bims-tremyl 2023-01-08 papers

bims-tremyl

Biomed News

on Therapy resistance biology in myeloid leukemia

Issue of 2023‒01‒08
25 papers selected by
Paolo Gallipoli
Barts Cancer Institute, Queen Mary University of London

Targeting RNA Splicing Overcomes Leukemia Resistance to BCL2 Inhibition.
Clinical and molecular spectrum and prognostic outcomes of U2AF1 mutant clonal hematopoiesis- a prospective mayo clinic cohort study.
Preclinical studies targeting CD74 with STRO-001 antibody-drug conjugate in acute leukemia.
Clinico-genetic and prognostic analyses of 716 patients with primary myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia based on the 2022 International Consensus Classification.
Post-allogeneic stem cell transplant FLT3- targeted maintenance therapy: updates and considerations for clinical practice.
Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia.
Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML.
Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management.
Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment.
N-terminal pro-brain natriuretic peptide is a prognostic marker for response to intensive chemotherapy, early death, and overall survival in acute myeloid leukemia.
Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.
Chronic Myeloid Leukemia Without Major Molecular Response After 2 Years of Treatment with Tyrosine Kinase Inhibitor.
Comparison of the International Consensus and 5th WHO edition classifications of adult myelodysplastic syndromes and acute myeloid leukemia.
Clonal hematopoiesis and inflammation - the perpetual cycle.
Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results.
Real world experience with ropeginterferon alpha-2b (Besremi) in essential thrombocythaemia and polycythaemia vera following exposure to pegylated interferon alfa-2a (Pegasys).
Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification and management.
MYB insufficiency disrupts proteostasis in hematopoietic stem cells leading to age-related neoplasia.
Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation.
Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor.
A comprehensive landscape of transcription profiles and data resource for human leukemia.
MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.
The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.
Outcomes after Allogeneic Hematopoietic Cell Transplant in patients diagnosed with Blast Phase of Myeloproliferative Neoplasms: a retrospective study from the Chronic Malignancies Working Party of the EBMT.
Idarubicin plus BuCy versus BuCy conditioning regimens for intermediate-risk acute myeloid leukemia in first complete remission undergoing auto-HSCT: An open-label, multicenter, randomized phase 3 trial.

Cancer Discov. 2023 Jan 06. OF1

Targeting RNA Splicing Overcomes Leukemia Resistance to BCL2 Inhibition.

Inactivation of RNA splicing factors enhances BCL2 inhibition in acute myeloid leukemia (AML).

DOI: https://doi.org/10.1158/2159-8290.CD-RW2023-003
Leuk Res. 2022 Dec 28. pii: S0145-2126(22)00383-6. [Epub ahead of print]125 107007

Clinical and molecular spectrum and prognostic outcomes of U2AF1 mutant clonal hematopoiesis- a prospective mayo clinic cohort study.

Stephanie L Pritzl, Mark Gurney, Talha Badar, Alejandro Ferrer, Terra Lasho, Christy Finke, Abhishek Mangaonkar, Kristen McCullough, Naseema Gangat, Jenna Fernandez, Aref Al-Kali, David Viswanatha, Rong He, James Foran, Mrinal M Patnaik.



Keywords:  BCOR; CCUS; CHIP; Clonal hematopoiesis; Splicing Genes; U2AF1

DOI:  https://doi.org/10.1016/j.leukres.2022.107007
Blood Adv. 2023 Jan 03. pii: bloodadvances.2022008303. [Epub ahead of print]

Preclinical studies targeting CD74 with STRO-001 antibody-drug conjugate in acute leukemia.

Quy H Le, Thao Tang, Amanda R Leonti, Sommer K Castro, Cyd Nourigat McKay, LaKeisha Perkins, Laura Pardo, Danielle C Kirkey, Tiffany Hylkema, Lindsey Call, Makia Manselle, Cristina Abrahams, Kristin Bedard, Arturo Molina, Lisa Eidenschink Brodersen, Michael R Loken, Katherine Tarlock, Soheil Meshinchi, Keith R Loeb.

DOI: https://doi.org/10.1182/bloodadvances.2022008303
Am J Hematol. 2023 Jan 01.

Clinico-genetic and prognostic analyses of 716 patients with primary myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia based on the 2022 International Consensus Classification.

Wan-Hsuan Lee, Chien-Chin Lin, Cheng-Hong Tsai, Feng-Ming Tien, Min-Yen Lo, Sao-Chih Ni, Ming Yao, Mei-Hsuan Tseng, Yuan-Yeh Kuo, Ming-Chih Liu, Jih-Luh Tang, Hsun-I Sun, Yi-Kuang Chuang, Wen-Chien Chou, Hsin-An Hou, Hwei-Fang Tien.

