bims-tremyl 2023-01-29 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023–01–29
33 papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London

Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells.
Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome.
FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile.
Abnormal Platelet Counts and Clonal Hematopoiesis in the General Population.
Synergistic targeting of DNA-PK and KIT signaling pathways in KIT mutant acute myeloid leukemia.
SAMHD1 Single Nucleotide Polymorphisms Impact Outcome in Children with Newly Diagnosed Acute Myeloid Leukemia.
Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia.
Clinical Significance of bZIP in-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia.
TET2 truncating mutations predict a worse outcome in blastic plasmacytoid dendritic cell neoplasm.
The Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-line BCR::ABL1 Tyrosine Kinase Inhibitors.
Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.
High BM plasma S100A8/A9 is associated with a perturbed microenvironment and poor prognosis in myelodysplastic syndromes.
Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT.
Chromatin complex dependencies reveal targeting opportunities in leukemia.
Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.
Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.
BET inhibitors rescue anti-PD1 resistance by enhancing TCF7 accessibility in leukemia-derived terminally exhausted CD8+ T cells.
Matching-adjusted indirect comparison of asciminib versus other treatments in chronic-phase chronic myeloid leukemia after failure of two prior tyrosine kinase inhibitors.
AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.
TP53 signal pathway confers potential therapy target in acute myeloid leukemia.
Comparison of haploidentical hematopoietic stem cell transplantation with chemotherapy in older adults with acute myeloid leukemia.
Molecular analysis of phenotypic heterogeneity in JAK2V617F-positive myeloproliferative neoplasms reveals a potential target for therapy.
Outcomes of Breakthrough COVID-19 Infections in Patients with Hematologic Malignancies.
Considerations for Drug Development in Myelodysplastic Syndromes.
Myelodysplastic syndromes, thy name is heterogeneity.
Differential inhibition of T cell receptor and STAT5 signalling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.
Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways.
Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.
Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.
The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial.
Targeted Therapy for MPNs: Going Beyond JAK Inhibitors.
Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations.
Mutant NPM1: nuclear export and the mechanism of leukemogenesis.

Blood Adv. 2023 Jan 27. pii: bloodadvances.2022008787. [Epub ahead of print]

Enhancer remodeling drives MLL oncogene-dependent transcriptional dysregulation in leukemia stem cells.

Feng Pan, Masayuki Iwasaki, Wenqi Wu, Yanan Jiang, Xin Yang, Li Zhu, Zhigang Zhao, Michael L Cleary.

Acute myeloid leukemia (AML) with MLL gene rearrangement (MLLr) comprises a cellular hierarchy in which a subpopulation of cells serves as functional leukemia stem cells (LSCs). They are maintained by a unique gene expression program and chromatin states, which are thought to reflect the actions of enhancers. Here, we delineate the active enhancer landscape and observe pervasive enhancer malfunction in LSCs. Reconstruction of regulatory networks revealed a master set of hematopoietic transcription factors. We show that EP300 is an essential transcriptional coregulator for maintaining LSC oncogenic potential, as it controls essential gene expression through modulation of H3K27 acetylation and assessments of transcription factor dependencies. Moreover, the EP300 inhibitor A-485 affects LSC growth by targeting enhancer activity via histone acetyltransferase domain inhibition. Together, these data implicate a perturbed MLLr-specific enhancer accessibility landscape, suggesting the possibility for disruption of the LSC enhancer regulatory axis as a promising therapeutic strategy in AML.

DOI: https://doi.org/10.1182/bloodadvances.2022008787
Blood Cancer J. 2023 Jan 24. 13(1): 18

Alterations of cohesin complex genes in acute myeloid leukemia: differential co-mutations, clinical presentation and impact on outcome.

Jan-Niklas Eckardt, Sebastian Stasik, Christoph Röllig, Tim Sauer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H Brümmendorf, Ralph Naumann, Björn Steffen, Volker Kunzmann, Hermann Einsele, Markus Schaich, Andreas Burchert, Andreas Neubauer, Kerstin Schäfer-Eckart, Christoph Schliemann, Stefan W Krause, Regina Herbst, Mathias Hänel, Maher Hanoun, Ulrich Kaiser, Martin Kaufmann, Zdenek Rácil, Jiri Mayer, Tiago Cerqueira, Frank Kroschinsky, Wolfgang E Berdel, Hubert Serve, Carsten Müller-Tidow, Uwe Platzbecker, Claudia D Baldus, Johannes Schetelig, Timo Siepmann, Martin Bornhäuser, Jan Moritz Middeke, Christian Thiede.

Functional perturbations of the cohesin complex with subsequent changes in chromatin structure and replication are reported in a multitude of cancers including acute myeloid leukemia (AML). Mutations of its STAG2 subunit may predict unfavorable risk as recognized by the 2022 European Leukemia Net recommendations, but the underlying evidence is limited by small sample sizes and conflicting observations regarding clinical outcomes, as well as scarce information on other cohesion complex subunits. We retrospectively analyzed data from a multi-center cohort of 1615 intensively treated AML patients and identified distinct co-mutational patters for mutations of STAG2, which were associated with normal karyotypes (NK) and concomitant mutations in IDH2, RUNX1, BCOR, ASXL1, and SRSF2. Mutated RAD21 was associated with NK, mutated EZH2, KRAS, CBL, and NPM1. Patients harboring mutated STAG2 were older and presented with decreased white blood cell, bone marrow and peripheral blood blast counts. Overall, neither mutated STAG2, RAD21, SMC1A nor SMC3 displayed any significant, independent effect on clinical outcomes defined as complete remission, event-free, relapse-free or overall survival. However, we found almost complete mutual exclusivity of genetic alterations of individual cohesin subunits. This mutual exclusivity may be the basis for therapeutic strategies via synthetic lethality in cohesin mutated AML.

DOI: https://doi.org/10.1038/s41408-023-00790-1
Onco Targets Ther. 2023 ;16 31-45

FMS-Like Tyrosine Kinase 3 Inhibitors in the Treatment of Acute Myeloid Leukemia: An Update on the Emerging Evidence and Safety Profile.

Sylvain Garciaz, Marie-Anne Hospital.

  FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia (AML). Approximately 30% of the adult cases harbor an internal tandem duplication (FLT3-ITD) and 5-10% a tyrosine kinase domain (TKD) amino acid substitution (FLT3-TKD). The treatment paradigm of AML patients harboring FLT3 mutations (30%) has been modified by the discovery of tyrosine kinase inhibitors. First- and second-generation inhibitors classify FLT3 inhibitors according to FLT3 specificity: first-generation FLT3 inhibitors include sorafenib and midostaurin and second-generation inhibitors are represented by quizartinib, gilteritinib and crenolanib, among others. Activity of these inhibitors depends on their mechanism of receptor binding (active vs inactive conformation) and efficacy against the FLT3-ITD and -TKD mutations (type 1 inhibitors are active both on FLT3-ITD and TKD, whereas type 2 inhibitors are active only on FLT3-ITD). The FLT3 inhibitors sorafenib, midostaurin, quizartinib and gilteritinib have been tested in monotherapy in several settings including refractory or relapsed AML (R/R AML), post-transplant maintenance as well as in combination with intensive chemotherapy (ICT) or non-intensity regimens. The results of published randomized studies support the use of sorafenib in a post-transplant setting (SORMAIN trial), midostaurin in combination with ICT based (RATIFY trial) and gilteritinib for R/R AML (ADMIRAL trial). Gilteritinib in combination with hypomethylating agent as well as quizartinib are not supported by solid randomized trial results for their use in FLT3-mutated AML patients.

