264
Views
4
CrossRef citations to date
0
Altmetric
Review

Emerging drugs for the treatment of chronic myelomonocytic leukemia

&
Pages 515-529 | Received 24 Sep 2020, Accepted 18 Nov 2020, Published online: 13 Dec 2020

References

  • Williamson PJ, Kruger AR, Reynolds PJ, et al. Establishing the incidence of myelodysplastic syndrome. Br J Haematol. 1994;87(4):743–745.
  • Rollison DE, Howlader N, Smith MT, et al. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008;112(1):45–52.
  • Mughal TI, Cross NCP, Padron E, et al. An International MDS/MPN Working Group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2015;100(9):1117–1130.
  • Srour SA, Devesa SS, Morton LM, et al. Incidence and patient survival of myeloproliferative neoplasms and myelodysplastic/myeloproliferative neoplasms in the United States, 2001-12. Br J Haematol. 2016;174(3):382–396.
  • Patnaik MM, Padron E, LaBorde RR, et al. Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia. 2013;27(7):1504–1510.
  • Onida F, Kantarjian HM, Smith TL, et al. Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99(3):840–849.
  • Patnaik MM, Itzykson R, Lasho TL, et al. ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia. 2014;28(11):2206–2212.
  • Itzykson R, Kosmider O, Renneville A, et al. Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol. 2013;31(19):2428–2436.
  • Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
  • Schuler E, Schroeder M, Neukirchen J, et al. Refined medullary blast and white blood cell count based classification of chronic myelomonocytic leukemias. Leuk Res. 2014;38(12):1413–1419.
  • Tang G, Zhang L, Fu B, et al. Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution. Am J Hematol. 2014;89(8):813–818.
  • Awada H, Nagata Y, Goyal A, et al. Invariant phenotype and molecular association of biallelic TET2 mutant myeloid neoplasia. Blood Advances. 2019;3(3):339–349. * This study was the first to report the frequency of biallelic mutaitons in TET2 as a characteristic of CMML.
  • Patel BJ, Przychodzen B, Thota S, et al. Genomic determinants of chronic myelomonocytic leukemia. Leukemia. 2017;31(12):2815–2823. .
  • Such E, Germing U, Malcovati L, et al. Development and validation of a prognostic scoring system for patients with chronic myelomonocytic leukemia. Blood. 2013;121(15):3005–3015.
  • Greenberg P, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–2088. .
  • Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–2465.
  • Padron E, Garcia-Manero G, Patnaik MM, et al. An international data set for CMML validates prognostic scoring systems and demonstrates a need for novel prognostication strategies. Blood Cancer J. 2015;5(7):e333.
  • Alfonso A, Montalban-Bravo G, Takahashi K, et al. Natural history of chronic myelomonocytic leukemia treated with hypomethylating agents. Am J Hematol. 2017;92(7):599–606.
  • Montalban-Bravo G, Takahashi K, Patel K, et al. Impact of the number of mutations in survival and response outcomes to hypomethylating agents in patients with myelodysplastic syndromes or myelodysplastic/myeloproliferative neoplasms. Oncotarget. 2018;9(11):9714–9727.
  • Elena C, Gallì A, Such E, et al. Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood. 2016;128(10):1408–1417.
  • Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML group. Blood. 1996;88(7):2480–2487.
  • Kantarjian H, Issa J-PJ, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106(8):1794–1803.
  • Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429–2440.
  • Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–232.
  • Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer. 2007;109(4):713–717.
  • Costa R, Abdulhaq H, Haq B, et al. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer. 2011;117(12):2690–2696.
  • Fianchi L, Criscuolo M, Breccia M, et al. High rate of remissions in chronic myelomonocytic leukemia treated with 5-azacytidine: results of an Italian retrospective study. Leuk Lymphoma. 2013;54(3):658–661.
  • Thorpe M, Montalvao A, Pierdomenico F, et al. Treatment of chronic myelomonocytic leukemia with 5-Azacitidine: a case series and literature review. Leuk Res. 2012;36(8):1071–1073.
  • Wijermans PW, Rüter B, Baer MR, et al. Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res. 2008;32(4):587–591.
  • Ades L, Sekeres MA, Wolfromm A, et al. Predictive factors of response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res. 2013;37(6):609–613.
