Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2019, vol. 28, nr 2, February, p. 271–276

doi: 10.17219/acem/81610

Publication type: review article

Language: English

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Creative Commons BY-NC-ND 3.0 Open Access

The new perspectives of targeted therapy in acute myeloid leukemia

Angela Walasek1,A,B,C,D,E,F

1 Department and Clinic of Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Poland

Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease and the results of previous treatment with cytotoxic drugs have not been satisfactory. This situation has prompted investigations into novel approaches. The breakthrough in therapy brought by all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL) and tyrosine kinase inhibitors in neoplasms with the Philadelphia chromosome has encouraged the search for other effective targeted therapies. Among the tested substances are higher molecular mass drugs such as antibodies and various small molecules: kinase inhibitors, cell pathway inhibitors and epigenetic modulators. So far, the U.S. Food and Drug Administration (FDA) has approved the antibody-drug conjugate gemtuzumab ozogamycin (GO), the tyrosine kinase inhibitor midostaurin and the IDH2 inhibitor enasidenib. These studies have led to a better understanding of the mechanisms of leukemogenesis and may soon allow for differentiating treatments depending on baseline mutational complements. Some innovative drugs described in this article have strong therapeutic potential, but there is still a long way to go before actual success in targeted treatment.

Key words

immunotherapy, target therapy, acute myeloid leukemia

References (60)