Keywords:  clinical trials; precision medicine; resistance; tyrosine kinase; venetoclax

DOI:  https://doi.org/10.2147/OTT.S236740
Hemasphere. 2023 Jan;7(1): e821

Abnormal Platelet Counts and Clonal Hematopoiesis in the General Population.

Priscilla Kamphuis, Maaike G J M van Bergen, Isabelle A van Zeventer, Aniek O de Graaf, Avinash G Dinmohamed, Jonas B Salzbrunn, Jan Jacob Schuringa, Bert A van der Reijden, Gerwin Huls, Joop H Jansen.

Clonal hematopoiesis (CH) is defined by the presence of somatic mutations that may cause clonal expansion of hematopoietic cells. Here, we investigated the association between platelet count abnormalities, CH and consequences on overall survival and the development of hematological malignancies. Individuals with thrombocytopenia (n = 631) or thrombocytosis (n = 178) ≥60 years, and their age- and sex-matched controls, were selected within the population-based Lifelines cohort (n = 167,729). Although the prevalence of CH was not increased in thrombocytopenia cases compared with their controls (37.9% vs 39.3%; P = 0.639), mutations in spliceosome genes (SF3B1, SRSF2, U2AF1) were significantly enriched in thrombocytopenia cases (P = 0.007). Overall, CH in combination with thrombocytopenia did not impact on survival, but thrombocytopenia in combination with multiple mutated genes (hazard ratio [HR] = 2.08, 95% confidence interval [CI], 1.24-3.50; P = 0.006), mutations in TP53 (HR = 5.83, 95% CI, 2.49-13.64; P < 0.001) or spliceosome genes (HR = 2.69, 95% CI, 1.29-5.63; P = 0.009) increased the risk of death. The prevalence of CH in thrombocytosis cases was higher compared with controls (55.8% vs 37.7%; P < 0.001). Especially mutations in JAK2 (P < 0.001) and CALR (P = 0.003) were enriched in individuals with thrombocytosis. The presence of CH in individuals with thrombocytosis did not impact on overall survival. However, during follow-up of 11 years 23% of the individuals with thrombocytosis and CH were diagnosed with hematological malignancies. From these, 81% were diagnosed with myeloproliferative disease and 76% carried driver mutations JAK2, CALR, or MPL.

DOI: https://doi.org/10.1097/HS9.0000000000000821
Mol Cell Proteomics. 2023 Jan 19. pii: S1535-9476(23)00012-9. [Epub ahead of print] 100503

Synergistic targeting of DNA-PK and KIT signaling pathways in KIT mutant acute myeloid leukemia.

Heather C Murray, Kasey Miller, Joshua S Brzozowski, Richard G S Kahl, Nathan D Smith, Sean J Humphrey, Matthew D Dun, Nicole M Verrills.

Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 mouse myeloid progenitor cell lines transduced with oncogenic mutant KIT (V560G, D816V), or vector control. Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK in the T2599/T2605/S2608/S2610 cluster in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Global phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib and M3814 single-agent treatments inhibited ERK and AKT/MTOR activity, with greater inhibition of both pathways when used in combination. Combined dasatinib and M3814 treatment also synergistically inhibited phosphorylation of the transcriptional regulators MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising therapeutic target for KIT mutant cancers.

DOI: https://doi.org/10.1016/j.mcpro.2023.100503
Blood Adv. 2023 Jan 23. pii: bloodadvances.2022009088. [Epub ahead of print]

SAMHD1 Single Nucleotide Polymorphisms Impact Outcome in Children with Newly Diagnosed Acute Myeloid Leukemia.

Richard James Marrero, Xueyuan Cao, Huiyun Wu, Abdelrahman H Elsayed, Jeffery M Klco, Raul C Ribeiro, Jeffrey E Rubnitz, Xiaotu Ma, Soheil Meshinchi, Richard Aplenc, E Anders Kolb, Rhonda E Ries, Todd Alonzo, Stanley B Pounds, Jatinder Kaur Lamba.

Cytarabine arabinoside (Ara-C) has been the cornerstone of AML chemotherapy for decades. Following cellular uptake, it is phosphorylated into its active triphosphate form (Ara-CTP), which primarily exerts its cytotoxic effects by inhibiting DNA synthesis in proliferating cells. Interpatient variation in the enzymes involved in the Ara-C metabolic pathway have been shown to impact intracellular abundance of Ara-CTP and thus its therapeutic benefit. Recently, SAMHD1 (SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1) has emerged to play a role in Ara-CTP inactivation, development of drug resistance and consequently, clinical response in AML. Despite this the impact of genetic variations in SAMHD1 on outcome in AML has not been investigated in depth. In this study, we evaluated 25 single nucleotide polymorphisms (SNPs) within SAMHD1 gene for association with clinical outcome in 400 newly diagnosed pediatric AML patients from two clinical trials- AML02 and AML08. Three SNPs, rs1291128, rs1291141, and rs7265241 located in the 3' region of SAMHD1 were significantly associated with at least one clinical outcome endpoint: minimal residual disease (MRD) after induction I, event free survival (EFS), or overall survival (OS) in the two cohorts. In an independent cohort of patients from COG-AAML1031 trial (n=854), rs7265241 A>G remained significantly associated with EFS and OS. In multivariable analysis, adjusting for other prognostic factors such as race, age, risk group, and white blood cell count, all the SNPs remained independent predictors of clinical outcome endpoints. These results highlight the relevance of the SAMHD1 pharmacogenomics in context of response to Ara-C in AML and warrants the need for further validation in expanded patient cohorts.

DOI: https://doi.org/10.1182/bloodadvances.2022009088
Blood Adv. 2023 Jan 23. pii: bloodadvances.2022008514. [Epub ahead of print]

Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia.

Falk Heidenreich, Bose Falk, Henning Baldauf, Carolin Massalski, Gesine Schäfer, Elke Rücker-Braun, Heidi Altmann, Jürgen Sauter, Ute Solloch, Vinzenz Lange, Friedrich Stölzel, Christoph Röllig, Jan Moritz Middeke, Malte von Bonin, Christian Thiede, Kerstin Schäfer-Eckart, Carsten Müller-Tidow, Stefan W Krause, Sabrina Kraus, Martin Kaufmann, Mathias Hänel, Hubert Serve, Andreas Neubauer, Martin Bornhäuser, Alexander H Schmidt, Johannes Schetelig.

