Acute Myeloid Leukemia: A Concise Review
Abstract
:1. Introduction
2. Morphology
3. Classification
4. Cytogenetics
5. Molecular Abnormalities
5.1. Nucleophosmin 1 (NPM1) Mutations
5.2. DNA Methyltansferase 3A (DNMT3A) Mutations
5.3. Fms-Like Tyrosine Kinase 3 (FLT3) Mutations
5.4. Isocitrate Dehydrogenase (IDH) Mutations
5.5. Ten–Eleven Translocation 2 (TET2) Mutations
5.6. Runt-Related Transcription Factor (RUNX1) Mutations
5.7. CCAAT Enhancer Binding Protein α (CEBPA) Mutations
5.8. Additional Sex Comb-Like 1 (ASXL1) Mutations
5.9. Mixed Lineage Leukemia (MLL) Mutations
5.10. Tumor Protein p53 (TP53) Mutations
5.11. c-KIT Mutations
5.12. Spilicing Factor Gene Mutations and Mutations in Cohesion Complex Members
6. Prognosis/Risk Stratification
7. Therapeutics
7.1. Induction Therapy
7.2. Consolidation Strategies
7.3. Relapsed Disease
8. Novel Targets
8.1. Fms-Like Tyrosine Kinase 3 (FLT3) Inhibitors
8.2. Isocitrate Dehydrogenase (IDH) Inhibitors
8.3. Nuclear Exporter Inhibitors
8.4. Immune Therapies
9. Conclusions
Conflicts of Interest
References
- Döhner, H.; Weisdorf, D.J.; Bloomfield, C.D. Acute myeloid leukemia. N. Engl. J. Med. 2015, 373, 1136–1152. [Google Scholar] [PubMed]
- Ding, L.; Ley, T.J.; Larson, D.E.; Miller, C.A.; Koboldt, D.C.; Welch, J.S.; Ritchey, J.K.; Young, M.A.; Lamprecht, T.; McLellan, M.D.; et al. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 2012, 481, 506–510. [Google Scholar] [CrossRef] [PubMed]
- Campos, L.; Guyotat, D.; Archimbaud, E.; Devaux, Y.; Treille, D.; Larese, A.; Maupas, J.; Gentilhomme, O.; Ehrsam, A.; Fiere, D. Surface marker expression in adult myeloid leukemia: Correlations with initial characteristics, morphology and response to therapy. Br. J. Haematol. 1989, 72, 161–166. [Google Scholar] [CrossRef] [PubMed]
- Wolach, O.; Stone, R.M. How I treat mixed-phenotype acute leukemia. Blood 2015, 125, 2477–2485. [Google Scholar] [CrossRef] [PubMed]
- Bennett, J.M.; Catovsky, D.; Daniel, M.T.; Flandrin, G.; Galton, D.A.; Gralnick, H.R.; Sultan, C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br. J. Haematol. 1976, 33, 451–458. [Google Scholar] [CrossRef] [PubMed]
- Vardiman, J.W.; Thiele, J.; Arber, D.A.; Brunning, R.D.; Borowitz, M.J.; Porwit, A.; Harris, N.L.; le Beau, M.M.; Hellstrom-Lindberg, E.; Tefferi, A.; et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009, 114, 937–951. [Google Scholar] [CrossRef] [PubMed]
- Lindsley, R.C.; Mar, B.G.; Mazzola, E.; Grauman, P.V.; Shareef, S.; Allen, S.L.; Pigneux, A.; Wetzler, M.; Stuart, R.K.; Erba, H.P.; et al. Acute myeloid leukemia ontogeny is defined by distinct somatic mutations. Blood 2015, 125, 1367–1376. [Google Scholar] [CrossRef] [PubMed]
- Byrd, J.C.; Mrózek, K.; Dodge, R.K.; Carroll, A.J.; Edwards, C.G.; Arthur, D.C.; Pettenati, M.J.; Patil, S.R.; Rao, K.W.; Watson, M.S.; et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: Results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002, 100, 4325–4336. [Google Scholar] [CrossRef] [PubMed]
- Gaidzik, V.; Dohner, K. Prognostic implications of gene mutations in acute myeloid leukemia with normal cytogenetics. Semin. Oncol. 2008, 35, 346–355. [Google Scholar] [CrossRef] [PubMed]
- Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N. Engl. J. Med. 2013, 368, 2059–2074. [Google Scholar]
