bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2021–12–19
twenty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo.
  2. Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
  3. Treatment patterns, economic burden, and overall survival in US Medicare Advantage beneficiaries newly diagnosed with acute myeloid leukemia (AML) in 2015-2020.
  4. Targeting chemotherapy to de-condensed H3K27me3-marked chromatin of AML cells enhances leukemia suppression.
  5. NPM1 gene mutations can be confidently identified in blood DNA months before de novo AML onset.
  6. European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol.
  7. Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine.
  8. Epigenetic silencing of UBXN8 contributes to leukemogenesis in t(8;21) acute myeloid leukemia.
  9. Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.
  10. Hemoglobin is a key determinant of quality of life before and during azacitidine-based therapy for myelodysplasia and low blast count acute myeloid leukemia.
  11. Phase Separation mediates NUP98 Fusion Oncoprotein Leukemic Transformation.
  12. Low dose of homoharringtonine and cytarabine-based priming induction regimens for patients with de novo acute myeloid leukemia and high-risk myelodysplastic syndrome aged over 70 years.
  13. Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal.
  14. R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability.
  15. Treatment intensification with FLAG-Ida may improve disease control in younger patients with secondary acute myeloid leukaemia: long-term follow up of the MRC AML15 trial.
  16. Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
  17. JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis.
  18. Risk of mortality and second malignancies in primary myelofibrosis before and after ruxolitinib approval.
  19. The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors.
  20. Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy: A Prospective Observational Study From the Acute Leukaemia French Association (ALFA) Group.
  21. Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-lineage Acute Lymphoblastic Leukemia.
  22. Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.
  1. Leukemia. 2021 Dec 13.
    Gab2 deficiency prevents Flt3-ITD driven acute myeloid leukemia in vivo.
    Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schönberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L Illert, Tilman Brummer.
      Internal tandem duplications (ITD) of the FMS-like tyrosine kinase 3 (FLT3) predict poor prognosis in acute myeloid leukemia (AML) and often co-exist with inactivating DNMT3A mutations. In vitro studies implicated Grb2-associated binder 2 (GAB2) as FLT3-ITD effector. Utilizing a Flt3-ITD knock-in, Dnmt3a haploinsufficient mouse model, we demonstrate that Gab2 is essential for the development of Flt3-ITD driven AML in vivo, as Gab2 deficient mice displayed prolonged survival, presented with attenuated liver and spleen pathology and reduced blast counts. Furthermore, leukemic bone marrow from Gab2 deficient mice exhibited reduced colony-forming unit capacity and increased FLT3 inhibitor sensitivity. Using transcriptomics, we identify the genes encoding for Axl and the Ret co-receptor Gfra2 as targets of the Flt3-ITD/Gab2/Stat5 axis. We propose a pathomechanism in which Gab2 increases signaling of these receptors by inducing their expression and by serving as downstream effector. Thereby, Gab2 promotes AML aggressiveness and drug resistance as it incorporates these receptor tyrosine kinases into the Flt3-ITD signaling network. Consequently, our data identify GAB2 as a promising biomarker and therapeutic target in human AML.
    DOI:  https://doi.org/10.1038/s41375-021-01490-0
  2. Nat Commun. 2021 Dec 13. 12(1): 7244
    Clonal architecture predicts clinical outcomes and drug sensitivity in acute myeloid leukemia.
    Brooks A Benard, Logan B Leak, Armon Azizi, Daniel Thomas, Andrew J Gentles, Ravindra Majeti.
      The impact of clonal heterogeneity on disease behavior or drug response in acute myeloid leukemia remains poorly understood. Using a cohort of 2,829 patients, we identify features of clonality associated with clinical features and drug sensitivities. High variant allele frequency for 7 mutations (including NRAS and TET2) associate with dismal prognosis; elevated GATA2 variant allele frequency correlates with better outcomes. Clinical features such as white blood cell count and blast percentage correlate with the subclonal abundance of mutations such as TP53 and IDH1. Furthermore, patients with cohesin mutations occurring before NPM1, or transcription factor mutations occurring before splicing factor mutations, show shorter survival. Surprisingly, a branched pattern of clonal evolution is associated with superior clinical outcomes. Finally, several mutations (including NRAS and IDH1) predict drug sensitivity based on their subclonal abundance. Together, these results demonstrate the importance of assessing clonal heterogeneity with implications for prognosis and actionable biomarkers for therapy.
    DOI:  https://doi.org/10.1038/s41467-021-27472-5
  3. Leuk Lymphoma. 2021 Dec 16. 1-11
    Treatment patterns, economic burden, and overall survival in US Medicare Advantage beneficiaries newly diagnosed with acute myeloid leukemia (AML) in 2015-2020.
