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Erschienen in: Drugs 11/2019

01.07.2019 | Leading Article

From DNA Sequencing to Clinical Trials: Finding New Targeted Drugs for Acute Myeloid Leukemia

verfasst von: Musa Yilmaz, Naval Daver

Erschienen in: Drugs | Ausgabe 11/2019

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Abstract

Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal expansion of myeloid progenitor cells, resulting in disturbed hematopoiesis and bone marrow failure. For decades, AML therapy was relatively straightforward: clinicians assessed whether the patient was fit or unfit for standard chemotherapy and selected the treatment from among limited choices. With the advent of high-throughput sequencing technologies, significant progress has been made in unraveling the AML genome and understanding leukemogenesis driven by recurrent mutations in signaling and kinase pathways, DNA methylation, and spliceosome complex genes. We are now poised to see our research-based advances translate clinically into the treatment of patients with AML. As recently as within the last 2 years, the United States Food and Drug Administration (FDA) approved eight novel therapies for patients with AML. In this review, we discuss recently approved agents targeting fms-like tyrosine kinase 3 (FLT3), isocitrate dehydrogenase (IDH), B-cell lymphoma-2 (BCL-2), and other promising novel AML agents that are in late stages of clinical development.
Literatur
1.
Zurück zum Zitat Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRef Cancer Genome Atlas Research N, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74.CrossRef
2.
3.
Zurück zum Zitat Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65(7):1143–52.CrossRefPubMed Matthews W, Jordan CT, Wiegand GW, Pardoll D, Lemischka IR. A receptor tyrosine kinase specific to hematopoietic stem and progenitor cell-enriched populations. Cell. 1991;65(7):1143–52.CrossRefPubMed
4.
Zurück zum Zitat Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D. Murine FLT3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991;6(9):1641–50.PubMed Rosnet O, Marchetto S, deLapeyriere O, Birnbaum D. Murine FLT3, a gene encoding a novel tyrosine kinase receptor of the PDGFR/CSF1R family. Oncogene. 1991;6(9):1641–50.PubMed
5.
Zurück zum Zitat Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80(10):2584–93.PubMed Birg F, Courcoul M, Rosnet O, et al. Expression of the FMS/KIT-like gene FLT3 in human acute leukemias of the myeloid and lymphoid lineages. Blood. 1992;80(10):2584–93.PubMed
6.
Zurück zum Zitat Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–8.PubMed Nakao M, Yokota S, Iwai T, et al. Internal tandem duplication of the FLT3 gene found in acute myeloid leukemia. Leukemia. 1996;10(12):1911–8.PubMed
7.
8.
Zurück zum Zitat Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.CrossRefPubMed Kottaridis PD, Gale RE, Frew ME, et al. The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood. 2001;98(6):1752–9.CrossRefPubMed
9.
Zurück zum Zitat Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312.CrossRefPubMedPubMedCentral Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. 2019;33(2):299–312.CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19(5):1485–92.CrossRefPubMed Propper DJ, McDonald AC, Man A, et al. Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C. J Clin Oncol. 2001;19(5):1485–92.CrossRefPubMed
11.
Zurück zum Zitat Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105(1):54–60.CrossRefPubMed Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105(1):54–60.CrossRefPubMed
12.
Zurück zum Zitat Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–8.CrossRefPubMedPubMedCentral Stone RM, Fischer T, Paquette R, et al. Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia. Leukemia. 2012;26(9):2061–8.CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454–64.CrossRefPubMedPubMedCentral Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. 2017;377(5):454–64.CrossRefPubMedPubMedCentral
14.
Zurück zum Zitat Dionne CA, Camoratto AM, Jani JP, et al. Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin Cancer Res. 1998;4(8):1887–98.PubMed Dionne CA, Camoratto AM, Jani JP, et al. Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587). Clin Cancer Res. 1998;4(8):1887–98.PubMed
15.
Zurück zum Zitat Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103(10):3669–76.CrossRefPubMed Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103(10):3669–76.CrossRefPubMed
16.
Zurück zum Zitat 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):1143–54.CrossRefPubMedPubMedCentral 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):1143–54.CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12(24):7271–8.CrossRefPubMed Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res. 2006;12(24):7271–8.CrossRefPubMed
18.