Immunogenetic association studies may give rise to new hypotheses on the immune surveillance of cancer. We hypothesized that certain combinations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA genotypes may enhance Natural Killer (NK)-cell immunity against nascent acute myeloid leukemia (AML) and thereby lead to a skewed genotype distribution among patients. For this purpose, we analyzed KIR and HLA genotypes of 1767 German patients with AML and compared the results to data of 51 890 German volunteers who had registered with DKMS. Patient samples were retrieved from the Collaborative Biobank (CoBi) and the Biorepository of the Study Alliance Leukemia (SAL). All samples were genotyped with high-resolution amplicon-based next-generation sequencing. Owing to the large number of controls this study was very sensitive to detect an impact of KIR genotype. Knowledge on KIRs and their cognate HLA ligands allowed for testing of several hypotheses of NK-cell mediated endogenous leukemia surveillance. We did not find significant differences between the two cohorts regarding presence or absence of single KIR genes. When grouped by telomeric or centromeric gene content, the major haplotypes A/A, A/B, and B/B were equally distributed among patients and controls. Using information on KIRs and their HLA ligands, we further tested receptor-ligand models and summation models without revealing markedly significant differences between patients and controls, albeit we observed a trend pointing at a minor protective effect of a low number of inhibitory KIR/KIR-ligand pairs. The results suggest that the KIR/KIR-ligand genotype has no effect on the susceptibility for the development of de novo AML.

DOI: https://doi.org/10.1182/bloodadvances.2022008514
Cancer Res Treat. 2023 Jan 26.

Clinical Significance of bZIP in-Frame CEBPA-Mutated Normal Karyotype Acute Myeloid Leukemia.

Seo-Yeon Ahn, TaeHyung Kim, Mihee Kim, Ga-Young Song, Sung-Hoon Jung, Deok-Hwan Yang, Je-Jung Lee, Mi Yeon Kim, Chul Won Jung, Jun-Ho Jang, Hee Je Kim, Joon Ho Moon, Sang Kyun Sohn, Jong-Ho Won, Sung-Hyun Kim, Hyeoung-Joon Kim, Jae-Sook Ahn, Dennis Dong Hwan Kim.

   Purpose: We evaluated the characteristics of CEBPA mutations and the significance of a basic leucine zipper in-frame mutation (bZIPin-f) of CEBPA in patients with acute myeloid leukemia with a normal karyotype.
Materials and Methods: Based on updated knowledge of CCAAT/enhancer-binding protein α (CEBPA) mutations, we conducted next-generation sequencing analyses in a previously established real-world cohort.
Results: Among 78 of a total of 395 patients (19.7%), 50 had bZIPin-f CEBPA, and 28 had non-bZIPin-f CEBPA. In the multivariate analysis, patients with NPM1mut, those with bZIPin-f CEBPA, and those who underwent allogeneic hematopoietic cell transplantation (allo-HCT) had favorable overall survival (OS), but FLT3-ITDmut was a poor prognostic indicator. For relapse-free survival (RFS) and cumulative incidence of relapse, bZIPin-f CEBPA, and allo-HCT were associated with favorable outcomes; FLT3-ITDpos was associated with worse outcomes. In the CEBPA double-mutated group (CEBPAdm), bZIPin-f CEBPA was associated with superior outcomes in terms of OS (p=0.007) and RFS (p=0.007) compared with non-bZIPin-f CEBPA. Of 50 patients with bZIPin-f CEBPA, 36 patients had at least one mutation. When grouped by the presence of mutations in chromatic/DNA modifiers (C), cohesion complex (C), and splicing genes (S) (CCS mutations), CCS-mutated bZIPin-f CEBPA was associated with poor OS (p=0.020, hazard ratio (HR):2.775) and a trend in inferior RFS (p=0.106, HR:2.106).
Conclusion: Only bZIPin-f CEBPA was associated with favorable outcomes in patients with CEBPAdm. However, some mutations accompanying bZIPin-f CEBPA showed inferior OS; thus, further studies with larger numbers of patients are required for clear conclusions of the significance of bZIPin-f CEBPA.

Keywords:  Acute; Allogeneic Transplantation; CEBPA; Leukemia; Myeloid; NGS

DOI:  https://doi.org/10.4143/crt.2022.1407
Blood Adv. 2023 Jan 23. pii: bloodadvances.2022007879. [Epub ahead of print]

TET2 truncating mutations predict a worse outcome in blastic plasmacytoid dendritic cell neoplasm.

Hannah C Beird, C Cameron Yin, Joseph D Khoury, Sherry R Pierce, Hussein A Abbas, Li Zhao, Anna Skwarska, Muzaffar H Qazilbash, Marina Y Konopleva, Andrew Futreal, Naveen Pemmaraju.

DOI: https://doi.org/10.1182/bloodadvances.2022007879
Am J Hematol. 2023 Jan 22.

The Outcomes of Patients with Chronic Myeloid Leukemia Treated with Third-line BCR::ABL1 Tyrosine Kinase Inhibitors.

Elias Jabbour, Koji Sasaki, Fadi G Haddad, Ghayas C Issa, Guillermo Garcia-Manero, Tapan M Kadia, Nitin Jain, Musa Yilmaz, Courtney D DiNardo, Keyur Patel, Rashmi Kanagal-Shamanna, Richard Champlin, Issa Khouri, Sara Dellasala, Sherry A Pierce, Hagop Kantarjian.

The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second-generation TKI (2G-TKI), the optimal third-line therapy in chronic phase CML (CML-CP) is not well established. We analyzed 354 patients with CML-CP treated with a third-line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G-TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes, and multivariate analysis to identify variables associated with survival. One hundred seventy-three (49%) patients received 2G-TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; P < 0.001) compared with the 2G-TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + -log reduction of baseline transcripts (20% 2-log reduction and 32% 3 + -log reduction). Among the 128 evaluable patients treated with 2G-TKIs, 44 (34%) achieved 2 + -log reduction of baseline transcripts (13% 2-log reduction and 21% 3 + -log reduction). With a median follow-up of 46 months, the 3-year progression-free survival was 59% (60% before matching) with 2G-TKI and 83% (81% before matching) with ponatinib (P < 0.001). The 3-year survival was 83% (81% before matching) with 2G-TKI and 87% (89% before matching) with ponatinib (P = 0.03). By multivariate analysis, third-line therapy with ponatinib was the only independent factor associated with better survival (P = 0.003). In conclusion, ponatinib is an optimal treatment for patients with CML-CP failing 2 prior TKIs. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ajh.26852
JCO Precis Oncol. 2023 Jan;7 e2200400

Clinicopathologic and Molecular Analysis of Normal Karyotype Therapy-Related and De Novo Acute Myeloid Leukemia: A Multi-Institutional Study by the Bone Marrow Pathology Group.

