and chemoresistance.
  9. Real-world validation study of the LSC17 score for risk prediction in patients with newly diagnosed acute myeloid leukemia.
  10. Tumor-Infiltrating Clonal Hematopoiesis. Reply.
  11. Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations.
  12. The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.
  13. EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.
  14. The hallmarks of hematopoietic stem cell transplantation for pediatric acute myeloid leukemia.
  15. Thrombocytopenia in myelofibrosis is characterized by inflammatory megakaryocytes with reduced G6B expression.
  16. Secondary malignancies after chronic myeloid leukaemia upon TKI treatment: Population trends and outcomes.
  17. SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.
  18. Impact of Cytogenetic Response to Therapy on Long-Term Survival in Acute Myeloid Leukemia.
  19. Tumor-Infiltrating Clonal Hematopoiesis.
  20. Venetoclax plus azacitidine as genetic-driven bridge-to-transplant therapy for IDH2-mutated acute myeloid leukaemia (AML) refractory to intensive chemotherapy: proof-of-concept case reports.
  21. The critical role of DNA damage-inducible transcript 4 (DDIT4) in stemness character of leukemia cells and leukemia initiation.
  22. HDAC3-YY1-RAB5A axis remodels AML-supportive niche by modulating mitochondrial homeostasis in bone marrow stromal cells.
  23. Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.
  24. Clonal hematopoiesis and risk of non-myeloid subsequent malignant neoplasms after autologous hematopoietic cell transplantation.
  25. Loss of DCAF8 impairs hematopoietic stem cell function with cellular senescence via the DOCK11-CDC42 axis.
  26. Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion.
  1. Nat Commun. 2025 Jul 08. 16(1): 6270
    JAK2 inhibition mediates clonal selection of RAS pathway mutations in myeloproliferative neoplasms.
    Nabih Maslah, Nina Kaci, Blandine Roux, Gabriela Alexe, Raphael Marie, Hélène Pasquer, Emmanuelle Verger, Rafael Daltro De Oliveira, Cécile Culeux, Bochra Mlayah, Nicolas Gauthier, Fanny Gonzales, Lin-Pierre Zhao, Saravanan Ganesan, Panhong Gou, Frank Ling, Juliette Soret-Dulphy, Nathalie Parquet, William Vainchenker, Emmanuel Raffoux, Rose Ann Padua, Stéphane Giraudier, Caroline Marty, Isabelle Plo, Camille Lobry, Kimberly Stegmaier, Alexandre Puissant, Jean-Jacques Kiladjian, Bruno Cassinat, Lina Benajiba.
      JAK (Janus Kinase) inhibitors, such as ruxolitinib, were introduced a decade ago for treatment of myeloproliferative neoplasms (MPN). To evaluate ruxolitinib's impact on MPN clonal evolution, we interrogate a myelofibrosis patient cohort with longitudinal molecular evaluation and discover that ruxolitinib is associated with clonal outgrowth of RAS pathway mutations. Single-cell DNA sequencing combined with ex vivo treatment of RAS mutated CD34+ primary patient cells, demonstrates that ruxolitinib induces RAS clonal selection both in a JAK/STAT wild-type and hyper-activated context. RAS mutations are associated with decreased transformation-free and overall survival only in patients treated with ruxolitinib. In vitro and in vivo competition assays demonstrate increased cellular fitness of RAS-mutated cells under ruxolitinib or JAK2 knock-down, consistent with an on-target effect. MAPK pathway activation is associated with JAK2 downregulation resulting in enhanced oncogenic potential of RAS mutations. Our results prompt screening for pre-existing RAS mutations in JAK inhibitor treated patients with MPN.
    DOI:  https://doi.org/10.1038/s41467-025-60884-1
  2. Blood Adv. 2025 Jul 11. pii: bloodadvances.2025016529. [Epub ahead of print]
    Landscape and clinicopathologic features of RAS pathway mutations in chronic myelomonocytic leukemia.
    Guillermo Montalban-Bravo, Sanam Loghavi, Ziyi Li, Kelly Sharon Chien, Rashmi Kanagal-Shamanna, Alex Bataller, Anuya Natu, Mark Gurney, Alexandre Bazinet, Danielle Hammond, Koji Sasaki, Gautam Borthakur, Mahesh Swaminathan, Courtney D DiNardo, Tapan M Kadia, Farhad Ravandi, Naval G Daver, Nicholas J Short, Naveen Pemmaraju, Ghayas C Issa, Terra L Lasho, Christy M Finke, Aref Al-Kali, Clifford M Csizmar, Hassan B Alkhateeb, Naseema Gangat, Abhishek A Mangaonkar, Carlos E Bueso-Ramos, Ayalew Tefferi, Hagop M Kantarjian, Guillermo Garcia-Manero, Mrinal M Patnaik.
      RAS pathway mutations (RASMT) induce proliferative features and promote transformation in chronic myelomonocytic leukemia (CMML). However, the unique clonal landscape and hierarchy of distinct RASMT remain unexplored. To characterize the landscape, architecture and implications of unique RASMT in CMML we evaluated a cohort of 814 patients with CMML. We identified 461 RASMT among 342 (42%) patients. N/KRAS and CBL mutations were the most common, frequently involved the P-loop or RING domains, respectively, and frequently appeared as dominant events (63% and 65%, respectively). BRAF, NF1 and PTPN11 mutations spanned throughout the gene structure and frequently appeared as subclonal events (75%, 64%, 59%, respectively). CBL mutations frequently occurred in co-dominance with SRSF2 and multihit TET2 and were enriched for KIT mutations. PTPN11 mutations more frequently co-occurred with SETBP1 and DNMT3A mutations and where infrequently co-dominant with TET2 or ASXL1. RASMT predicted for shorter overall-survival (HR 1.55, 95% CI 1.15-2.07, p=0.0075) and leukemia-free survival (LFS, HR 1.67, 95% CI 1.26-2.20, p=0.0011), influenced outcomes of myelodysplastic and TET2 mutant CMML and cooperated with IDH2 and RUNX1 mutations to induce shorter LFS. This data sets the bases for refined genomic classifications of CMML and underscores the need to develop RAS-directed therapies for patients with CMML.
    DOI:  https://doi.org/10.1182/bloodadvances.2025016529
  3. Haematologica. 2025 Jul 10.
    The small GTPase ARF6 regulates sphingolipid homeostasis and supports proliferation in acute myeloid leukemia.