    Scott F Huntington, Michael P Ingham, Linda Okonkwo, Ajaybir Singh, Ruibin Wang, Eric M Ammann.
      The present study assessed changes in patient management, economic burden, and overall survival (OS) in a contemporary cohort of 2775 US Medicare Advantage beneficiaries aged ≥66 years newly diagnosed with acute myeloid leukemia (AML) between 01 January 2015 and 30 June 2020. Use of venetoclax-based therapy increased and replaced hypomethylating agent (HMA) monotherapy as the most common first-line treatment choice in 2019-2020. In newly diagnosed AML patients aged ≥75 and 66-74 years, mean per-patient 1-year healthcare expenditures were $81,818 and $156,033 (2020 USD) and median OS was 2.3 and 8.5 months, respectively. In addition, 40% of Medicare Advantage patients with newly diagnosed AML continue to receive supportive care alone. These findings indicate that at the population level clinical outcomes remain poor for older adults with AML, pointing to a continuing unmet medical need.
    Keywords:  Acute myeloid leukemia; economic burden of disease; healthcare resource utilization; older adults; overall survival; treatment patterns
    DOI:  https://doi.org/10.1080/10428194.2021.2012666
  4. Cancer Res. 2021 Dec 13. pii: canres.1297.2021. [Epub ahead of print]
    Targeting chemotherapy to de-condensed H3K27me3-marked chromatin of AML cells enhances leukemia suppression.
    Patrizia Porazzi, Svetlana Petruk, Luca Pagliaroli, Marco De Dominici, David Deming, Matthew V Puccetti, Saul Kushinsky, Gaurav Kumar, Valentina Minieri, Elisa Barbieri, Sandra Deliard, Alexis Grande, Marco Trizzino, Alessandro Gardini, Eli Canaani, Neil Palmisiano, Pierluigi Porcu, Adam Ertel, Paolo M Fortina, Christine M Eischen, Alexander Mazo, Bruno Calabretta.
      Despite treatment with intensive chemotherapy, acute myeloid leukemia (AML) remains an aggressive malignancy with a dismal outcome in most patients. We found that AML cells exhibit an unusually rapid accumulation of the repressive histone mark H3K27me3 on nascent DNA. In cell lines, primary cells and xenograft mouse models, inhibition of the H3K27 histone methyltransferase EZH2 to de-condense the H3K27me3-marked chromatin of AML cells enhanced chromatin accessibility and chemotherapy-induced DNA damage, apoptosis, and leukemia suppression. These effects were further promoted when chromatin de-condensation of AML cells was induced upon S-phase entry after release from a transient G1 arrest mediated by CDK4/6 inhibition. In the p53-null KG-1 and THP-1 AML cell lines, EZH2 inhibitor and doxorubicin co-treatment induced transcriptional reprogramming that was, in part, dependent on de-repression of H3K27me3-marked gene promoters and led to increased expression of cell death-promoting and growth-inhibitory genes. In conclusion, decondensing H3K27me3-marked chromatin by EZH2 inhibition represents a promising approach to improve the efficacy of DNA-damaging cytotoxic agents in AML patients. This strategy might allow for a lowering of chemotherapy doses with a consequent reduction of treatment-related side effects in elderly AML patients or those with significant comorbidities.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-1297
  5. Blood Adv. 2021 Dec 17. pii: bloodadvances.2021005927. [Epub ahead of print]
    NPM1 gene mutations can be confidently identified in blood DNA months before de novo AML onset.
    Pedro M Quiros, Muxin Gu, Clea Barcena, Vivek Iyer, George S Vassiliou.
      
    DOI:  https://doi.org/10.1182/bloodadvances.2021005927
  6. Blood Adv. 2021 Dec 15. pii: bloodadvances.2021005585. [Epub ahead of print]
    European LeukemiaNet 2017 risk stratification for acute myeloid leukemia: validation in a risk-adapted protocol.
    Alex Bataller, Ana Garrido, Francesca Guijarro, Guadalupe Oñate, Marina Diaz-Beya, Montserrat Arnan, Mar Tormo, Susana Vives, Maria Paz Queipo DE Llano, Rosa Coll, David Gallardo, Ferran Vall-Llovera, Lourdes Escoda, Antonio García-Guiñon, Olga Salamero, Antònia Sampol, Brayan Merchan, Joan Bargay, Sandra Castaño-Díez, Daniel Esteban, Aina Oliver-Caldes, Andrea Rivero, Pablo Mozas, Mònica López-Guerra, Marta Pratcorona, Lurdes Zamora, Dolors Costa, María Rozman, Josep F Nomdedeu, Dolors Colomer, Salut Brunet, Jorge Sierra, Jordi Esteve.