  • Jabbour E, Short JS, Montalban-Bravo G, et al. A randomized phase II study of low-dose decitabine versus low-dose azacitidine in lower risk MDS and MDS/MPN. Blood. 2017. ** This study is the first to compare the efficacy of safety of azacitdiine and decitabine in lower dose schedules in lower risk MDS and CMML.
  • Montalban-Bravo G, Jabbour E, Class C, et al. Long-Term Follow up of a Randomized Phase 2 Study of Low-Dose Decitabine Versus Low-Dose Azacitidine in Lower-Risk Myelodysplastic Syndromes. Blood. 2019;134(Supplement_1):1715.
  • Gil-Perez A, Montalban-Bravo G. Management of myelodysplastic syndromes after failure of response to hypomethylating agents. Ther Adv Hematol. 2019;10:2040620719847059.
  • Montalban-Bravo G, Garcia-Manero G, Jabbour E. Therapeutic choices after hypomethylating agent resistance for myelodysplastic syndromes. Curr Opin Hematol. 2018;25(2):146–153.
  • Itzykson R, Kosmider O, Renneville A, et al. Clonal architecture of chronic myelomonocytic leukemias. Blood. 2013;121(12):2186–2198. .
  • Zhang Y, He L, Selimoglu-Buet D, et al. Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines. Blood Adv. 2017;1(14):972–979.
  • Niyongere S, Lucas N, Zhou J-M, et al. Heterogeneous expression of cytokines accounts for clinical diversity and refines prognostication in CMML. Leukemia. 2019;33(1):205–216.
  • Montalban-Bravo G, Class CA, Ganan-Gomez I, et al., Transcriptomic analysis implicates necroptosis in disease progression and prognosis in myelodysplastic syndromes. Leukemia, 2019.
  • Wei Y, Zheng H, Bao N, et al., KDM6B Overexpression and TET2 Deficiency Cooperatively Drive Development of Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia-like Phenotype in Mice. Blood, 2019. Presented at the 61st Annual Meeting of the American Society of Hematology (Abstract #562).
  • Wei Y, Dimicoli S, Bueso-Ramos C, et al. Toll-like receptor alterations in myelodysplastic syndrome. Leukemia. 2013;27(9):1832–1840.
  • Savona MR, Malcovati L, Komrokji R, et al. An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood. 2015;125(12):1857–1865.
  • Duchmann M, Yalniz FF, Sanna A, et al. Prognostic role of gene mutations in chronic myelomonocytic leukemia patients treated with hypomethylating agents. EBioMedicine. 2018;31:174–181.
  • Coston T, Pophali P, Vallapureddy R, et al. Suboptimal response rates to hypomethylating agent therapy in chronic myelomonocytic leukemia; a single institutional study of 121 patients. Am J Hematol. 2019;94(7):767–779.
  • Oganesian A, Redkar S, Taverna P, et al. Preclinical Data In Cynomolgus (cyn) Monkeys Of ASTX727, a Novel Oral Hypomethylating Agent (HMA) Composed Of Low-Dose Oral Decitabine Combined With a Novel Cytidine Deaminase Inhibitor (CDAi) E7727. Blood. 2013;122(21):2526.
  • Garcia-Manero G, Griffiths EA, Steensma DP, et al. Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. Blood. 2020;136(6):674–683.
  • Garcia-Manero G, McCloskey J, Griffiths EA, et al. Pharmacokinetic exposure equivalence and preliminary efficacy and safety from a randomized cross over phase 3 study (ASCERTAIN study) of an oral hypomethylating agent ASTX727 (cedazuridine/decitabine) compared to IV decitabine. Blood. 2019;134(Supplement_1):846.
  • Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol. 2015;16(9):1099–1110.
  • Garcia-Manero G, Roboz G, Walsh K, et al. Guadecitabine (SGI-110) in patients with intermediate or high-risk myelodysplastic syndromes: phase 2 results from a multicentre, open-label, randomised, phase 1/2 trial. Lancet Haematol. 2019;6(6):e317–e327.
  • Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. Final report of a phase II study of guadecitabine (SGI-110) in patients (pts) with previously untreated Myelodysplastic Syndrome (MDS). Blood. 2018;132(Supplement 1):232.