    Helong Gary Zhao, Nataly Cruz-Rodriguez, Kent C Johnson, Anthony D Pomicter, Briana Bates, Benjamin Bateman, Torsten Haferlach, Tongjun Gu, Jonathan Ahmann, Dongqing Yan, Greg S Lee, Weiquan Zhu, Jenna Bishop, Shannon J Odelberg, Michael W Deininger.
      Metabolic dependencies are emerging as promising therapy targets in cancer, including acute myeloid leukemia (AML). Several metabolic vulnerabilities have been identified in AML cells, including a requirement for balanced sphingolipid metabolism to maintain survival and proliferation. Here we describe a novel function of the RAS superfamily small GTPase ARF6 in maintaining sphingolipid homeostasis in AML. Genetic depletion of ARF6 inhibited the proliferation of AML cell lines and reduced colony formation of primary AML CD34+ cells. Mechanistically, ARF6 promotes conversion of ceramide to sphingomyelin by enhancing sphingomyelin synthase (SGMS1/2) expression, thereby preventing accumulation of cytotoxic ceramide levels. Accordingly, higher expression of ARF6 and its effectors SGMS1/2 in AML patient cells correlates with shorter survival in two independent AML cohorts, with ARF6 exhibiting an adverse prognostic effect independent of European Leukemia Net genetic risk. Small molecule inhibitors of ARF6 suppressed colony formation by primary AML CD34+ cells, but not cord blood CD34+ cells and showed activity in xenograft models. The dependency of AML cells on ARF6 to regulate sphingolipid homeostasis may present a therapeutic opportunity.
    DOI:  https://doi.org/10.3324/haematol.2024.286228
  4. Leukemia. 2025 Jul 10.
    ADH5/ALDH2 dehydrogenases and DNA polymerase theta protect normal and malignant hematopoietic cells from formaldehyde challenge: therapeutic implications.
    Jessica Atkins, Anna-Mariya Kukuyan, Monika Toma, Malgorzata Drzewiecka, Umeshkumar Vekariya, Adam Karami, Margaret Nieborowska-Skorska, Reza Nejati, Emir Hadzijusufovic, Peter Valent, Tomasz Stoklosa, Tomasz Sliwinski, Mariusz Wasik, Tomasz Skorski.
      Normal hematopoietic stem and progenitor cells (HSPCs) are exposed to physiological levels of formaldehyde but occasionally may be challenged by high levels of formaldehyde generated by endogenous and exogenous sources. In addition, leukemia cells stressed by oncogenic mutations continuously produce excessive amounts of formaldehyde. Here, we show that DNA polymerase theta (Polθ) cooperates with alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (ALDH2) to protect healthy and malignant HSPCs challenged by formaldehyde. ADH5 and ALDH2 metabolize formaldehyde while Polθ-mediated DNA repair by microhomology-dependent end-joining (TMEJ) protects cells from the lethal effect of DNA double strand breaks resulting from formaldehyde-mediated DNA-protein crosslinks. Genetic or pharmacological targeting of ADH5 or ALDH2 enhanced the effect of Polθ inhibitors in leukemic cells. Thus, ADH5/ALDH2 cooperate with Polθ to protect normal HSPCs sporadically challenged by high levels of formaldehyde, and inhibition of Polθ and ADH5 or ALDH2 may exert an anti-leukemic effect.
    DOI:  https://doi.org/10.1038/s41375-025-02687-3
  5. Haematologica. 2025 Jul 10.
    CSF3R mutations and variants in myeloid neoplasms: associated phenotypes, co-mutations, and survival trends.
    Abiola Bolarinwa, Natasha Szuber, Rong He, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi.
      Not available.
    DOI:  https://doi.org/10.3324/haematol.2025.288026
  6. Leukemia. 2025 Jul 09.
    Chemoresistance of TP53 mutant acute myeloid leukemia requires the mevalonate byproduct, geranylgeranyl pyrophosphate, for induction of an adaptive stress response.
    Sarah J Skuli, A'ishah Bakayoko, Marisa Kruidenier, Bryan Manning, Paige Pammer, Akmal Salimov, Owen Riley, Gisela Brake-Sillá, Derrick Dopkin, Michael Bowman, Leslie N Martinez-Gutierrez, Colin C Anderson, Julie A Reisz, Roberta Buono, Madhuri Paul, Estelle Saland, Francesca Liccardo, Ann DeVine, Sarah Wong, Jimmy P Xu, Eva Nee, Ryan Hausler, Steffen Boettcher, Said M Sebti, Catherine Lai, Kara N Maxwell, Jean-Emmanuel Sarry, David A Fruman, Angelo D'Alessandro, Clementina Mesaros, Brian Keith, M Celeste Simon, Pamela J Sung, Gerald Wertheim, Nicolas Skuli, Robert L Bowman, Andrew Matthews, Martin Carroll.
      Acute myeloid leukemia with mutations in TP53 (TP53mut AML) is fatal with a median survival of 6 months. RNA sequencing on purified AML patient samples showed that TP53mut AML had higher expression of mevalonate pathway genes. Using novel, isogenic TP53mut AML cell lines and primary samples, we determined that TP53mut AML resistance to AML chemotherapy cytarabine (AraC) correlated with increased mevalonate pathway activity, a lower induction of reactive oxygen species (ROS), and a mitochondrial response with increased mitochondrial mass and oxidative phosphorylation. Pretreatment with the statin class of mevalonate pathway inhibitors reversed these effects and chemosensitized TP53mut AML. The geranylgeranyl pyrophosphate (GGPP) branch of the mevalonate pathway was required for TP53mut AML chemoresistance. In addition to its role in mitochondria biogenesis, we identified a novel function of GGPP in regulating glutathione for management of AraC-induced ROS. However, statins alone were inadequate to fully reverse chemoresistance in vivo and in a retrospective study of 364 TP53mut AML patients who received chemotherapy concurrently with a statin. Finally, we identified clinical settings and strategies to successfully target the mevalonate pathway, particularly to address the unmet need of TP53mut AML.
    DOI:  https://doi.org/10.1038/s41375-025-02668-6
  7. Ann Hematol. 2025 Jul 09.
    VINCENT: A randomized-controlled trial evaluating venetoclax plus azacitidine versus intensive chemotherapy in patients with newly diagnosed, NPM1-mutated AML.