      The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and post-remission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the CETLAM-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, while it recommends allogeneic stem cell transplantation as a post-remission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%) and 245 (36%) patients allocated to the favorable, intermediate and adverse risk group, respectively. The 2 and 5 year-overall survival (OS) were 77 and 70% for favorable risk patients, 52 and 46% for intermediate risk patients, and 33 and 23% for adverse risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol, based on alloSCT after remission for non-favorable ELN subgroups, and identifies a genetic subset with a very poor outcome which warrants investigation of novel strategies.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005585
  7. J Clin Oncol. 2021 Dec 15. JCO2101546
    Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine.
    Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Christian Recher, Andre C Schuh, Michael J Thirman, Jacqueline S Garcia, Courtney D DiNardo, Vladimir Vorobyev, Nicola S Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Döhner.
       PURPOSE: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10-3 in the VIALE-A trial.
    METHODS: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10-3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS.
    RESULTS: One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10-3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10-3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10-3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10-3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10-3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001).
    CONCLUSION: Patients who achieved CRc and MRD < 10-3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10-3.
    DOI:  https://doi.org/10.1200/JCO.21.01546
  8. Exp Mol Med. 2021 Dec 17.
    Epigenetic silencing of UBXN8 contributes to leukemogenesis in t(8;21) acute myeloid leukemia.
    Erna Yang, Wei Guan, Desheng Gong, Jieying Li, Caixia Han, Juan Zhang, Hong Wang, Synat Kang, Xuefeng Gao, Yonghui Li, Li Yu.
      The formation of the RUNX1-RUNX1T1 fusion protein, resulting from the t(8;21) translocation, is considered to be one of the initiating events of t(8;21) acute myeloid leukemia (AML). However, the mechanisms of the oncogenic mechanism of RUNX1-RUNX1T1 remain unclear. In this study, we found that RUNX1-RUNX1T1 triggers the heterochromatic silencing of UBXN8 by recognizing the RUNX1-binding sites and recruiting chromatin-remodeling enzymes to the UBXN8 promoter region. Decitabine, a specific inhibitor of DNA methylation, upregulated the expression of UBXN8 in RUNX1-RUNX1T1+ AML cell lines. Overexpression of UBXN8 inhibited the proliferation and colony-forming ability of and promoted cell cycle arrest in t(8;21) AML cell lines. Enhancing UBXN8 levels can significantly inhibit tumor proliferation and promote the differentiation of RUNX1-RUNX1T1+ cells in vivo. In conclusion, our results indicated that epigenetic silencing of UBXN8 via methylation of its promoter region mediated by the RUNX1-RUNX1T1 fusion protein contributes to the leukemogenesis of t(8;21) AML and that UBXN8 targeting may be a potential therapeutic strategy for t(8;21) AML.
    DOI:  https://doi.org/10.1038/s12276-021-00695-8
  9. Nat Commun. 2021 Dec 14. 12(1): 7190
    Metabolic drug survey highlights cancer cell dependencies and vulnerabilities.
    Tea Pemovska, Johannes W Bigenzahn, Ismet Srndic, Alexander Lercher, Andreas Bergthaler, Adrián César-Razquin, Felix Kartnig, Christoph Kornauth, Peter Valent, Philipp B Staber, Giulio Superti-Furga.
      Interrogation of cellular metabolism with high-throughput screening approaches can unravel contextual biology and identify cancer-specific metabolic vulnerabilities. To systematically study the consequences of distinct metabolic perturbations, we assemble a comprehensive metabolic drug library (CeMM Library of Metabolic Drugs; CLIMET) covering 243 compounds. We, next, characterize it phenotypically in a diverse panel of myeloid leukemia cell lines and primary patient cells. Analysis of the drug response profiles reveals that 77 drugs affect cell viability, with the top effective compounds targeting nucleic acid synthesis, oxidative stress, and the PI3K/mTOR pathway. Clustering of individual drug response profiles stratifies the cell lines into five functional groups, which link to specific molecular and metabolic features. Mechanistic characterization of selective responses to the PI3K inhibitor pictilisib, the fatty acid synthase inhibitor GSK2194069, and the SLC16A1 inhibitor AZD3965, bring forth biomarkers of drug response. Phenotypic screening using CLIMET represents a valuable tool to probe cellular metabolism and identify metabolic dependencies at large.
    DOI:  https://doi.org/10.1038/s41467-021-27329-x
  10. Leuk Lymphoma. 2021 Dec 17. 1-8
    Hemoglobin is a key determinant of quality of life before and during azacitidine-based therapy for myelodysplasia and low blast count acute myeloid leukemia.
