bims-tremyl 2024-08-25 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2024–08–25
38 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia.
Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML).
Human Leukocyte Antigen Mismatching and Survival in Contemporary Hematopoietic Cell Transplantation for Hematologic Malignancies.
Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients.
Real-world outcomes of intensive induction approaches in core binding factor acute myeloid leukemia.
Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.
Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties.
RNA binding protein-directed control of leukemic stem cell evolution and function.
Health-Related Quality of Life with Gilteritinib versus Placebo Post-Transplant for FLT3-ITD+ Acute Myeloid Leukemia.
Young (<35 years) haploidentical versus old (≥35 years) mismatched unrelated donors and vice versa for allogeneic stem cell transplantation with post-transplant cyclophosphamide in patients with acute myeloid leukemia in first remission: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.
The role of the primitive marker CD133 in CD34-negative acute myeloid leukemia for the detection of leukemia stem cells.
Identifying disease-modifying potential in myelofibrosis clinical trials.
Trends in allogeneic transplantation for favorable risk acute myeloid leukemia in first remission: a longitudinal study of >15 years from the ALWP of the EBMT.
Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial.
Long-term outcome after allogeneic stem cell transplantation for GATA2 deficiency: An analysis of 67 adults and children from France and Belgium.
A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES.
RNA sequestration in P-bodies sustains myeloid leukaemia.
Artificial Intelligence Enabled Interpretation of ECG Images to Predict Hematopoietic Cell Transplantation Toxicity.
Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia.
Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse.
Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.
Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.
Haploidentical versus HLA-matched sibling donor HCT with PTCy prophylaxis: HLA factors and donor age considerations.
The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.
Starry sky pattern predicts RAS pathway activation in NPM1-mutated acute myeloid leukemia.
Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.
Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome.
Busulfan-fludarabine versus busulfan-cyclophosphamide for allogeneic transplant in acute myeloid leukemia: long term analysis of GITMO AML-R2 trial.
The use of metformin and risk of myeloproliferative neoplasms among patients with no registered markers of diabetes.
Cardiac Events after Allo-HCT in Patients with Acute Myeloid Leukemia. Study Conducted con Behalf of the GETH-TC.
Single-cell proteo-transcriptomic profiling reveals altered characteristics of stem and progenitor cells in patients receiving cytoreductive hydroxyurea in early-phase chronic myeloid leukemia.
AML, myelodysplasia related, with STAG2 and SRSF2 comutations with myelocyte arrest.
SOHO State of the Art Update and Next Questions: Current and Emerging Therapies for Systemic Mastocytosis.
Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation.
The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks.
Combination Therapy with Ruxolitinib and Pegylated Interferon-alpha2a in Newly Diagnosed Patients with Polycythemia Vera.
Endothelial LATS2 is a suppressor of bone marrow fibrosis.
Outcome of 421 adult patients with Philadelphia-negative acute lymphoblastic leukemia treated under an intensive program inspired by the GIMEMA LAL1913 clinical trial: a Campus ALL study.

Blood. 2024 Aug 16. pii: blood.2023023644. [Epub ahead of print]

Epigenetic Regulation of Non-canonical Menin Targets Modulates Menin Inhibitor Response in Acute Myeloid Leukemia.

Xinyue Zhou, Lixia Zhang, Sajesan Aryal, Virginia Veasey, Amanda Tajik, Cecilia Restelli, Steven Moreira, Pengcheng Zhang, Yanfeng Zhang, Kristin Hope, Yang Zhou, Changde Cheng, Ravi Bhatia, Rui Lu.

Menin inhibitors that disrupt Menin-MLL interaction hold promise for treating specific acute myeloid leukemia subtypes, including KMT2A rearrangements (KMT2A-r), yet resistance remains a challenge. Here, through systematic chromatin-focused CRISPR screens, along with genetic, epigenetic, and pharmacologic studies in a variety of human and mouse KMT2A-r AML models, we uncover a potential resistance mechanism independent of canonical Menin-MLL targets. We show that a group of non-canonical Menin targets, which are bivalently co-occupied by active Menin and repressive H2AK119ub marks, are typically downregulated following Menin inhibition. The loss of Polycomb Repressive Complex 1.1 (PRC1.1) subunits, such as PCGF1 or BCOR, leads to Menin inhibitor resistance by epigenetic reactivation of these non-canonical targets, including MYC. Genetic and pharmacological inhibition of MYC can resensitize PRC1.1-deficent leukemia cells to Menin inhibition. Moreover, we demonstrate that leukemia cells with the loss of PRC1.1 subunits exhibit reduced monocytic gene signatures and are susceptible to the BCL2 inhibition, and combinational treatment of venetoclax overcomes the resistance to Menin inhibition in PRC1.1-deficient leukemia cells. These findings highlight the important roles of PRC1.1 and its regulated non-canonical Menin targets in modulating Menin inhibitor response and provide potential strategies to treat leukemias with compromised PRC1.1 function.

DOI: https://doi.org/10.1182/blood.2023023644
Leukemia. 2024 Aug 21.

Optimal prognostic threshold for measurable residual disease positivity by multiparameter flow cytometry in acute myeloid leukemia (AML).

Eduardo Rodríguez-Arbolí, Megan Othus, Sylvie D Freeman, Francesco Buccisano, Lok Lam Ngai, Ian Thomas, Raffaele Palmieri, Jacqueline Cloos, Sean Johnson, Elisa Meddi, Nigel H Russell, Adriano Venditti, Patrycja Gradowska, Gert J Ossenkoppele, Bob Löwenberg, Roland B Walter.

DOI: https://doi.org/10.1038/s41375-024-02378-5
J Clin Oncol. 2024 Aug 21. JCO2400582

Human Leukocyte Antigen Mismatching and Survival in Contemporary Hematopoietic Cell Transplantation for Hematologic Malignancies.

Cellular Therapy and Immunobiology Working Party of the EBMT

PURPOSE: Human leukocyte antigen (HLA) mismatching can reduce survival of patients with blood cancer after hematopoietic cell transplantation (HCT). How recent advances in HCT practice, in particular graft-versus-host disease (GVHD) prophylaxis by post-transplantation cyclophosphamide (PTCy), influence HLA risk associations is unknown.
PATIENTS AND METHODS: The study included 17,292 unrelated HCTs with 6-locus high-resolution HLA typing, performed mainly for acute leukemia or related myeloid neoplasms between 2016 and 2020, including 1,523 transplants with PTCy. HLA risk associations were evaluated by multivariable Cox regression models, with overall survival (OS) as primary end point.
RESULTS: OS was lower in HLA mismatched compared with fully matched transplants (hazard ratio [HR], 1.23 [99% CI, 1.14 to 1.33]; P < .001). This was driven by class I HLA-A, HLA-B, HLA-C (HR, 1.29 [99% CI, 1.19 to 1.41]; P < .001) but not class II HLA-DRB1 and HLA-DQB1 (HR, 1.07 [99% CI, 0.93 to 1.23]; P = .19). Class I antigen-level mismatches were associated with worse OS than allele-level mismatches (HR, 1.36 [99% CI, 1.24 to 1.49]; P < .001), as were class I graft-versus-host peptide-binding motif (PBM) mismatches compared with matches (HR, 1.42 [99% CI, 1.28 to 1.59]; P < .001). The use of PTCy improved GVHD, relapse-free survival compared with conventional prophylaxis in HLA-matched transplants (HR, 0.77 [0.66 to 0.9]; P < .001). HLA mismatching increased mortality in PTCy transplants (HR, 1.32 [1.04 to 1.68]; P = .003) similarly as in non-PTCy transplants (interaction P = .43).
CONCLUSION: Class I but not class II HLA mismatches, especially at the antigen and PBM level, are associated with inferior survival in contemporary unrelated HCT. These effects are not significantly different between non-PTCy compared with PTCy transplants. Optimized HLA matching should still be considered in modern HCT.

DOI: https://doi.org/10.1200/JCO.24.00582
J Hematol Oncol. 2024 Aug 19. 17(1): 70

Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients.

Adriane Halik, Marlon Tilgner, Patricia Silva, Natalia Estrada, Robert Altwasser, Ekaterina Jahn, Michael Heuser, Hsin-An Hou, Marta Pratcorona, Robert K Hills, Klaus H Metzeler, Laurene Fenwarth, Anna Dolnik, Christine Terre, Klara Kopp, Olga Blau, Martin Szyska, Friederike Christen, Jan Krönke, Loïc Vasseur, Bob Löwenberg, Jordi Esteve, Peter J M Valk, Matthieu Duchmann, Wen-Chien Chou, David C Linch, Hartmut Döhner, Rosemary E Gale, Konstanze Döhner, Lars Bullinger, Kenichi Yoshida, Frederik Damm.

