bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2020–06–21
twenty papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.
  2. Quantitative proteomics reveals specific metabolic features of Acute Myeloid Leukemia stem cells.
  3. Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.
  4. CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis.
  5. Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation.
  6. Partitioning of cancer therapeutics in nuclear condensates.
  7. MicroRNA-92a as a marker of treatment response and survival in adult acute myeloid leukemia patients.
  8. A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.
  9. Synthesis of N-aryl and N-alkyl substituted imidazolium silver complexes. Cytotoxic screening using human cell lines modelling acute myeloid leukemia.
  10. Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia.
  11. Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities.
  12. Targeting GLUT1 in acute myeloid leukemia to overcome cytarabine resistance.
  13. A Real-world Perspective of CD123 Expression in Acute Leukemia as Promising Biomarker to Predict Treatment Outcome in B-ALL and AML.
  14. Arsenic trioxide and all-trans retinoic acid suppress the expression of FLT3-ITD.
  15. Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality.
  16. Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors.
  17. Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells.
  18. Lower Serum miR-145 Predicts Poor Prognosis in Patients with Acute Myeloid Leukemia.
  19. The efficacy and safety of daunorubicin versus idarubicin combined with cytarabine for induction therapy in acute myeloid leukemia: A meta-analysis of randomized clinical trials.
  20. First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis.
  1. Cancer Cell. 2020 Jun 01. pii: S1535-6108(20)30264-6. [Epub ahead of print]
    Targeting RSPO3-LGR4 Signaling for Leukemia Stem Cell Eradication in Acute Myeloid Leukemia.
    Basit Salik, Hangyu Yi, Nunki Hassan, Nancy Santiappillai, Binje Vick, Patrick Connerty, Alastair Duly, Toby Trahair, Andrew J Woo, Dominik Beck, Tao Liu, Karsten Spiekermann, Irmela Jeremias, Jianlong Wang, Maria Kavallaris, Michelle Haber, Murray D Norris, Dan A Liebermann, Richard J D'Andrea, Christopher Murriel, Jenny Y Wang.
      Signals driving aberrant self-renewal in the heterogeneous leukemia stem cell (LSC) pool determine aggressiveness of acute myeloid leukemia (AML). We report that a positive modulator of canonical WNT signaling pathway, RSPO-LGR4, upregulates key self-renewal genes and is essential for LSC self-renewal in a subset of AML. RSPO2/3 serve as stem cell growth factors to block differentiation and promote proliferation of primary AML patient blasts. RSPO receptor, LGR4, is epigenetically upregulated and works through cooperation with HOXA9, a poor prognostic predictor. Blocking the RSPO3-LGR4 interaction by clinical-grade anti-RSPO3 antibody (OMP-131R10/rosmantuzumab) impairs self-renewal and induces differentiation in AML patient-derived xenografts but does not affect normal hematopoietic stem cells, providing a therapeutic opportunity for HOXA9-dependent leukemia.
    Keywords:  AML; HOXA9; LGR4; LSC; RSPO; WNT/β-catenin; acute myeloid leukemia; leukemia stem cells; self-renewal; signaling pathway
    DOI:  https://doi.org/10.1016/j.ccell.2020.05.014
  2. Blood. 2020 Jun 18. pii: blood.2019003654. [Epub ahead of print]
    Quantitative proteomics reveals specific metabolic features of Acute Myeloid Leukemia stem cells.
    Simon Raffel, Daniel Klimmeck, Mattia Falcone, Aykut Demir, Alireza Pouya, Petra Zeisberger, Christoph Lutz, Marco Tinelli, Oliver Bischel, Lars Bullinger, Christian Thiede, Anne Flörcken, Jörg Westermann, Gerhard Ehninger, Anthony D Ho, Carsten Müller-Tidow, Zuguang Gu, Carl Herrmann, Jeroen Krijgsveld, Andreas Trumpp, Jenny Hansson.