    Australasian Leukaemia and Lymphoma Group (ALLG)
      Myelodysplastic syndromes (MDS) have a major impact on quality of life (QoL). We performed a post hoc analysis of two multicenter trials of azacitidine-based disease-modifying therapy for patients with MDS and low blast count acute myeloid leukemia (AML), to identify factors associated with QoL. 231 patients were included (median age 70 years). At baseline, higher initial hemoglobin, but not neutrophil or platelet count, was associated with better global QoL and physical function (p < 0.001 and p = 0.001, respectively). During therapy, increase in hemoglobin was associated with improvement in QoL and physical function (p = 0.005 and p < 0.001, respectively). Lower initial hemoglobin was associated with higher dyspnea and fatigue scores (p < 0.001 and p = 0.001, respectively), and hemoglobin response was associated with improvement in dyspnea and fatigue (p < 0.001 for each). In patients with MDS and low blast count AML, hemoglobin level was strongly correlated with global QoL, physical functioning, dyspnea and fatigue, both before and during azacitidine-based therapy.
    Keywords:  Myelodysplastic syndrome; acute myeloid leukemia; azacitidine; hemoglobin; quality of life; red cell transfusion
    DOI:  https://doi.org/10.1080/10428194.2021.2012664
  11. Cancer Discov. 2021 Dec 13. pii: candisc.0674.2021. [Epub ahead of print]
    Phase Separation mediates NUP98 Fusion Oncoprotein Leukemic Transformation.
    Bappaditya Chandra, Nicole L Michmerhuizen, Hazheen K Shirnekhi, Swarnendu Tripathi, Brittany J Pioso, David W Baggett, Diana M Mitrea, Ilaria Iacobucci, Michael R White, Jingjing Chen, Cheon-Gil Park, Huiyun Wu, Stanley Pounds, Anna Medyukhina, Khaled Khairy, Qingsong Gao, Chunxu Qu, Sherif Abdelhamed, Scott D Gorman, Simranjot Bawa, Carolyn Maslanka, Swati Kinger, Priyanka Dogra, Mylene C Ferrolino, Danika Di Giacomo, Cristina Mecucci, Jeffery M Klco, Charles G Mullighan, Richard W Kriwacki.
      NUP98 fusion oncoproteins (FOs) are drivers in pediatric leukemias and many transform hematopoietic cells. Most NUP98 FOs harbor an intrinsically disordered region from NUP98 that is prone to liquid-liquid phase separation (LLPS) in vitro. A predominant class of NUP98 FOs, including NUP98-HOXA9 (NHA9), retains a DNA-binding homeodomain, whereas others harbor other types of DNA- or chromatin-binding domains. NUP98 FOs have long been known to form puncta, but long-standing questions are how nuclear puncta form, and how they drive leukemogenesis. Here we studied NHA9 condensates and show that homotypic interactions and different types of heterotypic interactions are required to form nuclear puncta, which are associated with aberrant transcriptional activity and transformation of hematopoietic stem and progenitor cells. We also show that three additional leukemia-associated NUP98 FOs (NUP98-PRRX1, NUP98-KDM5A, NUP98-LNP1) form nuclear puncta and transform hematopoietic cells. These findings indicate that LLPS is critical for leukemogenesis by NUP98 FOs.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0674
  12. Hematology. 2021 Dec;26(1): 1040-1045
    Low dose of homoharringtonine and cytarabine-based priming induction regimens for patients with de novo acute myeloid leukemia and high-risk myelodysplastic syndrome aged over 70 years.
    Fang Wang, Wenyan Xu, Li Liu, Xiuhong Ren, Pingping Liu, Li Zheng, Hao Zhang, Songsong Zhang, Yaru Xu, Zhenxing Guo.
       OBJECTIVES: Our objective is to retrospectively analyze the response to low dose of homoharringtonine (HHT) and cytarabine-based priming induction regimens in patients above 70 years with de novo acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS).
    PATIENTS AND METHODS: We retrospectively analyzed these very elderly newly diagnosed patients with AML and high-risk MDS, who received low dose of HHT and cytarabine-based priming induction regimens between March 2006 and September 2019.
    RESULTS: Of the 24 patients, 11 patients (47.8%) achieved complete remission (CR) and 3 (13%) partial remission, and the overall response rate was 60.9%. The estimated median overall survival (OS) time was 12 months and the 1-year OS rate was 47.8%. Patients without CR and Charlson's Comorbidity Index > 2 may be the two independent prognostic factors. The median OS was significantly higher for patients with CR after induction chemotherapy than those without CR (22.93 vs. 8.5 months, p < .01).