   BACKGROUND: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood.
METHODS: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines.
RESULTS: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7-most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or -7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66-3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56-3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25-4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33-4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30-0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26-0.96]; P = 0.036).
CONCLUSION: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation.

Keywords:   IDH2 ; KMT2C ; PTPN11 ; TP53 ; AML; Complex karyotype; Monosomy 7; del(7q)

DOI:  https://doi.org/10.1186/s13045-024-01590-1
EJHaem. 2024 Aug;5(4): 728-737

Real-world outcomes of intensive induction approaches in core binding factor acute myeloid leukemia.

Alexandra E Rojek, Benjamin J McCormick, Joanna Cwykiel, Oluwatobi Odetola, Yasmin Abaza, Nhi Nai, Charles E Foucar, Rohan K Achar, Rory M Shallis, Danielle Bradshaw, Meaghan Standridge, Vamsi Kota, Guru Subramanian Guru Murthy, Talha Badar, Anand A Patel.

  Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21) and is classified as a favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. The CD33-targeting antibody-drug conjugate, gemtuzumab ozogamicin (GO), is commonly added to intensive chemotherapy (IC) in CBF-AML. We sought to compare outcomes in patients treated with IC with or without GO in CBF-AML. We included 200 patients with CBF-AML treated with IC across seven academic centers. Induction treatment regimens were categorized as IC alone, IC with GO, or IC with KIT inhibitor (dasatinib or midostaurin). Median follow-up for the whole cohort was 2.5 years. Three-year overall survival (OS) was 70% and 3-year event-free survival (EFS) was 51%. Patients treated with IC with GO experienced a 3-year EFS of 50% compared to those treated with IC alone who experienced a 3-year EFS of 47%, with no statistically significant difference (p = 0.62). Similarly, those treated with IC with GO did not experience an improved OS compared to those treated with IC alone (p = 0.67). Patients treated with IC with KIT inhibitor experienced a significantly improved 3-year EFS of 85% compared to those with IC with or without GO (p = 0.04). We find in our study that there is no survival benefit in patients treated with IC with the addition of GO; improved EFS was seen in patients with CBF-AML treated with IC plus KIT inhibitors, consistent with outcomes noted in prospective studies utilizing this approach.

Keywords:  acute myeloid leukemia; core binding factor; intensive chemotherapy

DOI:  https://doi.org/10.1002/jha2.981
Front Pharmacol. 2024 ;15 1409210

Impact of p53-associated acute myeloid leukemia hallmarks on metabolism and the immune environment.

Monika Chomczyk, Luca Gazzola, Shubhankar Dash, Patryk Firmanty, Binsah S George, Vakul Mohanty, Hussein A Abbas, Natalia Baran.

  Acute myeloid leukemia (AML), an aggressive malignancy of hematopoietic stem cells, is characterized by the blockade of cell differentiation, uncontrolled proliferation, and cell expansion that impairs healthy hematopoiesis and results in pancytopenia and susceptibility to infections. Several genetic and chromosomal aberrations play a role in AML and influence patient outcomes. TP53 is a key tumor suppressor gene involved in a variety of cell features, such as cell-cycle regulation, genome stability, proliferation, differentiation, stem-cell homeostasis, apoptosis, metabolism, senescence, and the repair of DNA damage in response to cellular stress. In AML, TP53 alterations occur in 5%-12% of de novo AML cases. These mutations form an important molecular subgroup, and patients with these mutations have the worst prognosis and shortest overall survival among patients with AML, even when treated with aggressive chemotherapy and allogeneic stem cell transplant. The frequency of TP53-mutations increases in relapsed and recurrent AML and is associated with chemoresistance. Progress in AML genetics and biology has brought the novel therapies, however, the clinical benefit of these agents for patients whose disease is driven by TP53 mutations remains largely unexplored. This review focuses on the molecular characteristics of TP53-mutated disease; the impact of TP53 on selected hallmarks of leukemia, particularly metabolic rewiring and immune evasion, the clinical importance of TP53 mutations; and the current progress in the development of preclinical and clinical therapeutic strategies to treat TP53-mutated disease.

Keywords:  AML; TP53 mutations; drug resistance; immunosuppression; metabolic rewiring; therapeutic approaches

DOI:  https://doi.org/10.3389/fphar.2024.1409210
Leukemia. 2024 Aug 21.

Identification of leukemia stem cell subsets with distinct transcriptional, epigenetic and functional properties.

Héléna Boutzen, Alex Murison, Alexa Oriecuia, Suraj Bansal, Christopher Arlidge, Jean C Y Wang, Mathieu Lupien, Kerstin B Kaufmann, John E Dick.

The leukemia stem cell (LSC) compartment is a complex reservoir fueling disease progression in acute myeloid leukemia (AML). The existence of heterogeneity within this compartment is well documented but prior studies have focused on genetic heterogeneity without being able to address functional heterogeneity. Understanding this heterogeneity is critical for the informed design of therapies targeting LSC, but has been hampered by LSC scarcity and the lack of reliable cell surface markers for viable LSC isolation. To overcome these challenges, we turned to the patient-derived OCI-AML22 cell model. This model includes functionally, transcriptionally and epigenetically characterized LSC broadly representative of LSC found in primary AML samples. Focusing on the pool of LSC, we used an integrated approach combining xenograft assays with single-cell analysis to identify two LSC subtypes with distinct transcriptional, epigenetic and functional properties. These LSC subtypes differed in depth of quiescence, differentiation potential, repopulation capacity, sensitivity to chemotherapy and could be isolated based on CD112 expression. A majority of AML patient samples had transcriptional signatures reflective of either LSC subtype, and some even showed coexistence within an individual sample. This work provides a framework for investigating the LSC compartment and designing combinatorial therapeutic strategies in AML.

DOI: https://doi.org/10.1038/s41375-024-02358-9
Hemasphere. 2024 Aug;8(8): e116

RNA binding protein-directed control of leukemic stem cell evolution and function.

Pratik Joshi, Ava Keyvani Chahi, Lina Liu, Steven Moreira, Ana Vujovic, Kristin J Hope.

Strict control over hematopoietic stem cell decision making is essential for healthy life-long blood production and underpins the origins of hematopoietic diseases. Acute myeloid leukemia (AML) in particular is a devastating hematopoietic malignancy that arises from the clonal evolution of disease-initiating primitive cells which acquire compounding genetic changes over time and culminate in the generation of leukemic stem cells (LSCs). Understanding the molecular underpinnings of these driver cells throughout their development will be instrumental in the interception of leukemia, the enabling of effective treatment of pre-leukemic conditions, as well as the development of strategies to target frank AML disease. To this point, a number of precancerous myeloid disorders and age-related alterations are proving as instructive models to gain insights into the initiation of LSCs. Here, we explore this myeloid dysregulation at the level of post-transcriptional control, where RNA-binding proteins (RBPs) function as core effectors. Through regulating the interplay of a myriad of RNA metabolic processes, RBPs orchestrate transcript fates to govern gene expression in health and disease. We describe the expanding appreciation of the role of RBPs and their post-transcriptional networks in sustaining healthy hematopoiesis and their dysregulation in the pathogenesis of clonal myeloid disorders and AML, with a particular emphasis on findings described in human stem cells. Lastly, we discuss key breakthroughs that highlight RBPs and post-transcriptional control as actionable targets for precision therapy of AML.

DOI: https://doi.org/10.1002/hem3.116
Blood Adv. 2024 Aug 21. pii: bloodadvances.2024013746. [Epub ahead of print]

Health-Related Quality of Life with Gilteritinib versus Placebo Post-Transplant for FLT3-ITD+ Acute Myeloid Leukemia.

Betty K Hamilton, Bhavik J Pandya, Cristina Ivanescu, Dina Elsouda, Mehdi Hamadani, Yi-Bin Chen, Mark J Levis, Masumi Ueda Oshima, Mark R Litzow, Robert J Soiffer, Celalettin Ustun, Alexander E Perl, Anurag K Singh, Nancy L Geller, Nahla Hasabou, Matt Rosales, David Cella, Laura Corredoira, Carolina Pestana, Mary M Horowitz, Brent R Logan.