  • ASTEX pharmaceuticals. https://astx.com/astex-and-otsuka-announce-results-of-phase-3-astral-2-and-astral-3-studies-of-guadecitabine-sgi-110-in-patients-with-previously-treated-acute-myeloid-leukemia-aml-and-myelodysplastic-syndromes-or/. 2020 [ cited 2020 Nov 1].
  • Daud A, Gill J, Kamra S, et al. Indirect treatment comparison of dabrafenib plus trametinib versus vemurafenib plus cobimetinib in previously untreated metastatic melanoma patients. J Hematol Oncol. 2017;10(1):3.
  • Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2019;20(6):849–861.
  • Tong X, Wang Q, Wu D, et al. MEK inhibition by cobimetinib suppresses hepatocellular carcinoma and angiogenesis in vitro and in vivo. Biochem Biophys Res Commun. 2020;523(1):147–152.
  • Caeser R, Collord G, Yao W-Q, et al. Targeting MEK in vemurafenib-resistant hairy cell leukemia. Leukemia. 2019;33(2):541–545.
  • Indini A, Tondini CA, Mandala M. Cobimetinib in malignant melanoma: how to MEK an impact on long-term survival. Future Oncol. 2019;15(9):967–977.
  • Wong H, Vernillet L, Peterson A, et al. Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor. Clin Cancer Res. 2012;18(11):3090–3099.
  • Abdel-Wahab O, Klimek VM, Gaskell AA, et al. Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies. Cancer Discov. 2014;4(5):538–545.
  • Kloos A, et al., Effective drug treatment identified by in vivo screening in a transplantable patient-derived xenograft model of chronic myelomonocytic leukemia. Leukemia, 2020.* This study provides evidence of the potential use of patient xenograft models in CMML to evaluate therapies for clinical purposes.
  • Borthakur G, Popplewell L, Boyiadzis M, et al. Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies. Cancer. 2016;122(12):1871–1879.
  • Shakeel I, et al., Polo-like Kinase 1 as an emerging drug target: structure, function and therapeutic implications. J Drug Target, 2020: 1–17.
  • Elsayed I, Wang X. PLK1 inhibition in cancer therapy: potentials and challenges. Future Med Chem. 2019;11(12):1383–1386.
  • Posch C, Cholewa BD, Vujic I, et al. Combined Inhibition of MEK and Plk1 Has Synergistic Antitumor Activity in NRAS Mutant Melanoma. J Invest Dermatol. 2015;135(10):2475–2483.
  • Carr RM, et al., RAS mutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis. bioRxiv, 2019: p. 2019.12.23.874487.
  • Baker SJ, Cosenza SC, Ramana Reddy MV, et al. Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia. Oncotarget. 2019;10(20):1932–1942.
  • Navada SC, et al. Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: results of a phase 1 study. Leuk Res. 2020;94:106369.
  • Garcia-Manero G, Fenaux P, Al-Kali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial. Lancet Oncol. 2016;17(4):496–508.
  • Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10.
  • Yang H, Bueso-Ramos C, DiNardo C, et al., Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia, 2013. ** This was the first study to show that PD-1, PDL-1 and other immune checkpoint regulatory molecules are upregulated in MDS and CMML after exposure to HMAs.
  • Cheng P, et al., S100A9-induced overexpression of PD-1/PD-L1 contributes to ineffective hematopoiesis in myelodysplastic syndromes. Leukemia, 2019.
  • Davids MS, Kim HT, Bachireddy P, et al. Ipilimumab for patients with relapse after allogeneic transplantation. N Engl J Med. 2016;375(2):143–153.
  • Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. A phase II study of Nivolumab or Ipilimumab with or without azacitidine for patients with Myelodysplastic Syndrome (MDS). Blood. 2018;132(Suppl 1):465.
  • Garcia-Manero G, Tallman MS, Martinelli G, et al. Pembrolizumab, a PD-1 Inhibitor, in Patients with Myelodysplastic Syndrome (MDS) after Failure of Hypomethylating Agent Treatment. Blood. 2016;128(22):345.
  • Chien KS, Borthakur GM, Naqvi K, et al. Updated Preliminary Results from a Phase II Study Combining Azacitidine and Pembrolizumab in Patients with Higher-Risk Myelodysplastic Syndrome. Blood. 2019;134(Supplement_1):4240.
  • Garcia-Manero G, et al. A phase II study of Nivolumab or Ipilimumab with or without Azacitidine for patients with Myelodysplastic Syndrome (MDS). Blood. 2018;132(Supplement 1):465.