    CONCLUSION: Our study provides a hint of the efficacy of low dose of HHT and cytarabine-based priming induction regimens for patients aged over 70 years with de novo AML and high-risk MDS should be further studied.
    Keywords:  70 years old; Acute myeloid leukemia; Charlson’s comorbidity index; HHT; overall survival
    DOI:  https://doi.org/10.1080/16078454.2021.2009642
  13. Hemasphere. 2021 Nov;5(11): e646
    Updated Diagnostic Criteria and Classification of Mast Cell Disorders: A Consensus Proposal.
    Peter Valent, Cem Akin, Karin Hartmann, Ivan Alvarez-Twose, Knut Brockow, Olivier Hermine, Marek Niedoszytko, Juliana Schwaab, Jonathan J Lyons, Melody C Carter, Hanneke Oude Elberink, Joseph H Butterfield, Tracy I George, Georg Greiner, Celalettin Ustun, Patrizia Bonadonna, Karl Sotlar, Gunnar Nilsson, Mohamad Jawhar, Frank Siebenhaar, Sigurd Broesby-Olsen, Selim Yavuz, Roberta Zanotti, Magdalena Lange, Boguslaw Nedoszytko, Gregor Hoermann, Mariana Castells, Deepti H Radia, Javier I Muñoz-Gonzalez, Wolfgang R Sperr, Massimo Triggiani, Hanneke C Kluin-Nelemans, Stephen J Galli, Lawrence B Schwartz, Andreas Reiter, Alberto Orfao, Jason Gotlib, Michel Arock, Hans-Peter Horny, Dean D Metcalfe.
      Mastocytosis is a hematologic neoplasm characterized by expansion and focal accumulation of neoplastic mast cells (MC) in diverse organs, including the skin, bone marrow (BM), spleen, liver, and gastrointestinal tract. The World Health Organization classification divides the disease into prognostically distinct variants of cutaneous mastocytosis (CM) and systemic mastocytosis (SM). Although this classification remains valid, recent developments in the field and the advent of new diagnostic and prognostic parameters created a need to update and refine definitions and diagnostic criteria in MC neoplasms. In addition, MC activation syndromes (MCAS) and genetic features predisposing to SM and MCAS have been identified. To discuss these developments and refinements in the classification, we organized a Working Conference comprised of experts from Europe and the United States in August 2020. This article reports on outcomes from this conference. Of particular note, we propose adjustments in the classification of CM and SM, refinements in diagnostic criteria of SM variants, including smoldering SM and BM mastocytosis (BMM), and updated criteria for MCAS and other conditions involving MC. CD30 expression in MC now qualifies as a minor SM criterion, and BMM is now defined by SM criteria, absence of skin lesions and absence of B- and C-findings. A basal serum tryptase level exceeding 20 ng/mL remains a minor SM criterion, with recognition that hereditary alpha-tryptasemia and various myeloid neoplasms may also cause elevations in tryptase. Our updated proposal will support diagnostic evaluations and prognostication in daily practice and the conduct of clinical trials in MC disorders.
    DOI:  https://doi.org/10.1097/HS9.0000000000000646
  14. Nat Commun. 2021 Dec 16. 12(1): 7314
    R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability.
    Thorsten Mosler, Francesca Conte, Gabriel M C Longo, Ivan Mikicic, Nastasja Kreim, Martin M Möckel, Giuseppe Petrosino, Johanna Flach, Joan Barau, Brian Luke, Vassilis Roukos, Petra Beli.
      Transcription poses a threat to genomic stability through the formation of R-loops that can obstruct progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with a displaced non-template DNA strand. We developed RNA-DNA Proximity Proteomics to map the R-loop proximal proteome of human cells using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DDX41 in opposing R-loop and double strand DNA break accumulation in promoters. DDX41 is enriched in promoter regions in vivo, and can unwind RNA-DNA hybrids in vitro. R-loop accumulation upon loss of DDX41 is accompanied with replication stress, an increase in the formation of double strand DNA breaks and transcriptome changes associated with the inflammatory response. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia in adulthood. We propose that R-loop accumulation and genomic instability-associated inflammatory response may contribute to the development of familial AML with mutated DDX41.
    DOI:  https://doi.org/10.1038/s41467-021-27530-y
  15. Br J Haematol. 2021 Dec 13.
    Treatment intensification with FLAG-Ida may improve disease control in younger patients with secondary acute myeloid leukaemia: long-term follow up of the MRC AML15 trial.
    Nigel Russell, Robert Hills, Lars Kjeldsen, Mike Dennis, Alan Burnett.