Zurück zum Zitat Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62.CrossRefPubMedPubMedCentral Ravandi F, Alattar ML, Grunwald MR, et al. Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation. Blood. 2013;121(23):4655–62.CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Rollig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–9.CrossRefPubMed Rollig C, Serve H, Huttmann A, et al. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol. 2015;16(16):1691–9.CrossRefPubMed
22.
Zurück zum Zitat Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–7.CrossRefPubMedPubMedCentral Cortes JE, Kantarjian H, Foran JM, et al. Phase I study of quizartinib administered daily to patients with relapsed or refractory acute myeloid leukemia irrespective of FMS-like tyrosine kinase 3-internal tandem duplication status. J Clin Oncol. 2013;31(29):3681–7.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Cortes J. Final results of a Phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. Blood. 2012;2012:48 (Proc ASH, Abtract 48). Cortes J. Final results of a Phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. Blood. 2012;2012:48 (Proc ASH, Abtract 48).
24.
Zurück zum Zitat Levis MJ, Perl AE, Dombret H, Döhner H, Steffen B, Rousselot P, Martinelli G, Estey EH, Burnett AK, Gammon G, Trone D, Leo E, Cortes JE. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. ASH Abstract. 2012;673:2012. Levis MJ, Perl AE, Dombret H, Döhner H, Steffen B, Rousselot P, Martinelli G, Estey EH, Burnett AK, Gammon G, Trone D, Leo E, Cortes JE. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients with FLT3-ITD positive or negative relapsed/refractory acute myeloid leukemia after second-line chemotherapy or hematopoietic stem cell transplantation. ASH Abstract. 2012;673:2012.
25.
Zurück zum Zitat Cortes J, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Yu-Hung Leung A, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ, EHA Library. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication–mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled quantum-R trial. EHA Abstract LB2600. 2018. Cortes J, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Yu-Hung Leung A, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, Levis MJ, EHA Library. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication–mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled quantum-R trial. EHA Abstract LB2600. 2018.
26.
Zurück zum Zitat Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, DiNardo CD, Jain N, Estrov Z, Ferrajoli A, Garcia-Manero G, Konopleva M, Andreeff M, Pemmaraju N, Jabbour EJ, Wierda WG, Ravandi F, Pinsoy MR, Cortes JE. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Blood. 2017 (abstract 723). Swaminathan M, Kantarjian HM, Daver N, Borthakur G, Ohanian M, Kadia T, DiNardo CD, Jain N, Estrov Z, Ferrajoli A, Garcia-Manero G, Konopleva M, Andreeff M, Pemmaraju N, Jabbour EJ, Wierda WG, Ravandi F, Pinsoy MR, Cortes JE. The combination of quizartinib with azacitidine or low dose cytarabine is highly active in patients (Pts) with FLT3-ITD mutated myeloid leukemias: interim report of a phase I/II trial. Blood. 2017 (abstract 723).
27.
Zurück zum Zitat Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P, Martinelli G, Estey EH, Burnett AK, Gammon G, Trone D, Leo E, Levis MJ. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. ASH Abstr. 2012;48:2012. Cortes JE, Perl AE, Dombret H, Kayser S, Steffen B, Rousselot P, Martinelli G, Estey EH, Burnett AK, Gammon G, Trone D, Leo E, Levis MJ. Final results of a phase 2 open-label, monotherapy efficacy and safety study of quizartinib (AC220) in patients ≥ 60 years of age with FLT3 ITD positive or negative relapsed/refractory acute myeloid leukemia. ASH Abstr. 2012;48:2012.
28.
Zurück zum Zitat Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123(1):94–100.CrossRefPubMedPubMedCentral Galanis A, Ma H, Rajkhowa T, et al. Crenolanib is a potent inhibitor of FLT3 with activity against resistance-conferring point mutants. Blood. 2014;123(1):94–100.CrossRefPubMedPubMedCentral
29.
Zurück zum Zitat Cortes JE, Kantarjian HM, Kadia TM, Borthakur G, Konopleva M, Garcia-Manero G, Daver NG, Pemmaraju N, Jabbour E, Estrov Z, Ramachandran A, Paradela J, Pond B, Ravandi F, Vusirikala M, Patel PA, Levis MJ, Perl AE, Andreeff M, Collins R. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. ASCO meeting abtract 7008. 2016. Cortes JE, Kantarjian HM, Kadia TM, Borthakur G, Konopleva M, Garcia-Manero G, Daver NG, Pemmaraju N, Jabbour E, Estrov Z, Ramachandran A, Paradela J, Pond B, Ravandi F, Vusirikala M, Patel PA, Levis MJ, Perl AE, Andreeff M, Collins R. Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML. ASCO meeting abtract 7008. 2016.