The 2022 International Consensus Classification (ICC) recategorized myeloid neoplasms based on recent advances in the understanding of the biology of hematologic malignancies, in which myelodysplastic syndrome (MDS) with blasts of 10%-19% is classified as MDS/acute myeloid leukemia (AML), MDS with mutated SF3B1, irrespective of the number of ring sideroblasts, as MDS-SF3B1, and those with multi-hit TP53 mutations as MDS with mutated TP53. In the analysis of 716 patients with MDS diagnosed according to the 2016 WHO classification, we found that 75.3% of patients remained in the MDS group based on the ICC, while 24.7% of patients were reclassified to the MDS/AML group after the exclusion of 15 patients who were classified to the AML group. Patients with MDS/AML showed a distinct mutational landscape and had poorer outcomes, compared to those with MDS. In the MDS group, patients with MDS-SF3B1 had higher frequencies of DNMT3A and TET2 mutations than those with MDS, not otherwise specified, with single lineage dysplasia or multilineage dysplasia. Patients with mutated TP53 were associated with dismal outcomes, irrespective of the blast percentage. In conclusion, this study showed that the ICC facilitates efficient segregation and risk-stratification of MDS which can help guide the treatment choice of patients with the disease.

DOI: https://doi.org/10.1002/ajh.26799
Arch Stem Cell Ther. 2022 ;3(1): 23-27

Post-allogeneic stem cell transplant FLT3- targeted maintenance therapy: updates and considerations for clinical practice.

Jonathan Cohen, Richard T Maziarz.

  Acute myeloid leukemia (AML) is characterized by multiple molecular and cytogenetic abnormalities, with increasing data to support clinical and prognostic implications to guide clinical decision making. One of the most well described mutations involves fms-like tyrosine kinase 3 (FLT3) that results in a constitutively active tyrosine kinase and is generally associated with poor prognosis involving shorter overall survival and higher rates of relapse. Advancements in targeted therapies have greatly influenced available treatment options in a landscape that has remained largely unchanged for the past five decades. Tyrosine kinase inhibitors (TKI), specifically FLT3-targeted therapies, are now integral treatment options for patients with this targetable mutation. As allogeneic hematopoietic cell transplant (alloHCT) remains the primary curative therapy for most adult AML patients, the goal is for eligible patients to proceed to transplant. However, post-alloHCT relapse remains exceedingly high even in patients achieving deep responses to therapy. Limited evaluation of FLT3-targeted TKIs as post-alloHCT maintenance therapy in FLT3-positive patients suggest improved outcomes and tolerable safety profiles, with ongoing studies further investigating second-generation agents. Thus, this commentary aims to review the role of post-alloHCT FLT3-targeted maintenance therapy and considerations for clinical practice.

Keywords:  Allogeneic stem cell transplant; FLT3; Maintenance

DOI:  https://doi.org/10.46439/stemcell.3.015
Front Immunol. 2022 ;13 1085978

Targets for chimeric antigen receptor T-cell therapy of acute myeloid leukemia.

Christopher Schorr, Fabiana Perna.

  Acute Myeloid Leukemia (AML) is an aggressive myeloid malignancy associated with high mortality rates (less than 30% 5-year survival). Despite advances in our understanding of the molecular mechanisms underpinning leukemogenesis, standard-of-care therapeutic approaches have not changed over the last couple of decades. Chimeric Antigen Receptor (CAR) T-cell therapy targeting CD19 has shown remarkable clinical outcomes for patients with acute lymphoblastic leukemia (ALL) and is now an FDA-approved therapy. Targeting of myeloid malignancies that are CD19-negative with this promising technology remains challenging largely due to lack of alternate target antigens, complex clonal heterogeneity, and the increased recognition of an immunosuppressive bone marrow. We carefully reviewed a comprehensive list of AML targets currently being used in both proof-of-concept pre-clinical and experimental clinical settings. We analyzed the expression profile of these molecules in leukemic as well normal tissues using reliable protein databases and data reported in the literature and we provide an updated overview of the current clinical trials with CAR T-cells in AML. Our study represents a state-of-art review of the field and serves as a potential guide for selecting known AML-associated targets for adoptive cellular therapies.

Keywords:  AML – acute myeloid leukaemia; CAR (chimeric antigen receptor) T cells; clinical trial; efficacy; safety; target antigen

DOI:  https://doi.org/10.3389/fimmu.2022.1085978
Blood Cancer J. 2023 Jan 04. 13(1): 4

Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML.

Xavier Cheng-Hong Tsai, Kuo-Jui Sun, Min-Yen Lo, Feng-Ming Tien, Yuan-Yeh Kuo, Mei-Hsuan Tseng, Yen-Ling Peng, Yi-Kuang Chuang, Bor-Sheng Ko, Jih-Luh Tang, Hsun-I Sun, Ming-Chih Liu, Chia-Wen Liu, Chien-Chin Lin, Ming Yao, Wen-Chien Chou, Hsin-An Hou, Hwei-Fang Tien.