      Acute Myeloid Leukemia (AML) is characterized by the accumulation of clonal myeloid blast cells unable to differentiate into mature leukocytes. Chemotherapy induces remission in the majority of patients, but relapse rates are high and lead to poor clinical outcomes. Since this is primarily caused by chemotherapy-resistant leukemic stem cells (LSCs), it is essential to eradicate LSCs to improve patient survival. LSCs have predominantly been studied at the transcript level, thus lacking information about post-transcriptionally regulated genes and associated networks. Here we extend our previous report on LSC proteomes to healthy age-matched hematopoietic stem and progenitor cells (HSPCs) and correlate the proteomes to the corresponding transcriptomes. By comparing LSCs to leukemic blasts and healthy HSPCs, we validate candidate LSC markers and highlight novel and potentially targetable proteins that are absent or only lowly expressed in HSPCs. In addition, our data provide strong evidence that LSCs harbor a characteristic energy metabolism, adhesion molecule composition, as well as RNA processing properties. Furthermore, correlating proteome and transcript data of the same individual samples highlights the strength of proteome analyses, which are particularly potent in detecting alterations in metabolic pathways. In summary, our study provides a comprehensive proteomic and transcriptomic characterization of functionally validated LSCs, blasts and healthy HSPCs, representing a valuable resource helping to design LSC-directed therapies.
    DOI:  https://doi.org/10.1182/blood.2019003654
  3. Nat Commun. 2020 Jun 15. 11(1): 3021
    Hematopoietic stem and progenitor cell-restricted Cdx2 expression induces transformation to myelodysplasia and acute leukemia.
    Therese Vu, Jasmin Straube, Amy H Porter, Megan Bywater, Axia Song, Victoria Ling, Leanne Cooper, Gabor Pali, Claudia Bruedigam, Sebastien Jacquelin, Joanne Green, Graham Magor, Andrew Perkins, Alistair M Chalk, Carl R Walkley, Florian H Heidel, Pamela Mukhopadhyay, Nicole Cloonan, Stefan Gröschel, Jan-Philipp Mallm, Stefan Fröhling, Claudia Scholl, Steven W Lane.
      The caudal-related homeobox transcription factor CDX2 is expressed in leukemic cells but not during normal blood formation. Retroviral overexpression of Cdx2 induces AML in mice, however the developmental stage at which CDX2 exerts its effect is unknown. We developed a conditionally inducible Cdx2 mouse model to determine the effects of in vivo, inducible Cdx2 expression in hematopoietic stem and progenitor cells (HSPCs). Cdx2-transgenic mice develop myelodysplastic syndrome with progression to acute leukemia associated with acquisition of additional driver mutations. Cdx2-expressing HSPCs demonstrate enrichment of hematopoietic-specific enhancers associated with pro-differentiation transcription factors. Furthermore, treatment of Cdx2 AML with azacitidine decreases leukemic burden. Extended scheduling of low-dose azacitidine shows greater efficacy in comparison to intermittent higher-dose azacitidine, linked to more specific epigenetic modulation. Conditional Cdx2 expression in HSPCs is an inducible model of de novo leukemic transformation and can be used to optimize treatment in high-risk AML.
    DOI:  https://doi.org/10.1038/s41467-020-16840-2
  4. Int J Mol Sci. 2020 Jun 15. pii: E4266. [Epub ahead of print]21(12):
    CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis.
    Evgenia Sarrou, Laura Richmond, Ruaidhrí J Carmody, Brenda Gibson, Karen Keeshan.
      Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.
    Keywords:  CRISPR/Cas9; chromosomal translocation; mixed lineage leukaemia; stem cells; tumourigenesis
    DOI:  https://doi.org/10.3390/ijms21124266
  5. Ther Adv Hematol. 2020 ;11 2040620720930614
    Gilteritinib in the treatment of relapsed and refractory acute myeloid leukemia with a FLT3 mutation.
    Serena Chew, Melissa C Mackey, Elias Jabbour.