  • Borate U, Esteve J, Porkka K, et al. Phase Ib study of the anti-TIM-3 antibody MBG453 in combination with decitabine in patients with high-risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML). Blood. 2019;134(Supplement_1):570.
  • Jaiswal S, Jamieson CHM, Pang WW, et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell. 2009;138(2):271–285.
  • Carosella ED, et al. HLA-G: an immune checkpoint molecule. Adv Immunol. 2015;127:33–144.
  • Kang X, Kim J, Deng M, et al. Inhibitory leukocyte immunoglobulin-like receptors: immune checkpoint proteins and tumor sustaining factors. Cell Cycle. 2016;15(1):25–40.
  • Suciu-Foca N, Feirt N, Zhang Q-Y, et al. Soluble Ig-like transcript 3 inhibits tumor allograft rejection in humanized SCID mice and T cell responses in cancer patients. J Immunol. 2007;178(11):7432–7441.
  • Chien KS, Class CA, Montalban-Bravo G, et al. LILRB4 expression in chronic myelomonocytic leukemia and myelodysplastic syndrome based on response to hypomethylating agents. Leuk Lymphoma. 2020;61(6):1493–1499.
  • Anami Y, et al., LILRB4-targeting antibody-drug conjugates for the treatment of acute myeloid leukemia. Mol Cancer Ther, 2020.
  • Padron E, Painter JS, Kunigal S, et al. GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121(25):5068–5077.
  • Molfino NA, Kuna P, Leff JA, et al. Phase 2, randomised placebo-controlled trial to evaluate the efficacy and safety of an anti-GM-CSF antibody (KB003) in patients with inadequately controlled asthma. BMJ Open. 2016;6(1):e007709.
  • Patnaik MM, Sallman DA, Mangaonkar AA, et al. Phase 1 study of lenzilumab, a recombinant anti-human GM-CSF antibody, for chronic myelomonocytic leukemia. Blood. 2020;136(7):909–913.
  • Riether C, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020;26(9):1459–1467.
  • Riether C, Schürch CM, Bührer ED, et al. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia. J Exp Med. 2017;214(2):359–380.
  • Suda T, Suda J, Ogawa M, et al. Permissive role of interleukin 3 (IL-3) in proliferation and differentiation of multipotential hemopoietic progenitors in culture. J Cell Physiol. 1985;124(2):182–190.
  • Feuring-Buske M, et al. A diphtheria toxin-interleukin 3 fusion protein is cytotoxic to primitive acute myeloid leukemia progenitors but spares normal progenitors. Cancer Res. 2002;62(6):1730–1736.
  • Jordan CT, Upchurch D, Szilvassy SJ, et al. The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia. 2000;14(10):1777–1784.
  • Hammond D, Pemmaraju N. Tagraxofusp for blastic plasmacytoid dendritic cell neoplasm. Hematol Oncol Clin North Am. 2020;34(3):565–574.
  • Ramshaw HS, BARDY P, LEE M, et al. Chronic myelomonocytic leukemia requires granulocyte-macrophage colony-stimulating factor for growth in vitro and in vivo. Exp Hematol. 2002;30(10):1124–1131.
  • Hansen G, Hercus TR, McClure BJ, et al. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell. 2008;134(3):496–507.
  • Parganas E, Wang D, Stravopodis D, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell. 1998;93(3):385–395.
  • Hercus TR, Thomas D, Guthridge MA, et al. The granulocyte-macrophage colony-stimulating factor receptor: linking its structure to cell signaling and its role in disease. Blood. 2009;114(7):1289–1298.
  • Padron E, et al. GM-CSF–dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood. 2013;121(25):5068–5077.
  • Padron E, Dezern A, Andrade-Campos M, et al. A multi-institution phase I trial of ruxolitinib in patients with Chronic Myelomonocytic Leukemia (CMML). Clin Cancer Res. 2016;22(15):3746–3754. * This study was the first to report the potential efficacy of JAK-STAT inhibition in CMML.
  • Assi R, Kantarjian HM, Garcia-Manero G, et al. A phase II trial of ruxolitinib in combination with azacytidine in myelodysplastic syndrome/myeloproliferative neoplasms. Am J Hematol. 2018;93(2):277–285.