30.
Zurück zum Zitat Wang ES, Tallman MS, Stone RM, Walter RB, Karanes C, Jain V, Collins RH. Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. ASH Abstract 566. 2017. Wang ES, Tallman MS, Stone RM, Walter RB, Karanes C, Jain V, Collins RH. Low relapse rate in younger patients ≤ 60 years old with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) treated with crenolanib and cytarabine/anthracycline chemotherapy. ASH Abstract 566. 2017.
31.
Zurück zum Zitat Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061–75.CrossRefPubMedPubMedCentral Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study. Lancet Oncol. 2017;18(8):1061–75.CrossRefPubMedPubMedCentral
32.
Zurück zum Zitat Pratz K, Cherry M, Altman JK, Cooper BW, Cruz JC, Jurcic JG, Levis MJ, Lin TL, Perl AE, Podoltsev NA, Schiller GJ, Liu C, Bahceci E. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia. ASH Abstract #722. 2017. Pratz K, Cherry M, Altman JK, Cooper BW, Cruz JC, Jurcic JG, Levis MJ, Lin TL, Perl AE, Podoltsev NA, Schiller GJ, Liu C, Bahceci E. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia. ASH Abstract #722. 2017.
33.
Zurück zum Zitat Esteve J, Schots J, Del Castillo TB, Lee J-H, Wang ES, Bahceci E. Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 mutated (FLT3mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Ash Abstract 2736. 2018. Esteve J, Schots J, Del Castillo TB, Lee J-H, Wang ES, Bahceci E. Multicenter, open-label, 3-arm study of gilteritinib, gilteritinib plus azacitidine, or azacitidine alone in newly diagnosed FLT3 mutated (FLT3mut+) acute myeloid leukemia (AML) patients ineligible for intensive induction chemotherapy: findings from the safety cohort. Ash Abstract 2736. 2018.
34.
Zurück zum Zitat Perl AEGM, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, MJ Levis. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the Phase III ADMIRAL trial. ACCR Meeting abstract #CT184. 2019. Perl AEGM, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, MJ Levis. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): results from the Phase III ADMIRAL trial. ACCR Meeting abstract #CT184. 2019.
35.
Zurück zum Zitat Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K. KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood. 2005;105(8):3319–21.CrossRefPubMed Kohl TM, Schnittger S, Ellwart JW, Hiddemann W, Spiekermann K. KIT exon 8 mutations associated with core-binding factor (CBF)-acute myeloid leukemia (AML) cause hyperactivation of the receptor in response to stem cell factor. Blood. 2005;105(8):3319–21.CrossRefPubMed
36.
Zurück zum Zitat Chen W, Xie H, Wang H, et al. Prognostic Significance of KIT mutations in core-binding factor acute myeloid leukemia: a systematic review and meta-analysis. PLoS One. 2016;11(1):e0146614.CrossRefPubMedPubMedCentral Chen W, Xie H, Wang H, et al. Prognostic Significance of KIT mutations in core-binding factor acute myeloid leukemia: a systematic review and meta-analysis. PLoS One. 2016;11(1):e0146614.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27(9):1891–901.CrossRefPubMed Allen C, Hills RK, Lamb K, et al. The importance of relative mutant level for evaluating impact on outcome of KIT, FLT3 and CBL mutations in core-binding factor acute myeloid leukemia. Leukemia. 2013;27(9):1891–901.CrossRefPubMed
38.
Zurück zum Zitat Marcucci G, Geyer S, Zhao W, Caroll AJ, Bucci D, Uy GL, Blum W, Pardee T, Wetzler M, Stock W, Kolitz JE, Eisfeld A-K, Bloomfield CD, Stone RM, Larson RA. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of kit mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance). ASH Abstract 124. 2014. Marcucci G, Geyer S, Zhao W, Caroll AJ, Bucci D, Uy GL, Blum W, Pardee T, Wetzler M, Stock W, Kolitz JE, Eisfeld A-K, Bloomfield CD, Stone RM, Larson RA. Adding KIT inhibitor dasatinib (DAS) to chemotherapy overcomes the negative impact of kit mutation/over-expression in core binding factor (CBF) acute myeloid leukemia (AML): results from CALGB 10801 (Alliance). ASH Abstract 124. 2014.