      Acute myeloid leukemia (AML) is a malignancy of uncontrolled proliferation of immature myeloid blasts characterized by clonal evolution and genetic heterogeneity. FMS-like tyrosine kinase 3 (FLT3) mutations occur in up to a third of AML cases and are associated with highly proliferative disease, shorter duration of remission, and increased rates of disease relapse. The known impact of activating mutations in FLT3 in AML on disease pathogenesis, prognosis, and response to therapy has led to the development of tyrosine kinase inhibitors targeting FLT3. Gilteritinib is a potent, second generation inhibitor of both FLT3 and AXL, designed to address the limitations of other FLT3 inhibitors, particularly in targeting mechanisms of resistance to other drugs. In this review, we present comprehensive data on recent and ongoing studies evaluating the role of gilteritinib in the relapsed and refractory FLT3 mutated AML setting.
    Keywords:  FLT3; FMS-like tyrosine kinase 3 inhibitors; acute myeloid leukemia; gilteritinib
    DOI:  https://doi.org/10.1177/2040620720930614
  6. Science. 2020 Jun 19. 368(6497): 1386-1392
    Partitioning of cancer therapeutics in nuclear condensates.
    Isaac A Klein, Ann Boija, Lena K Afeyan, Susana Wilson Hawken, Mengyang Fan, Alessandra Dall'Agnese, Ozgur Oksuz, Jonathan E Henninger, Krishna Shrinivas, Benjamin R Sabari, Ido Sagi, Victoria E Clark, Jesse M Platt, Mrityunjoy Kar, Patrick M McCall, Alicia V Zamudio, John C Manteiga, Eliot L Coffey, Charles H Li, Nancy M Hannett, Yang Eric Guo, Tim-Michael Decker, Tong Ihn Lee, Tinghu Zhang, Jing-Ke Weng, Dylan J Taatjes, Arup Chakraborty, Phillip A Sharp, Young Tae Chang, Anthony A Hyman, Nathanael S Gray, Richard A Young.
      The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.
    DOI:  https://doi.org/10.1126/science.aaz4427
  7. Leuk Lymphoma. 2020 Jun 14. 1-7
    MicroRNA-92a as a marker of treatment response and survival in adult acute myeloid leukemia patients.
    Reham A Rashed, Naglaa M Hassan, Marwa M Hussein.
      This prospective study assessed circulating miR-92a levels in acute myeloid leukemia (AML) at diagnosis and after induction therapy and followed patients for a maximum of 30 months. The study included 63 consecutive adult AML patients. Circulating miR-92a levels were assessed using real-time polymerase chain reaction (RT-PCR). There was significant rise of miR-92a expression after induction (median (range): 0.297 (0.001-3.438)) in comparison to the reported levels at diagnosis (median (range): 0.236 (0.001-3.305)). Post-induction levels of miR-92a are significantly higher in patients who achieved CR in comparison to patients without CR (median (range): 0.408 (0.017-3.438) vs. 0.01 (0.001-1.010), p<.001). Cox hazard regression analysis identified miR-92a as a significant predictor of OS and DFS in univariate and multivariate analyses. In conclusion, baseline circulating miR-92a in AML patients may be a useful prognostic marker of treatment response and survival over 2.5 years follow up.
    Keywords:  Acute myeloid leukemia; miR-92a; micro-RNAs
    DOI:  https://doi.org/10.1080/10428194.2020.1775218
  8. Leukemia. 2020 Jun 19.
    A proof of concept phase I/II pilot trial of LSD1 inhibition by tranylcypromine combined with ATRA in refractory/relapsed AML patients not eligible for intensive therapy.