  • Dinarello CA. Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Curr Opin Pharmacol. 2004;4(4):378–385.
  • Basiorka AA, McGraw KL, Eksioglu EA, et al. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016;128(25):2960–2975.
  • Zhang Q, Zhao K, Shen Q, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525(7569):389–393.
  • Neves-Costa A, Moita LF. TET1 is a negative transcriptional regulator of IL-1beta in the THP-1 cell line. Mol Immunol. 2013;54(3–4):264–270.
  • Im AP, Sehgal AR, Carroll MP, et al. DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies. Leukemia. 2014;28(9):1774–1783.
  • DiNardo CD, Jabbour E, Ravandi F, et al. IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression. Leukemia. 2016;30(4):980–984.
  • Richard-Carpentier G, DeZern AE, Takahashi K, et al. Preliminary results from the phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-Mutated Myelodysplastic Syndromes (MDS). Blood. 2019;134(Supplement_1):678.
  • Patnaik MM, Tefferi A. Cytogenetic and molecular abnormalities in chronic myelomonocytic leukemia. Blood Cancer J. 2016;6(2):e393–e393.
  • Schwaab J, Ernst T, Erben P, et al. Activating CBL mutations are associated with a distinct MDS/MPN phenotype. Ann Hematol. 2012;91(11):1713–1720.
  • Dunbar AJ, Gondek LP, O’Keefe CL, et al. 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008;68(24):10349–10357.
  • Naramura M, Nadeau S, Mohapatra B, et al. Mutant Cbl proteins as oncogenic drivers in myeloproliferative disorders. Oncotarget. 2011;2(3):245–250.
  • Reindl C, Quentmeier H, Petropoulos K, et al. CBL exon 8/9 mutants activate the FLT3 pathway and cluster in core binding factor/11q deletion acute myeloid leukemia/myelodysplastic syndrome subtypes. Clin Cancer Res. 2009;15(7):2238–2247.
  • Nakata Y, et al. Acquired expression of Cbl(Q367P) in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia. Blood. 2017;129(15):2148–2160.
  • Sargin B, Choudhary C, Crosetto N, et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood. 2007;110(3):1004–1012.
  • Polzer H, Janke H, Schmid D, et al. Casitas B-lineage lymphoma mutants activate AKT to induce transformation in cooperation with class III receptor tyrosine kinases. Exp Hematol. 2013;41(3):271–280. e4.
  • Rathinam C, Thien CBF, Flavell RA, et al. Myeloid leukemia development in c-Cbl RING finger mutant mice is dependent on FLT3 signaling. Cancer Cell. 2010;18(4):341–352.
  • Lin H, Wang M, Zhang YW, et al. Discovery of potent and selective covalent protein arginine methyltransferase 5 (PRMT5) inhibitors. ACS Med Chem Lett. 2019;10(7):1033–1038.
  • Blanc RS, Richard S. Arginine Methylation: the Coming of Age. Mol Cell. 2017;65(1):8–24.
  • Yang Y, Bedford MT. Protein arginine methyltransferases and cancer. Nat Rev Cancer. 2013;13(1):37–50.
  • Mavrakis KJ, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science. 2016;351(6278):1208–1213.
  • Chan-Penebre E, Kuplast KG, Majer CR, et al. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat Chem Biol. 2015;11(6):432–437.
  • Chung J, Karkhanis V, Tae S, et al. Protein arginine methyltransferase 5 (PRMT5) inhibition induces lymphoma cell death through reactivation of the retinoblastoma tumor suppressor pathway and polycomb repressor complex 2 (PRC2) silencing. J Biol Chem. 2013;288(49):35534–35547.
  • Fong JY, Pignata L, Goy P-A, et al. Therapeutic targeting of RNA splicing catalysis through inhibition of protein arginine methylation. Cancer Cell. 2019;36(2):194–209. e9.
  • Gerhart SV, et al. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci Rep. 2018;8(1):9711.
  • Kim E, Ilagan J, Liang Y, et al. SRSF2 mutations contribute to myelodysplasia by mutant-specific effects on exon recognition. Cancer Cell. 2015;27(5):617–630.
  • Lee SC, Dvinge H, Kim E, et al. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins. Nat Med. 2016;22(6):672–678.