- Marcucci, G.; Haferlach, T.; Dohner, H. Molecular genetic of adult acute myeloid leukemia: Prognostic and therapeutic implications. J. Clin. Oncol. 2011, 29, 475–486. [Google Scholar] [CrossRef] [PubMed]
- Schnittger, S.; Schoch, C.; Kern, W.; Mecucci, C.; Tschulik, C.; Martelli, M.F.; Haferlach, T.; Hiddemann, W.; Falini, B. Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. Blood 2005, 106, 3733–3739. [Google Scholar] [CrossRef] [PubMed]
- Falini, B.; Nicoletti, I.; Martelli, M.F.; Mecucci, C. Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc + AML): Biologic and clinical features. Blood 2007, 109, 874–885. [Google Scholar] [CrossRef] [PubMed]
- Falini, B.; Bolli, N.; Shan, J.; Martelli, M.P.; Liso, A.; Pucciarini, A.; Bigerna, B.; Pasqualucci, L.; Mannucci, R.; Rosati, R.; et al. Both carboxy-terminus NES motif and mutated tryptophan(s) are crucial for aberrant nuclear export of nucleophosmin leukemic mutants in NPMc + AML. Blood 2006, 107, 4514–4523. [Google Scholar] [CrossRef] [PubMed]
- Cheng, K.; Sportoletti, P.; Ito, K.; Clohessy, J.G.; Teruya-Feldstein, J.; Kutok, J.L.; Pandolfi, P.P. The cytoplasmic NPM mutant induces myeloproliferation in a transgenic mouse model. Blood 2010, 115, 3341–3345. [Google Scholar] [CrossRef] [PubMed]
- Dohner, K.; Schlenk, R.F.; Habdank, M.; Scholl, C.; Rucker, F.G.; Corbacioglu, A.; Bullinger, L.; Frohling, S.; Dohner, H. Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: Interaction with other gene mutations. Blood 2005, 106, 3740–3746. [Google Scholar] [CrossRef] [PubMed]
- Marcucci, G.; Metzeler, K.H.; Schwind, S.; Becker, H.; Maharry, K.; Mrozek, K.; Radmacher, M.D.; Kohlschmidt, J.; Nicolet, D.; Whitman, S.P.; et al. Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia. J. Clin. Oncol. 2012, 30, 742–750. [Google Scholar] [CrossRef] [PubMed]
- Ley, T.J.; Ding, L.; Walter, M.J.; McLellan, M.D.; Lamprecht, T.; Larson, D.E.; Kandoth, C.; Payton, J.E.; Baty, J.; Welch, J.; et al. DNMT3A mutations in acute myeloid leukemia. N. Engl. J. Med. 2010, 363, 2424–2433. [Google Scholar] [CrossRef] [PubMed]
- Shlush, L.I.; Zandi, S.; Mitchell, A.; Chen, W.C.; Brandwein, J.M.; Gupta, V.; Kennedy, J.A.; Schimmer, A.D.; Schuh, A.C.; Yee, K.; et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014, 506, 328–333. [Google Scholar] [CrossRef] [PubMed]
- Gaidzik, V.I.; Schlenk, R.F.; Paschka, P.; Stölzle, A.; Späth, D.; Kuendgen, A.; von Lilienfeld-Toal, M.; Brugger, W.; Derigs, H.G.; Kremer, S.; et al. Clinical impact of DNMT3A mutations in younger adult patient with acute myeloid leukemia: A comprehensive analysis of the AML study Group (AMLSG). Blood 2013, 121, 4769–4777. [Google Scholar] [CrossRef] [PubMed]
- Sehgal, A.R.; Gimotty, P.A.; Zhao, J.; Hsu, J.M.; Daber, R.; Morrissette, J.D.; Luger, S.; Loren, A.W.; Carroll, M. DNMT3A mutational status affects the results of dose-escalated induction therapy in acute myelogenous leukemia. Clin. Cancer Res. 2015, 21, 1614–1620. [Google Scholar] [CrossRef] [PubMed]
- Patel, J.P.; Gonen, M.; Figueroa, M.E.; Fernandez, H.; Sun, Z.; Racevskis, J. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012, 366, 1079–1089. [Google Scholar] [CrossRef] [PubMed]
- Maroc, N.; Rottapel, R.; Rosnet, O.; Marchetto, S.; Lavezzi, C.; Mannoni, P.; Birnbaum, D.; Dubreuil, P. Biochemical characterization and analysis of the transforming potential of the FLT3/FLK2 receptor tyrosine kinase. Oncogene 1993, 8, 909–918. [Google Scholar] [PubMed]