A set of myelodysplasia-related (MDS-R) gene mutations are incorporated into the 2022 European LeukemiaNet risk classification as adverse genetic factors for acute myeloid leukemia (AML) based on their poor prognostic impact on older patients. The impact of these mutations on younger patients (age < 60 years) remains elusive. In the study of 1213 patients with de novo non-M3 AML, we identified MDS-R mutations in 32.7% of the total cohort, 44.9% of older patients and 23.4% of younger patients. The patients with MDS-R mutations had a significantly lower complete remission rate in both younger and older age groups. With a median follow-up of 9.2 years, the MDS-R group experienced shorter overall survival (P = 0.034 for older and 0.035 for younger patients) and event-free survival (P = 0.004 for older and 0.042 for younger patients). Furthermore, patients with MDS-R mutations more frequently harbored measurable residual disease that was detectable using next generation sequencing at morphological CR than those without MDS-R mutations. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) might ameliorate the negative impact of MDS-R mutations. In summary, AML patients with MDS-R mutations have significantly poorer outcomes regardless of age. More intensive treatment, such as allo-HSCT and/or novel therapies, is warranted for AML patients with MDS-R mutations.

DOI: https://doi.org/10.1038/s41408-022-00774-7
Am J Hematol. 2023 Jan 04.

Atypical chronic myeloid leukemia and myelodysplastic/myeloproliferative neoplasm, not otherwise specified: 2023 update on diagnosis, risk stratification, and management.

Mrinal M Patnaik, Ayalew Tefferi.

DISEASE OVERVIEW: Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow.DIAGNOSIS: aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML.
MUTATIONS AND KARYOTYPE: Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively.
RISK STRATIFICATION: The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R.
TREATMENT: Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality.

DOI: https://doi.org/10.1002/ajh.26828
Blood Cancer J. 2023 Jan 04. 13(1): 5

Lymphoid clonal hematopoiesis: implications for malignancy, immunity, and treatment.

Kelly von Beck, Troy von Beck, P Brent Ferrell, Alexander G Bick, Ashwin Kishtagari.

Clonal hematopoiesis (CH) is the age-related expansion of hematopoietic stem cell clones caused by the acquisition of somatic point mutations or mosaic chromosomal alterations (mCAs). Clonal hematopoiesis caused by somatic mutations has primarily been associated with increased risk of myeloid malignancies, while mCAs have been associated with increased risk of lymphoid malignancies. A recent study by Niroula et al. challenged this paradigm by finding a distinct subset of somatic mutations and mCAs that are associated with increased risk of lymphoid malignancy. CH driven by these mutations is termed lymphoid clonal hematopoiesis (L-CH). Unlike myeloid clonal hematopoiesis (M-CH), L-CH has the potential to originate at both stem cells and partially or fully differentiated progeny stages of maturation. In this review, we explore the definition of L-CH in the context of lymphocyte maturation and lymphoid malignancy precursor disorders, the evidence for L-CH in late-onset autoimmunity and immunodeficiency, and the development of therapy-related L-CH following chemotherapy or hematopoietic stem cell transplantation.

DOI: https://doi.org/10.1038/s41408-022-00773-8
Am J Hematol. 2023 Jan 01.

N-terminal pro-brain natriuretic peptide is a prognostic marker for response to intensive chemotherapy, early death, and overall survival in acute myeloid leukemia.

Irene Graf, Georg Greiner, Rodrig Marculescu, Karoline V Gleixner, Susanne Herndlhofer, Gabriele Stefanzl, Paul Knoebl, Ulrich Jäger, Alexander Hauswirth, Ilse Schwarzinger, Renate Thalhammer, Michael Kundi, Gregor Hoermann, Gerlinde Mitterbauer-Hohendanner, Peter Valent, Wolfgang R Sperr.

Patient-related factors are of prognostic importance in acute myeloid leukemia (AML). Likewise, cardiac disorders may limit the tolerance of intensive therapy. Little is known about the prognostic value of N-terminal pro-brain natriuretic peptide (NT-proBNP). We analyzed NT-proBNP levels at diagnosis in 312 AML patients (median age: 61 years; range 17-89 years) treated with 3 + 7-based induction-chemotherapy and consolidation with up to four cycles of intermediate or high-dose ARA-C. NT-proBNP levels were elevated in 199 patients (63.8%), normal (0-125 pg/ml) in 113 (36.2%), and highly elevated (>2000 pg/ml) in 20 patients (6.4%). Median NT-proBNP levels differed significantly among patients with complete remission (153.3 pg/ml), no remission (225.9 pg/ml), or early death (735.5 pg/ml) (p = .002). In multivariate analysis, NT-proBNP, age, and the 2009 European LeukemiaNet (ELN-2009) classification were independent predictors of outcome after induction chemotherapy. Overall survival (OS) differed significantly between patients with normal, moderately elevated, and highly elevated NT-proBNP (p < .001). These differences were observed in all patients and in patients <60 years but not in those ≥60 years. In multivariate analysis, NT-proBNP, age, and ELN-2009 remained independent prognostic variables for OS (p < .01). Together, NT-proBNP is an independent prognostic factor indicating the risk of induction failure, early death, and reduced OS in patients with AML.