    Study Alliance Leukemia (SAL)
      All-trans-retinoic acid (ATRA) is highly active in acute promyelocytic leukemia but not in other types of acute myeloid leukemia (AML). Previously, we showed that ATRA in combination with Lysine-specific demethylase 1 (LSD1) inhibition by tranylcypromine (TCP) can induce myeloid differentiation in AML blasts. This phase I/II clinical trial investigated the safety and efficacy of TCP/ATRA treatment as salvage therapy for relapsed/refractory (r/r) AML. The combination was evaluated in 18 patients, ineligible for intensive treatment. The overall response rate was 20%, including two complete remissions without hematological recovery and one partial response. We also observed myeloid differentiation upon TCP/ATRA treatment in patients who did not reach clinical remission. Median overall survival (OS) was 3.3 months, and one-year OS 22%. One patient developed an ATRA-induced differentiation syndrome. The most frequently reported adverse events were vertigo and hypotension. TCP plasma levels correlated with intracellular TCP concentration. Increased H3K4me1 and H3k4me2 levels were observed in AML blasts and white blood cells from some TCP/ATRA treated patients. Combined TCP/ATRA treatment can induce differentiation of AML blasts and lead to clinical response in heavily pretreated patients with r/r AML with acceptable toxicity. These findings emphasize the potential of LSD1 inhibition combined with ATRA for AML treatment.
    DOI:  https://doi.org/10.1038/s41375-020-0892-z
  9. ChemMedChem. 2020 Jun 17.
    Synthesis of N-aryl and N-alkyl substituted imidazolium silver complexes. Cytotoxic screening using human cell lines modelling acute myeloid leukemia.
    Eirin Alme, Karl Wilhelm Törnroos, Bjørn Tore Gjertsen, Hans-René Bjørsvik.
      A series of N- aryl and N- alkyl substituted imidazoles were synthesized and complexed with Ag + to obtain silver-NHC complexes of the form [Ag(NHC)2 ]X. These silver-NHC complexes were tested in-vitro versus the human cell lines HL-60 and MOLM-13 that both model acute myeloid leukemia (AML). A substantial difference in cytotoxicity was revealed varying in the range 13 - 4 μ M (for HL-60) and 22 - 9 μ M (for MOLM-13), respectively. Furthermore, this study revealed that when an alkyl group was installed on the imidazole scaffold, its position influenced substantially the cytotoxicity of the corresponding silver NHC complex.
    Keywords:  cytotoxicity leukemia metallodrugs imidazoles NHC-silver
    DOI:  https://doi.org/10.1002/cmdc.202000138
  10. Cancers (Basel). 2020 Jun 14. pii: E1574. [Epub ahead of print]12(6):
    Cotargeting of XPO1 Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Acute Myeloid Leukemia.
    Lindsey T Brinton, Steven Sher, Katie Williams, Daniel Canfield, Shelley Orwick, Ronni Wasmuth, Casey Cempre, Jordan Skinner, Amy Lehman, James S Blachly, John C Byrd, Rosa Lapalombella.
      Acute myeloid leukemia (AML) is a hematopoietic stem-cell-derived leukemia with often successive derived driver mutations. Late onset acquisition of internal tandem duplication in FLT3 (FLT3-ITD) at a high variant allele frequency often contributes to full transformation to a highly proliferative, rapidly progressive disease with poor outcome. The FLT3-ITD mutation is targetable with approved FLT3 small molecule inhibitors, including midostaurin and gilteritinib. However, outside of patients receiving allogeneic transplant, most patients fail to respond or relapse, suggesting alternative approaches of therapy will be required. We employed genome-wide pooled CRISPR knockout screening as a method for large-scale identification of targets whose knockout produces a phenotypic effect that enhances the antitumor properties of FLT3 inhibitors. Among the candidate targets we identified the effect of XPO1 knockout to be synergistic with midostaurin treatment. Next, we validated the genetic finding with pharmacologic combination of the slowly reversible XPO1 inhibitor selinexor with midostaurin and gilteritinib in FLT3-ITD AML cell lines and primary patient samples. Lastly, we demonstrated improved survival with either combination therapy compared to its monotherapy components in an aggressive AML murine model, supporting further evaluation and rapid clinical translation of this combination strategy.
    Keywords:  AML; CRISPR-Cas9 screening; FLT3; XPO1; synergism
    DOI:  https://doi.org/10.3390/cancers12061574
  11. Trends Cancer. 2020 Jun 12. pii: S2405-8033(20)30167-9. [Epub ahead of print]
    Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities.