  1. Kell J. Considerations and challenges for patients with refractory and relapsed acute myeloid leukaemia. Leuk Res. 2016;47:149–160. doi: 10.1016/j.leukres.2016.05.025
  2. Almeida AM, Ramos F. Acute myeloid leukemia in the older adults. Leuk Res Rep. 2016;16(6):1–7. doi: 10.1016/j.lrr.2016.06.001
  3. von dem Borne PA, de Wreede LC, Halkes CJ, Marijt WA, Falkenburg JH, Veelken H. Effectivity of a strategy in elderly AML patients to reach allogeneic stem cell transplantation using intensive chemotherapy: Long-term survival is dependent on complete remission after first induction therapy. Leuk Res. 2016;46:45–50. doi: 10.1016/j.leukres.2016.03.010
  4. Kayser S, Krzykalla J, Elliott MA, et al. Characteristics and outcome of patients with therapy-related acute promyelocytic leukemia front-line treated with or without arsenic trioxide. Leukemia. 2017;31(11):2347–2354. doi: 10.1038/leu.2017.92
  5. Platzbecker U, Avvisati G, Cicconi L, et al. Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: Final results of the randomized Italian-German APL0406 trial. J Clin Oncol. 2017;35(6):605–612. doi: 10.1200/JCO.2016.67.1982
  6. Hołowiecki J, Hołowiecka A. Targeted therapy in acute myeloid leukemia [in Polish]. Acta Haematol Pol. 2013;44(2):85–92.
  7. De Witte T, Amadori S. The optimal dosing of gemtuzumab ozagamicin: Where to go from here? Haematologica. 2016;101(6):653–654. doi: 10.3324/haematol.2016.145763
  8. Laszlo GS, Harrington KH, Gudgeon CJ, et al. Expression and functional characterization of CD33 transcript variants in human acute myeloid leukemia. Oncotarget. 2016;7(28):43281–43294. doi: 10.18632/ oncotarget.9674
  9. Paubelle E, Ducastelle-Leprêtre S, Labussière-Wallet H, et al. Fractionated gemtuzumab ozogamicin combined with intermediate-dose cytarabine and daunorubicin as salvage therapy in very high-risk AML patients: A bridge to reduced intensity conditioning transplant? Ann Hematol. 2017;96(3):363–371. doi: 10.1007/s00277-016-2899-0
  10. Zahler S, Bhatia M, Ricci A, et al. A phase I study of reduced-intensity conditioning and allogeneic stem cell transplantation followed by dose escalation of targeted consolidation immunotherapy with gemtuzumab ozogamicin in children and adolescents with CD33+ acute myeloid leukemia. Biol Blood Marrow Transplant. 2016;22(4): 698–704. doi: 10.1016/j.bbmt.2016.01.019
  11. Bixby DA, Fathi AT, Kovacsovics TJ, et al. Vadastuximab talirine monotherapy in older patients with treatment naive CD33-positive acute myeloid leukemia (AML) Blood. 2016;128(22):590.
  12. Erba HP, Vasu S, Stein AS, et al. A phase 1b study of vadastuximab talirine in combination with 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Blood. 2016;128 (22):211.
  13. Masarova L, Kantarjian H, Garcia-Mannero G, Ravandi F, Sharma P, Daver N. Harnessing the immune system against leukemia: Monoclonal antibodies and checkpoint strategies for AML. Adv Exp Med Biol. 2017;995:73–95. doi: 10.1007/978-3-319-53156-4_4
  14. Leong SR, Sukumaran S, Hristopoulos M, et al. An anti-CD3/anti-CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Blood. 2017;129(5):609–618. doi: 10.1182/blood-2016-08-735365
  15. Cho BS, Kim HJ, Konopleva M. Targeting the CXCL12/CXCR4 axis in acute myeloid leukemia: From bench to bedside. Korean J Intern Med. 2017;32(2):248–257. doi: 10.3904/kjim.2016.244
  16. Hassanein M, Almahayni MH, Ahmed SO, Gaballa S, El Fakih R. FLT3 inhibitors for treating acute myeloid leukemia. Clin Lymphoma Myeloma Leuk. 2016;16(10):543–549. doi: 10.1016/j.clml.2016.06.002
  17. Nguyen B, Williams AB, Young DJ, et al. FLT3 activating mutations display differential sensitivity to multiple tyrosine kinase inhibitors. Oncotarget. 2017;8(7):10931–10944. doi: 10.18632/oncotarget.14539
  18. Ju HQ, Zhan G, Huang A, et al. ITD mutation in FLT3 tyrosine kinase promotes Warburg effect and renders therapeutic sensitivity to glycolytic inhibition. Leukemia. 2017;31(10):2143–2150. doi: 10.1038/leu.2017.45
  19. Roolf C, Dybowski N, Sekora A, et al. Phosphoproteome analysis reveals differential mode of action of sorafenib in wildtype and mutated FLT3 AML cells. Mol Cell Proteomics. 2017;16(7):1365–1376. doi: 10.1074/mcp.M117.067462