DOI: https://doi.org/10.1002/ajh.26805
Nat Commun. 2023 Jan 05. 14(1): 77

Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.

Nicholas Light, Mehdi Layeghifard, Ayush Attery, Vallijah Subasri, Matthew Zatzman, Nathaniel D Anderson, Rupal Hatkar, Sasha Blay, David Chen, Ana Novokmet, Fabio Fuligni, James Tran, Richard de Borja, Himanshi Agarwal, Larissa Waldman, Lisa M Abegglen, Daniel Albertson, Jonathan L Finlay, Jordan R Hansford, Sam Behjati, Anita Villani, Moritz Gerstung, Ludmil B Alexandrov, Gino R Somers, Joshua D Schiffman, Varda Rotter, David Malkin, Adam Shlien.

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis.

DOI: https://doi.org/10.1038/s41467-022-35727-y
Am J Hematol. 2023 Jan 06.

Chronic Myeloid Leukemia Without Major Molecular Response After 2 Years of Treatment with Tyrosine Kinase Inhibitor.

Aram Bidikian, Elias Jabbour, Ghayas C Issa, Nicholas J Short, Koji Sasaki, Hagop Kantarjian.

  Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after one year has been highlighted as "suboptimal" or "warning" sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long-term outcome. In this analysis, we report the long-term outcome of 131 patients who did not achieve MMR within the first two years of TKI therapy. Patients who achieved major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long-term overall survival (OS) (10-year OS of 88%) and CML-related overall survival (CML-OS) (10-year CML-OS of 95%). Achievement of MCyR within the first two years of treatment predicted for better OS (HR=0.43, P=0.03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10-year OS of 55% vs 10-year CML-OS of 100%). In conclusion, achievement of MCyR within two years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved. This article is protected by copyright. All rights reserved.

Keywords:  Chronic myeloid leukemia; major molecular response; survival; tyrosine kinase inhibitors

DOI:  https://doi.org/10.1002/ajh.26836
Am J Hematol. 2023 Jan 05.

Comparison of the International Consensus and 5th WHO edition classifications of adult myelodysplastic syndromes and acute myeloid leukemia.

Brunangelo Falini, Maria Paola Martelli.

Several editions of the World Health Organization (WHO) classifications of lympho-hemopoietic neoplasms in 2001, 2008, and 2016 served as the international standard for diagnosis. Since the 4th WHO edition, here referred as WHO-HAEM4, significant clinico-pathological, immunophenotypic, and molecular advances have been made in the field of myeloid neoplasms, which have contributed to refine diagnostic criteria, to upgrade entities previously defined as provisional and to identify new entities. This process has resulted in two recent classification proposals of myeloid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO-HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, with a focus on adult myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML). The goal is to provide a tool to facilitate the work of pathologists, hematologists and researchers involved in the diagnosis and treatment of these hematological malignancies.

DOI: https://doi.org/10.1002/ajh.26812
Trends Cell Biol. 2022 Dec 31. pii: S0962-8924(22)00275-6. [Epub ahead of print]

Clonal hematopoiesis and inflammation - the perpetual cycle.

Serine Avagyan, Leonard I Zon.

  Acquired genetic or cytogenetic alterations in a blood stem cell that confer clonal fitness promote its relative expansion leading to clonal hematopoiesis (CH). Despite a largely intact hematopoietic output, CH is associated with a heightened risk of progression to hematologic malignancies and with non-hematologic health manifestations, including cardiovascular disease and overall mortality. We focus on the evidence for the role of inflammation in establishing, maintaining and reciprocally being affected by CH. We describe the known pro-inflammatory signals associated with CH and preclinical studies that elucidated the cellular mechanisms involved. We review the evolving literature on early-onset CH in germline predisposition conditions and the possible role of immune dysregulation in this context.

Keywords:  anti-inflammatory survival; clonal hematopoiesis; germline predisposition; inflammation; proinflammatory macrophages

DOI:  https://doi.org/10.1016/j.tcb.2022.12.001
Am J Hematol. 2023 Jan 04.

Frontline combination of ponatinib and hyper-CVAD in Philadelphia chromosome-positive acute lymphoblastic leukemia: 80-months follow-up results.

Hagop Kantarjian, Nicholas J Short, Nitin Jain, Koji Sasaki, Xuelin Huang, Fadi G Haddad, Issa Khouri, Courtney D DiNardo, Naveen Pemmaraju, William Wierda, Guillermo Garcia-Manero, Partow Kebriaei, Rebecca Garris, Sanam Loghavi, Jeffrey Jorgensen, Monica Kwari, Susan O'Brien, Farhad Ravandi, Elias Jabbour.