    Ali Khateb, Ze'ev A Ronai.
      Understanding genetic and epigenetic changes that underlie abnormal proliferation of hematopoietic stem and progenitor cells is critical for development of new approaches to monitor and treat leukemia. The unfolded protein response (UPR) is a conserved adaptive signaling pathway that governs protein folding, secretion, and energy production and serves to maintain protein homeostasis in various cellular compartments. Deregulated UPR signaling, which often occurs in hematopoietic stem cells and leukemia, defines the degree of cellular toxicity and perturbs protein homeostasis, and at the same time, offers a novel therapeutic target. Here, we review current knowledge related to altered UPR signaling in leukemia and highlight possible strategies for exploiting the UPR as treatment for this disease.
    Keywords:  endoplasmic reticulum stress; hematological malignancy; hematopoietic stem cell; lymphoid leukemia; myeloid leukemia; unfolded protein response
    DOI:  https://doi.org/10.1016/j.trecan.2020.05.012
  12. Haematologica. 2020 Jun 18. pii: haematol.2020.246843. [Epub ahead of print]
    Targeting GLUT1 in acute myeloid leukemia to overcome cytarabine resistance.
    Hannah Åbacka, Jesper S Hansen, Peng Huang, Raminta Venskutonytė, Axel Hyrenius-Wittsten, Giulio Poli, Tiziano Tuccinardi, Carlotta Granchi, Filippo Minutolo, Anna K Hagström-Andersson, Karin Lindkvist-Petersson.
      
    Keywords:  Acute Myeloid Leukemia; Molecular Pharmacology; structural biology
    DOI:  https://doi.org/10.3324/haematol.2020.246843
  13. Clin Lymphoma Myeloma Leuk. 2020 May 11. pii: S2152-2650(20)30220-2. [Epub ahead of print]
    A Real-world Perspective of CD123 Expression in Acute Leukemia as Promising Biomarker to Predict Treatment Outcome in B-ALL and AML.
    Nupur Das, Ritu Gupta, Sanjeev Kumar Gupta, Sameer Bakhshi, Ankit Malhotra, Sandeep Rai, Saroj Singh, Vijay Kumar Prajapati, Ranjeet Kumar Sahoo, Ajay Gogia, Atul Sharma, Lalit Kumar.
       INTRODUCTION: CD123 is overexpressed in many hematologic malignancies and found to be useful in characterizing leukemic blasts of both acute myeloid leukemia (AML) and B-acute lymphoblastic leukemia (B-ALL). CD123 has been recently found to be a marker of leukemic stem cells, and its utility to measure residual disease and potential role in disease relapse is under evaluation.
    MATERIALS AND METHODS: Herein, we have evaluated the expression of CD123 in 757 samples of acute leukemia including 479 treatment-naive and 278 follow-up samples and compared with post-induction morphologic complete remission and measurable residual disease (MRD) status. Multiparametric flow cytometry was used for assessment of CD123 expression and immunophenotypic characterization of leukemic blasts at diagnostic and MRD assessment time points.
    RESULTS: Using variable cutoffs of 5%, 10%, and 20% to define a case as CD123-positive, expression of CD123 was observed in 75.6%, 66.2%, and 50% of AML and 88.6%, 81.8%, and 75% of B-ALL, respectively. Of 11 patients, 7 (63.63%) had mixed phenotype acute leukemia, but none of the 12 patients with T-acute lymphoblastic leukemia showed positivity for CD123. CD123 expression at diagnosis was associated with post-induction MRD-positive status in both B-ALL (P < .001) and AML (P = .001). We also evaluated the utility of CD123 as a leukemia-associated aberrant immunophenotype and found it to be useful in both patients with AML (baseline, 50.6%; follow-up, 53%) and B-ALL (baseline, 75%; follow-up, 73.07%).
    CONCLUSIONS: In conclusion, CD123 may be considered as a cardinal marker for residual disease assessment and response evaluation in AML and B-ALL.