BMT CTN 1506 was a phase III randomized trial comparing gilteritinib versus placebo after allogeneic HCT for FLT3-ITD-positive AML. The primary analysis comparing relapse-free survival (RFS) was not statistically significant, however, patients with detectable FLT3-ITD MRD peri-HCT had significantly longer RFS with gilteritinib. The aim of this analysis is to describe the effect of post-HCT gilteritinib versus placebo on health-related quality of life (HRQOL). HRQOL was measured using the Functional Assessment of Cancer Therapy (FACT)-BMT, FACT-Leukemia (-Leu), and EQ-5D-5L at post-HCT randomization, day 29, month 3, 6, 12, 18, 24, and/or end of therapy. HRQOL and clinically meaningful differences were summarized using descriptive statistics and compared using mixed model repeated measures to evaluate longitudinal change from baseline and stratified Cox model to evaluate time to improvement. Between 8/2017 and 7/2020, 356 patients were randomized. HRQOL completion rate was acceptable (>70%) across all time points and measures. There were no differences in FACT-BMT, FACT-Leu, or EQ-5D-5L scores at any time point between cohorts. There was an increase in scores over time, indicating improvement in HRQOL post-HCT. Clinically meaningful improvement and time to improvement in HRQOL was similar in both arms. Despite higher TEAEs with gilteritinib, response to the question of being "bothered by side effects of treatment" did not differ between groups. Subgroup analysis of MRD detectable and negative patients demonstrated no differences in HRQOL between arms. For FLT3-ITD+ AML patients undergoing HCT, gilteritinib maintenance was not associated with any difference in HRQOL or patient-reported impact of side effects. Trial Registration: NCT02997202.

DOI: https://doi.org/10.1182/bloodadvances.2024013746
Bone Marrow Transplant. 2024 Aug 18.

Young (<35 years) haploidentical versus old (≥35 years) mismatched unrelated donors and vice versa for allogeneic stem cell transplantation with post-transplant cyclophosphamide in patients with acute myeloid leukemia in first remission: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Arnon Nagler, Myriam Labopin, Ryszard Swoboda, Didier Blaise, Emanuele Angelucci, Jan Vydra, Lucía López Corral, Stefania Bramanti, Patrizia Chiusolo, Mi Kwon, Yener Koc, Maija Itäla-Remes, Massimo Martino, Alexander Kulagin, Alessandro Busca, Fabio Ciceri, Mohamad Mohty.

We compared transplantation (HSCT) outcomes in AML patients undergoing HSCT with post-transplant cyclophosphamide (PTCy) in first complete remission from 1065 young (<35 years) haploidentical (Haplo) donors (yHaplo) vs. 147 old (≥35 years) mismatched unrelated donors (oMMUD) (first comparison) and from 271 young (<35 years) MMUD (yMMUD) vs. 1315 old (≥35 years) Haplo donors (oHaplo) (second comparison). Acute graft-versus-host disease (aGVHD) grades II-IV were significantly lower in the yHaplo vs. oMMUD group (HR = 0.62, p = 0.007). There were no significant differences in chronic GVHD, non-relapse mortality (NRM), relapse incidence, leukemia-free survival, overall survival, and GVHD-free and relapse-free survival. As for the second comparison, more patients in the oHaplo group had de novo AML, 86.6% vs. 81.9% in the yMMUD group (p = 0.044), while myeloablative conditioning was used more frequently in the yMMUD group, 53.3% vs. 46.8% in the oHaplo group (p = 0.049). aGVHD grades II-IV and NRM were significantly lower in the yMMUD vs. oHaplo group (HR = 0.69, p = 0.013 and HR = 0.60, p = 0.022). All other transplant outcomes did not differ. In conclusion, HSCT from young alternative donors (<35 years) results in a lower incidence of grades II-IV aGVHD. In addition, NRM is lower in HSCT from yMMUD compared to HSCT from oHaplo.

DOI: https://doi.org/10.1038/s41409-024-02400-5
Cytometry B Clin Cytom. 2024 Aug 23.

The role of the primitive marker CD133 in CD34-negative acute myeloid leukemia for the detection of leukemia stem cells.

Tom Reuvekamp, Luca L G Janssen, Lok Lam Ngai, Jannemieke Carbaat-Ham, Daphne den Hartog, Willemijn J Scholten, Angèle Kelder, Diana Hanekamp, Eliza Wensink, Noortje van Gils, Patrycja Gradowska, Bob Löwenberg, Gert J Ossenkoppele, Arjan A van de Loosdrecht, Theresia M Westers, Linda Smit, Costa Bachas, Jacqueline Cloos.

  The most important reason for dismal outcomes in acute myeloid leukemia (AML) is the development of relapse. Leukemia stem cells (LSCs) are hypothesized to initiate relapse, and high CD34+CD38- LSC load is associated with poor prognosis. In 10% of AML patients, CD34 is not or is low expressed on the leukemic cells (<1%), and CD34+CD38- LSCs are absent. These patients are classified as CD34-negative. We aimed to determine whether the primitive marker CD133 can detect LSCs in CD34-negative AML. We retrospectively quantified 148 CD34-negative patients for proportions of CD34-CD133+ and CD133+CD38- cell fractions in the diagnostic samples of CD34-negative patients in the HOVON102 and HOVON132 trials. No prognostic difference was found between patients with high or low proportions of CD34-CD133+, which is found to be aberrantly expressed in AML. A high level of CD133+CD38- cells was not associated with poor overall survival, and expression in AML was similar to normal bone marrow. To conclude, CD133 is useful as an additional primitive marker for the detection of leukemic blast cells in CD34-negative AML. However, CD133+CD38 alone is not suitable for the detection of LSCs at diagnosis.

Keywords:  CD133; acute myeloid leukemia; flow cytometry; leukemia stem cells; measurable residual disease

DOI:  https://doi.org/10.1002/cyto.b.22201
Blood. 2024 Aug 20. pii: blood.2024024220. [Epub ahead of print]

Identifying disease-modifying potential in myelofibrosis clinical trials.

David M Ross, Steven W Lane, Claire N Harrison.

The ultimate goal of bringing most new drugs to the clinic in hematological malignancy is to improve overall survival. However, the use of surrogate endpoints for overall survival is increasingly considered standard practice, since a well validated surrogate endpoint can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma. However, what happens when a clinical trial endpoint that is not a good surrogate for disease-modifying potential becomes ingrained as an expected outcome, and new agents are expected or required to meet this endpoint to demonstrate "efficacy"? JAK inhibitors for myelofibrosis have a specific impact on reducing symptom burden and splenomegaly, but limited impact on the natural history of the disease. Since the introduction of ruxolitinib more than a decade ago there has been modest incremental success in clinical trials for myelofibrosis, but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for myelofibrosis will be accelerated by moving away from using endpoints that are specifically tailored to measure the beneficial effects of JAK inhibitors. We propose that specific measures of relevant disease burden, such as reduction in mutation burden as determined by molecular endpoints, should replace established endpoints. Careful re-analysis of existing data and trials in progress is needed to identify the most useful surrogate endpoints for future MF trials and better serve patient interest.

DOI: https://doi.org/10.1182/blood.2024024220
Bone Marrow Transplant. 2024 Aug 20.

Trends in allogeneic transplantation for favorable risk acute myeloid leukemia in first remission: a longitudinal study of >15 years from the ALWP of the EBMT.

Arnon Nagler, Myriam Labopin, Urpu Salmenniemi, Depei Wu, Didier Blaise, Alessandro Rambaldi, Péter Reményi, Edouard Forcade, Gérard Socié, Patrice Chevallier, Peter von dem Borne, David Burns, Christoph Schmid, Johan Maertens, Nicolaus Kröger, Gesine Bug, Mahmoud Aljurf, Jan Vydra, Kazimierz Halaburda, Fabio Ciceri, Mohamad Mohty.

We assessed outcomes of allogeneic transplantation (HSCT) in favorable risk AML in CR1 over 3 time periods. 1850 patients were included, 2005 to 2009- 222, 2010 to 2014 -392, and 2015 to 2021-1236; 526 with t (8:21), 625 with inv (16), and 699 with NPM1mutFLT3WT. Patients transplanted in 2015-2021 were older (p < 0.0001) with more patients ≥60 years of age (p < 0.0001). The most frequent diagnosis in 2015-2021 was NPM1mutFLT3WT vs. t (8:21) in the 2 earlier periods, (p < 0001). Haploidentical transplants (Haplo) increased from 5.9% to 14.5% (p < 0.0001). Graft-versus-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) was more frequent in 2015-2021 vs. the other 2 periods (p < 0.0001). On multivariate analysis, incidence of total chronic GVHD was reduced in HSCTs performed ≥2015 vs. those performed in 2005-2009, hazard ratio (HR) = 0.74 (95% CI 0.56-0.99, p = 0.046) and GVHD-free, relapse-free survival (GRFS) improved for patients transplanted from 2010-2014 vs. those transplanted in 2005-2009, HR = 0.74 (95% CI 0.56-0.98, p = 0.037). Other HSCT outcomes did not differ with no improvement ≥2015. LFS, OS, and GRFS were inferior in patients with t (8:21) with HR = 1.32 (95% CI 1.03-1.68, p = 0.026), HR = 1.38 (95% CI 1.04-1.83, p = 0.027) and HR = 01.25 (95% CI 1.02-1.53, p = 0.035), respectively. In conclusion, this retrospective analysis of HSCT in patients with favorable risk AML, transplanted over 16 years showed an increased number of transplants in patients ≥60 years, from Haplo donors with PTCy. Most importantly, 3-year GRFS improved ≥2010 and total chronic GVHD reduced ≥2015, with no significant change in other HSCT outcomes.