39.
Zurück zum Zitat Paschka P, Schlenk RF, Weber D, et al. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018. Paschka P, Schlenk RF, Weber D, et al. Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. Leukemia. 2018.
40.
Zurück zum Zitat Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773(8):1177–95.CrossRefPubMed Rajalingam K, Schreck R, Rapp UR, Albert S. Ras oncogenes and their downstream targets. Biochim Biophys Acta. 2007;1773(8):1177–95.CrossRefPubMed
42.
Zurück zum Zitat 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):1871–9.CrossRefPubMedPubMedCentral 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):1871–9.CrossRefPubMedPubMedCentral
43.
Zurück zum Zitat Jain N, Curran E, Iyengar NM, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014;20(2):490–8.CrossRefPubMed Jain N, Curran E, Iyengar NM, et al. Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial. Clin Cancer Res. 2014;20(2):490–8.CrossRefPubMed
44.
45.
Zurück zum Zitat Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016;165(3):643–55.CrossRefPubMedPubMedCentral Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A Small Molecule RAS-Mimetic Disrupts RAS Association with Effector Proteins to Block Signaling. Cell. 2016;165(3):643–55.CrossRefPubMedPubMedCentral
46.
Zurück zum Zitat Navada SC, Fruchtman SM, Odchimar-Reissig R, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res. 2018;64:10–6.CrossRefPubMed Navada SC, Fruchtman SM, Odchimar-Reissig R, et al. A phase 1/2 study of rigosertib in patients with myelodysplastic syndromes (MDS) and MDS progressed to acute myeloid leukemia. Leuk Res. 2018;64:10–6.CrossRefPubMed
47.
Zurück zum Zitat Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114–21.CrossRefPubMed Rucker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood. 2012;119(9):2114–21.CrossRefPubMed
48.
Zurück zum Zitat Andersen MK, Christiansen DH, Pedersen-Bjergaard J. Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study. Genes Chromosomes Cancer. 2005;42(4):358–71.CrossRefPubMed Andersen MK, Christiansen DH, Pedersen-Bjergaard J. Centromeric breakage and highly rearranged chromosome derivatives associated with mutations of TP53 are common in therapy-related MDS and AML after therapy with alkylating agents: an M-FISH study. Genes Chromosomes Cancer. 2005;42(4):358–71.CrossRefPubMed
49.
Zurück zum Zitat Sallman DA, DeZem AE, Steensma DP, Sweet KL, Cluzeau T, Sekeres MA, Garcia-Manero G, Roboz GJ, McLemore AF, McGraw KL, Puskas J, Zhang L, Bhagat CK, Yao J, Al Ali N, Padron E, Tell R, Lancet JE, Fenaux P, List AF, Komrokji RS. Phase 1b/2 combination study of APR-246 and Azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). ASH Abstract #3091. 2018. Sallman DA, DeZem AE, Steensma DP, Sweet KL, Cluzeau T, Sekeres MA, Garcia-Manero G, Roboz GJ, McLemore AF, McGraw KL, Puskas J, Zhang L, Bhagat CK, Yao J, Al Ali N, Padron E, Tell R, Lancet JE, Fenaux P, List AF, Komrokji RS. Phase 1b/2 combination study of APR-246 and Azacitidine (AZA) in patients with TP53 mutant myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). ASH Abstract #3091. 2018.
50.
Zurück zum Zitat DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732–6.CrossRefPubMedPubMedCentral DiNardo CD, Ravandi F, Agresta S, et al. Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML. Am J Hematol. 2015;90(8):732–6.CrossRefPubMedPubMedCentral
51.
Zurück zum Zitat Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.CrossRefPubMedPubMedCentral Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18(6):553–67.CrossRefPubMedPubMedCentral
52.
53.
Zurück zum Zitat DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386–98.CrossRefPubMed DiNardo CD, Stein EM, de Botton S, et al. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML. N Engl J Med. 2018;378(25):2386–98.CrossRefPubMed
54.
55.
Zurück zum Zitat 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):672–8.CrossRefPubMedPubMedCentral 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):672–8.CrossRefPubMedPubMedCentral
56.
Zurück zum Zitat Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504.CrossRefPubMedPubMedCentral Seiler M, Yoshimi A, Darman R, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med. 2018;24(4):497–504.CrossRefPubMedPubMedCentral
58.