  20. Battipaglia G, Ruggeri A, Massoud R, et al. Efficacy and feasibility of sorafenib as a maintenance agent after allogeneic hematopoietic stem cell transplantation for Fms-like tyrosine kinase 3-mutated acute myeloid leukemia. Cancer. 2017;123(15):2867–2874. doi: 10.1002/cncr.30680
  21. De Freitas T, Marktel S, Piemontese S, et al. High rate of hematological responses to sorafenib in FLT3-ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation. Eur J Haematol. 2016;96(6):629–636. doi: 10.1111/ejh.12647
  22. Brunner AM, Li S, Fathi AT, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. 2016;175(3):496–504. doi: 10.1111/bjh.14260
  23. Ernst J, Schäfer V, Rinke J, et al. Continuous molecular remission and regression of side effects after discontinuation of salvage therapy with sorafenib and donor lymphocyte infusions in a young patient with relapsed AML. Ann Hematol. 2016;95(6):1027–1030. doi: 10.1007/s00277-016-2637-7
  24. Wang R, Xia L, Gabrilove J, Waxman S, Jing Y. Sorafenib inhibition of Mcl-1 accelerates ATRA-induced apoptosis in differentiation-responsive AML cells. Clin Cancer Res. 2016;22(5):1211–1221. doi: 10.1158/1078-0432.CCR-15-0663
  25. Lam SS, Ho ES, He BL, et al. Homoharringtonine (omacetaxine mepesuccinate) as an adjunct for FLT3-ITD acute myeloid leukemia. Sci Transl Med. 2016;8(359):359ra129.
  26. Latuske EM, Stamm H, Klokow M, et al. Combined inhibition of GLI and FLT3 signaling leads to effective anti-leukemic effects in human acute myeloid leukemia. Oncotarget. 2017;8(17):29187–29201. doi: 10.18632/oncotarget.16304
  27. Knapper S, Russell N, Gilkes A, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. 2017;129(9):1143–1154. doi: 10.1182/blood-2016-07-730648
  28. Gallogly MM, Lazarus HM. Midostaurin: An emerging treatment for acute myeloid leukemia patients. J Blood Med. 2016;7:73–83. doi: 10.2147/JBM.S100283
  29. Starr P. Midostaurin the first targeted therapy to improve survival in AML: Potentially practice-changing. Am Health Drug Benefits. 2016;9(Spec Issue):1–21.
  30. Mazzarella L. Orlando Magic: Report from the 57th meeting of the American Society of Haematology, 5–7 December 2015, Orlando, USA. Ecancermedicalscience. 2016;10:612. doi: 10.3332/ecancer. 2016.612.
  31. Smuga-Otto K. Midostaurin + chemo ups AML survival. Cancer Discov. 2016;6(2):OF2. doi: 10.1158/2159-8290.CD-NB2015-177
  32. Levis M. Midostaurin approved for FLT3-mutated AML. Blood. 2017;129(26):3403-3406. doi: 10.1182/blood-2017-05-782292
  33. Cooper TM, Cassar J, Eckroth E, et al. A phase I study of quizartinib combined with chemotherapy in relapsed childhood leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Clin Cancer Res. 2016;22(16):4014–4022. doi: 10.1158/1078-0432.CCR-15-1998
  34. Kasi PM, Litzow MR, Patnaik MM, Hashmi SK, Gangat N. Clonal evolution of AML on novel FMS-like tyrosine kinase-3 (FLT3) inhibitor therapy with evolving actionable targets. Leuk Res Rep. 2016;5:7–10. doi: 10.1016/j.lrr.2016.01.002
  35. Talati C, Griffiths EA, Wetzler M, Wang ES. Polo-like kinase inhibitors in hematologic malignancies. Crit Rev Oncol Hematol. 2016;98:200–210. doi: 10.1016/j.critrevonc.2015.10.013
  36. van den Bossche J, Lardon F, Deschoolmeester V, et al. Spotlight on volasertib: Preclinical and clinical evaluation of a promising Plk1 inhibitor. Med Res Rev. 2016;36(4):749–786. doi: 10.1002/med.21392
  37. Doshi KA, Trotta R, Natarajan K, et al. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress. Oncotarget. 2016;7(30):48280–48295. doi: 10.18632/oncotarget.10209
  38. Amatangelo MD, Quek L, Shih A, et al. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood. 2017;130(6):732–741. doi: 10.1182/blood-2017-04-779447
  39. Travins J, Wang F, David MD, et al. AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 2017;7(5):478–493. doi: 10.1158/2159-8290.CD-16-1034
  40. Kats LM, Vervoort SJ, Cole R, et al. A pharmacogenomic approach validates AG-221 as an effective and on-target therapy in IDH2 mutant AML. Leukemia. 2017;31(6):1466–1470. doi: 10.1038/leu.2017.84
  41. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6): 722–731. doi: 10.1182/blood-2017-04-779405