DOI: https://doi.org/10.1038/s41409-024-02379-z
Leukemia. 2024 Aug 20.

Efficacy and safety of bosutinib in previously treated patients with chronic myeloid leukemia: final results from the BYOND trial.

Carlo Gambacorti-Passerini, Tim H Brümmendorf, Elisabetta Abruzzese, Kevin R Kelly, Vivian G Oehler, Valentín García-Gutiérrez, Henrik Hjorth-Hansen, Thomas Ernst, Eric Leip, Simon Purcell, Gerald Luscan, Andrea Viqueira, Francis J Giles, Andreas Hochhaus.

This final analysis from the phase 4 BYOND trial reports outcomes with bosutinib in patients with previously treated chronic myeloid leukemia (CML); 163 patients with CML resistant/intolerant to previous tyrosine kinase inhibitors received bosutinib (starting dose: 500 mg QD). At study completion (median follow-up, 47.8 months), 48.1% (n = 75/156) of patients with Philadelphia chromosome-positive chronic phase CML were still receiving treatment. Among evaluable patients, 71.8% (95% CI, 63.9-78.9) and 59.7% (95% CI, 51.4-67.7) attained or maintained major molecular response (MMR) and molecular response (MR)4, respectively, at any time on treatment. The majority of patients achieved a deeper molecular response relative to baseline while on bosutinib. Kaplan-Meier probabilities (95% CI) of maintaining MMR and MR4 at 36 months were 87.2% (78.0-92.7) and 80.7% (69.4-88.1), respectively. At 48 months, the Kaplan-Meier overall survival rate was 88.3% (95% CI, 81.8-92.6); there were 17 deaths, including 2 that were considered CML related. Long-term adverse events (AEs) were consistent with the known safety profile of bosutinib, and no new safety issues were identified. The management of AEs through dose reduction maintained efficacy while improving tolerability. These results support the use of bosutinib in patients with previously treated CML.ClinicalTrials.gov, NCT02228382.

DOI: https://doi.org/10.1038/s41375-024-02372-x
Br J Haematol. 2024 Aug 19.

Long-term outcome after allogeneic stem cell transplantation for GATA2 deficiency: An analysis of 67 adults and children from France and Belgium.

Flore Sicre de Fontbrune, Florian Chevillon, Mony Fahd, Kristell Desseaux, Xavier Poiré, Edouard Forcade, Arthur Sterin, Bénédicte Neven, Virginie Gandemer, Sylvain Thepot, Alice Garnier, Bruno Lioure, Ambroise Marcais, Stephanie Nguyen-Quoc, Suzanne Tavitian, Laure Vincent, Jean Donadieu, Matthieu Resche Riggon, Sylvie Chevret, Marlene Pasquet, Regis Peffault de Latour.

  Modalities and timing of haematopoietic stem cell transplant (HSCT) in patients with GATA2 deficiency are still subject to debate. On June 2022, 67 patients (median age 20.6 years) underwent a first allogeneic HSCT among 21 centres. Indications for HSCT were myelodysplastic syndrome (MDS) ≤5% blasts ± immunodeficiency (66%), MDS >5% blasts (15%), acute myeloid leukaemia (19%). Conditioning regimen was myeloablative in 85% and anti-thymocyte globulins were used in 67%. The cumulative incidence (CInc) of acute graft versus host disease (GvHD) grade II-IV and III-IV at day 100 were 42% and 13%, and CInc of chronic and extensive chronic GvHD at 2 years were 42% and 23%. CInc of relapses was 3% and 11% at 1 and 5 years. Overall survival (OS) at 1 and 5 years was 83% and 72% (median follow-up 5.6 years). The factors associated with worse OS in multivariable analysis were the year of HSCT, a history of excess blasts before transplant and peripheral blood stem cell (PBSC) grafts. Age at HSCT, non-myeloablative conditioning and PBSC grafts were associated with increased non-relapse mortality. In conclusion, bone marrow monitoring to identify clonal evolution and perform HSCT before the appearance of excess blast is mandatory.

Keywords:  GATA2; allogeneic; excess blasts; myeloid malignancies; relapse

DOI:  https://doi.org/10.1111/bjh.19691
Clin Cancer Res. 2024 Aug 21.

A PHASE 1 FIRST-IN-HUMAN STUDY OF THE MCL-1 INHIBITOR AZD5991 IN PATIENTS WITH RELAPSED/REFRACTORY HEMATOLOGIC MALIGNANCIES.

Pinkal Desai, Sagar Lonial, Amanda Cashen, Manali Kamdar, Ian Flinn, Susan O'Brien, Jacqueline S Garcia, Neha Korde, Javid Moslehi, Margaret Wey, Patricia Cheung, Shringi Sharma, Damilola Olabode, Hong Chen, Firasath Ali Syed, Mary Liu, Marcio Andrade-Campos, Tapan M Kadia, James S Blachly.

BACKGROUND: AZD5991, a human MCL-1 inhibitor, was assessed for safety, tolerability, pharmacokinetics (PK), and antitumor activity as monotherapy and in combination with venetoclax in patients with relapsed or refractory (R/R) hematologic malignancies.
METHODS: In the monotherapy cohort (n=61), patients with hematologic malignancies received AZD5991 intravenously in escalating doses either once or twice weekly, following intrapatient dose escalation, on a 3-week cycle. In the combination cohort (n=17), patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) received escalating doses of AZD5991 and venetoclax on either a 3-week or 4-week cycle. Primary objectives were safety and maximum tolerated dose; secondary objectives included plasma PK and antitumor activity.
RESULTS: The most common (≥30%) adverse events (AEs) were diarrhea (59.0%), nausea (55.1%), and vomiting (47.4%). Four deaths occurred due to AEs: cardiac arrest, sepsis, tumor lysis syndrome (TLS), and acute respiratory failure; only TLS was related to AZD5991. Dose-limiting toxicities occurred in 5 patients. Three patients with MDS achieved an objective response: 1 marrow complete remission (mCR) without hematologic improvement, 1 partial remission with AZD5991 monotherapy, and 1 mCR with AZD5991+venetoclax. Asymptomatic elevations of troponin I or T were observed in 8 (10.3%) patients. Post hoc retrospective analysis revealed elevated troponin T in 14/31 patients before any AZD5991 dose and in 54/65 patients after any AZD5991 dose at or after cycle 1. There were no associations between elevated troponin and cardiovascular risk factors.
CONCLUSIONS: Treatment with AZD5991 was associated with high incidence of laboratory troponin elevation and a low overall response rate.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-0028
Nat Cell Biol. 2024 Aug 21.

RNA sequestration in P-bodies sustains myeloid leukaemia.

Srikanth Kodali, Ludovica Proietti, Gemma Valcarcel, Anna V López-Rubio, Patrizia Pessina, Thomas Eder, Junchao Shi, Annie Jen, Núria Lupión-Garcia, Anne C Starner, Mason D Bartels, Yingzhi Cui, Caroline M Sands, Ainoa Planas-Riverola, Alba Martínez, Talia Velasco-Hernandez, Laureano Tomás-Daza, Bernhard Alber, Gabriele Manhart, Isabella Maria Mayer, Karoline Kollmann, Alessandro Fatica, Pablo Menendez, Evgenia Shishkova, Rachel E Rau, Biola M Javierre, Joshua Coon, Qi Chen, Eric L Van Nostrand, Jose L Sardina, Florian Grebien, Bruno Di Stefano.

Post-transcriptional mechanisms are fundamental safeguards of progenitor cell identity and are often dysregulated in cancer. Here, we identified regulators of P-bodies as crucial vulnerabilities in acute myeloid leukaemia (AML) through genome-wide CRISPR screens in normal and malignant haematopoietic progenitors. We found that leukaemia cells harbour aberrantly elevated numbers of P-bodies and show that P-body assembly is crucial for initiation and maintenance of AML. Notably, P-body loss had little effect upon homoeostatic haematopoiesis but impacted regenerative haematopoiesis. Molecular characterization of P-bodies purified from human AML cells unveiled their critical role in sequestering messenger RNAs encoding potent tumour suppressors from the translational machinery. P-body dissolution promoted translation of these mRNAs, which in turn rewired gene expression and chromatin architecture in leukaemia cells. Collectively, our findings highlight the contrasting and unique roles of RNA sequestration in P-bodies during tissue homoeostasis and oncogenesis. These insights open potential avenues for understanding myeloid leukaemia and future therapeutic interventions.

DOI: https://doi.org/10.1038/s41556-024-01489-6
Blood Adv. 2024 Aug 16. pii: bloodadvances.2024013636. [Epub ahead of print]

Artificial Intelligence Enabled Interpretation of ECG Images to Predict Hematopoietic Cell Transplantation Toxicity.