The combination of ponatinib, a third-generation BCR::ABL1 tyrosine kinase inhibitor, with hyper-CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)-positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow-up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph-positive ALL were treated with the hyper-CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase-chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine-prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty-six patients were treated. Their median age was 46 years (range, 21-80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty- patients (23%) underwent allogeneic SCT. With a median follow-up of 80 months (range, 16-129 months), the estimated 6-year event-free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3-5 adverse events included infection (n = 80, 93%), increased liver transaminases (n = 26, 31%) and total bilirubin (n = 13, 15%), hypertension (n = 15, 17%), pancreatitis (n = 13, 15%), hemorrhage (n = 12, 13%), and skin rash (n = 9, 10%). Two ponatinib-related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose-modifications mentioned earlier, with no further ponatinib-related deaths observed. The long-term results of ponatinib and hyper-CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph-positive ALL.

DOI: https://doi.org/10.1002/ajh.26816
Leuk Res Rep. 2023 ;19 100360

Real world experience with ropeginterferon alpha-2b (Besremi) in essential thrombocythaemia and polycythaemia vera following exposure to pegylated interferon alfa-2a (Pegasys).

Jumoke Okikiolu, Claire Woodley, Llywelyn Cadman-Davies, Jennifer O'Sullivan, Deepti Radia, Natalia Curto Garcia, Patrick Harrington, Shahram Kordasti, Susan Asirvatham, Priya Sriskandarajah, Jamie Saunders, Chandan Saha, Irene Sanchez, Hugues deLavallade, Donal P McLornan, Claire N Harrison.

  Despite widespread use of Pegylated forms of Inteferon in the management of Myeloproliferative Neoplasms (MPN), most clinicians have experience predominantly with peginterferon alfa-2a (Pegasys). Third generation pegylated IFNα, ropeginterferon alfa-2b (ropegIFN; Besremi), was recommended by the European Medicine Authority (EMA) for treatment of Polycythaemia Vera (PV) following a Phase III trial (PROUD-PV / CONTINUATION-PV). FDA approval for PV, regardless of treatment history, was subsequently granted in November 2021. We hereby demonstrate the safety and tolerability of ropegIFN in a series of MPN patients at variable doses. It corroborates reports of efficacy of ropegIFN in patients with PV and use in pregnancy.

Keywords:  Essential Thrombocythaemia; IFN; MPN; Polycythaemia Vera

DOI:  https://doi.org/10.1016/j.lrr.2022.100360
Am J Hematol. 2023 Jan 02.

Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification and management.

Shai Shimony, Maximilian Stahl, Richard M Stone.

Both an improved understanding of acute myeloid leukemia (AML) pathophysiology plus improvements in measurement technology have led to revamping the diagnostic, prognostic, and therapeutic landscape of AML. New classification systems integrating molecular insights, updated risk assessment, improved ability to measure low levels of disease as well as least ten recently approved therapies may promote better outcomes including cures in a larger fraction of AML patients. The diagnostic and therapeutic complexity makes the decision-making process ever more individualized and requires integration of patient goals of care, comorbidities and disease characteristics including the specific mutational profile of the patient. In this review we present recent advances in diagnosis, classification, risk stratification and treatment options for patients with newly diagnosed (ND) or relapsed and refractory (R/R) AML. Such advances are welcome, but the increased options also lead to many controversies concerning the optimal selection of the timing and combinatorial use of the new drugs and how best to leverage our burgeoning ability to measure a small number of potentially malignant myeloid cells. In this context, we will present our approach for AML management noting current limitations and potential future directions. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ajh.26822
Blood. 2023 Jan 05. pii: blood.2022019138. [Epub ahead of print]

MYB insufficiency disrupts proteostasis in hematopoietic stem cells leading to age-related neoplasia.

Mary L Clarke, Roza Berhanu Lemma, David Scott Walton, Giacomo Volpe, Boris Noyvert, Odd Stokke Gabrielsen, Jon Frampton.

MYB plays a key role in gene regulation throughout the hematopoietic hierarchy and is critical for the maintenance of normal hematopoietic stem cells (HSC). Acquired genetic dysregulation of MYB is involved in the etiology of a number of leukemias, while inherited non-coding variants of the MYB gene are a factor in susceptibility to many hematological conditions, including myeloproliferative neoplasms (MPN). The mechanisms that connect variations in MYB levels to disease predisposition, especially in relation to age-dependency in disease initiation, are completely unknown. Here, we describe a model of Myb insufficiency in mice that leads in later life to MPN, myelodysplasia, and leukemia, mirroring the age profile of equivalent human diseases. We show that this age-dependence is intrinsic to HSC, involving a combination of an initial defective cellular state resulting from small effects on the expression of multiple genes and a progressive accumulation of further subtle changes. Linking to previous studies showing the importance of proteostasis in HSC maintenance, we observed altered proteosomal activity in young Myb-insufficient mice as well as elevated proliferation indicators, followed later by elevated ribosome activity. We propose that these alterations combine to cause an imbalance in proteostasis, potentially creating a cellular milieu favoring disease initiation.