      Secondary acute myeloid leukaemia (AML) has a poor outcome following "3 + 7-like" chemotherapy. While CPX-351 has been approved for patients aged 60-75, the optimal treatment, or comparator, in younger patients is less clear. The MRC AML15 trial randomised younger patients between daunorubicin and ara-C (DA) and DA plus etoposide (ADE) and ADE and fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor (FLAG-Ida) induction. Overall results failed to show an overall survival benefit for FLAG-Ida despite a reduction in relapse, the outcome of patients <60 years with secondary AML compared to DA/ADE was not reported. In this group (n = 115) response to induction was not different [complete remission/complete remission with incomplete haematological response 81% vs. 79%), however, 5-year overall survival and relapse free survival was superior for FLAG-Ida [37% vs. 27%, stratified hazard ratio (HR) 0·45 (0·33-0·90) P = 0·02 and 41% vs. 22%; stratified HR 0·54 (0·31-0·96) P = 0·04] respectively, suggesting that younger patients with secondary AML may benefit from treatment intensification and that "3 + 7" may not be the optimal comparator in trials for this group of patients.
    Keywords:  chemotherapy; clinical trial; secondary acute myeloid leukaemia
    DOI:  https://doi.org/10.1111/bjh.17974
  16. EMBO Rep. 2021 Dec 16. e54384
    Pyruvate metabolism guides definitive lineage specification during hematopoietic emergence.
    Leal Oburoglu, Els Mansell, Isaac Canals, Valgardur Sigurdsson, Carolina Guibentif, Shamit Soneji, Niels-Bjarne Woods.
      During embryonic development, hematopoiesis occurs through primitive and definitive waves, giving rise to distinct blood lineages. Hematopoietic stem cells (HSCs) emerge from hemogenic endothelial (HE) cells, through endothelial-to-hematopoietic transition (EHT). In the adult, HSC quiescence, maintenance, and differentiation are closely linked to changes in metabolism. However, metabolic processes underlying the emergence of HSCs from HE cells remain unclear. Here, we show that the emergence of blood is regulated by multiple metabolic pathways that induce or modulate the differentiation toward specific hematopoietic lineages during human EHT. In both in vitro and in vivo settings, steering pyruvate use toward glycolysis or OXPHOS differentially skews the hematopoietic output of HE cells toward either an erythroid fate with primitive phenotype, or a definitive lymphoid fate, respectively. We demonstrate that glycolysis-mediated differentiation of HE toward primitive erythroid hematopoiesis is dependent on the epigenetic regulator LSD1. In contrast, OXPHOS-mediated differentiation of HE toward definitive hematopoiesis is dependent on cholesterol metabolism. Our findings reveal that during EHT, metabolism is a major regulator of primitive versus definitive hematopoietic differentiation.
    Keywords:  OXPHOS; endothelial-to-hematopoietic transition; glycolysis; hematopoiesis; pyruvate metabolism
    DOI:  https://doi.org/10.15252/embr.202154384
  17. Blood Cancer J. 2021 Dec 11. 11(12): 199
    JAK2V617F variant allele frequency >50% identifies patients with polycythemia vera at high risk for venous thrombosis.
    Paola Guglielmelli, Giuseppe G Loscocco, Carmela Mannarelli, Elena Rossi, Francesco Mannelli, Francesco Ramundo, Giacomo Coltro, Silvia Betti, Chiara Maccari, Sara Ceglie, Patrizia Chiusolo, Chiara Paoli, Tiziano Barbui, Ayalew Tefferi, Valerio De Stefano, Alessandro M Vannucchi.
      Arterial (AT) and venous (VT) thrombotic events are the most common complications in patients with polycythemia vera (PV) and are the leading causes of morbidity and mortality. In this regard, the impact of JAK2V617F variant allele frequency (VAF) is still debated. The purpose of the current study was to analyze the impact of JAK2V617F VAF in the context of other established risk factors for thrombosis in a total of 865 2016 WHO-defined PV patients utilizing two independent cohorts: University of Florence (n = 576) as a training cohort and Policlinico Gemelli, Catholic University, Rome (n = 289) as a validation cohort. In the training cohort VT free-survival was significantly shorter in the presence of a JAK2V617F VAF > 50% (HR 4; p < 0.0001), whereas no difference was found for AT (HR 0.9; p = 0.8). Multivariable analysis identified JAK2V617F VAF > 50% (HR 3.8, p = 0.001) and previous VT (HR 2.2; p = 0.04) as independent risk factors for future VT whereas diabetes (HR 2.4; p = 0.02), hyperlipidemia (HR 2.3; p = 0.01) and previous AT (HR 2; p = 0.04) were independent risk factors for future AT. Similarly, JAK2V617F VAF > 50% (HR 2.4; p = 0.01) and previous VT (HR 2.8; p = 0.005) were confirmed as independent predictors of future VT in the validation cohort. Impact of JAK2V617F VAF > 50% on VT was particularly significant in conventional low-risk patients, both in Florence (HR 10.6, p = 0.005) and Rome cohort (HR 4; p = 0.02). In conclusion, we identified JAK2V617F VAF > 50% as an independent strong predictor of VT, supporting that AT and VT are different entities which might require distinct management.