Brian C Shaffer, Samantha Brown, Stephanie Chinapen, Kathryn Mangold, Oscar B Lahoud, Francisco Lopez-Jimenez, Wendy L Schaffer, Jennifer E Liu, Sergio A Giralt, Sean M Devlin, Gunjan L Shah, Michael Scordo, Esperanza B Papadopoulos, Heather J Landau, Saad Z Usmani, Miguel-Angel Perales, Paul Friedman, Bernard Gersh, Itzhak Attia, Peter Noseworthy, Ioanna Kosmidou.

Artificial intelligence enabled interpretation of electrocardiogram waveform images (AI-ECG) can identify patterns predictive of future adverse cardiac events. We hypothesized such an approach, which is well described in general medical and surgical patients, would provide prognostic information with respect to the risk of cardiac complications and overall mortality in patients undergoing hematopoietic cell transplantation (HCT) for blood malignancy. We retrospectively subjected ECGs obtained pre-HCT to an externally trained, deep learning model designed to predict risk of atrial fibrillation (AF). Included were 1,377 patients (849 autologous HCT and 528 allogeneic HCT recipients). Median follow-up was 2.9 years. The three-year cumulative incidence of AF was 9% (95% CI: 7-12%) in autologous HCT patients and 13% (10-16%) in allogeneic HCT patients. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with development of clinical AF (Hazard Ratio (HR) 7.37, 3.53-15.4, p <0.001), inferior overall survival (HR: 2.4; 1.3-4.5, p = 0.004), and greater risk of non-relapse mortality (HR 3.36, 1.39-8.13, p = 0.007), without increased risk of relapse. Significant associations with mortality were only noted in allo HCT recipients, where the risk of non-relapse mortality was greater. Compared to calcineurin inhibitor-based graft versus host disease prophylaxis, the use of post-transplantation cyclophosphamide resulted in greater 90-day incidence of AF (13% versus 5%, p = 0.01), corresponding to temporal changes in AI-ECG AF prediction post HCT. In summary, AI-ECG can inform risk of post-transplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment after HCT.

DOI: https://doi.org/10.1182/bloodadvances.2024013636
Biol Open. 2024 Aug 23. pii: bio.060523. [Epub ahead of print]

Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia.

Robyn Lints, Christina A Walker, Omid Delfi, Matthew Prouse, Mandy PohLui De Silva, Stefan K Bohlander, Andrew C Wood.

  RUNX1::RUNX1T1 (R::RT1) Acute Myeloid Leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.

Keywords:  NRAS(G12D); RUNX1::RUNXT1; leukaemia; model; oncogene cooperation; zebrafish

DOI:  https://doi.org/10.1242/bio.060523
Leukemia. 2024 Aug 22.

Evolution of T-cell fitness through AML progression: enhanced bispecific T-cell engager-mediated function of bone marrow T cells at remission compared to initial diagnosis and relapse.

Maryam Kazerani, Anetta Marcinek, Nora Philipp, Bettina Brauchle, Jonathan Jonas Taylor, Helena Domínguez Moreno, Andrea Terrasi, Benjamin Tast, Lisa Rohrbacher, Yingshuai Wang, Maximilian Warm, Alica-Joana Emhardt, Giulia Magno, Karsten Spiekermann, Tobias Herold, Tobias Straub, Sebastian Theurich, Gunnar Schotta, Roman Kischel, Veit L Bücklein, Marion Subklewe.

DOI: https://doi.org/10.1038/s41375-024-02387-4
Sci Immunol. 2024 Aug 23. 9(98): eadk3469

Hematopoietic stem cell heterogeneity and age-associated platelet bias are evolutionarily conserved.

Merve Aksöz, Grigore-Aristide Gafencu, Bilyana Stoilova, Mario Buono, Ying Zhang, Sven Turkalj, Yiran Meng, Niels Asger Jakobsen, Marlen Metzner, Sally-Ann Clark, Ryan Beveridge, Supat Thongjuea, Paresh Vyas, Claus Nerlov.

Hematopoietic stem cells (HSCs) reconstitute multilineage human hematopoiesis after clinical bone marrow (BM) transplantation and are the cells of origin of some hematological malignancies. Although HSCs provide multilineage engraftment, individual murine HSCs are lineage biased and contribute unequally to blood cell lineages. Here, we performed high-throughput single-cell RNA sequencing in mice after xenograft with molecularly barcoded adult human BM HSCs. We demonstrated that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identified platelet-biased and multilineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young and aged BM showed that both the proportion of platelet-biased HSCs and their level of transcriptional platelet priming increase with age. Therefore, platelet-biased HSCs and their increased prevalence and transcriptional platelet priming during aging are conserved features of mammalian evolution.

DOI: https://doi.org/10.1126/sciimmunol.adk3469
Exp Hematol Oncol. 2024 Aug 16. 13(1): 84

Enhanced depletion of MLL-fusion proteins in acute leukemia: potential for improved therapeutic outcomes.

Noelia Che, Sandra Cantilena, Remi Looi-Somoye, Danesh Sundar, Kent Fung, Jasper de Boer, Owen Williams.

  Rearrangements of the MLL (KMT2A) locus are associated with aggressive leukaemia of both myeloid and lymphoid lineages, that present profound therapeutic challenges in pediatric and adult patient populations. MLL-fusion genes resulting from these rearrangements function as driving oncogenes and have been the focus of research aimed at understanding mechanisms underlying their leukemogenic activity and revealing novel therapeutic opportunities. Inspired by the paradigm of depleting the PML-RARA fusion protein in acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide, we conducted a screen to identify FDA-approved drugs capable of depleting MLL-fusion protein expression in leukemia cells. Previously, we reported potent anti-leukemia effects of disulfiram (DSF), identified through this screen. In the present study, we demonstrate that another hit compound, niclosamide (NSM), is also able to deplete MLL-fusion proteins derived from a range of different MLL-fusion genes in both acute myeloid (AML) and acute lymphoid (ALL) leukemias. Loss of MLL-fusion protein appeared to result from inhibition of global protein translation by NSM. Importantly, combination of DSF with NSM enhanced MLL-fusion protein depletion. This led to more profound inhibition of downstream transcriptional leukemogenic programs regulated by MLL-fusion proteins and more effective killing of both MLL-rearranged AML and ALL cells. In contrast, DSF/NSM drug combination had little impact on normal hematopoietic progenitor cell differentiation. This study demonstrates that two FDA-approved drugs with excellent safety profiles can be combined to increase the efficacy of MLL-fusion protein depletion and elimination of MLL-rearranged leukaemia.

Keywords:  Acute lymphoblastic leukemia; Acute myeloid leukemia,; KMT2A; MLL

DOI:  https://doi.org/10.1186/s40164-024-00556-w
Blood Adv. 2024 Aug 21. pii: bloodadvances.2024013853. [Epub ahead of print]

Haploidentical versus HLA-matched sibling donor HCT with PTCy prophylaxis: HLA factors and donor age considerations.

Rohtesh S Mehta, Jeremy Leon Ramdial, Partow Kebriaei, Richard E Champlin, Uday R Popat, Katayoun Rezvani, Elizabeth J Shpall.

HLA-matched sibling donors (MSDs) are preferred for hematopoietic cell transplantation (HCT). However, the use of alternative donors, especially haploidentical, is increasing, as is our understanding of the impact of HLA factors such as B-leader and DRB1-matching on its outcomes. Yet, data comparing these donor types, particularly considering these HLA factors, is lacking. Herein, we compared haploidentical-HCT (n=1052) to MSD-HCT (n=400), both with posttransplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis. The haploidentical group included older patients (median 49 vs. 46 years) with younger donors (39 vs. 45 years) compared to MSD recipients. Other characteristics were similar. In multivariate analysis, haploidentical group had similar overall survival (OS) [hazard ratio (HR), [95% confidence interval] 0.94, [0.78-1.14], p=.54], non-relapse mortality (HR 0.98 [0.72-1.32], p=.87) and relapse (HR 0.87, [0.70-1.08], p=.20) as the MSD group. Younger donors age was a significant predictor of improved OS. Next, we directly compared the outcomes of 'younger' haploidentical (donor age <35 years, n=347) versus an 'older' MSD (donor age >=50 years, n=143) in 'older' recipients (patient age >=50 years). Patients with 'younger' haploidentical B-leader matched donors had significantly superior OS (HR 0.65, [0.48-0.90], p=.009) compared to 'older' MSD group. Additionally, patients with 'younger' DRB1-mismatched haploidentical donors (HR 0.63 [0.46-0.87], p=.004) had significantly lower risk of relapse than 'older' MSDs. Our study suggests that haploidentical-HCT may offer comparable outcomes to MSD-PTCy HCT. Moreover, among 'older' patients, a 'younger' haploidentical B-leader matched donor might be preferable to an 'older' MSD. These findings need validation in larger datasets.