DOI: https://doi.org/10.1182/blood.2022019138
Nat Commun. 2023 Jan 03. 14(1): 12

Endogenous IL-1 receptor antagonist restricts healthy and malignant myeloproliferation.

Alicia Villatoro, Vincent Cuminetti, Aurora Bernal, Carlos Torroja, Itziar Cossío, Alberto Benguría, Marc Ferré, Joanna Konieczny, Enrique Vázquez, Andrea Rubio, Peter Utnes, Xiaona You, Christopher G Fenton, Ruth H Paulssen, Jing Zhang, Fátima Sánchez-Cabo, Ana Dopazo, Anders Vik, Endre Anderssen, Andrés Hidalgo, Lorena Arranz.

Here we explored the role of interleukin-1β (IL-1β) repressor cytokine, IL-1 receptor antagonist (IL-1rn), in both healthy and abnormal hematopoiesis. Low IL-1RN is frequent in acute myeloid leukemia (AML) patients and represents a prognostic marker of reduced survival. Treatments with IL-1RN and the IL-1β monoclonal antibody canakinumab reduce the expansion of leukemic cells, including CD34+ progenitors, in AML xenografts. In vivo deletion of IL-1rn induces hematopoietic stem cell (HSC) differentiation into the myeloid lineage and hampers B cell development via transcriptional activation of myeloid differentiation pathways dependent on NFκB. Low IL-1rn is present in an experimental model of pre-leukemic myelopoiesis, and IL-1rn deletion promotes myeloproliferation, which relies on the bone marrow hematopoietic and stromal compartments. Conversely, IL-1rn protects against pre-leukemic myelopoiesis. Our data reveal that HSC differentiation is controlled by balanced IL-1β/IL-1rn levels under steady-state, and that loss of repression of IL-1β signaling may underlie pre-leukemic lesion and AML progression.

DOI: https://doi.org/10.1038/s41467-022-35700-9
Blood Cancer J. 2023 Jan 04. 13(1): 3

Determinants of survival and retrospective comparisons of 183 clinical trial patients with myelofibrosis treated with momelotinib, ruxolitinib, fedratinib or BMS- 911543 JAK2 inhibitor.

Naseema Gangat, Kebede H Begna, Aref Al-Kali, William Hogan, Mark Litzow, Animesh Pardanani, Ayalew Tefferi.

Between October 2007 and July 2013, 183 Mayo Clinic patients (median age 65 years; 58% males) with high/intermediate risk myelofibrosis (MF) were enrolled in consecutive phase 1/2 JAK2 inhibitor (JAKi) clinical trials with momelotinib (n = 79), ruxolitinib (n = 50), fedratinib (n = 23) and BMS-911543 (n = 31). Using conventional criteria, the respective response rates for spleen and "transfusion-dependent anemia" were 47%, 32%, 83%, 62% and 51%, 30%, 10%, 44%, respectively, favoring momelotinib for anemia response (p = 0.02) and fedratinib for spleen response (p < 0.01). All study patients were followed to death or 2022, during which time 177 (97%) drug discontinuations, 27 (15%) leukemic transformations, and 22 (12%) allogeneic stem cell transplants (ASCT) were recorded. 5/10-year survival rate for all 183 patients was 41%/16% and not significantly different across the four drug cohorts (p = 0.33). Multivariable analysis of pre-treatment variables identified age >65 years (HR 3.5), absence of type 1/like CALR mutation (HR 2.8), baseline transfusion need (HR 2.1), and presence of ASXL1/SRSF2 mutation (HR 1.6) as risk factors for overall survival; subsequent HR-based modeling segregated three risk categories with 5/10-year survival rates of 84%/60%, 44%/14%, and 21%/5% (p < 0.01). In addition, spleen (p < 0.01) and anemia (p = 0.01) responses were independently associated with improved short-term survival while long-term survival was secured only by ASCT (5/10-year survival rate 91%/45% vs 47%/19% in non-transplanted patients; p < 0.01). The current retrospective study suggests the value of specific pre-treatment variables in identifying long-lived MF patients receiving JAKi and also confirms recent observations on the favorable impact of treatment response on short-term and of ASCT on long-term survival.

DOI: https://doi.org/10.1038/s41408-022-00780-9
Blood Adv. 2023 01 03. pii: bloodadvances.2022008410. [Epub ahead of print]

A comprehensive landscape of transcription profiles and data resource for human leukemia.

Mei Luo, Yaru Miao, Yajuan Ke, An-Yuan Guo, Qiong Zhang.