    Keywords:  Aberrant immunophenotype; Leukemia associated immunophenotype (LAIP); Measurable residual disease (MRD); Morphologic remission (CR); Multi-parametric flow cytometry (MFC)
    DOI:  https://doi.org/10.1016/j.clml.2020.05.004
  14. Leuk Lymphoma. 2020 Jun 14. 1-8
    Arsenic trioxide and all-trans retinoic acid suppress the expression of FLT3-ITD.
    Cong Liang, Chun-Jin Peng, Li-Na Wang, Yu Li, Li-Min Zheng, Zhong Fan, Dan-Ping Huang, Wen-Yan Tang, Xiao-Li Zhang, Li-Bin Huang, Yan-Lai Tang, Xue-Qun Luo.
      The prognosis of patients with acute myeloid leukemia (AML) caused by the FLT3-ITD mutation is poor. Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) can down-regulate FLT3-ITD level and selectively kill leukemia cells carrying the FLT3-ITD mutation. However, the mechanisms of action of these two compounds are unknown. Here, we found that ATO could bind FLT3-ITD at Lys91 and Asp225, whereas ATRA could bind FLT3-ITD at Lys5 and Gln6. Both compounds could not bind wild-type FLT3. Further studies revealed that ATO/ATRA may suppress the Expression of FLT3-ITD by promoting the UBE2L6-mediated ubiquitination pathway and decreasing the expression of C-MYC. However, further studies are needed to define the mechanisms of these compounds on AML. Our research provides an experimental basis for the use of ATO/ATRA in FLT3-ITD AML in clinical practice.
    Keywords:  Degradation; FLT3-ITD; acute myeloid leukemia; all-trans-retinoic acid; arsenic trioxide
    DOI:  https://doi.org/10.1080/10428194.2020.1775212
  15. Leukemia. 2020 Jun 16.
    Phase II trial of CPX-351 in patients with acute myeloid leukemia at high risk for induction mortality.
    Ghayas C Issa, Hagop M Kantarjian, Lianchun Xiao, Jing Ning, Yesid Alvarado, Gautam Borthakur, Naval Daver, Courtney D DiNardo, Elias Jabbour, Prithviraj Bose, Nitin Jain, Tapan M Kadia, Kiran Naqvi, Naveen Pemmaraju, Koichi Takahashi, Srdan Verstovsek, Micheal Andreeff, Steven M Kornblau, Zeev Estrov, Alessandra Ferrajoli, Guillermo Garcia-Manero, Maro Ohanian, William G Wierda, Farhad Ravandi, Jorge E Cortes.
      CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m2 on days 1, 3, and 5. Once safety was established, a 100 units/m2 arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m2 arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m2 (19%) compared with 75 units/m2 (38%) and 100 units/m2 (44%) (P = 0.35). The 50 units/m2 arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m2 respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m2 has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m2.
    DOI:  https://doi.org/10.1038/s41375-020-0916-8
  16. Cancers (Basel). 2020 Jun 16. pii: E1596. [Epub ahead of print]12(6):
    Targeting Pharmacokinetic Drug Resistance in Acute Myeloid Leukemia Cells with CDK4/6 Inhibitors.
    Ales Sorf, Simona Sucha, Anselm Morell, Eva Novotna, Frantisek Staud, Alzbeta Zavrelova, Benjamin Visek, Vladimir Wsol, Martina Ceckova.