    DOI:  https://doi.org/10.1038/s41408-021-00581-6
  18. Leuk Res. 2021 Dec 09. pii: S0145-2126(21)01771-9. [Epub ahead of print]112 106770
    Risk of mortality and second malignancies in primary myelofibrosis before and after ruxolitinib approval.
    John W Thomas, Omer Jamy, Mithun Vinod Shah, Pankit Vachhani, Ronald S Go, Gaurav Goyal.
       BACKGROUND: Primary myelofibrosis (PMF) is associated with morbidity and mortality. Ruxolitinib gained US FDA approval for treatment of intermediate/high-risk PMF in November 2011. We evaluated differences in survival and second primary malignancy (SPM) incidence among US PMF patients in the years before and after ruxolitinib approval.
    METHODS: We conducted a retrospective study utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER)-18 database for PMF patients. We divided patients into five-year cohorts pre- (2007-2011) and post-ruxolitinib (2012-2016) approval and compared relative survival rates (RSRs) to the standard population and standardized incidence rates (SIRs) of SPMs between cohorts.
    RESULTS: We included 2020 patients diagnosed with PMF from 2007-2016 in this study. There was no difference in the four-year RSRs between cohorts (54 % vs. 57 %, p = 0.776). More patients developed SPMs in the post-ruxolitinib cohort (8% vs. 6%, p = 0.041). The majority of SPMs were hematologic with higher incidence of AML transformation in the post-ruxolitinib cohort (SIR 125.29 vs. 70.55).
    CONCLUSIONS: PMF prognosis remains poor in the years following ruxolitinib's approval. SPM incidence including AML transformation is higher in the years after approval. Further studies are needed to determine the true impact of ruxolitnib on population outcomes.
    Keywords:  Leukemia transformation; Mortality; Primary myelofibrosis; Ruxolitinib; Second primary neoplasms
    DOI:  https://doi.org/10.1016/j.leukres.2021.106770
  19. Biochim Biophys Acta Rev Cancer. 2021 Dec 08. pii: S0304-419X(21)00164-5. [Epub ahead of print]1877(1): 188666
    The molecular mechanisms behind activation of FLT3 in acute myeloid leukemia and resistance to therapy by selective inhibitors.
    Ran Friedman.
      Acute myeloid leukemia is an aggressive cancer, which, in spite of increasingly better understanding of its genetic background remains difficult to treat. Mutations in the FLT3 gene are observed in ≈30% of the patients. Most of these mutations are internal tandem duplications (ITDs) of a sequence within the protein coding region, an activation mechanism that is almost non-existent with other genes and cancers. As patients each carry their own unique set of mutations, it is challenging to understand how ITDs activate the protein, and ascertain the risk for each individual patient. Available treatment options are limited due to development of drug resistance. Here, recent studies are reviewed that help to better understand the molecular mechanism behind activation of the FLT3 protein due to mutations. It is argued that difference in mutation sequences and especially location might be coupled to prognosis. When it comes to FLT3 inhibitors, key differences between them can be attributed to the mode of inhibition (type-1 and type-2 inhibitors), effective inhibitory coefficient in the blood plasma and off-target binding. Accounting for the position and length of insertions may in the future be used to predict prognosis and rationalise treatment. Development of new inhibitors must take into account the potential for resistance mutations. Inhibitors aimed at multiple specific targets are currently being developed. These, and as well as combination therapies will hopefully lead to longer periods during which targeted FLT3 therapy will remain effective.
    Keywords:  Acute myeloid leukemia; Gilteritinib; Kinase inhibitors; Midostaurin; Quizartinib
    DOI:  https://doi.org/10.1016/j.bbcan.2021.188666
  20. Clin Lymphoma Myeloma Leuk. 2021 Oct 25. pii: S2152-2650(21)02415-0. [Epub ahead of print]
    Antifungal Prophylaxis in AML Patients Receiving Intensive Induction Chemotherapy: A Prospective Observational Study From the Acute Leukaemia French Association (ALFA) Group.