DOI: https://doi.org/10.1182/bloodadvances.2024013853
Br J Haematol. 2024 Aug 20.

The CALR mutations enhance the expression of the immunosuppressive proteins GARP and LAP on peripheral blood lymphocytes through increased binding of activated platelets.

Morten Orebo Holmström, Josephine Hallundbæk Ruders, Caroline Hasselbalch Riley, Morten Kranker Larsen, Jacob Handlos Grauslund, Lasse Kjær, Vibe Skov, Christina Ellervik, Belinda B Guo, Matthew Linden, Hans Carl Hasselbalch, Mads Hald Andersen.

  Recently, an antibody which inhibits the glycoprotein A repetitions predominant (GARP)-mediated release of active transforming growth factor beta (TGFβ) from the TGFβ propeptide latency-associated peptide (LAP) showed preclinical activity in a murine model of the chronic myeloproliferative neoplasms (MPN). Consequently, we investigated the expression of the immunosuppressive molecules LAP and GARP on peripheral blood lymphocytes from 56 MPN patients and 11 healthy donors (HD). We found that lymphocytes from patients with MPN express higher levels of LAP and GARP with no strong differences found between the different MPN diagnoses. The impact of clinical parameters on the expression of LAP and GARP by lymphocytes showed that patients with calreticulin (CALR)mut MPN have increased expression compared with HD and patients with the Januskinase2 (JAK2) mutation. The fraction of lymphocytes bound to activated platelets (aPLT) strongly correlate to LAP and GARP expression suggesting that it is not the lymphocytes themselves but aPLT, which confer the increased expression of GARP and LAP on MPN patient lymphocytes. Notably, no differences in neither platelet counts nor anti-thrombotic therapy was identified between patients with JAK2- and CALRmut patients. Analysis of platelet gene expression failed to identify differences in expression of relevant genes between JAK2- and CALRmut patients.

Keywords:  CALR; GARP; TGFβ; adaptive immunity; immune escape; myeloproliferative neoplasms; platelets

DOI:  https://doi.org/10.1111/bjh.19711
Am J Hematol. 2024 Jun 22.

Starry sky pattern predicts RAS pathway activation in NPM1-mutated acute myeloid leukemia.

Alessandra Venanzi, Valeria Cardinali, Vincenzo Perriello, Francesco Albano, Gaetano Cimino, Giovanni Martino, Andrea Marra, Paolo Sportoletti, Vibeke Andresen, Bjorn T Gjertsen, Simona Sica, Patrizia Chiusolo, Maria Paola Martelli, Enrico Tiacci, Brunangelo Falini.

DOI: https://doi.org/10.1002/ajh.27415
Nat Genet. 2024 Aug 21.

Organismal metabolism regulates the expansion of oncogenic PIK3CA mutant clones in normal esophagus.

Albert Herms, Bartomeu Colom, Gabriel Piedrafita, Argyro Kalogeropoulou, Ujjwal Banerjee, Charlotte King, Emilie Abby, Kasumi Murai, Irene Caseda, David Fernandez-Antoran, Swee Hoe Ong, Michael W J Hall, Christopher Bryant, Roshan K Sood, Joanna C Fowler, Albert Pol, Christian Frezza, Bart Vanhaesebroeck, Philip H Jones.

Oncogenic PIK3CA mutations generate large clones in aging human esophagus. Here we investigate the behavior of Pik3ca mutant clones in the normal esophageal epithelium of transgenic mice. Expression of a heterozygous Pik3caH1047R mutation drives clonal expansion by tilting cell fate toward proliferation. CRISPR screening and inhibitor treatment of primary esophageal keratinocytes confirmed the PI3K-mTOR pathway increased mutant cell competitive fitness. The antidiabetic drug metformin reduced mutant cell advantage in vivo and in vitro. Conversely, metabolic conditions such as type 1 diabetes or diet-induced obesity enhanced the competitive fitness of Pik3caH1047R cells. Consistently, we found a higher density of PIK3CA gain-of-function mutations in the esophagus of individuals with high body mass index compared with those with normal weight. We conclude that the metabolic environment selectively influences the evolution of the normal epithelial mutational landscape. Clinically feasible interventions to even out signaling imbalances between wild-type and mutant cells may limit the expansion of oncogenic mutants in normal tissues.

DOI: https://doi.org/10.1038/s41588-024-01891-8
Ann Hematol. 2024 Aug 22.

Role of allogeneic hematopoietic cell transplantation in VEXAS syndrome.

Ajoy L Dias, Emma M Groarke, Dennis Hickstein, Bhavisha Patel.

  VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a newly diagnosed syndrome comprising severe systemic inflammatory and hematological manifestations including myelodysplastic syndrome and plasma cell dyscrasia. Since its discovery four years ago, several groups have identified pleomorphic clinical phenotypes, but few effective medical therapies exist which include Janus Kinase (JAK) inhibitors, interleukin inhibitors (IL-1 and IL-6), and hypomethylating agents. Prospective trials are lacking at this time and most patients remain corticosteroid dependent. VEXAS has a high morbidity from frequent life threatening inflammatory symptoms and risk of progression to hematological malignancies and has an overall survival of 50% at 10 years. Allogeneic stem cell transplant (allo-HCT) is a curative option for this disease caused by somatic mutations in the UBA1 gene. Here we outline the role of allo-HCT in treating patients with VEXAS syndrome, highlighting the outcomes from several single-institution studies and case reports. Prospective trials will be required to precisely define the role of allo-HCT in the management of VEXAS syndrome.

Keywords:  Allogeneic stem cell transplantation (Allo-HCT); Janus Kinase (JAK) inhibitors; Myelodysplastic syndrome (MDS); VEXAS syndrome

DOI:  https://doi.org/10.1007/s00277-024-05942-2
Blood Cancer J. 2024 Aug 21. 14(1): 141

Busulfan-fludarabine versus busulfan-cyclophosphamide for allogeneic transplant in acute myeloid leukemia: long term analysis of GITMO AML-R2 trial.

Gianluca Cavallaro, Anna Grassi, Chiara Pavoni, Maria Caterina Micò, Alessandro Busca, Irene Maria Cavattoni, Stella Santarone, Carlo Borghero, Attilio Olivieri, Giuseppe Milone, Patrizia Chiusolo, Pellegrino Musto, Riccardo Saccardi, Francesca Patriarca, Fabrizio Pane, Giorgia Saporiti, Paolo Rivela, Elisabetta Terruzzi, Raffaella Cerretti, Giuseppe Marotta, Angelo Michele Carella, Arnon Nagler, Domenico Russo, Paolo Corradini, Paolo Bernasconi, Anna Paola Iori, Luca Castagna, Nicola Mordini, Elena Oldani, Carmen Di Grazia, Andrea Bacigalupo, Alessandro Rambaldi.

We report the long-term results of a randomized trial (GITMO, AML-R2), comparing 1:1 the combination of busulfan and cyclophosphamide (BuCy2, n = 125) and the combination of busulfan and fludarabine (BuFlu, n = 127) as conditioning regimen in acute myeloid leukemia patients (median age 51 years, range 40-65) undergoing allogeneic hematopoietic stem cell transplantation. With a median follow-up of 6 years, significantly better non-relapse mortality (NRM) was confirmed in BuFlu recipients, which is sustained up to 4 years after transplant (10% vs. 20%, p = 0.0388). This difference was higher in patients older than 51 years (11% in BuFlu vs. 27% in BuCy2, p = 0.0262). The cumulative incidence of relapse, which was the first cause of death in the entire study population, did not differ between the two randomized arms. Similarly, the leukemia-free survival (LFS) and overall survival (OS) were not different in the two cohorts, even when stratifying patients per median age. Graft-and relapse-free survival (GRFS) in BuFlu arm vs. the BuCy2 arm was 25% vs. 20% at 4 years and 20% vs. 17% at 10 years. Hence, the benefit gained by NRM reduction is not offsets by an increased relapse. Leukemia relapse remains a major concern, urging the development of new therapeutic approaches.

DOI: https://doi.org/10.1038/s41408-024-01116-5
Blood Adv. 2024 Aug 20. pii: bloodadvances.2024014173. [Epub ahead of print]

The use of metformin and risk of myeloproliferative neoplasms among patients with no registered markers of diabetes.

Daniel Tuyet Kristensen, Andreas Kiesbye Øvlisen, Tarec Christoffer El Galaly, Anne Stidsholt Roug.

DOI: https://doi.org/10.1182/bloodadvances.2024014173
Blood Adv. 2024 Aug 23. pii: bloodadvances.2024013535. [Epub ahead of print]

Cardiac Events after Allo-HCT in Patients with Acute Myeloid Leukemia. Study Conducted con Behalf of the GETH-TC.