Miguel D Cantu, Rashmi Kanagal-Shamanna, Sa A Wang, Tapan Kadia, Carlos E Bueso-Ramos, Sanjay S Patel, Julia T Geyer, Wayne Tam, Yazan Madanat, Peng Li, Tracy I George, Meredith M Nichols, Heesun J Rogers, Yen-Chun Liu, Nidhi Aggarwal, Jason H Kurzer, Danielle L V Maracaja, Eric D Hsi, Feras Zaiem, Daniel Babu, Kathryn Foucar, Dorottya Laczko, Adam Bagg, Attilio Orazi, Daniel A Arber, Robert P Hasserjian, Olga K Weinberg.

PURPOSE: Therapy-related acute myeloid leukemias (t-AML) are a heterogenous group of aggressive neoplasms that arise following exposure to cytotoxic chemotherapy and/or ionizing radiation. Many therapy-related myeloid neoplasms (t-MN) are associated with distinct chromosomal aberrations and/or TP53 alterations, but little is known about the clinicopathologic and molecular features of normal karyotype t-AML (NK-t-AML) and whether this t-MN subtype is distinctly different from NK de novo AML (NK-dn-AML).
METHODS: This multi-institutional study by the Bone Marrow Pathology Group retrospectively evaluated clinicopathologic and molecular characteristics of 335 patients with NK-AML, comprising 105 t-AML and 230 dn-AML cases.
RESULTS: Patients with t-AML compared with dn-AML exhibit significantly shorter overall survival (OS; median months: 17.6 v 44.2; P < .0001) and relapse-free survival (RFS; median months: 9.1 v 19.2; P = .0018). Frequency of NPM1, FLT3, KRAS, and GATA2 mutations were significantly different in NK-t-AML compared with NK-dn-AML (NPM1 35% v 49%; P = .0493; FLT3 23% v 36%; P = 0494; KRAS 12% v 5%; P = .0465; GATA2 9% v 2% P = .0105), while TP53 mutations were rare. Patients with t-AML more often stratified into intermediate or adverse 2017 ELN genetic risk groups. Favorable ELN risk predicted favorable OS (hazard ratio [HR], 0.4056; 95% CI, 0 to 0.866; P = .020) and RFS (HR, 0.355; 95% CI, 0 to 0.746; P = .006). Among all patients with NK-AML, stem-cell transplant and favorable ELN risk both significantly affected RFS, while therapy-relatedness and age had a borderline significant impact on OS (HR, 1.355; 95% CI, 0.975 to 1.882; P = .070).
CONCLUSION: To our knowledge, this is the largest study to date to comprehensively evaluate NK-t-AML and provides a framework that may inform our understanding of NK-t-AML disease biology and could potentially help guide therapeutic management and improved disease classification in t-MNs that lack cytogenetic aberrations.

DOI: https://doi.org/10.1200/PO.22.00400
Blood Adv. 2023 Jan 27. pii: bloodadvances.2022008958. [Epub ahead of print]

High BM plasma S100A8/A9 is associated with a perturbed microenvironment and poor prognosis in myelodysplastic syndromes.

Yu-Hung Wang, Chien-Chin Lin, Chi-Yuan Yao, Fabio Amaral, Shan-Chi Yu, Chein-Jun Kao, Pin-Tsen Shih, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien.

S100A8/A9 is a proinflammatory protein and plays an essential role in the pathogenesis of myelodysplastic syndromes (MDS) via the S100A8/A9-Toll-like receptors axis. While S100A8/A9 levels have been used as biomarkers in many inflammatory diseases, their clinical relevance has not been conclusively resolved in MDS. To address this, we used an enzyme-linked immunosorbent assay to quantify S100A8/A9 heterodimers in bone marrow (BM) plasma from 215 MDS patients and compared S100A8/A9 levels across patients with various disease risks and genotypes. S100A8/A9 levels correlated with ASXL1 variant allele frequencies significantly. Moreover, mutant ASXL1 with concurrent RUNX1, STAG2, ZRSR2, or EZH2 mutations was associated with higher S100A8/A9 levels. We further showed that higher S100A8/A9 independently predicted inferior leukemia-free survival and overall survival in MDS patients, irrespective of age, Revised International Prognostic Scoring System subgroups, and known detrimental mutations. Lastly, through deep-sequenced transcriptomic analysis, we demonstrated that higher S100A8/A9 in the BM intimated a perturbed microenvironment with enhanced myeloid-derived suppressor cell-mediated tumor immune escape signal, altered metabolism, and impairment in the functions and quantities of CD8+ T cells and NK cells. S100A8/A9 in the BM microenvironment may be a potential biomarker in the prognostication of MDS and target for novel therapy.

DOI: https://doi.org/10.1182/bloodadvances.2022008958
Hemasphere. 2023 Jan;7(1): e812

Reduced 8-Gray Compared to Standard 12-Gray Total Body Irradiation for Allogeneic Transplantation in First Remission Acute Lymphoblastic Leukemia: A Study of the Acute Leukemia Working Party of the EBMT.

Alexandros Spyridonidis, Myriam Labopin, Bipin Savani, Sebastian Giebel, Gesine Bug, Stefan Schönland, Nicolaus Kröger, Matthias Stelljes, Thomas Schroeder, Andrew McDonald, Igor-Wolfgang Blau, Martin Bornhäuser, Montse Rovira, Wolfgang Bethge, Andreas Neubauer, Arnold Ganser, Jean Henri Bourhis, Matthias Edinger, Bruno Lioure, Gerald Wulf, Kerstin Schäfer-Eckart, Mutlu Arat, Zinaida Peric, Christoph Schmid, Ali Bazarbachi, Fabio Ciceri, Arnon Nagler, Mohamad Mohty.

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray.

DOI: https://doi.org/10.1097/HS9.0000000000000812
Nat Commun. 2023 Jan 27. 14(1): 448

Chromatin complex dependencies reveal targeting opportunities in leukemia.

Fadi J Najm, Peter DeWeirdt, Molly M Moore, Samantha M Bevill, Chadi A El Farran, Kevin A Macias, Mudra Hegde, Amanda L Waterbury, Brian B Liau, Peter van Galen, John G Doench, Bradley E Bernstein.

Chromatin regulators are frequently mutated in human cancer and are attractive drug targets. They include diverse proteins that share functional domains and assemble into related multi-subunit complexes. To investigate functional relationships among these regulators, here we apply combinatorial CRISPR knockouts (KOs) to test over 35,000 gene-gene pairings in leukemia cells, using a library of over 300,000 constructs. Top pairs that demonstrate either compensatory non-lethal interactions or synergistic lethality enrich for paralogs and targets that occupy the same protein complex. The screen highlights protein complex dependencies not apparent in single KO screens, for example MCM histone exchange, the nucleosome remodeling and deacetylase (NuRD) complex, and HBO1 (KAT7) complex. We explore two approaches to NuRD complex inactivation. Paralog and non-paralog combinations of the KAT7 complex emerge as synergistic lethal and specifically nominate the ING5 PHD domain as a potential therapeutic target when paired with other KAT7 complex member losses. These findings highlight the power of combinatorial screening to provide mechanistic insight and identify therapeutic targets within redundant networks.