Zurück zum Zitat Pullarkat VA, Newman EM. BCL2 inhibition by venetoclax: targeting the achilles’ heel of the acute myeloid leukemia stem cell? Cancer Discov. 2016;6(10):1082–3.CrossRefPubMed Pullarkat VA, Newman EM. BCL2 inhibition by venetoclax: targeting the achilles’ heel of the acute myeloid leukemia stem cell? Cancer Discov. 2016;6(10):1082–3.CrossRefPubMed
59.
Zurück zum Zitat Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.CrossRefPubMed Konopleva M, Contractor R, Tsao T, et al. Mechanisms of apoptosis sensitivity and resistance to the BH3 mimetic ABT-737 in acute myeloid leukemia. Cancer Cell. 2006;10(5):375–88.CrossRefPubMed
60.
Zurück zum Zitat Vo TT, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–55.CrossRefPubMedPubMedCentral Vo TT, Ryan J, Carrasco R, et al. Relative mitochondrial priming of myeloblasts and normal HSCs determines chemotherapeutic success in AML. Cell. 2012;151(2):344–55.CrossRefPubMedPubMedCentral
61.
Zurück zum Zitat Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75.CrossRefPubMed Pan R, Hogdal LJ, Benito JM, et al. Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia. Cancer Discov. 2014;4(3):362–75.CrossRefPubMed
62.
Zurück zum Zitat Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.CrossRefPubMedPubMedCentral Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106–17.CrossRefPubMedPubMedCentral
63.
Zurück zum Zitat Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018;93:E202.CrossRefPubMedCentral Chyla B, Daver N, Doyle K, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018;93:E202.CrossRefPubMedCentral
64.
Zurück zum Zitat Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70.CrossRefPubMedPubMedCentral Tsao T, Shi Y, Kornblau S, et al. Concomitant inhibition of DNA methyltransferase and BCL-2 protein function synergistically induce mitochondrial apoptosis in acute myelogenous leukemia cells. Ann Hematol. 2012;91(12):1861–70.CrossRefPubMedPubMedCentral
65.
Zurück zum Zitat Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9.CrossRefPubMed Bogenberger JM, Delman D, Hansen N, et al. Ex vivo activity of BCL-2 family inhibitors ABT-199 and ABT-737 combined with 5-azacytidine in myeloid malignancies. Leuk Lymphoma. 2015;56(1):226–9.CrossRefPubMed
66.
Zurück zum Zitat DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–28.CrossRefPubMed DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-randomised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216–28.CrossRefPubMed
67.
Zurück zum Zitat Dinardo CD, Pratz KW, Potluri J, Pullarkat VA, Jonas BA, Wei AH, Becker PS, Frankfurt O, Xu T, Hong W-J, Chyla B, Pollyea DA, Letai AG. Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML). ASCO Abstract 7010. 2018. Dinardo CD, Pratz KW, Potluri J, Pullarkat VA, Jonas BA, Wei AH, Becker PS, Frankfurt O, Xu T, Hong W-J, Chyla B, Pollyea DA, Letai AG. Durable response with venetoclax in combination with decitabine or azacitadine in elderly patients with acute myeloid leukemia (AML). ASCO Abstract 7010. 2018.
68.
Zurück zum Zitat Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277–84.CrossRefPubMed Wei AH, Strickland SA Jr, Hou JZ, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277–84.CrossRefPubMed
69.
Zurück zum Zitat Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia. Sci Rep. 2016;6:27696.CrossRefPubMedPubMedCentral Lin KH, Winter PS, Xie A, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia. Sci Rep. 2016;6:27696.CrossRefPubMedPubMedCentral
70.
Zurück zum Zitat Lyle L, Daver N. Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway. Am J Manag Care. 2018;24(16 Suppl):S356–65.PubMed Lyle L, Daver N. Current and emerging therapies for patients with acute myeloid leukemia: a focus on MCL-1 and the CDK9 pathway. Am J Manag Care. 2018;24(16 Suppl):S356–65.PubMed
Metadaten
Titel
From DNA Sequencing to Clinical Trials: Finding New Targeted Drugs for Acute Myeloid Leukemia
verfasst von
Musa Yilmaz
Naval Daver
Publikationsdatum
01.07.2019
Verlag
Springer International Publishing
Erschienen in
Drugs / Ausgabe 11/2019
Print ISSN: 0012-6667
Elektronische ISSN: 1179-1950
DOI
https://doi.org/10.1007/s40265-019-01144-7

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