    Lydia Kretschmer, Leo Ruhnke, Christoph Schliemann, Lars Fransecky, Björn Steffen, Martin Kaufmann, Andreas Burchert, Christoph Schmid, Maher Hanoun, Tim Sauer, Klaus H Metzeler, Kerstin Schäfer-Eckart, Mathias Hänel, Martina Crysandt, Paul Jäger, Stefan W Krause, Christine Dierks, Stefan Klein, Nadia Maguire, Lukas P Frenzel, Veit L Bücklein, Wolfgang Blau, Ulrich Kaiser, Kai Wegehenkel, Alexander Höllein, Ruth Seggewiss-Bernhardt, Wenke Markgraf, Frank Fiebig, Anna Harig, Katharina Schmidt-Brücken, Christian Thiede, Jan Moritz Middeke, Richard Dillon, Claudia D Baldus, Hubert Serve, Karsten Spiekermann, Wolfgang Hiddemann, Richard F Schlenk, Carsten Müller-Tidow, Martin Bornhäuser, Christoph Röllig.
      For younger, medically fit patients with NPM1-mutated, FLT3-wildtype acute myeloid leukemia (AML) intensive chemotherapy represents standard of care (SOC), with complete remission (CR) rates observed in up to 85% of patients and 5-year overall survival (OS) rates of 40-50%. However, significant toxicity and need for hospitalization pose challenges on patients' outcome and quality of life (QoL). Venetoclax (VEN) combined with azacitidine (AZA) has demonstrated encouraging efficacy in older, unfit AML patients, achieving high CR/CRi rates and promising OS with lower toxicity. Prospective, randomized data comparing VEN/AZA to SOC in younger, fit patients are currently missing. VINCENT is a randomized-controlled, multicenter, non-inferiority, phase 2 trial (NCT05904106) evaluating VEN/AZA versus SOC in adults aged 18-70 years with newly diagnosed, NPM1-mutated, FLT3-wildtype AML. Patients medically fit for intensive chemotherapy (ECOG ≤ 2) with adequate organ function are eligible, while patients with relapsed/refractory AML or prior cytotoxic treatment are excluded. A total of 146 patients will be randomized 1:1 to receive either VEN/AZA or SOC. Hematologic remission is evaluated according to ELN 2022 guidelines. The primary endpoint is the modified event-free survival, defined as either primary induction failure, hematologic relapse, molecular failure or death. Secondary endpoints include safety, tolerability, CR/CRi/CRh/CRMRD- rates, MRD kinetics (using NPM1 RT-qPCR and MFC), relapse-free survival, OS, early mortality, health-related QoL and cumulative health-care-resource use. Patients will be followed up for at least two years post enrollment. The VINCENT trial will be the first study to provide comprehensive prospective data comparing VEN/AZA to SOC, addressing both efficacy and patient-centered outcomes.
    Keywords:   NPM1 ; AML; Azacitidine; Fit patients; Intensive chemotherapy; Venetoclax
    DOI:  https://doi.org/10.1007/s00277-025-06496-7
  8. Blood Cancer Discov. 2025 Jul 09.
    An isoform-specific RUNX1C-BTG2 axis governs AML quiescence and chemoresistance.
    Cuijuan Han, Zhiping Zhang, Edie I Crosse, Sogand Sajedi, Bin Lu, Xiyue Wang, Sadik Karma, Mitch Kostich, Sakthi Harini Rajendran, Dylan B Udy, Steven Chen, Alexander Arnuk, Abimbola Eunice Lawal, Kayla R Koenig, Meryl McKenna, Patrick K Reville, Hussein A Abbas, Omar Abdel-Wahab, Pedro Miura, Robert K Bradley, Eric Wang.
      Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet its role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in AML patients before therapy and at relapse post-chemotherapy, identifying and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long isoform RUNX1C through its alternative distal promoter. The N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted ribosomal RNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of ribosomal RNA's increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineate an isoform-specific transcriptional circuit that governs chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0327
  9. Haematologica. 2025 Jul 10.
    Real-world validation study of the LSC17 score for risk prediction in patients with newly diagnosed acute myeloid leukemia.
    Tracy Murphy, Boyang Zhang, Tong Zhang, Ian King, Jose-Mario Capo-Chichi, Vikas Gupta, Dawn Maze, Caroline J McNamara, Mark D Minden, Aaron D Schimmer, Andre C Schuh, Hassan Sibai, Karen W L Yee, Andrea Arruda, Zhibin Lu, Dina Khalaf, Chantal Rockwell, Brian Leber, Mitchell Sabloff, Anne Tierens, Tracy L Stockley, Steven M Chan, Stanley W K Ng, Jean C Y Wang.
      Acute myeloid leukemia (AML) patients exhibit diverse molecular and cytogenetic changes with heterogeneous outcomes. The functionally-derived LSC17 gene expression score has demonstrated strong prognostic significance in retrospective analyses of adult and pediatric AML cohorts, where above-median scores are associated with worse outcomes compared to below-median scores in intensively-treated patients. Here we used a laboratory-developed clinically-validated NanoStringbased LSC17 assay to test the prognostic value of the LSC17 score in a prospective multicentre study of 276 newly-diagnosed AML patients. Each patient's score was classified as high or low by comparison to a previously-established reference score. In the entire cohort, a high LSC17 score was associated with poor risk features, including advanced age and unfavorable genetic mutations. In the subset of 190 patients treated intensively, a high LSC17 score was associated with lower remission rates (63% vs 94% after induction, P.
    DOI:  https://doi.org/10.3324/haematol.2025.287777
  10. N Engl J Med. 2025 Jul 10. pii: 10.1056/NEJMc2507106#sa2. [Epub ahead of print]393(2): 204-205
    Tumor-Infiltrating Clonal Hematopoiesis. Reply.
    Elsa Bernard, Oriol Pich, Charles Swanton.
      
    DOI:  https://doi.org/10.1056/NEJMc2507106
  11. Transl Oncol. 2025 Jul 08. pii: S1936-5233(25)00198-6. [Epub ahead of print]59 102467
    Sitravatinib combined with venetoclax exerts effective synergy to eliminate acute myeloid leukemia cells with FLT3-ITD mutations.
    Jie Yang, Yvyin Zhang, Qingshan Li, Peihong Wang.