- Gilliland, D.G.; Griffin, J.D. The roles of FLT3 in hematopoiesis and leukemia. Blood 2002, 100, 1532–1542. [Google Scholar] [CrossRef] [PubMed]
- Kelly, L.M.; Liu, Q.; Kutok, J.L.; Williams, I.R.; Boulton, C.L.; Gilliland, D.G. FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. Blood 2002, 99, 310–318. [Google Scholar] [CrossRef] [PubMed]
- Kayser, S.; Schlenk, R.F.; Londono, M.C.; Breitenbuecher, F.; Wittke, K.; Du, J.; Groner, S.; Späth, D.; Krauter, J. Insertion of FLT3 internal tandem duplication in the tyrosine kinase domain-1 is associated with resistance to chemotherapy and inferior outcome. Blood 2009, 114, 2386–2392. [Google Scholar] [CrossRef] [PubMed]
- Kussick, S.J.; Stirewalt, D.L.; Yi, H.S.; Sheets, K.M.; Pogosova-Agadjanyan, E.; Braswell, S.; Norwood, T.H.; Radich, J.; Wood, B.L. A distinctive nuclear morphology in acute myeloid leukemia is strongly associated with loss of HLA-DR expression and FLT3 internal tandem duplication. Leukemia 2004, 18, 1591–1598. [Google Scholar] [CrossRef] [PubMed]
- Gale, R.E.; Green, C.; Allen, C.; Mead, A.J.; Burnett, A.K.; Hills, R.K.; Linch, D.C.; Medical Research Council Adult Leukaemia Working Party. The impact on FLT3 internal tandem duplication mutant level, number, size and interaction with NPM1 mutation in a large cohort of young adult patient with acute myeoid leukemia. Blood 2008, 111, 2776–2784. [Google Scholar] [CrossRef] [PubMed]
- Pratcorona, M.; Brunet, S.; Nomdedeu, J.; Ribera, J.M.; Tormo, M.; Duarte, R.; Escoda, L.; Guàrdia, R.; Queipo de Llano, M.P.; Salamero, O.; et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden LFT3-ITD mutation and concomitant NPM1 mutations: Relevance to post-remission therapy. Blood 2013, 121, 2734–2738. [Google Scholar] [CrossRef] [PubMed]
- Small, D. Targeting FLT3 for the treatment of leukemia. Semin. Hematol. 2008, 45, S17–S21. [Google Scholar] [CrossRef] [PubMed]
- Marcucci, G.; Maharry, K.; Wu, Y.Z.; Radmacher, M.D.; Mrózek, K.; Margeson, D.; Holland, K.B.; Whitman, S.P.; Becker, H.; Schwind, S.; et al. IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: A cancer and leukemia group B study. J. Clin. Oncol. 2010, 28, 2348–2355. [Google Scholar] [CrossRef] [PubMed]
- Paschka, P.; Schlenk, R.F.; Gaidzik, V.I.; Habdank, M.; Krönke, J.; Bullinger, L.; Späth, D.; Kayser, S.; Zucknick, M.; Götze, K.; et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J. Clin. Oncol. 2010, 28, 3636–3643. [Google Scholar] [CrossRef] [PubMed]
- Fathi, A.T.; Wander, S.A.; Faramand, R.; Emadi, A. Biochemical, epigenetic, and metabolic approaches to target IDH mutations in acute myeloid leukemia. Semin. Hematol. 2015, 52, 165–171. [Google Scholar] [CrossRef] [PubMed]
- Chou, W.C.; Chou, S.C.; Liu, C.Y.; Chen, C.Y.; Hou, H.A.; Kuo, Y.Y.; Lee, M.C.; Ko, B.S.; Tang, J.L.; Yao, M.; et al. TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. Blood 2011, 118, 3803–3810. [Google Scholar] [CrossRef] [PubMed]
- Metzeler, K.H.; Maharry, K.; Radmacher, M.D.; Mrozek, K.; Margeson, D.; Becker, H. TET2 mutations improve the new European LeukemiaNet risk classification of acute myeloid leukemia: A cancer and leukemia group B study. J. Clin. Oncol. 2011, 29, 1373–1381. [Google Scholar] [CrossRef] [PubMed]