As a heterogeneous group of hematological malignancies, leukemia has been widely studied at the transcriptome level. However, a comprehensive transcriptomic landscape and resources for different leukemia subtypes are lacking. Thus, in this study, we integrated the RNA-Seq datasets of more than 3,000 samples from 14 leukemia subtypes and 53 related cell lines through a unified analysis pipeline. We depicted the corresponding transcriptomic landscape and developed a user-friendly data portal LeukemiaDB (http://bioinfo.life.hust.edu.cn/LeukemiaDB/). LeukemiaDB was designed with five main modules: Protein-coding gene, LncRNA, CircRNA, Alternative splicing, and Fusion gene modules. In LeukemiaDB, users can search and browse the expression level, regulatory modules, and molecular information across leukemia subtypes or cell lines. In addition, a comprehensive analysis of data in LeukemiaDB demonstrates that (1) different leukemia subtypes or cell lines have similar expression distribution of protein-coding gene and lncRNA; (2) some alternative splicing events are shared among nearly all leukemia subtypes, e.g., MYL6 in A3SS, MYB in A5SS, HMBS in RI, GTPBP10 in MXE, and POLL in SE; (3) some leukemia-specific protein-coding genes, e.g., ABCA6, ARHGAP44, WNT3, and BLACE, and fusion genes, e.g., BCR-ABL1 and KMT2A-AFF1 are involved in leukemogenesis; (4) some highly correlated regulatory modules were also identified in different leukemia subtypes, e.g., the HOXA9 module in AML and the NOTCH1 module in T-ALL. In summary, the developed LeukemiaDB provides valuable insights into oncogenesis and progression of leukemia and, to the best of our knowledge, is the most comprehensive transcriptome resource of human leukemia available to the research community.

DOI: https://doi.org/10.1182/bloodadvances.2022008410
Nat Cell Biol. 2023 Jan 05.

MLL3 loss drives metastasis by promoting a hybrid epithelial-mesenchymal transition state.

Jihong Cui, Chi Zhang, Ji-Eun Lee, Boris A Bartholdy, Dapeng Yang, Yu Liu, Piril Erler, Phillip M Galbo, Dayle Q Hodge, Danwei Huangfu, Deyou Zheng, Kai Ge, Wenjun Guo.

Phenotypic plasticity associated with the hybrid epithelial-mesenchymal transition (EMT) is crucial to metastatic seeding and outgrowth. However, the mechanisms governing the hybrid EMT state remain poorly defined. Here we showed that deletion of the epigenetic regulator MLL3, a tumour suppressor frequently altered in human cancer, promoted the acquisition of hybrid EMT in breast cancer cells. Distinct from other EMT regulators that mediate only unidirectional changes, MLL3 loss enhanced responses to stimuli inducing EMT and mesenchymal-epithelial transition in epithelial and mesenchymal cells, respectively. Consequently, MLL3 loss greatly increased metastasis by enhancing metastatic colonization. Mechanistically, MLL3 loss led to increased IFNγ signalling, which contributed to the induction of hybrid EMT cells and enhanced metastatic capacity. Furthermore, BET inhibition effectively suppressed the growth of MLL3-mutant primary tumours and metastases. These results uncovered MLL3 mutation as a key driver of hybrid EMT and metastasis in breast cancer that could be targeted therapeutically.

DOI: https://doi.org/10.1038/s41556-022-01045-0
Cell Rep. 2022 Dec 23. pii: S2211-1247(22)01798-3. [Epub ahead of print] 111899

The endoplasmic reticulum kinase PERK interacts with the oxidoreductase ERO1 to metabolically adapt mitochondria.

Arthur Bassot, Junsheng Chen, Kei Takahashi-Yamashiro, Megan C Yap, Christine Silvia Gibhardt, Giang N T Le, Saaya Hario, Yusuke Nasu, Jack Moore, Tomas Gutiérrez, Lucas Mina, Heather Mast, Audric Moses, Rakesh Bhat, Klaus Ballanyi, Hélène Lemieux, Roberto Sitia, Ester Zito, Ivan Bogeski, Robert E Campbell, Thomas Simmen.

  Endoplasmic reticulum (ER) homeostasis requires molecular regulators that tailor mitochondrial bioenergetics to the needs of protein folding. For instance, calnexin maintains mitochondria metabolism and mitochondria-ER contacts (MERCs) through reactive oxygen species (ROS) from NADPH oxidase 4 (NOX4). However, induction of ER stress requires a quick molecular rewiring of mitochondria to adapt to new energy needs. This machinery is not characterized. We now show that the oxidoreductase ERO1⍺ covalently interacts with protein kinase RNA-like ER kinase (PERK) upon treatment with tunicamycin. The PERK-ERO1⍺ interaction requires the C-terminal active site of ERO1⍺ and cysteine 216 of PERK. Moreover, we show that the PERK-ERO1⍺ complex promotes oxidization of MERC proteins and controls mitochondrial dynamics. Using proteinaceous probes, we determined that these functions improve ER-mitochondria Ca2+ flux to maintain bioenergetics in both organelles, while limiting oxidative stress. Therefore, the PERK-ERO1⍺ complex is a key molecular machinery that allows quick metabolic adaptation to ER stress.