DOI: https://doi.org/10.1038/s41467-023-36150-7
Ann Hematol. 2023 Jan 25.

Different treatment strategies versus a common standard arm (CSA) in patients with newly diagnosed AML over the age of 60 years: a randomized German inter-group study.

Dietger Niederwieser, Thomas Lang, Rainer Krahl, Thomas Heinicke, Georg Maschmeyer, Haifa Kathrin Al-Ali, Sebastian Schwind, Madlen Jentzsch, Michael Cross, Christoph Kahl, Hans-Heinrich Wolf, Herbert Sayer, Antje Schulze, Peter Dreger, Ute Hegenbart, Alwin Krämer, Christian Junghanss, Lars-Olof Mügge, Detlev Hähling, Carsten Hirt, Christian Späth, Norma Peter, Bernhard Opitz, Axel Florschütz, Kolja Reifenrath, Niklas Zojer, Sebastian Scholl, Wolfram Pönisch, Simone Heyn, Vladan Vucinic, Andreas Hochhaus, Carlo Aul, Aristoteles Giagounidis, Leopold Balleisen, Bernd Oldenkott, Peter Staib, Michael Kiehl, Wolfgang Schütte, Ralph Naumann, Hartmut Eimermacher, Bernd Dörken, Cristina Sauerland, Eva Lengfelder, Wolfgang Hiddemann, Bernhard Wörmann, Carsten Müller-Tidow, Hubert Serve, Christoph Schliemann, Rüdiger Hehlmann, Wolfgang E Berdel, Markus Pfirrmann, Utz Krug, Verena S Hoffmann.

  A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA.

Keywords:  Acute myeloid leukemia; Allogeneic stem cell transplantation; Complete remission; Consolidation therapy; Induction therapy; Prognostic factors

DOI:  https://doi.org/10.1007/s00277-023-05087-8
Blood. 2023 Jan 27. pii: blood.2022018246. [Epub ahead of print]

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.

Livius Penter, Yang Liu, Jacquelyn O Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole Cullen, Kathleen Lindahl Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A Morgan, Helen Chen, Minkyung H Song, Magdalena Thurin, Shuqiang Li, Scott J Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna Neuberg, F Stephen Hodi, Sacha Gnjatic, Matthew S Davids, Kenneth J Livak, Jennifer Altreuter, Franziska Michor, Robert J Soiffer, Jacqueline S Garcia, Catherine J Wu.

The challenge of eradicating leukemia for patients with acute myelogenous leukemia (AML) following initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 (NCT02890329) study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either following allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304,961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent following ipilimumab exposure, which altered CD4+ T cell gene expression, in line with ongoing T cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemia cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses.

DOI: https://doi.org/10.1182/blood.2022018246
Leukemia. 2023 Jan 21.

BET inhibitors rescue anti-PD1 resistance by enhancing TCF7 accessibility in leukemia-derived terminally exhausted CD8+ T cells.

Kyle A Romine, Kevin MacPherson, Hyun-Jun Cho, Yoko Kosaka, Patrick A Flynn, Kaelan H Byrd, Jesse L Coy, Matthew T Newman, Ravina Pandita, Christopher P Loo, Jaime Scott, Andrew C Adey, Evan F Lind.

Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid-derived suppressor cells, suppressive regulatory T cells and dysfunctional T cells. Similarly, we have identified the same immune-related features, including exhausted CD8+ T cells (TEx) in a mouse model of AML. Here we show that inhibitors that target bromodomain and extra-terminal domain (BET) proteins affect tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8+ T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor-exhausted T cells. This reversal was enhanced by combined BETi and anti-PD1 treatment. BETi synergized with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8+ T cells in the bone marrow, and increase in expression of Tcf7, Slamf6, and Cxcr5 in CD8+ T cells. Finally, we profiled the epigenomes of in vivo JQ1-treated AML-derived CD8+ T cells by single-cell ATAC-seq and found that JQ1 increases Tcf7 accessibility specifically in Tex cells, suggesting that BETi likely acts mechanistically by relieving repression of progenitor programs in Tex CD8+ T cells and maintaining a pool of anti-PD1 responsive CD8+ T cells.

DOI: https://doi.org/10.1038/s41375-023-01808-0
J Cancer Res Clin Oncol. 2023 Jan 28.

Matching-adjusted indirect comparison of asciminib versus other treatments in chronic-phase chronic myeloid leukemia after failure of two prior tyrosine kinase inhibitors.

Ehab Atallah, Michael J Mauro, Andreas Hochhaus, Carla Boquimpani, Yosuke Minami, Vikalp Kumar Maheshwari, Lovneet Saini, Regina Corbin, Delphine Réa.

   PURPOSE: The current standard of care for chronic-phase chronic myeloid leukemia (CP-CML) is tyrosine kinase inhibitors (TKIs). Treatment recommendations are unclear for CP-CML failing ≥ 2 lines of treatment, partly due to the paucity of head-to-head trials evaluating TKIs. Thus, matching-adjusted indirect comparisons (MAICs) were conducted to compare asciminib with competing TKIs in third- or later line (≥ 3L) CP-CML.
METHODS: Individual patient-level data for asciminib (ASCEMBL; follow-up: ≥ 48 weeks) and published aggregate data for comparator TKIs (ponatinib, nilotinib, and dasatinib) informed the analyses. Major molecular response (MMR), complete cytogenetic response (CCyR), and time to treatment discontinuation (TTD) were assessed, where feasible.
RESULTS: Asciminib was associated with statistically significant improvements in MMR by 6 (relative risk [RR]: 1.55; 95% confidence interval [CI]: 1.02, 2.36) and 12 months (RR: 1.48; 95% CI: 1.03, 2.14) vs ponatinib. For CCyR, the results vs ponatinib were similar by 6 (RR: 1.11; 95% CI: 0.81, 1.52) and 12 months (RR: 0.97; 95% CI: 0.73, 1.28). Asciminib was associated with improvements in MMR by 6 months vs dasatinib but with a CI overlapping one (RR 1.52; 95% CI: 0.66, 3.53). Asciminib was associated with statistically significant improvements in CCyR by 6 (RR: 3.57; 95% CI: 1.42, 8.98) and 12 months (RR: 2.03; 95% CI: 1.12, 3.67) vs nilotinib/dasatinib. Median TTD was unreached for asciminib in ASCEMBL. However, post-adjustment asciminib implied prolonged TTD vs nilotinib and dasatinib, but not vs ponatinib.
CONCLUSION: These analyses demonstrate favorable outcomes with asciminib versus competing TKIs, highlighting its therapeutic potential in ≥ 3L CP-CML.

Keywords:  ASCEMBL; Asciminib; Chronic myeloid leukemia; Indirect treatment comparison; Tyrosine kinase inhibitors

DOI:  https://doi.org/10.1007/s00432-022-04562-5
Cancer. 2023 Jan 24.

AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.

AVALON Cooperative Group

   BACKGROUND: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia.
METHODS: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here.
RESULTS: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event.
CONCLUSIONS: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

Keywords:  acute myeloid leukemia; hypomethylating agents; real-life data; relapsed and refractory AML; venetoclax

DOI:  https://doi.org/10.1002/cncr.34608
Eur J Haematol. 2023 Jan 24.

TP53 signal pathway confers potential therapy target in acute myeloid leukemia.

Gelan Zhu, Jiayi Cai, Hua Zhong.

  TP53 mutation is a frequent tumor suppressor mutation and a critical prognostic indicator across studies in many malignant tumors including hematologic malignancies. However, the role of TP53 and its correlative pathway in AML is enigmatic, which may provide possible emerging strategies with the potential to improve outcomes in AML. Accordingly, we focus not only on the TP53 mutation but also on the underlying mechanisms of the mutated TP53 signal pathway. While it is now generally accepted that TP53 mutations are widely associated with a dismal prognosis, resistance to chemotherapy, and high incidence of relapse and refractory AML. Hereby, the current therapeutics targeting TP53 mutant AML are summarized in this review. This will address emerging TP53-based therapeutic approaches, facilizing the TP53-targeted treatment options. This article is protected by copyright. All rights reserved.

Keywords:  Leukemia, Myeloid, Acute; Signal Transduction; TP53 mutation; Therapy Target; Underlying Mechanisms

DOI:  https://doi.org/10.1111/ejh.13934
Bone Marrow Transplant. 2023 Jan 25.

Comparison of haploidentical hematopoietic stem cell transplantation with chemotherapy in older adults with acute myeloid leukemia.

Yu-Qian Sun, Xiao-Hui Zhang, Qian Jiang, Hao Jiang, Ying-Jun Chang, Yu Wang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang.

Acute myeloid leukemia (AML) outcomes are very poor in older patients. Haploidentical stem cell transplantation (haplo-SCT) helps to achieve long-term survival. However, the benefit of haplo-SCT versus chemotherapy is unclear in older adults with AML. Outcomes were retrospectively compared among patients aged 55‒65 years for chemotherapy consolidation or haplo-SCT for AML in the first complete remission with intermediate to high-risk disease. Forty-six patients who underwent chemotherapy and 38 patients who underwent haplo-SCT were evaluated in the final analysis. Compared with the chemotherapy group, patients in the haplo-SCT group had significantly better overall survival (OS) (74.0% versus 23.9% at 36 months, p = 0.005) and leukemia-free survival (LFS) (74.0% versus 21.6%, p < 0.001). The cumulative incidence of relapse (CIR) was significantly lower in the haplo-SCT group (17.3% versus 75.4%, p < 0.001). Treatment-related mortality (TRM) was similar in the haplo-SCT and chemotherapy groups (7.9% versus 4.8%, p = 0.587). In the multivariate analysis, haplo-SCT was associated with improved OS, LFS, and decreased CIR. Haplo-SCT did not affect TRM. In conclusion, our data suggest that haploidentical transplant may be an alternative to consolidation chemotherapy as post-remission therapy in patients with intermediate or high-risk AML aged 55‒65 years. Further well-designed studies are needed to validate this result.

DOI: https://doi.org/10.1038/s41409-023-01925-5
Br J Haematol. 2023 Jan 28.

Molecular analysis of phenotypic heterogeneity in JAK2V617F-positive myeloproliferative neoplasms reveals a potential target for therapy.

Wenjing Gu, Jingyuan Tong, Rongfeng Fu, Ting Sun, Mankai Ju, Yanhong Zhao, Di Wang, Jie Gao, Jinhua Liu, Yuchen Gao, Huiyuan Li, Wentian Wang, Ying Chi, Renchi Yang, Lu Chen, Lihong Shi, Lei Zhang.

  JAK2V617F is the most frequent mutation in BCR-ABL-negative myeloproliferative neoplasms (MPNs). It is an important but not the only determinant of MPN phenotype. We performed high-throughput sequencing on JAK2V617F+ essential thrombocythaemia (ET) and polycythaemia vera (PV) patient samples to unveil factors involved in phenotypic heterogeneity and to identify novel therapeutic targets for MPN. Two concurrent mutations that may affect phenotype were identified, including mutations in SH2B3, which is primarily prevalent in PV, and SF3B1, which is more commonly mutated in ET. Next, we conducted transcriptomic analysis at the haematopoietic stem cell (HSC) and megakaryocyte (MK)-erythroid progenitor (MEP) levels. Inflammatory signalling pathways were elevated in both ET HSCs and MEPs, unlike in PV HSCs and MEPs. Notably, Wnt/β-catenin signalling was uniquely upregulated during ET haematopoietic differentiation from HSC to MEP, and inhibiting Wnt/β-catenin signalling blocked MK differentiation in vitro. Consistently, Wnt/β-catenin inhibitor administration decreased platelet counts in JAK2V617F+ MPN mice by blocking MEPs and MK progenitors and by inhibiting maturation of MKs, while in wild-type mice, Wnt/β-catenin inhibitor did not significantly reduce platelet counts. In conclusion, our findings provide new insights into the mechanisms underlying phenotypic differentiation of JAK2V617F+ PV and ET and indicate Wnt/β-catenin signalling as a potential therapeutic target for MPN.

Keywords:  Wnt/β-catenin signalling; myeloproliferative neoplasm; phenotypic heterogeneity; sequencing; therapeutic target

DOI:  https://doi.org/10.1111/bjh.18669
Blood Adv. 2023 Jan 25. pii: bloodadvances.2022008827. [Epub ahead of print]

Outcomes of Breakthrough COVID-19 Infections in Patients with Hematologic Malignancies.

Kelly Sharon Chien, Christine Peterson, Elliana Young, Dai Chihara, Elizabet E Manasanch, Jeremy Ramdial, Philip A Thompson.

Patients with hematologic malignancies have both an increased risk for SARS-CoV2 infections and higher morbidity/mortality. They have lower seroconversion rates post-vaccination, potentially leading to inferior COVID-19 outcomes, despite vaccination. We consequently evaluated the clinical outcomes of COVID-19 infections in 243 vaccinated and 175 unvaccinated patients with hematologic malignancies. Hospitalization rates were lower in the vaccinated group when compared to the unvaccinated group (31.3% vs 52.6%, p≤0.001). However, the rates of COVID-associated death were similar at 7.0% and 8.6% in vaccinated and unvaccinated patients, respectively (p=0.61). By univariate logistic regression, females (odds ratio (OR) 2.77, p=0.01), older patients (OR 1.03, p=0.02), and individuals with higher modified Charlson Co-morbidity Index scores (OR 1.32, p=0.003) were at a higher risk of death from COVID-19 infections. To account for the non-randomized nature of COVID-19 vaccination status, a propensity score weighting approach was utilized. In the final propensity weighted model, vaccination status was not significantly associated with the risk of death from COVID-19 infections (OR 0.70, p=0.36) but associated with the risk of hospitalizations (OR 0.38, p<0.001). The predicted benefit of vaccination was an absolute decrease in the probability of death and hospitalization from COVID-19 infections by 2.3% and 22.9%, respectively. In conclusion, COVID-19 vaccination status in patients with hematologic malignancies was associated with a decreased risk of hospitalization but not associated with a decreased risk of death from COVID-19 infections in the pre-Omicron era. Protective strategies, in addition to immunization, are warranted in this vulnerable patient population.