- Gaidzik, V.I.; Paschka, P.; Spath, D.; Habdank, M.; Kohne, C.H.; Germing, U.; von Lilienfeld-Toal, M.; Held, G.; Horst, H.A.; Haase, D.; et al. TET2 mutations in acute myeloid leukemia (AML): Results from a comprehensive genetic and clinical analysis of the AML study group. J. Clin. Oncol. 2012, 30, 1350–1357. [Google Scholar] [CrossRef] [PubMed]
- Meyers, S.; Downing, J.R.; Hiebert, S.W. Identification of AML-1 and the (8;21) translocation protein (AML-1/ETO) as sequence-specific DNA-binding proteins: The runt homology domain is required for DNA binding and protein-protein interactions. Mol. Cell Biol. 1993, 13, 6336–6345. [Google Scholar] [CrossRef] [PubMed]
- Tang, J.L.; Hou, H.A.; Chem, C.Y.; Liu, C.Y.; Chou, W.C.; Tseng, M.H. AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: Prognostic implication and interaction with other gene alternations. Blood 2009, 114, 5352–5361. [Google Scholar] [CrossRef] [PubMed]
- Mendler, J.H.; Maharry, K.; Radmacher, M.D.; Mrozek, K.; Becker, H.; Metzeler, K.H. RUNX1 mutations are associated with poor outcome in younger and older patients with cytogenetically normal acute myeloid leukemia and with distinct gene and MicroRNA expression signatures. J. Clin. Oncol. 2012, 30, 3109–3118. [Google Scholar] [CrossRef] [PubMed]
- Mrózek, K.; Marcucci, G.; Paschka, P.; Whitman, S.P.; Bloomfield, C.D. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: Are we ready for a prognostically prioritized molecular classification? Blood 2007, 109, 431–448. [Google Scholar] [CrossRef] [PubMed]
- Koschmieder, S.; Halmos, B.; Levantini, E.; Tenen, D.G. Dysregulation of the C/EBPα differentiation pathway in human cancer. J. Clin. Oncol. 2009, 27, 619–628. [Google Scholar] [CrossRef] [PubMed]
- Fasan, A.; Haferlach, C.; Alpermann, T.; Jeromin, S.; Grossmann, V.; Eder, C.; Weissmann, S.; Dicker, F.; Kohlmann, A.; Schindela, S.; et al. The role of different genetic subtypes of CEBPA mutated AML. Leukemia 2014, 28, 794–803. [Google Scholar] [CrossRef] [PubMed]
- Wouters, B.J.; Lowenberg, B.; Erpelinck-Verschueren, C.A.; van Putten, W.L.; Valk, P.J.; Delwel, R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood 2009, 113, 3088–3091. [Google Scholar] [CrossRef] [PubMed]
- Metzeler, K.H.; Becker, H.; Maharry, K.; Radmacher, M.D.; Kohlschmidt, J.; Mrózek, K.; Nicolet, D.; Whitman, S.P.; Wu, Y.Z.; Schwind, S.; et al. ASXL1 mutations identify a high risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category. Blood 2011, 118, 6920–6929. [Google Scholar] [CrossRef] [PubMed]
- Alpermann, T.; Haferlach, C.; Eder, C.; Nadarajah, N.; Meggendorfer, M.; Kern, W.; Haferlach, T.; Schnittger, S. AML with gain of chromosome 8 as the sole chromosomal abnormality (+8sole) is associated with a specific molecular mutation pattern including ASXL1 mutation in 46.8% of the patients. Leuk. Res. 2015, 39, 265–272. [Google Scholar] [CrossRef] [PubMed]
- Micol, J.B.; Duployez, N.; Boissel, N.; Petit, A.; Geffroy, S.; Nibourel, O.; Lacombe, C.; Lapillonne, H.; Etancelin, P.; Figeac, M.; et al. Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations. Blood 2014, 124, 1445–1449. [Google Scholar] [CrossRef] [PubMed]
- Ernest, P.; Wang, J.; Korsmeyer, S.J. The role of MLL in hematopoiesis and leukemia. Curr. Opin. Hematol. 2002, 9, 282–287. [Google Scholar] [CrossRef]