  • Steensma DP, Wermke M, Klimek VM, et al. Results of a clinical trial of H3B-8800, a splicing modulator, in patients with Myelodysplastic Syndromes (MDS), Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML). Blood. 2019;134(Supplement_1):673.
  • Jacque N, Ronchetti AM, Larrue C, et al. Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 2015;126(11):1346–1356.
  • Guerra VA, Burger JA, Borthakur GM, et al. Interim analysis of a phase II study of the glutaminase inhibitor telaglenastat (CB-839) in combination with azacitidine in advanced Myelodysplastic Syndrome (MDS). Blood. 2019;134(Supplement_1):567.
  • Ganan-Gomez I, Alfonso A, Yang H, et al. Cell-type specific mechanisms of Hematopoietic Stem Cell (HSC) expansion underpin progressive disease in Myelodysplastic Syndromes (MDS) and provide a rationale for targeted therapies. Blood. 2018;132(Supplement 1):1798.
  • DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17.
  • DiNardo CD, et al., 10-day decitabine with venetoclax for newly diagnosed intensive chemotherapy ineligible, and relapsed or refractory acute myeloid leukaemia: a single-centre, phase 2 trial.Lancet Haematol, 2020
  • DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617–629.
  • Wei AH, Garcia JS, Borate U, et al. A phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(Supplement_1):568.
  • Zeidan AM, Pollyea DA, Garcia JS, et al. A phase 1b study evaluating the safety and efficacy of venetoclax as monotherapy or in combination with azacitidine for the treatment of relapsed/refractory myelodysplastic syndrome. Blood. 2019;134(Supplement_1):565.
  • DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and treatment failure after frontline venetoclax combinations in older patients with AML. Blood. 2020;135(11):791–803.
  • Ciechanover A. Intracellular protein degradation: from a vague idea, through the lysosome and the ubiquitin-proteasome system, and onto human diseases and drug targeting (Nobel lecture). Angew Chem Int Ed Engl. 2005;44(37):5944–5967.
  • Chiba T, Tanaka K. Cullin-based ubiquitin ligase and its control by NEDD8-conjugating system. Curr Protein Pept Sci. 2004;5(3):177–184.
  • Swords RT, Kelly KR, Smith PG, et al. Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood. 2010;115(18):3796–3800.
  • Swords RT, Erba HP, DeAngelo DJ, et al. Pevonedistat (MLN4924), a First-in-Class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukaemia and myelodysplastic syndromes: a phase 1 study. Br J Haematol. 2015;169(4):534–543.
  • Swords RT, Coutre S, Maris MB, et al. Pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, combined with azacitidine in patients with AML. Blood. 2018;131(13):1415–1424.
  • Ades L, Watts JM, Radinoff A, et al. Phase II study of pevonedistat (P) + azacitidine (A) versus A in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML), or low-blast acute myelogenous leukemia (LB AML) (NCT02610777). J clin oncol. 2020;38(15_suppl):7506.
  • Irvine DA, Copland M. Targeting hedgehog in hematologic malignancy. Blood. 2012;119(10):2196–2204.
  • Hoy SM. Glasdegib: first global approval. Drugs. 2019;79(2):207–213.
  • Patnaik MM, Tefferi A. Chronic Myelomonocytic leukemia: 2020 update on diagnosis, risk stratification and management. Am J Hematol. 2020;95(1):97–115.
  • Xicoy B, Germing U, Jimenez M-J, et al. Response to erythropoietic-stimulating agents in patients with chronic myelomonocytic leukemia. Eur J Haematol. 2016;97(1):33–38.
  • Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140–151.
  • Komrokji RS, Garcia-Manero G, Ades L, et al. An open-label, phase 2, dose-finding study of sotatercept (ACE-011) in patients with low or intermediate-1 (Int-1)-risk Myelodysplastic Syndromes (MDS) or non-proliferative Chronic Myelomonocytic Leukemia (CMML) and anemia requiring transfusion. Blood. 2014;124(21):3251.
  • Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) liposome for injection versus conventional cytarabine plus daunorubicin in older patients with newly diagnosed secondary acute myeloid leukemia. J Clin Oncol. 2018;36(26):2684–2692.
  • Montalban BG, Jabbour E, TM K, et al. Initial results of a phase 1 dose escalation study of CPX-351 for patients with Int-2 or high risk IPSS Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) after failure to hypomethylating agents. Blood. 2020;136(Supplement 1):1–3.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.