      Pharmacotherapy of acute myeloid leukemia (AML) remains challenging, and the disease has one of the lowest curability rates among hematological malignancies. The therapy outcomes are often compromised by the existence of a resistant AML phenotype associated with overexpression of ABCB1 and ABCG2 transporters. Because AML induction therapy frequently consists of anthracycline-like drugs, their efficiency may also be diminished by drug biotransformation via carbonyl reducing enzymes (CRE). In this study, we investigated the modulatory potential of the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib on AML resistance using peripheral blood mononuclear cells (PBMC) isolated from patients with de novo diagnosed AML. We first confirmed inhibitory effect of the tested drugs on ABCB1 and ABCG2 in ABC transporter-expressing resistant HL-60 cells while also showing the ability to sensitize the cells to cytotoxic drugs even as no effect on AML-relevant CRE isoforms was observed. All tested CDK4/6 inhibitors elevated mitoxantrone accumulations in CD34+ PBMC and enhanced accumulation of mitoxantrone was found with abemaciclib and ribociclib in PBMC of FLT3-ITD- patients. Importantly, the accumulation rate in the presence of CDK4/6 inhibitors positively correlated with ABCB1 expression in CD34+ patients and led to enhanced apoptosis of PBMC in contrast to CD34- samples. In summary, combination therapy involving CDK4/6 inhibitors could favorably target multidrug resistance, especially when personalized based on CD34- and ABCB1-related markers.
    Keywords:  ABC transporters; CDK4/6 inhibitors; acute myeloid leukemia; drug resistance
    DOI:  https://doi.org/10.3390/cancers12061596
  17. Signal Transduct Target Ther. 2019 Jun 19. 4(1): 20
    Effects of insulin and pathway inhibitors on the PI3K-Akt-mTOR phosphorylation profile in acute myeloid leukemia cells.
    Ina Nepstad, Kimberley Joanne Hatfield, Ida Sofie Grønningsæter, Elise Aasebø, Maria Hernandez-Valladares, Karen Marie Hagen, Kristin Paulsen Rye, Frode S Berven, Frode Selheim, Håkon Reikvam, Øystein Bruserud.
      The phosphatidylinositol 3-kinase (PI3K)-Akt-mechanistic target of rapamycin (mTOR) pathway is constitutively activated in human acute myeloid leukemia (AML) cells and is regarded as a possible therapeutic target. Insulin is an agonist of this pathway and a growth factor for AML cells. We characterized the effect of insulin on the phosphorylation of 10 mediators in the main track of the PI3K-Akt-mTOR pathway in AML cells from 76 consecutive patients. The overall results showed that insulin significantly increased the phosphorylation of all investigated mediators. However, insulin effects on the pathway activation profile varied among patients, and increased phosphorylation in all mediators was observed only in a minority of patients; in other patients, insulin had divergent effects. Global gene expression profiling and proteomic/phosphoproteomic comparisons suggested that AML cells from these two patient subsets differed with regard to AML cell differentiation, transcriptional regulation, RNA metabolism, and cellular metabolism. Strong insulin-induced phosphorylation was associated with weakened antiproliferative effects of metabolic inhibitors. PI3K, Akt, and mTOR inhibitors also caused divergent effects on the overall pathway phosphorylation profile in the presence of insulin, although PI3K and Akt inhibition caused a general reduction in Akt pT308 and 4EBP1 pT36/pT45 phosphorylation. For Akt inhibition, the phosphorylation of upstream mediators was generally increased or unaltered. In contrast, mTOR inhibition reduced mTOR pS2448 and S6 pS244 phosphorylation but increased Akt pT308 phosphorylation. In conclusion, the effects of both insulin and PI3K-Akt-mTOR inhibitors differ between AML patient subsets, and differences in insulin responsiveness are associated with differential susceptibility to metabolic targeting.
    DOI:  https://doi.org/10.1038/s41392-019-0050-0
  18. Clin Lab. 2020 Jun 01. 66(6):
    Lower Serum miR-145 Predicts Poor Prognosis in Patients with Acute Myeloid Leukemia.
    Qingfen Shi, Guanqun Xing, Min Qi, Youzhong Xing.
       BACKGROUND: The current study mainly aims to evaluate the role and clinical significance of miR-145 in the progression of AML.
    METHODS: Serum and bone marrow nucleated cells (BMNc) were collected and the level of miR-145 was detected by RT-PCR. Pearson's correlation assay was carried out to analyze the correlation between serum miR-145 and clinical index. The receiver operating characteristic (ROC) curve was constructed to determine the diagnosis value of serum miR-145.