      We have previously identified sitravatinib as a potent inhibitor of FLT3, capable of overcoming resistance to gilteritinib in the treatment of acute myeloid leukemia (AML). The combination of venetoclax and FLT3 inhibitors gilteritinib and quizartinib has shown promising results in reducing leukemia burden and improving survival in pre-clinical studies and clinical trials of AML with FLT3 mutation. In this study, we aimed to investigate the therapeutic effect of treating AML with sitravatinib combined with venetoclax. Our findings indicated that the combination of sitravatinib and venetoclax significantly decreased cell viability and increased cell apoptosis in AML cell lines harboring FLT3 mutation, more so than either treatment alone. These two agents exerted strong synergistic effects in FLT3-ITD AML cell lines and patient bone marrow cells in vitro. The activation of MAPK/ERK signaling are common causes that weaken the efficacy of FLT3 inhibitors, while the upregulation of anti-apoptotic proteins including BCL-xL and MCL-1 leads to venetoclax resistance. Our data demonstrated that sitravatinib plus venetoclax further suppressed the phosphorylation of AKT and ERK as well as downregulated MCL-1 and BCL-xL, which mechanically explain the synergistic effect. Finally, we tested the potential application of sitravatinib plus venetoclax in vivo using patient-derived xenografts, and found that the combined therapy was significantly more effective in inhibiting leukemia cell expansion, reducing infiltration in the spleen, and prolonging survival time compared to a single administration. Our study demonstrates the potential use of sitravatinib plus venetoclax as an alternative therapeutic strategy to treat AML patients with FLT3-ITD mutation.
    Keywords:  BCL-2 inhibitor; FLT3-ITD mutation; Sitravatinib; Synergistic effect; Venetoclax
    DOI:  https://doi.org/10.1016/j.tranon.2025.102467
  12. Proc Natl Acad Sci U S A. 2025 Jul 15. 122(28): e2421159122
    The WWP1-JARID1B axis sustains acute myeloid leukemia chemoresistance.
    Claudia Fierro, Sara Giovannini, Valeria Moriconi, Claudia Fiorilli, Emanuele Panatta, Valentina Frezza, Federica Corigliano, Rosalba Pecorari, Yanan Li, Ji Zhou, Vincenza Simona Delvecchio, Artem Smirnov, Jose Manuel Garcia Manteiga, Andrea Brendolan, Jinping Zhang, Yufang Shi, Ivano Amelio, Eleonora Candi, Gerry Melino, Francesca Bernassola.
      To uncover substrates mediating the oncogenic activity of WWP1 in acute myeloid leukemia (AML), we performed a proteomic analysis that identified the histone demethylase KDM5B/JARID1B as a candidate target. Of note, JARID1B is indispensable for efficient recruitment of several DNA damage repair factors and for damage resolution, thus negatively influencing the sensitivity of cancer cells to chemo- and radiation therapies. Validation of JARID1B as a substrate of WWP1 revealed a positive regulation of JARID1B half-life by WWP1 through the establishment of K63-linked polyubiquitin chains. As a result, downregulation of JARID1B rising from WWP1 inactivation was associated with higher H3K4me3 enrichment at JARID1B target genes in WWP1-depleted relatively to control AML cells. Integration of RNA-seq and H3K4me3 ChIP-seq data uncovered a highly significant overlap between upregulated gene expression and enriched H3K4me3 peaks after shWWP1 inactivation. We confirmed transcriptional activation of JARID1B targets in WWP1-depleted cells, supporting a role for WWP1 in regulating JARID1B activity. Coherently, upon WWP1 inactivation, we observed a defective recruitment of repair proteins after DNA damage, with subsequent reduced DNA damage repair efficiency and enhanced sensitization of AML cells to the cytotoxic activity of chemotherapeutic drugs. All together, these data identify JARID1B as a bona fide target of WWP1 and imply that WWP1-mediated regulation of JARID1B impacts its ability to modify chromatin and to recruit DNA damage repair factors, thus ultimately affecting chemosensitivity of AML cells.
    Keywords:  DNA repair; acute myeloid leukemia; protein degradation; protein ubiquitination
    DOI:  https://doi.org/10.1073/pnas.2421159122
  13. Nat Commun. 2025 Jul 07. 16(1): 6247
    EMP1 safeguards hematopoietic stem cells by suppressing sphingolipid metabolism and alleviating endoplasmic reticulum stress.
    Lei Li, Yufei Lei, Yan Li, Yuxin Xie, Pusheng Hui, Xiaoyan Zang, Weiru Wu, Feng Wu, Jiankun Fan, Jianming Wang, Jieping Chen, Zhe Chen, Yu Hou.
      The long-term maintenance of hematopoietic stem cells (HSCs) relies on the regulation of endoplasmic reticulum (ER) stress at a low level, but the underlying mechanism remains poorly understood. Here, we demonstrate that suppression of ER stress improves the functions of HSCs and protects HSCs against ionizing radiation (IR)-induced injury. We identify epithelial membrane protein 1 (EMP1) as a key regulator that mitigates ER stress in HSCs. Emp1 deficiency leads to the accumulation of protein aggregates and elevated ER stress, ultimately resulting in impaired HSC maintenance and self-renewal. Mechanistically, EMP1 is located within the ER and interacts with ceramide synthase 2 (CERS2) to limit the production of a class of sphingolipids, dihydroceramides (dhCers). DhCers accumulate in Emp1-deficient HSCs and induce protein aggregation. Furthermore, Emp1 deficiency renders HSCs more susceptible to IR, while overexpression of Emp1 or inhibition of CERS2 protects HSCs against IR-induced injury. These findings highlight the critical role played by the EMP1-CERS2-dhCers axis in constraining ER stress and preserving HSC potential.
    DOI:  https://doi.org/10.1038/s41467-025-61552-0
  14. Leukemia. 2025 Jul 09.
    The hallmarks of hematopoietic stem cell transplantation for pediatric acute myeloid leukemia.
    Pediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation
      Allogeneic hematopoietic stem cell transplantation (HSCT) has significantly improved the outcome of children with high-risk (HR) acute myeloid leukemia (AML). Implementing allogeneic HSCT depends on numerous factors, including adverse cytogenetics, molecular abnormalities, poor response to first-line treatment, or relapsed or primary refractory disease. In HR AML, allogeneic HSCT is considered to be the consolidation strategy of choice in first complete remission (CR1) and offers the best chance of cure for patients with relapsed disease. Advances in donor/recipient typing, conditioning regimens, graft-versus-host-disease (GvHD) management, and supportive care have contributed to this improvement in overall-and transplant-outcome. This review will comprehensively discuss indications for HSCT and its modalities in pediatric AML by examining past, current, and future strategies for disease- and response-related stratification. We will examine the key importance of low/negative measurable residual disease (MRD) before transplantation and discuss conditioning regimens and graft variables, as well as novel approaches to harness the graft-versus-leukemia (GvL) effect, including targeted immunotherapy. The review will also address toxicities associated with HSCT, GvHD prophylaxis, and the management of treatment failure. Ultimately, this review seeks to inform clinical practice and highlights how improved outcomes have been achieved through the collective efforts of international study groups.