M Queralt Salas, Enric Cascos, Alberto Lopez-Garcia, Estefanía Pérez López, Mónica Baile, Carlos Martín-Rodriguez, María Jesús Pascual-Cascón, Marta Luque Garrido, Albert Esquirol, Inmaculada Heras, Felipe Peña-Muñóz, Itziar Oiartzabal Ormategi, Adolfo Jesús Sáez-Marín, Sara Fernández-Luis, Juan Jose Dominguez-Garcia, Sara Villar, Miguel Fernández de Sanmamed Girón, Leslie González-Pinedo, Lucia Garcia-Maño, Ana Pilar Gonzalez-Rodriguez, Tamara Torrado Chedas, Silvia Filafferro, Angel Cedillo, Guillermo Ortí, Manuel Jurado.

This multicenter study sponsored by GETH-TC aimed to investigate the incidence and predictors of early (within the first 100 days) and late cardiac events (CE) (ECE and LCE) following allo-HCT in AML patients treated with anthracyclines, focusing on exploring the impact of PTCY on cardiac complications and the impact of CE on overall survival (OS) and non-relapse mortality (NRM). 1020 AML patients were included. PTCY was given to 450 (44.1%) adults. Overall, 94 (9.2) patients experienced CE and being arrythmias, pericardial complications, and heart failure the most prevalent ones. ECE occurred in 49 (4.8%) patients in a median of 13 days after allo-HCT, while LCE were diagnosed in 45 (4.4%) patients in a median of 3.6 years after transplant. Using PTCY increased the risk for ECE in multivariate analysis (HR 2.86, P=0.007), but did not not significantly affect the risk for LCE (HR 1.06, P=0.892). The impact of variables on outcomes revealed was investigated using multivariate regression analyses and revealed that the diagnosis of CE significantly decreased the likelihood of OS (HR 1.66, P=0.005) and increased the likelihood of NRM (HR 2.88, P<0.001). Furthermore, despite using PTCY increased the risk for ECE, its administration was found to be beneficial for OS (HR 0.71, P=0.026). The study suggests that while the incidence of CE was relatively low, it significantly impacted mortality. Standard doses of PTCY increased ECE risk but were associated with improved OS. Therefore, implementing protocols to prevent cardiac complications is recommended, considering the widespread adoption of PTCY in allo-HCT.

DOI: https://doi.org/10.1182/bloodadvances.2024013535
Haematologica. 2024 Aug 15. 0

Single-cell proteo-transcriptomic profiling reveals altered characteristics of stem and progenitor cells in patients receiving cytoreductive hydroxyurea in early-phase chronic myeloid leukemia.

Hana Komic, Malin S Nilsson, Lovisa Wennström, Tagore Sanketh Bandaru, Pekka Jaako, Kristoffer Hellstrand, Fredrik B Thorén, Anna Martner.

Hydroxyurea (HU) is frequently used in the early phase of chronic myeloid leukemia (CML) to achieve cytoreduction prior to tyrosine kinase inhibitor (TKI) therapy. However, its impact on CML stem and progenitor cells (SPC) remains largely unknown. This study utilized targeted proteo-transcriptomic expression data on 596 genes and 51 surface proteins in 60,000 CD14-CD34+ cells from chronic phase CML patients to determine effects of shortterm HU treatment (4-19 days) on CML SPC. Peripheral blood and bone marrow samples were obtained from 17 CML patients eligible for short-term HU treatment (three patients before and after HU; seven patients before HU; and seven patients after HU) and subjected to single-cell CITE-seq and/or flow cytometry analysis. The analysis revealed enhanced frequencies of hemoglobin-expressing (HBA1, HBA2, HBB) erythroid progenitor cells in blood and bone marrow following HU treatment. In addition, there was an accumulation of cell subsets with S/G2/M phase-related gene and protein expression, likely representing cells arrested in, or progressing slowly through, the cell cycle. The increased frequency of cells in S/G2/M phase after HU was observed already among the most immature leukemic stem cells (LSC), and patients with a high fraction of LSC in the S/G2/M phase showed poor responsiveness to TKI treatment. We conclude that short-term HU treatment entails differentiation of erythroid progenitor cells and alters the characteristics of LSC in CML. The results imply that studies of LSC and progenitor populations in CML should take effects of initial HU therapy into account.

DOI: https://doi.org/10.3324/haematol.2024.285071
Blood. 2024 Aug 22. 144(8): 918

AML, myelodysplasia related, with STAG2 and SRSF2 comutations with myelocyte arrest.

Zhaodong Xu, Ruth Padmore.

DOI: https://doi.org/10.1182/blood.2024025049
Clin Lymphoma Myeloma Leuk. 2024 Jun 25. pii: S2152-2650(24)00239-8. [Epub ahead of print]

SOHO State of the Art Update and Next Questions: Current and Emerging Therapies for Systemic Mastocytosis.

Helen T Chifotides, Prithviraj Bose.

  Systemic mastocytosis (SM) is a heterogeneous myeloid neoplasm, characterized by clonal proliferation of mast cells (MCs) in ≥ 1 extracutaneous organs, including the bone marrow (BM) and gastrointestinal tract. Aberrant MC proliferation is driven by mutation KIT D816V in ≈90-95% of SM patients. Indolent SM (ISM) is the most common SM subtype with various symptoms that can be severe. Advanced SM (AdvSM) has markedly poor prognosis. The advent of KIT inhibitors, targeting mutant KIT and neoplastic MCs, led to a paradigm shift in SM management and markedly improved outcomes. Midostaurin inaugurated the era of KIT inhibitors and was approved for AdvSM in 2017. Avapritinib is the first highly potent and selective inhibitor of KIT D816V that was approved to treat AdvSM and symptomatic ISM (platelets ≥ 50 × 109/L), in the US, in 2021 and 2023, respectively. Pooled analysis of the EXPLORER and PATHFINDER studies, assessing avapritinib in AdvSM, demonstrated rapid and profound reductions (≥ 50%) in markers of MC burden, high response rates (71-75%), and prolonged survival. In the PIONEER study, avapritinib significantly and rapidly improved symptoms/quality of life, and reduced markers of MC burden in ISM patients. The investigational agents bezuclastinib and elenestinib are highly potent and selective inhibitors of KIT D816V with minimal blood-brain barrier penetration. Bezuclastinib reduced markers of MC burden by ≥ 50% in ≈50% of AdvSM patients and ≈90-100% of nonAdvSM patients and reduced symptoms (≥ 50%) in the APEX and SUMMIT studies, respectively. Elenestinib demonstrated dose-dependent efficacy in reducing MC burden markers and improved symptoms in ISM patients in the HARBOR study.

Keywords:  KIT inhibtitor; SM-AHN; advanced systemic mastocytosis (AdvSM); avapritinib; bezuclastinib; elenestinib; indolent systemic mastocytosis (ISM); mast cells; midostaurin

DOI:  https://doi.org/10.1016/j.clml.2024.06.005
Nat Biotechnol. 2024 Aug 21.

Systematic identification of minor histocompatibility antigens predicts outcomes of allogeneic hematopoietic cell transplantation.

Nicoletta Cieri, Nidhi Hookeri, Kari Stromhaug, Liang Li, Julia Keating, Paula Díaz-Fernández, Valle Gómez-García de Soria, Jonathan Stevens, Raphael Kfuri-Rubens, Yiren Shao, Kameron A Kooshesh, Kaila Powell, Helen Ji, Gabrielle M Hernandez, Jennifer Abelin, Susan Klaeger, Cleo Forman, Karl R Clauser, Siranush Sarkizova, David A Braun, Livius Penter, Haesook T Kim, William J Lane, Giacomo Oliveira, Leslie S Kean, Shuqiang Li, Kenneth J Livak, Steven A Carr, Derin B Keskin, Cecilia Muñoz-Calleja, Vincent T Ho, Jerome Ritz, Robert J Soiffer, Donna Neuberg, Chip Stewart, Gad Getz, Catherine J Wu.

T cell alloreactivity against minor histocompatibility antigens (mHAgs)-polymorphic peptides resulting from donor-recipient (D-R) disparity at sites of genetic polymorphisms-is at the core of the therapeutic effect of allogeneic hematopoietic cell transplantation (allo-HCT). Despite the crucial role of mHAgs in graft-versus-leukemia (GvL) and graft-versus-host disease (GvHD) reactions, it remains challenging to consistently link patient-specific mHAg repertoires to clinical outcomes. Here we devise an analytic framework to systematically identify mHAgs, including their detection on HLA class I ligandomes and functional verification of their immunogenicity. The method relies on the integration of polymorphism detection by whole-exome sequencing of germline DNA from D-R pairs with organ-specific transcriptional- and proteome-level expression. Application of this pipeline to 220 HLA-matched allo-HCT D-R pairs demonstrated that total and organ-specific mHAg load could independently predict the occurrence of acute GvHD and chronic pulmonary GvHD, respectively, and defined promising GvL targets, confirmed in a validation cohort of 58 D-R pairs, for the prevention or treatment of post-transplant disease recurrence.