  42. Long B, Wang LX, Zheng FM, et al. Targeting GLI1 suppresses cell growth and enhances chemosensitivity in CD34+ enriched acute myeloid leukemia progenitor cells. Cell Physiol Biochem. 2016;38(4): 1288–1302. doi: 10.1159/000443075
  43. Masetti R, Bertuccio SN, Astolfi A, et al. Hh/Gli antagonist in acute myeloid leukemia with CBFA2T3-GLIS2 fusion gene. J Hematol Oncol. 2017;10(1):26. doi: 10.1186/s13045-017-0396-0
  44. Soderquist R, Eastman A. BCL2 Inhibitors as anticancer drugs: A plethora of misleading BH3 mimetics. Mol Cancer Ther. 2016;15(9):2011–2017. doi: 10.1158/1535-7163.MCT-16-0031
  45. Ruvolo PP, Ruvolo VR, Benton CB, et al. Combination of galectin inhibitor GCS-100 and BH3 mimetics eliminates both p53 wild type and p53 null AML cells. Biochim Biophys Acta. 2016;1863(4):562–571. doi: 10.1016/j.bbamcr.2015.12.008
  46. Mawad R, Becker PS, Hendrie P, et al. Phase II study of tosedostat with cytarabine or decitabine in newly diagnosed older patients with acute myeloid leukaemia or high-risk MDS. Br J Haematol. 2016;172(2): 238–245. doi: 10.1111/bjh.13829
  47. Jamieson GC, Fox JA, Poi M, Strickland SA. Molecular and pharmacologic properties of the anticancer quinolone derivative vosaroxin: A new therapeutic agent for acute myeloid leukemia. Drugs. 2016; 76(13):1245–1255. doi: 10.1007/s40265-016-0614-z
  48. Saenz DT, Fiskus W, Qian Y, et al. Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells. Leukemia. 2017;31(9):1951–1961. doi: 10.1038/leu.2016.393
  49. Maiques-Diaz A, Somervaille TC. LSD1: Biologic roles and therapeutic targeting. Epigenomics. 2016;8(8):1103–1116. doi: 10.2217/epi-2016-0009
  50. Zheng YC, Yu B, Jiang GZ, et al. Irreversible LSD1 inhibitors: Application of tranylcypromine and its derivatives in cancer treatment. Curr Top Med Chem. 2016;16(19):2179–2188.
  51. Przespolewski A, Wang ES. Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia. Expert Opin Investig Drugs. 2016;25(7):771–780. doi: 10.1080/13543784.2016.1175432
  52. Zhao J, Xie C, Edwards H, Wang G, Taub JW, Ge Y. Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells. Oncotarget. 2017;8(4):6319–6329. doi:10.18632/oncotarget.14062
  53. Montalban-Bravo G, Huang X, Jabbour E, et al. A clinical trial for patients with acute myeloid leukemia or myelodysplastic syndromes not eligible for standard clinical trials. Leukemia. 2017;31(2):318–324. doi: 10.1038/leu.2016.303
  54. Norsworthy KJ, Cho E, Arora J, et al. Differentiation therapy in poor risk myeloid malignancies: Results of companion phase II studies. Leuk Res. 2016;49:90–97. doi: 10.1016/j.leukres.2016.09.003
  55. Prebet T, Sun Z, Ketterling RP, et al.; Eastern Cooperative Oncology Group and North American Leukemia intergroup. Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: Further results of the E1905 North American Leukemia Intergroup study. Br J Haematol. 2016;172(3):384–391. doi: 10.1111/bjh.13832
  56. Waters NJ. Preclinical pharmacokinetics and pharmacodynamics of pinometostat (EPZ-5676), a first-in-class, small molecule s-adenosyl methionine competitive inhibitor of DOT1L. Eur J Drug Metab Pharmacokinet. 2017;42(6):891–901. doi: 10.1007/s13318-017-0404-3
  57. Smith SA, Gagnon S, Waters NJ. Mechanistic investigations into the species differences in pinometostat clearance: Impact of binding to alpha-1-acid glycoprotein and permeability-limited hepatic uptake. Xenobiotica. 2017;47(3):185–193. doi: 10.3109/00498254.2016.1173265
  58. Daver N, Basu S, Garcia-Manero G, et al. Phase Ib/II study of nivolumab in combination with azacitidine (AZA) in patients (pts) with relapsed acute myeloid leukemia (AML). Abstract #763. Presented at the ASH Annual Meeting and Exhibition, December 6, 2016; San Diego, CA.
  59. Andreeff M, Kelly KR, Yee K, et al. Results of the phase I trial of RG 7112, a small-molecule MDM2 antagonist in leukemia. Clin Cancer Res. 2016; 22(4):868–876. doi: 10.1158/1078-0432.CCR-15-0481
  60. Reis B, Jukofsky L, Chen G, et al. Acute myeloid leukemia patients’ clinical response to idasanutlin (RG7388) is associated with pre-treatment MDM2 protein expression in leukemic blasts. Haematologica. 2016;101(5):e185–188. doi: 10.3324/haematol.2015.139717