    DOI:  https://doi.org/10.1038/s41375-025-02685-5
  15. Blood. 2025 Jul 10. pii: blood.2024027363. [Epub ahead of print]
    Thrombocytopenia in myelofibrosis is characterized by inflammatory megakaryocytes with reduced G6B expression.
    Lilian Varricchio, Gohar Mosoyan, Sebastian El Ghaity-Beckley, Md Babu Mia, Shivani Handa, Christian Salib, John O Mascarenhas, Ronald Hoffman.
      The megakaryocytic (MK) specific immunoreceptor G6b-B plays an essential role in MK development. Since germline loss-of-function mutations of G6b-B in man and its deletion in mouse models leads to thrombocytopenia and a myelofibrosis-like clinical phenotype (MF-MPIG6B), we explored the role of G6b-B in patients with MF due to a myeloproliferative neoplasm (MPN) with thrombocytopenia (MPN-MF-T). We demonstrated that MKs generated from mononuclear cells (MNCs) from a patient with MF-MPIG6B as well as patients with MPN-MF-T, failed to express GATA1 and G6B and possessed a protein pattern expression characteristic of MKs primed for inflammation rather than platelet production. MNCs from MPN-MF-T patients also generated fewer MK biased hematopoietic stem cells (HSCs) and greater numbers of small cytoplasmic immature MKs (CD41+CD42-G6B-) as compared to MNCs from non-thrombocytopenic MPN-MF patients (MPN-MF-NT). Plasma levels of TGFβ1 and YKL-40 which were shown to arrest normal MK maturation were elevated in the MF-MPIG6B patient. Although TGFβ1 plasma levels were similarly elevated in MPN-MF-T and MPN-MF-NT patients, TNFα and YKL-40 levels were upregulated to a greater extent in MPN-MF-T than MPN-MF-NT patients. Moreover, we identified a reciprocal positive regulatory loop involving TGFβ1 and YKL-40 in MF MKs. These findings indicate that impaired MK maturation, and reduced G6B expression lead to the predominance of pro-inflammatory MKs which produce factors that further arrest MK development in MF-MPIG6B and MPN-MF-T patients. NCT03895112.
    DOI:  https://doi.org/10.1182/blood.2024027363
  16. Br J Haematol. 2025 Jul 07.
    Secondary malignancies after chronic myeloid leukaemia upon TKI treatment: Population trends and outcomes.
    Yingling Zu, Xipeng Yue, Xinrong Zhan, Xiaojuan Liu, Hongxia Ma, Fuli Qin, Lijuan Duan, Hongmian Zhao, Yan Zhang, Shiqiang He, Huifang Zhao, Chunlei Zhang, Xiangke Xin, Wenli Zhang, Yongping Song, Bingcheng Liu, Weiming Li, Yanli Zhang.
      The life expectancy of most chronic myeloid leukaemia (CML) patients is nearly comparable to that of the general population owing to the application of tyrosine kinase inhibitors (TKIs). Hence, focus has shifted towards long-term adverse effects, especially the emergence of secondary malignancies. A retrospective study from 11 institutions was performed in 139 CML patients with secondary malignancies. The median ages at diagnosis of CML and secondary malignancy were 51 years (range, 13-88 years) and 53 years (range, 18-91 years). After a median follow-up of 85 months, the median time from diagnosis of CML to secondary malignancy was 48 months (range, 1-264 months). The use of two or more TKIs was a significant risk factor for the latency period of secondary malignancies (odds risk [OR] of 4.281, 95% confidence interval [CI] 1.369-13.390, p = 0.012). Male sex was an independent risk factor associated with worse overall survival (hazard ratio [HR] of 0.329, 95% CI 0.138-0.779, p = 0.012) and event-free survival (HR of 3.640, 95% CI 1.485-8.925, p = 0.005). Endocrine neoplasm was the most common subtype (28.8%, 40/139). Gastrointestinal, genitourinary and cutaneous malignancies demonstrated a male predominance. Then, male sex was associated with inferior outcomes in CML patients with secondary malignancies, and prospective studies are warranted to elucidate the underlying biological mechanisms.
    Keywords:  chronic myeloid leukaemia; male; outcomes; secondary malignancy; tyrosine kinase inhibitor
    DOI:  https://doi.org/10.1111/bjh.20226
  17. EMBO Mol Med. 2025 Jul 10.
    SFX-01 is therapeutic against myeloproliferative disorders caused by activating mutations in Shp2.
    Hyun-Ju Cho, Joy Smith, Christopher H Switzer, Eleni Louka, Rebecca L Charles, Oleksandra Prysyazhna, Ewald Schroder, Mariana Fernandez-Caggiano, Daniel Simoes de Jesus, Seda Eminaga, Xiaoke Yin, Xiaoping Yang, Steven Lynham, Manuel Mayr, Valle Morales, Katiuscia Bianchi, Vinothini Rajeeve, Pedro R Cutillas, Adam J Mead, Philip Eaton.
      Activating mutations of Src homology-2 domain-containing protein tyrosine phosphatase-2 (Shp2) cause multiple childhood conditions for which there is an unmet therapeutic need, including juvenile myelomonocytic leukemia (JMML) and Noonan syndrome. SFX-01, an α-cyclodextrin-stabilized sulforaphane complex currently in clinical development, covalently adducts cysteine residues. Using unbiased proteomics, its protein targets were identified, including Shp2. SFX-01 induced an inhibitory dithiolethione modification at the Shp2 active site cysteine. Importantly, in a transgenic mouse model of human Noonan syndrome with hyperactive D61G Shp2, SFX-01 concomitantly normalized their phosphatase activity and myeloid cell count. Furthermore, SFX-01 also attenuated JMML human patient-derived hematopoietic stem cell proliferation that was linked to STAT1 signaling and decreased cyclin D1 expression, resulting in cell-cycle arrest. We conclude that SFX-01 is an activating mutant Shp2 inhibitor and may offer beneficial effects in patients with JMML or Noonan syndrome.