DOI: https://doi.org/10.1182/bloodadvances.2022008827
Clin Cancer Res. 2023 Jan 23. pii: CCR-22-3348. [Epub ahead of print]

Considerations for Drug Development in Myelodysplastic Syndromes.

Mikkael A Sekeres, Nina Kim, Amy E DeZern, Kelly J Norsworthy, Jacqueline S Garcia, R Angelo de Claro, Marc R Theoret, Emily Y Jen, Lori A Ehrlich, Amer M Zeidan, Rami S Komrokji.

MDS has historically been a challenging disease for drug development due to its biology, pre-clinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in MDS patients include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of MDS patients, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk MDS patients, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3348
Br J Haematol. 2023 Jan 23.

Myelodysplastic syndromes, thy name is heterogeneity.

Peter L Greenberg.

  Classification of the heterogeneous spectrum of myelodysplastic syndromes (MDS) requires both morphologic and molecular analysis to effectively subgroup patients. The paper by Zhang et al demonstrated the positive impact of combining the International Consensus Consortium (ICC) morphologic approach with prior clinical (IPSS-R) and mutational (IPSS-M) categorization to provide useful clinical evaluation of MDS patients. Commentary on: Zhang et al. Impact of the International Consensus Classification of Myelodysplastic Syndromes. Br J Haematol 2022 (Online ahead of print). doi: 10.1111/bjh.18628.

Keywords:  hematologic entity; heterogeneity; myelodysplastic syndromes

DOI:  https://doi.org/10.1111/bjh.18649
Haematologica. 2023 Jan 26.

Differential inhibition of T cell receptor and STAT5 signalling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.

Patrick Harrington, Richard Dillon, Deepti Radia, Philippe Rousselot, Donal P McLornan, Mark Ong, Anna Green, Alessandro Verde, Farzana Hussain, Kavita Raj, Shahram Kordasti, Claire Harrison, Hugues De Lavallade.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signalling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumour immunity in a subset of patients. We studied the impact of dasatinib in CML patients and compared with patients taking other TKI and healthy controls. We found that patients on dasatinib showed inhibition of both TCR and STAT5 signalling pathways, and reduced expression of T effector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of Tregs and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T-cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signalling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signalling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3 mediated T cell exhaustion and preserve anti-tumour immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

DOI: https://doi.org/10.3324/haematol.2022.282005
Cell Rep. 2023 Jan 25. pii: S2211-1247(23)00030-X. [Epub ahead of print]42(2): 112019

Modulating mutational outcomes and improving precise gene editing at CRISPR-Cas9-induced breaks by chemical inhibition of end-joining pathways.

Joost Schimmel, Núria Muñoz-Subirana, Hanneke Kool, Robin van Schendel, Sven van der Vlies, Juliette A Kamp, Femke de Vrij, Steven A Kushner, Graeme C M Smith, Simon J Boulton, Marcel Tijsterman.

  Gene editing through repair of CRISPR-Cas9-induced chromosomal breaks offers a means to correct a wide range of genetic defects. Directing repair to produce desirable outcomes by modulating DNA repair pathways holds considerable promise to increase the efficiency of genome engineering. Here, we show that inhibition of non-homologous end joining (NHEJ) or polymerase theta-mediated end joining (TMEJ) can be exploited to alter the mutational outcomes of CRISPR-Cas9. We show robust inhibition of TMEJ activity at CRISPR-Cas9-induced double-strand breaks (DSBs) using ART558, a potent polymerase theta (Polϴ) inhibitor. Using targeted sequencing, we show that ART558 suppresses the formation of microhomology-driven deletions in favor of NHEJ-specific outcomes. Conversely, NHEJ deficiency triggers the formation of large kb-sized deletions, which we show are the products of mutagenic TMEJ. Finally, we show that combined chemical inhibition of TMEJ and NHEJ increases the efficiency of homology-driven repair (HDR)-mediated precise gene editing. Our work reports a robust strategy to improve the fidelity and safety of genome engineering.

Keywords:  CP: Molecular biology; CRISPR/Cas9; HDR; NHEJ; TMEJ; double-strand breaks; end-joining; gene editing

DOI:  https://doi.org/10.1016/j.celrep.2023.112019
Haematologica. 2023 Jan 26.

Venetoclax and dinaciclib elicit synergistic preclinical efficacy against hypodiploid acute lymphoblastic leukemia.

Holly Pariury, Joshua Fandel, Stefanie Bachl, Kenny K Ang, Sarine Markossian, Chris G Wilson, Benjamin S Braun, Bogdan Popescu, Margo Wohlfeil, Kyle Beckman, Simayijiang Xirenayi, Ritu P Roy, Adam B Olshen, Catherine Smith, Michelle R Arkin, Mignon L Loh, Ernesto Diaz-Flores.

Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive blood cancer with a poor prognosis despite intensive chemotherapy or stem cell transplant. Children and adolescents with positive end-of-induction minimal residual disease (MRD) have an overall survival lower than 30%. However, data regarding therapeutic alternatives for this disease is nearly nonexistent, emphasizing the critical need for new or adjunctive therapies that can improve outcomes. We previously reported on the therapeutic efficacy of venetoclax (ABT-199) in hypodiploid B-ALL but with limitations as monotherapy. In this study, we set out to identify drugs enhancing the anti-leukemic effect of venetoclax in hypodiploid ALL. Using a high throughput drug screen, we identified dinaciclib, a cyclin-dependent kinase (CDK) inhibitor that worked synergistically with venetoclax to induce cell death in hypodiploid cell lines. This combination eradicated leukemic blasts within hypodiploid ALL PDX mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

DOI: https://doi.org/10.3324/haematol.2022.281443
Blood. 2023 Jan 25. pii: blood.2022016101. [Epub ahead of print]

Potentiating antibody-dependent killing of cancers with CAR T cells secreting CD47-SIRPα checkpoint blocker.

Megan M Dacek, Keifer Kurtz, Patrick Wallisch, Stephanie A Pierre, Shireen Shiraz Khayat, Christopher M Bourne, Thomas J Gardner, Kristen C Vogt, Nica Aquino, Anas Younes, David A Scheinberg.