Keywords:  CP: Metabolism; CP: Molecular biology; ER; ER stress; ERO1; MAMs; MERCs; PERK; bioenergetics; endoplasmic reticulum; mitochondria; mitochondria-associated membranes; mitochondria-endoplasmic reticulum contacts; oxidoreductase

DOI:  https://doi.org/10.1016/j.celrep.2022.111899
Am J Hematol. 2023 Jan 06.

Outcomes after Allogeneic Hematopoietic Cell Transplant in patients diagnosed with Blast Phase of Myeloproliferative Neoplasms: a retrospective study from the Chronic Malignancies Working Party of the EBMT.

Guillermo Ortí, Luuk Gras, Nienke Zinger, Maria Chiara Finazzi, Katja Sockel, Marie Robin, Edouard Forcade, Daniele Avenoso, Nicolaus Kröger, Jürgen Finke, Aleksandar Radujkovic, Mathilde Hunault-Berger, Wilfried Schroyens, Tsila Zuckerman, Jean Henri Bourhis, Yves Chalandon, Adrian Bloor, Rik Schots, Liesbeth C de Wreede, Joana Drozd-Sokolowska, Kavita Raj, Nicola Polverelli, Tomasz Czerw, Juan Carlos Hernández-Boluda, Donal McLornan, Ibrahim Yakoub-Agha.

Allogeneic haematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective EBMT registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005-2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year OS was 36% (95% CI, 32-36). Factors associated with lower OS were Karnofsky Performance Status (KPS) <90 (HR 1.65, p<0.001) and active disease at allo-HCT (HR 1.45, p<0.001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p=0.008). In a selected patients population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS<90 (HR 1.4, p=0.001) and active disease (HR 1.44, p=0.0004) were associated with a lower PFS. Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p=0.008). Active disease at allo-HCT (HR 1.34, p=0.03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p=0.02) associated with a lower RI. Lastly, KPS<90 (HR 1.91, p<0.001), active disease (HR 1.74, p=0.003) and allo-HCT from mismatched related donors were associated with a higher NRM (HR 2.66, p=0.003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS≥90 and in CR at transplant had a better prognosis. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ajh.26833
Am J Hematol. 2023 Jan 01.

Idarubicin plus BuCy versus BuCy conditioning regimens for intermediate-risk acute myeloid leukemia in first complete remission undergoing auto-HSCT: An open-label, multicenter, randomized phase 3 trial.

Hui Liu, Fen Huang, Yu Zhang, Meiqing Wu, Na Xu, Zhiping Fan, Zhiqiang Sun, Xudong Li, Dongjun Lin, Yiying Xiong, Xiaodan Liu, Ren Lin, Pengcheng Shi, Jun Xu, Zhixiang Wang, Xiaofang Li, Jing Sun, Qifa Liu, Li Xuan.

We report a randomized prospective phase 3 study, designed to evaluate the efficacy and tolerability of idarubicin plus busulfan and cyclophosphamide (IDA-BuCy) versus BuCy in autologous hematopoietic stem-cell transplantation (auto-HSCT) for intermediate-risk acute myeloid leukemia (IR-AML) patients in first complete remission (CR1). One hundred and fifty-four patients were enrolled and randomized to receive IDA-BuCy (IDA 15 mg/m2/day on days -12 to -10, Bu 3.2 mg/kg/day on days -7 to -4, and Cy 60 mg/kg/day on days -3 to -2) or BuCy. The 2-year incidence of relapse was 15.6% and 19.5% in IDA-BuCy and BuCy groups (p = 0.482), respectively. There was no significant overall survival (OS) and disease-free survival (DFS) benefit for IR-AML patients receiving IDA-BuCy (2-year OS 81.8% in IDA-BuCy vs. 83.1% in BuCy, p = 0.798; 2-year DFS 76.6% in IDA-BuCy vs. 79.2% in BuCy, p = 0.693). Grade 3 or worse regimen-related toxicity (RRT) was reported for 22 (28.9%) of 76 and 9 (12.0%) of 75 patients in two groups (p = 0.015), respectively. AEs within 100 days with an outcome of death were reported for 4 (5.3%) and 0 patients in two groups. In conclusion, IDA-BuCy has higher RRT and similar anti-leukemic activity compared with BuCy in IR-AML patients in CR1 undergoing auto-HSCT. Thus, caution should be taken when choosing IDA-BuCy for IR-AML patients in CR1 with auto-HSCT. This trial is registered with ClinicalTrials.gov, NCT02671708, and is complete.

DOI: https://doi.org/10.1002/ajh.26800