    Keywords:  Myeloproliferative Disorders; Noonan Syndrome; SFX-01; Shp2; Sulforaphane
    DOI:  https://doi.org/10.1038/s44321-025-00267-7
  18. Am J Hematol. 2025 Jul 11.
    Impact of Cytogenetic Response to Therapy on Long-Term Survival in Acute Myeloid Leukemia.
    John Hanna, Emily C Zabor, Moath Albliwi, Jessica El-Asmar, Daniel P Nurse, Ameed Bawwab, Hasan Abuamsha, Yomna Abu-Farsakh, Heya Batah, Asad Rauf, Joy Nakitandwe, David S Bosler, Akriti G Jain, John C Molina, Sophia Balderman, Abhay Singh, Aaron T Gerds, Sudipto Mukherjee, Ronald M Sobecks, Anjali S Advani, Hetty E Carraway, Caroline Astbury, Moaath K Mustafa Ali.
      Prognostication in acute myeloid leukemia (AML) relies on clinical, molecular, and cytogenetic factors. In this retrospective study, we examined the impact of different levels of cytogenetic response on overall survival (OS) and event-free survival (EFS) in AML. Among 973 adult AML patients treated at Cleveland Clinic (5/2017-9/2023), 563 patients had baseline cytogenetic data and post-treatment response assessment available. Based on baseline and response cytogenetic status, patients were categorized into: normal to normal (NL-Cy to NL-Cy, n = 221, 39%), normal or abnormal to gain (NL/Abnl-Cy to Gain-Cy, n = 46, 8.2%), abnormal to persistent (Abnl-Cy to Persistent-Cy, n = 81, 14%), abnormal to partial response (Abnl-Cy to Partial-Cy, n = 20, 3.6%), and abnormal to complete response (Abnl-Cy to NL-Cy, n = 195, 35%). Landmark analysis was used to account for post-treatment assessments. The cohort had a median age of 62 years (interquartile range: 52-69), 256 females (45%), 90% were White, and median follow-up of 45.8 months (range: 0.73-191.3). The median OS and hazard ratios (HRs) from multivariable regression analysis were as follows: NL-Cy to NL-Cy: 37 months (95% CI: 27-91), HR = reference; NL/Abnl-Cy to Gain-Cy: 14 months (95% CI: 8.6-30), HR = 1.5 (95% CI: 0.99-2.39); Abnl-Cy to Persistent-Cy: 13 months (95% CI: 12-18), HR = 1.61 (95% CI: 1.13-2.31); Abnl-Cy to Partial-Cy: 25 months (95% CI: 14-NC), HR = 0.76 (95% CI: 0.39-1.49); and Abnl-Cy to NL-Cy: 27 months (95% CI: 19-101), HR = 1.25 (95% CI: 0.93-1.68) (p = 0.038). Achieving cytogenetic remission, complete or partial, was associated with better survival outcomes. These findings highlight the importance of monitoring cytogenetic responses to inform treatment decisions and support integrating cytogenetic response into risk-adapted, personalized AML management strategies.
    Keywords:  acute myeloid leukemia; cytogenetic response; karyotype; prognosis; survival
    DOI:  https://doi.org/10.1002/ajh.70000
  19. N Engl J Med. 2025 Jul 10. pii: 10.1056/NEJMc2507106#sa1. [Epub ahead of print]393(2): 203-204
    Tumor-Infiltrating Clonal Hematopoiesis.
    David Spetzler, Emmanuel S Antonarakis, George Sledge.
      
    DOI:  https://doi.org/10.1056/NEJMc2507106
  20. Ann Hematol. 2025 Jul 08.
    Venetoclax plus azacitidine as genetic-driven bridge-to-transplant therapy for IDH2-mutated acute myeloid leukaemia (AML) refractory to intensive chemotherapy: proof-of-concept case reports.
    Gaetano Cimino, Matteo Caridi, Valeria Cardinali, Sofia Sciabolacci, Sara De Santis, Camilla Rellini, Caterina Matteucci, Cristina Mecucci, Paolo Sportoletti, Francesco Zorutti, Alessandra Carotti, Roberta La Starza, Antonio Pierini, Maria Paola Martelli.
      Despite the greater biological understanding and the new drugs available, acute myeloid leukaemia (AML) patients who are refractory to intensive induction chemotherapy represents an unmet clinical need, especially in young/fit adults who are eligible for bone marrow transplantation. Since venetoclax/azacitidine (ven/aza) was introduced in AML management in 2020, survival of elderly/unfit patients has dramatically improved, especially in those carrying NPM1 or IDH2 mutations. However, the use of ven/aza in young and fit adults remains limited, raising ongoing debate about its potential role beyond patients ineligible to intensive chemotherapy. Here, we discuss three under 60 years chemorefractory AML patients, who, given the concomitant IDH2 mutations, were started to ven/aza as bridge-to-transplant and successfully treated. These cases confirm the extraordinary sensitivity of IDH2-mutated AML to aza/ven even in the refractoriness setting and show that such less-intensive regimen can be driven by genetics offering a promising alternative to intensive salvage chemotherapy, while preserving patient fitness for allo-transplant.
    Keywords:  AML; Allo-HSC; Azacitidine/venetoclax; IDH2; Relapse/refractoriness; Salvage treatment
    DOI:  https://doi.org/10.1007/s00277-025-06500-0
  21. Mol Oncol. 2025 Jul 07.
    The critical role of DNA damage-inducible transcript 4 (DDIT4) in stemness character of leukemia cells and leukemia initiation.
    Yishuang Li, Zhijie Cao, Haiyan Xing, Zhenya Xue, Wenbing Liu, Jiayuan Chen, Yihan Mei, Runxia Gu, Hui Wei, Shaowei Qiu, Min Wang, Qing Rao, Jianxiang Wang.