DOI: https://doi.org/10.1038/s41587-024-02348-3
Nat Commun. 2024 Aug 16. 15(1): 7076

The Fanconi anemia core complex promotes CtIP-dependent end resection to drive homologous recombination at DNA double-strand breaks.

Bert van de Kooij, Fenna J van der Wal, Magdalena B Rother, Wouter W Wiegant, Pau Creixell, Merula Stout, Brian A Joughin, Julia Vornberger, Matthias Altmeyer, Marcel A T M van Vugt, Michael B Yaffe, Haico van Attikum.

During the repair of interstrand crosslinks (ICLs) a DNA double-strand break (DSB) is generated. The Fanconi anemia (FA) core complex, which is recruited to ICLs, promotes high-fidelity repair of this DSB by homologous recombination (HR). However, whether the FA core complex also promotes HR at ICL-independent DSBs, for example induced by ionizing irradiation or nucleases, remains controversial. Here, we identified the FA core complex members FANCL and Ube2T as HR-promoting factors in a CRISPR/Cas9-based screen. Using isogenic cell line models, we further demonstrated an HR-promoting function of FANCL and Ube2T, and of their ubiquitination substrate FANCD2. We show that FANCL and Ube2T localize at DSBs in a FANCM-dependent manner, and are required for the DSB accumulation of FANCD2. Mechanistically, we demonstrate that FANCL ubiquitin ligase activity is required for the accumulation of CtIP at DSBs, thereby promoting end resection and Rad51 loading. Together, these data demonstrate a dual genome maintenance function of the FA core complex and FANCD2 in promoting repair of both ICLs and DSBs.

DOI: https://doi.org/10.1038/s41467-024-51090-6
Blood Adv. 2024 Aug 20. pii: bloodadvances.2024013170. [Epub ahead of print]

Combination Therapy with Ruxolitinib and Pegylated Interferon-alpha2a in Newly Diagnosed Patients with Polycythemia Vera.

Anders Lindholm Soerensen, Vibe Skov, Lasse Kjær, Mads Emil Bjørn, Christina Schjellerup Eickhardt-Dalbøge, Morten Kranker Larsen, Claus Henrik Nielsen, Carsten Thomsen, Lise Mette Rahbek Gjerdrum, Trine A Knudsen, Christina Ellervik, Ulrik Malthe Overgaard, Christen Lykkegaard Andersen, Hans Carl Hasselbalch.

We report the two-year end-of-study results from the phase 2 COMBI II clinical trial (#EudraCT2018-004150-13) investigating the combination treatment of ruxolitinib and low-dose pegylated interferon-α2a in patients with newly diagnosed polycythemia vera. The primary outcome was safety and key secondary endpoints were efficacy, based on hematological parameters, quality of life measurements, and JAK2V617F variant allele frequency (VAF). We used the 2013 ELN and IWG-MRT remission criteria. The remission criteria included remissions in symptoms, splenomegaly, peripheral blood counts, and bone marrow. We included 25 patients with PV with a median age of 70 years; 5 of those had prior thromboembolic events and three had CT-verified splenomegaly. Two patients stopped both study drugs, one of these due to progression to post-PV myelofibrosis; only that patient had a grade 3 infection. No events of herpes zoster infections were observed. No patients discontinued treatment due to psychiatric symptoms. The peripheral blood cell count remission rate was 92% at 24 months. Using the 2013 ELN and IWG-MRT remission criteria, 14 (56%) achieved remission at 24 months; 3 (12%) achieved complete remission, and 11 (44%) achieved partial remission. The following items from the Myeloproliferative Neoplasm Symptom Total Symptom Score were significantly reduced: abdominal discomfort, night sweats, itching, and bone pain. The median JAK2V617F VAF decreased from 47% (95%CI, 35-59%) to 7% (95%CI, 3-15%), and 60% of patients achieved molecular remission. In conclusion, combination treatment improved cell counts; bone marrow cellularity, and fibrosis; and decreased JAK2V617F VAF; with acceptable toxicity in patients with polycythemia vera. EudraCT2018-004150-13.

DOI: https://doi.org/10.1182/bloodadvances.2024013170
Nat Cardiovasc Res. 2024 ;3(8): 951-969

Endothelial LATS2 is a suppressor of bone marrow fibrosis.

Kishor K Sivaraj, Paul-Georg Majev, Backialakshmi Dharmalingam, Silke Schröder, Bella Banjanin, Martin Stehling, Dagmar Zeuschner, Alfred Nordheim, Rebekka K Schneider, Ralf H Adams.

  Myelofibrosis and osteosclerosis are fibrotic diseases disrupting bone marrow function that occur in various leukemias but also in response to non-malignant alterations in hematopoietic cells. Here we show that endothelial cell-specific inactivation of the Lats2 gene, encoding Hippo kinase large tumor suppressor kinase 2, or overexpression of the downstream effector YAP1 induce myofibroblast formation and lead to extensive fibrosis and osteosclerosis, which impair bone marrow function and cause extramedullary hematopoiesis in the spleen. Mechanistically, loss of LATS2 induces endothelial-to-mesenchymal transition, resulting in increased expression of extracellular matrix and secreted signaling molecules. Changes in endothelial cells involve increased expression of serum response factor target genes, and, strikingly, major aspects of the LATS2 mutant phenotype are rescued by inactivation of the Srf gene. These findings identify the endothelium as a driver of bone marrow fibrosis, which improves understanding of myelofibrotic and osteosclerotic diseases, for which drug therapies are currently lacking.

Keywords:  Calcification; Cardiovascular biology

DOI:  https://doi.org/10.1038/s44161-024-00508-x
Haematologica. 2024 Aug 15. 0

Outcome of 421 adult patients with Philadelphia-negative acute lymphoblastic leukemia treated under an intensive program inspired by the GIMEMA LAL1913 clinical trial: a Campus ALL study.

Davide Lazzarotto, Marco Cerrano, Cristina Papayannidis, Sabina Chiaretti, Federico Mosna, Nicola Fracchiolla, Patrizia Zappasodi, Silvia Imbergamo, Maria Ilaria Del Principe, Monia Lunghi, Federico Lussana, Matteo Piccini, Monica Fumagalli, Michelina Dargenio, Prassede Salutari, Fabio Forghieri, Teresa Giulia Da Molin, Massimiliano Bonifacio, Matteo Olivi, Fabio Giglio, Silvia Trappolini, Matteo Leoncin, Antonino Mule, Mario Delia, Crescenza Pasciolla, Francesco Grimaldi, Benedetta Cambo, Lidia Santoro, Fabio Guolo, Paola Minetto, Marzia Defina, Patrizia Chiusolo, Matteo Fanin, Endri Mauro, Lara Aprile, Carla Mazzone, Fabio Trastulli, Maria Ciccone, Marco De Gobbi, Alessandro Cignetti, Eleonora De Bellis, Valentina Mancini, Alfonso Piciocchi, Marco Vignetti, Giovanni Marsili, Irene Della Starza, Renato Fanin, Mario Luppi, Felicetto Ferrara, Giovanni Pizzolo, Renato Bassan, Robin Foa, Anna Candoni.

The introduction of pediatric-inspired regimens in adult Philadelphia-negative acute lymphoblastic leukemia (Ph-ALL) has significantly improved patients' prognosis. Within the Campus ALL network we analyzed the outcome of adult Ph-ALL patients treated according to the GIMEMA LAL1913 protocol outside the clinical trial, to compare the real-life data with the study results. We included 421 consecutive patients, with a median age of 42 years. The complete remission (CR) rate after the first course of chemotherapy was 94% and a measurable residual disease (MRD) negativity after the third course was achieved in 72% of patients. The 3-year overall survival (OS) and disease-free survival (DFS) were 67% and 57%, respectively. In a multivariate analysis, MRD positivity negatively influenced DFS. In a time-dependent analysis including only very high risk (VHR) and MRD positive cases, transplanted (HSCT) patients had a significantly better DFS than non-HSCT ones (P=0.0017). During induction, grade ≥2 pegaspargase-related hepato-toxicity was observed in 25% of patients (vs 12% in the GIMEMA LAL1913 trial, P=0.0003). In this large real-life cohort of Ph-ALL, we confirmed the very high CR rate and a superimposable OS and DFS compared to the GIMEMA LAL1913 clinical trial: CR rate after C1 94% vs 85%, P=0.0004; 3-year OS 67% vs 67%, P=0.94; 3-year DFS 57% vs 63%, P=0.17. HSCT confirms its important role in VHR and MRD-positive patients. The rate of pegaspargase-related toxicity was significantly higher in the real-life setting, emphasizing the importance of dose adjustment in the presence of risk factors to avoid excessive toxicity.

DOI: https://doi.org/10.3324/haematol.2024.285638