Chimeric antigen receptor (CAR) T cell therapy has shown success in the treatment of hematopoietic malignancies; however, relapse remains a significant issue. To overcome this, we engineered "Orexi" CAR T cells to locally secrete a high affinity CD47-blocker, CV1, at the tumor, and treated tumors in combination with an orthogonally targeted monoclonal antibody. Traditional CAR T cells plus antibody were additive in effect in xenograft models and this effect was potentiated by CAR T cell local CV1 secretion. Furthermore, OrexiCAR-secreted CV1 reversed immunosuppression of myelomonocytoid cells, both in vitro and within the tumor microenvironment. Local secretion of the CD47 inhibitor bypasses the CD47 sink found on all cells in the body and may prevent systemic toxicities. This combination of CAR T cell therapy, local CD47 blockade, and orthogonal antibody may be a combinatorial strategy to overcome the limitations of each individual monotherapy.

DOI: https://doi.org/10.1182/blood.2022016101
Lancet Haematol. 2023 Jan 23. pii: S2352-3026(22)00375-1. [Epub ahead of print]

The effect of granulocyte-colony stimulating factor, decitabine, and busulfan-cyclophosphamide versus busulfan-cyclophosphamide conditioning on relapse in patients with myelodysplastic syndrome or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation: an open-label, multicentre, randomised, phase 3 trial.

Li Xuan, Min Dai, Erlie Jiang, Yu Wang, Fen Huang, Zhiping Fan, Na Xu, Danian Nie, Xinquan Liang, Hong Chen, Jieyu Ye, Pengcheng Shi, Hui Liu, Hua Jin, Ren Lin, Chenhua Yan, Yu Zhang, Jing Sun, Mingzhe Han, Qifa Liu.

BACKGROUND: Relapse remains high in patients with myelodysplastic syndrome-refractory anaemia with excess blasts (RAEB) or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate whether granulocyte-colony stimulating factor (G-CSF) and decitabine plus busulfan-cyclophosphamide conditioning reduced relapse compared with busulfan-cyclophosphamide in this population.
METHODS: We did an open-label, randomised, phase 3 trial at six hospitals in China. Eligible patients (aged 14-65 years) had myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2 and HSCT comorbidity index of 0-2. Patients were randomly assigned (1:1) to receive G-CSF, decitabine, and busulfan-cyclophosphamide conditioning or busulfan-cyclophosphamide conditioning. Randomisation was done with permuted blocks (block size four) with no stratification and was implemented through an interactive web-based response system, which was independent of study site staff and investigators. G-CSF, decitabine, and busulfan-cyclophosphamide conditioning comprised G-CSF 5 μg/kg daily subcutaneously (days -17 to -10), decitabine 20 mg/m2 daily intravenously (days -14 to -10), busulfan 3·2 mg/kg daily intravenously (days -7 to -4), and cyclophosphamide 60 mg/kg daily intravenously (days -3 and -2). Busulfan-cyclophosphamide conditioning comprised the same dose and duration of busulfan and cyclophosphamide. The primary endpoint was 2 year cumulative incidence of relapse. All efficacy and safety endpoints were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02744742; the trial is complete.
FINDINGS: Between April 18, 2016, and Sept 30, 2019, 297 patients were screened for eligibility, 202 of whom were randomly assigned to G-CSF, decitabine, and busulfan-cyclophosphamide (n=101) or busulfan-cyclophosphamide (n=101) conditioning. 123 (61%) participants were male and 79 (31%) were female. Median follow-up was 32·4 months (IQR 10·0-43·0). The 2-year cumulative incidence of relapse was 10·9% (95% CI 5·8-17·9) in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 24·8% (16·8-33·5) in the busulfan-cyclophosphamide group (hazard ratio 0·39 [95% CI 0·19-0·79]; p=0·011). Within 100 days after transplantation, the most common grade 3-4 adverse events in the G-CSF, decitabine, and busulfan-cyclophosphamide group and the busulfan-cyclophosphamide group were infections (34 [34%] and 32 [32%]), acute graft-versus-host disease (30 [30%] and 30 [30%]), and gastrointestinal toxicity (28 [28%] and 29 [29%]). 11 (11%) patients in the G-CSF, decitabine, and busulfan-cyclophosphamide group and 13 (13%) in the busulfan-cyclophosphamide group died of adverse events. There were no treatment related deaths.
INTERPRETATION: Our results suggest that G-CSF, decitabine, and busulfan-cyclophosphamide conditioning is a better choice than busulfan-cyclophosphamide conditioning for patients with myelodysplastic syndrome-RAEB or secondary acute myeloid leukaemia evolving from myelodysplastic syndrome undergoing allogeneic HSCT. This conditioning could be a suitable therapuetic option for this patient population.
FUNDING: None.
TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

DOI: https://doi.org/10.1016/S2352-3026(22)00375-1
Curr Hematol Malig Rep. 2023 Jan 27.

Targeted Therapy for MPNs: Going Beyond JAK Inhibitors.

Evan C Chen, Hannah Johnston, Anand Ashwin Patel.

   PURPOSE OF REVIEW: JAK inhibition is an effective means of controlling symptom burden and improving splenomegaly in patients with myeloproliferative neoplasms (MPNs). However, a majority of patients treated with JAK inhibition will have disease progression with long-term use. In In this review, we focus on the investigation of novel targeted agents beyond JAK inhibitors both in the chronic phase of disease and in the accelerated/blast phase of disease.
RECENT FINDINGS: Relevant targeted therapies in MPNs include BET inhibitors, BCL inhibitors, LSD1 inhibitors, PI3K inhibitors, IDH inhibitors, telomerase inhibitors, and MDM2 inhibitor. Agents within these classes have been investigated either as monotherapy or in combination with a JAK inhibitor. We summarize the prospective data for these agents along with detailing the ongoing phase III trials incorporating these agents. While JAK inhibition has been a mainstay of therapy in MPNs, a majority of patients will have disease of progression. JAK inhibitors also have limited anti-clonal effect and do not impact the rate of progression to the blast phase of disease. The novel therapies detailed in this review not only show promise in ameliorating the symptom burden of MPNs but may be able to alter the natural history of disease.

Keywords:  JAK inhibitor; MPN; Targeted therapies

DOI:  https://doi.org/10.1007/s11899-023-00690-y
Leukemia. 2023 Jan 27.

Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations.

Stephanie Sembill, Maria Ampatzidou, Sonali Chaudhury, Michael Dworzak, Krzysztof Kalwak, Axel Karow, Alexander Kiani, Manuela Krumbholz, Maaike Luesink, Nora Naumann-Bartsch, Barbara De Moerloose, Michael Osborn, Kirk R Schultz, Petr Sedlacek, Fiorina Giona, Christian Michel Zwaan, Hiroyuki Shimada, Birgitta Versluijs, Frederic Millot, Nobuko Hijiya, Meinolf Suttorp, Markus Metzler.

Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

DOI: https://doi.org/10.1038/s41375-023-01822-2
Am J Hematol. 2023 Jan 25.

Mutant NPM1: nuclear export and the mechanism of leukemogenesis.

Brunangelo Falini, Maria Paola Martelli, Lorenzo Brunetti.

DOI: https://doi.org/10.1002/ajh.26862