      Leukemia stem cells (LSCs) are critical for leukemia initiation, and the stemness properties of LSCs are related to disease relapse. Stemness properties, including quiescence, self-renewal, and chemoresistance, are maintained through an interplay between leukemia cells and the bone marrow (BM) niche. Here, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) can be induced in a hypoxic BM niche and is required for the quiescence and self-renewal of AML1-ETO9a (AE9a)-transformed leukemia cells in vitro. More importantly, analysis of publicly available transcriptional data from adult acute myeloid leukemia (AML) patients revealed that elevated DDIT4 expression correlates with poor prognosis. Furthermore, DDIT4 knockout markedly suppressed leukemia initiation, quiescence, chemoresistance, and self-renewal of AE9a-transformed leukemia cells in vivo. Mechanistically, DDIT4 upregulates the expression of HOXA gene cluster, and re-expression of HOXA6 in DDIT4 knockout AE9a cells can rescue the impaired leukemia initiation. Our findings demonstrate the critical role of DDIT4 in the stemness of AE9a leukemia cells and elucidate its underlying mechanism, suggesting that targeting DDIT4 may represent a promising therapeutic strategy for eliminating LSCs in AML1-ETO leukemia.
    Keywords:  DDIT4; HOXA; acute myeloid leukemia; leukemogenesis; self‐renewal; stemness
    DOI:  https://doi.org/10.1002/1878-0261.70090
  22. Cell Death Dis. 2025 Jul 07. 16(1): 498
    HDAC3-YY1-RAB5A axis remodels AML-supportive niche by modulating mitochondrial homeostasis in bone marrow stromal cells.
    Chao He, Yue Xiong, Yuqing Zeng, Jianhua Feng, Fuxia Yan, Manqi Zhang, Zhili Tan, Yaling Zheng, Hongbo Chen, Rui Huang, Fang Cheng.
      Recent studies have shown that the interaction between acute myeloid leukemia (AML) and bone marrow stromal cells (BMSCs) plays a vital role in the progression of leukemia and the development of drug resistance, while the underlying mechanisms remain inconclusive. In this study, we found that AML patient-derived BMSCs exhibit a hyperinflammatory phenotype. Histone deacetylase 3 (HDAC3) in BMSCs enhances mitochondrial reactive oxygen species (ROS) production by RAB5A-mediated blockade of mitophagy. Furthermore, we confirmed that HDAC3 regulates RAB5A expression through transcription factor YY1. Excessive ROS accelerates the senescence of BMSCs and promotes the secretion of senescence-associated secretory phenotype, creating a hyperinflammatory bone marrow niche, activating the NF-κB pathway in AML cells to promote their survival and drug resistance. The inhibition of HDAC3 in BMSCs reduces the mitochondrial ROS production and thus delays BMSCs senescence. Consequently, HDAC3 inhibition in BMSCs decreases AML proliferation and synergizes with the anti-AML efficacy of venetoclax. Therefore, our study suggests that targeting HDAC3 in BMSCs may be used for the combination therapy of AML by remodeling the AML-supportive niche.
    DOI:  https://doi.org/10.1038/s41419-025-07777-9
  23. J Exp Med. 2025 Sep 01. pii: e20242180. [Epub ahead of print]222(9):
    Gut microbiota-derived TMAVA is a modulator of acute CNS-GVHD.
    Sangya Chatterjee, Tamina Rückert, Ina Martin, Elisa Michaeli, Joerg Buescher, Petya Apostolova, Daniel Erny, Maria-Eleni Lalioti, Francesca Biavasco, Alina Hartmann, Solveig Runge, Lukas M Braun, Nana Talvard-Balland, Rachael C Adams, Annette Schmitt-Graeff, James Cook, Valentin Wenger, Dimitrios Athanassopoulos, Dilara Hasavci, Alexander Paolo Vallejo-Janeta, Thomas Blank, Philipp Schaible, Janaki Manoja Vinnakota, Alexander Zähringer, Stephanie C Ganal-Vonarburg, Wolfgang Melchinger, Dietmar Pfeifer, Natalie Köhler, Stephan P Rosshart, David Michonneau, Gérard Socié, Geoffroy Andrieux, Nina Cabezas-Wallscheid, Melanie Boerries, Marco Prinz, Robert Zeiser.
      Acute graft-versus-host disease (aGVHD) can affect the central nervous system (CNS) through microglial activation and T cell infiltration, but the role of gut microbiota in CNS-aGVHD remains unclear. Here, we investigated the role of microbiota in microglial activation during aGVHD using antibiotic-treated specific pathogen-free (SPF), germ-free (GF), and wildling mice. Antibiotic-mediated microbiota depletion led to infiltration of IFN-γ-producing T cells in the brain, activation of microglia via the TLR4/p38 MAPK pathway, and neurocognitive deficits in SPF aGVHD mice. Microglial depletion reversed the neurocognitive deficits. GF and wildling mice treated with antibiotics exhibited similar microglial activation after allogeneic hematopoietic cell transplantation (allo-HCT). Mechanistically, the bacteria-derived metabolite N,N,N-trimethyl-5-aminovaleric acid (TMAVA) was decreased in microglia following antibiotic treatment. TMAVA administration suppressed TLR4/p38 MAPK pathway activity in microglia and alleviated gut microbiota depletion-mediated neurocognitive deficits. Additionally, TMAVA abundance decreased in patient blood after allo-HCT and after GVHD onset. In summary, we identify TMAVA loss as a central causative factor for CNS-aGVHD, opening new perspectives for a metabolite-based therapy.
    DOI:  https://doi.org/10.1084/jem.20242180
  24. J Natl Cancer Inst. 2025 Jul 10. pii: djaf181. [Epub ahead of print]
    Clonal hematopoiesis and risk of non-myeloid subsequent malignant neoplasms after autologous hematopoietic cell transplantation.
    June-Wha Rhee, Sitong Chen, Raju Pillai, Alysia Bosworth, Artem Oganesyan, Emma Grigorian, Liezl Atencio, Caitlyn Estrada, Mareen Kassabian, Lanie Lindenfeld, Rusha Bhandari, Scott Goldsmith, Michael Rosenzweig, Alex F Herrera, Matthew G Mei, Ryotaro Nakamura, F Lennie Wong, Stephen J Forman, Saro H Armenian.
       PURPOSE: Examine the association between clonal hematopoiesis (CH) and non-myeloid subsequent malignant neoplasms (SMNs) after autologous hematopoietic cell transplantation (HCT).
    METHODS: This was a retrospective cohort study of 1,931 consecutive patients who underwent HCT between 2010 and 2016 at a single center. DNA from pre-HCT mobilized blood products was sequenced to identify CH variants (variant allele frequency [VAF] ≥2%). The primary outcome was 8-year(y) cumulative incidence (CI) of non-myeloid SMNs. Multivariable regression analysis was used to evaluate the association between CH and non-myeloid SMNs, as well as cause-specific mortality.