    RESULTS: MiR-145 was significantly decreased in serum and BMNc of patients with AML compared with the control group. Pearson's correlation assay showed that serum miR-145 was positively correlated with miR-145 levels in BMNc. Further study showed that the level of serum miR-145 was much lower in AML patients with initial WBC count ≥ 50 x 109/L than that of WBC count < 50 x 109/L. Moreover, the level of serum miR-145 in prednisone poor responders was significantly lower than that in prednisone good responders. Compared with minimal residual disease (MRD) < 0.01% group, serum miR-145 was much lower in AML patients with MRD ≥ 0.01% group. Pearson's correlation analysis showed that serum miR-145 was positively correlated with MRD. In addition, miR-145 diagnosed AML with an AUC of 0.915 (95% confidence interval: 0.828 to 1.000; p < 0.001).
    CONCLUSIONS: The level of miR-145 in serum and BMNc of AML patients was significantly lower than those of the control group. Serum miR-145 was related to poor prognosis and disease recurrence of AML.
    DOI:  https://doi.org/10.7754/Clin.Lab.2019.191143
  19. Medicine (Baltimore). 2020 Jun 12. 99(24): e20094
    The efficacy and safety of daunorubicin versus idarubicin combined with cytarabine for induction therapy in acute myeloid leukemia: A meta-analysis of randomized clinical trials.
    Hanyu Wang, Xueting Xiao, Qirong Xiao, Yanhong Lu, Yong Wu.
       OBJECTIVE: To ascertain the efficacy and safety of daunorubicin combined with cytarabine comparing with idarubicin combined with cytarabine as a standard induction therapy for acute Myeloid leukemia by a meta-analysis.
    METHODS: The randomized controlled trials included were retrieved from PubMed, Embase, and Cochrane library. We evaluated and cross-checked the randomized clinical trials (RCTs) comparing daunorubicin combined with cytarabine (DA) and idarubicin combined with cytarabine (IA) by two reviewers independently according to Cochrane Handbook for Systematic Reviewers of Interventions. The data of meta-analysis was conducted using Review Manager 5.3 and Stata 12.0 software.
    RESULTS: A total of 6 studies containing 3140 patients were included. The primary outcomes were complete remission (CR), CR in one course (CR1), CR in two courses (CR2), overall survival (OS), and relapse rate. The secondary outcomes included adverse events and cytogenetic risk in subgroup analyses. IA showed a statistically significant in CR (RR = 1.05; 95%CI = 1.00-1.09, P = .03) and CR1 (RR = 1.11; 95%CI = 1.04-1.18, P = .003), but not in CR2 (RR = 0.97; 95%CI = 0.77-1.24, P = .83), and relapse rate (RR = 1.08; 95%CI = 0.98-1.43, P = .08). In high dose daunorubicin group, OS was significantly improved with IA compared to DA (HR = 0.89, 95%CI = 0.8-1.0, P = .041, I = 0). At grade 3/4 adverse events, the difference between IA and DA was not statistically significant (infection, P = .28; cardiac toxicity, P = .15; bleeding, P = .29). In the subgroup analysis, the genotypes of the IA and DA groups were not statistically significant for comparison of CR between the two groups (P = .07).
    CONCLUSION: This meta-analysis showed that IA had a better efficacy in the treatment of acute myeloid leukemia than DA, even with increased doses of DA. The OS of a standard dose of IA patients was longer than that of DA patients. Our research shows that anthracycline dose intensification of daunorubicin is of no clinically relevant benefit in AML patients comparing with a standard dose of IA. When it comes to adverse drug reactions, it is not a significant difference. Therefore, in clinical practice, IA should be the first choice for induction regimen in patients with acute myeloid leukemia.
    DOI:  https://doi.org/10.1097/MD.0000000000020094
  20. Blood Adv. 2020 Jun 23. 4(12): 2723-2735
    First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis.
    Claudia Vener, Rita Banzi, Federico Ambrogi, Annalisa Ferrero, Giuseppe Saglio, Gabriella Pravettoni, Milena Sant.
      Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.
    DOI:  https://doi.org/10.1182/bloodadvances.2019001329
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