    Mauricette Michallet, Mohamad Sobh, Stephane Morisset, Alexandre Deloire, Emmanuel Raffoux, Stephane de Botton, Denis Caillot, Sylvain Chantepie, Stephane Girault, Celine Berthon, Sarah Bertoli, Stephane Lepretre, Thibaut Leguay, Sylvie Castaigne, Jean-Pierre Marolleau, Cecile Pautas, Jean-Valere Malfuson, Norbert Veyn, Thorsten Braun, Lauris Gastaud, Felipe Suarez, Aline Schmidt, Remy Gressin, Caroline Bonmati, Karine Celli-Lebras, Mohamed El-Hamri, Patricia Ribaud, Herve Dombret, Xavier Thomas, Anne Bergeron.
       BACKGROUND: Although recommended in patients with acute myeloblastic leukaemia (AML) after induction chemotherapy, real-life use of antifungal prophylaxis (AFP) is different among centres.
    MATERIALS AND METHODS: This is an ancillary study to a randomized trial on intensive induction chemotherapy in AML patients (ALFA-0702/NCT00932412), where AFP with posaconazole was recommended. IFIs were graded by investigators and by central reviewers according to the revised EORTC definitions. Experts conclusions were compared to the investigators' ones.
    RESULTS: A total of 677 patients were included. Four AFP strategies were reported: Group-1: no AFP (n = 203, 30%), Group-2: posaconazole (n = 241, 36%), Group-3: posaconazole with other AFP (n = 142, 21%), Group-4: other AFP (n = 91, 13%). Experts graded more IFI than investigators: proven/probable IFI, 9.0% (n = 61) versus 6.2% (n = 42). The cumulative incidence at day60 of probable/proven IFI was 13.9% (Group-1); 7.9% (Group-2); 5.6% (Group-3); and 6.6% (Group-4). IFI onset was 26 (19-31) days after induction in Groups 2-3, versus 16 (9-25) days in Group 1 and 20 (12-24) days in Group 4 (P< .001). After a median follow-up of 27.5 months (0.4-73.4), the mortality rate was 38.3%, with 5.4% attributed to IFI. In multivariate analysis, IFI occurrence was an independent risk of death (HR5.63, 95%-CI 2.62-12.08, P< .001). EORTC recommendations were applied in only 57% of patients. In patients without IFI, the rate of AML complete remission was higher.
    CONCLUSIONS: In AML patients, AFP delayed the onset of IFI in addition of decreasing their rate. The frequent misidentification of IFI impacts their appropriate management according to recommendations. hematological remission was more frequent in patients without IFI.
    Keywords:  Acute myeloid leukemia; Antifungal prophylaxis; Fungal infection; induction chemotherapy; recommendations
    DOI:  https://doi.org/10.1016/j.clml.2021.10.011
  21. Blood. 2021 Dec 16. pii: blood.2021013290. [Epub ahead of print]
    Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-lineage Acute Lymphoblastic Leukemia.
    Mahmoud R Gaballa, Pinaki Prosad Banerjee, Denái R Milton, Xianli Jiang, Christina Ganesh, Sajad J Khazal, Vandana Nandivada, Sanjida Islam, Mecit Kaplan, May Daher, Rafet Basar, Amin Alousi, Rohtesh S Mehta, Gheath Alatrash, Issa F Khouri, Betul Oran, David Marin, Uday R Popat, Amanda L Olson, Priti Tewari, Nitin Jain, Elias J Jabbour, Farhad Ravandi, Hagop M Kantarjian, Ken Chen, Richard E Champlin, Elizabeth J Shpall, Katayoun Rezvani, Partow Kebriaei.
      Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single center phase II study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least one cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44-105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute GVHD grades 2-4 and 3-4 were 33% and 5%, respectively; two cases of mild (10%) and one case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival, progression-free survival, and non-relapse mortality rates were 85%, 71%, and 0%, respectively. In a matched-analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and post-treatment samples identified patients with specific T-cell profiles as "responders" or "non-responders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Non-responders were T-cell deficient and expressed more inhibitory checkpoint molecules, including TIM3. We found that blinatumomab post-allogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment.
    DOI:  https://doi.org/10.1182/blood.2021013290
  22. Lancet Haematol. 2021 Dec 10. pii: S2352-3026(21)00370-7. [Epub ahead of print]
    Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.
    Mhairi Copland, Daniel Slade, Graham McIlroy, Gillian Horne, Jenny L Byrne, Kate Rothwell, Kristian Brock, Hugues De Lavallade, Charles Craddock, Richard E Clark, Matthew L Smith, Rachel Fletcher, Rebecca Bishop, Dragana Milojkovic, Christina Yap.
       BACKGROUND: Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability.
    METHODS: MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib-FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented.
    FINDINGS: Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36-48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3-4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia).
    INTERPRETATION: Ponatinib-FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers.
    FUNDING: Blood Cancer UK and Incyte.
    DOI:  https://doi.org/10.1016/S2352-3026(21)00370-7
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