    RESULTS: Median age at HCT was 58.8 y (range 18.4-78.1y); 389 patients (20.1% of the cohort) had at least one CH variant and 94 (4.9%) had ≥2 variants. The 8 y CI of non-myeloid SMNs was significantly higher in patients with CH compared to those without (15.1% vs 7.2%, p < .001), and increased by VAF: 7.2% (VAF <2%), 14.0% (VAF 2- <10%), 19.4% (VAF ≥10%); p = .001. Patients with CH had a two-fold increased risk of non-myeloid SMNs (standardized incidence ratio = 1.9), compared with the general population. In multivariable analysis, CH was an independent and significant risk factor for non-myeloid SMNs (hazard ratio [HR]=1.72, 95%CI 1.15-2.59). Finally, patients with CH had significantly worse survival, primarily due to the higher risk of non-relapse mortality (HR: 2.97, 95%CI: 1.90-4.64).
    CONCLUSIONS: CH was significantly associated with risk of non-myeloid SMNs after HCT, and the magnitude of association increased by VAF. CH may serve as a biomarker for identifying HCT survivors at higher risk for developing non-myeloid SMNs.
    Keywords:  Clonal hematopoiesis of indeterminate potential; autologous hematopoietic cell transplantation; lymphoma; multiple myeloma; non-relapse mortality; subsequent malignant neoplasm
    DOI:  https://doi.org/10.1093/jnci/djaf181
  25. Blood. 2025 Jul 10. pii: blood.2024027335. [Epub ahead of print]
    Loss of DCAF8 impairs hematopoietic stem cell function with cellular senescence via the DOCK11-CDC42 axis.
    Pengfei Xu, Xiuli Zhang, Donghe Li, Bo Jiao, Jiawei Nie, Yi Huang, Zhizhou Xia, Jiaoyang Li, Yuqing Dan, Xu Huang, Lei Yan, Rui Zhang, Wei Huang, Xinru Wang, Shiyu Ji, Yong Cang, Ruibao Ren, Ping Liu.
      Hematopoietic stem cells (HSCs) are responsible for sustaining hematopoietic system throughout life, and their functional decline contributes to hematological disorders and organismal aging. Understanding the molecular mechanisms that govern HSC function is critical for developing interventions for treating and preventing aging-related diseases. Here, we show that DCAF8, a substrate recognition component of Cullin-RING E3 ubiquitin ligases, is highly expressed in HSCs and undergoes a progressive decline with age. Loss of DCAF8 in mice results in impaired function in HSCs, characterized by increased number yet decreased self-renewal capacity, which associates with cellular senescence and elevated DNA damage. Mechanistically, DCAF8 mediates the degradation of DOCK11, a guanine nucleotide exchange factor for CDC42. In the absence of DCAF8, DOCK11 accumulates, leading to elevated CDC42 activity and consequential loss of polarity of HSCs. Knocking out Dock11 mitigates the senescence, DNA damage, and self-renewal defects of Dcaf8-/- HSCs. This study highlights a critical role of DCAF8 in preventing HSC senescence via the DOCK11-CDC42 axis and suggests potential therapeutic targets for preventing functional decline in HSCs.
    DOI:  https://doi.org/10.1182/blood.2024027335
  26. Blood. 2025 Jul 10. pii: blood.2025028790. [Epub ahead of print]
    Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion.
    Claire Roddie, Juliana Dias, Maeve O'Reilly, Mahnaz Abbasian, Amaia Cadinanos-Garai, Ketki Vispute, Leticia Bosshard-Carter, Marina Mitsikakou, Eftychia Charalambous, Vedika Mehra, Harriet Roddy, Gordon Weng-Kit Cheung, John A Hartley, Nasir Galal Mahmoud, Leah Ensell, Yashma Patel, Maria A V Marzolini, Farzin Farzaneh, Lauren Nickolay, Nourredine Himoudi, Farhatullah Syed, Bilyana Popova, Sevasti Galani, Alexander Day, Mark W Lowdell, Karl S Peggs.
      Autologous CD19-targeting CAR-T has transformed management of relapsed/refractory adult B-cell acute lymphoblastic leukaemia(B-ALL) but relapse post-allogeneic stem cell transplant(allo-SCT) is frequently accompanied by profound lymphopenia, impaired T-cell fitness and aggressive disease requiring urgent treatment, making autologous CAR-T challenging to deliver. We developed an allogeneic matched-donor CD19CAR product (CAR-DLI) for adult B-ALL following allo-SCT failure. Here we evaluate the risks/benefits of pre-CAR-DLI lymphodepleting chemotherapy (LD), and the efficacy of repeat CAR-DLI dosing as per conventional DLI scheduling/protocols. Patients aged 16-70y with r/r B-ALL post-allo-SCT were eligible. Primary outcomes were toxicity and feasibility of CAR-DLI manufacture; secondary outcomes included CAR-DLI engraftment/ expansion/ persistence. 17 allo-SCT donors were leukapheresed and 14 patients (median age,43y) were infused. Median disease burden at registration was 63.5% bone marrow blasts (range, MRD-100%). Patients 1-7 received CAR-DLI-alone; patients 8-14 received CAR-DLI+LD with fludarabine/cyclophosphamide. CAR-DLI+LD vs CAR-DLI-alone was associated with superior peak CAR-DLI engraftment (93,134 vs. 8010 copies/ug gDNA), expansion (858,101 vs. 39,038 copies/ug gDNA/28d) and persistence (median 197 days vs. 32 days). CAR-DLI+LD was not associated with more immunotoxicity than CAR-DLI-alone, and GvHD (grade-1/skin) affected only 2/14(14%) patients. CAR-DLI+LD vs CAR-DLI-alone conferred superior event-free-survival (EFS) and overall-survival (OS) at 12m (57% vs 29%; 83% vs 29%). Repeat CAR-DLI dosing was administered to 8/14(57%) patients with morphological/MRD+ relapse, but with minimal engraftment/expansion or toxicity/efficacy. CAR-DLI+LD has a tolerable safety profile without significant GvHD and is associated with significantly better outcomes than CAR-DLI-alone. Repeat CAR-DLI dosing beyond dose 1 was not found to be effective in this analysis. NCT02893189.
    DOI:  https://doi.org/10.1182/blood.2025028790
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