- Caligiuri, M.A.; Schichman, S.A.; Strout, M.P.; Mrózek, K.; Baer, M.R.; Frankel, S.R.; Barcos, M.; Herzig, G.P.; Croce, C.M.; Bloomfield, C.D. Molecular rearrangement of the ALL-1 gene in acute myeloid leukemia without cytogenetic evidence of 11q23 chromosomal translocations. Cancer Res. 1994, 54, 370–373. [Google Scholar] [PubMed]
- Caligiuri, M.A.; Strout, M.P.; Lawrence, D.; Arthur, D.C.; Baer, M.R.; Yu, F.; Knuutila, S.; Mrozek, K.; Oberkircher, A.R.; Marcucci, G.; et al. Rearrangement of ALL1 (MLL) in acute myeloid leukemia with normal cytogenetics. Cancer Res. 1998, 58, 55–59. [Google Scholar] [PubMed]
- Dohner, K.; Tobis, K.; Ulrich, R.; Frohling, S.; Benner, A.; Schlenk, R.F.; Dohner, H. Prognostic significance of partial tandem duplications of the MLL gene in adult patients 16 to 60 years old with acute myeloid leukemia and normal cytogenetics: A study of the acute myeloid leukemia study group Ulm. J. Clin. Oncol. 2002, 20, 3254–3261. [Google Scholar] [CrossRef] [PubMed]
- Haferlach, C.; Dicker, F.; Herholz, H.; Schnittger, S.; Kern, W.; Haferlach, T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008, 22, 1539–1541. [Google Scholar] [CrossRef] [PubMed]
- Sattler, M.; Salgia, R. Targeting c-Kit mutations: Basic science to novel therapies. Leuk. Res. 2004, 28, S11–S20. [Google Scholar] [CrossRef] [PubMed]
- Paschka, P.; Marcucci, G.; Ruppert, A.S.; Mrozek, K.; Chen, H.; Kittles, R.A.; Vukosavljevic, T.; Perrotti, D.; Vardiman, J.W.; Carroll, A.J.; et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A cancer and leukemia group B study. J. Clin. Oncol. 2006, 24, 3904–3911. [Google Scholar] [CrossRef] [PubMed]
- Boissel, N.; Leroy, H.; Brethon, B.; Philippe, N.; de Botton, S.; Auvrignon, A.; Raffoux, E.; Leblanc, T.; Thomas, X.; Hermine, O.; et al. Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 2006, 20, 965–970. [Google Scholar] [CrossRef] [PubMed]
- Marcucci, G.; Geyer, S.; Zhao, W.; Caroll, A.J.; Bucci, D.; Uy, G.L.; Blum, W.; Pardee, T.; Wetzler, M.; Stock, W.; et al. 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 CLGB 10801 (Alliance). Blood 2014, 124, 8. [Google Scholar]
- Boissel, N.; Renneville, A.; Leguay, T.; Lefebvre, P.C.; Recher, C.; Lecerf, T.; Delabesse, E.; Berthon, C.; Blanchet, O.; Prebet, T.; et al. Dasatinib in high-risk core binding factor acute myeloid leukemia in first complete remission: A french acute myeloid leukemia intergroup trial. Haematologica 2015, 100, 780–785. [Google Scholar] [CrossRef] [PubMed]
- Cazzola, M.; Della Porta, M.G.; Malcovati, L. The genetic basis of myelodysplasia and its clinical relevance. Blood 2013, 122, 4021–4034. [Google Scholar] [CrossRef] [PubMed]
- Thota, S.; Viny, A.D.; Makishima, H.; Spitzer, B.; Radivoyevitch, T.; Przychodzen, B.; Sekeres, M.A.; Levine, R.L.; Maciejewski, J.P. Genetic alterations of the cohesin complex genes in myeloid malignancies. Blood 2014, 124, 1790–1798. [Google Scholar] [CrossRef] [PubMed]
- Dohner, H.; Estey, E.H.; Amadori, S.; Appelbaum, F.R.; Buchner, T.; Burnett, A.K.; Dombret, H.; Fenaux, P.; Grimwade, D.; Larson, R.A.; et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010, 115, 453–474. [Google Scholar] [CrossRef] [PubMed]
- Mrozek, K.; Marcucci, G.; Nicolet, D.; Maharry, K.S.; Becker, H.; Whitman, S.P.; Metzeler, K.H.; Schwind, S.; Wu, Y.Z.; Kohlschmidt, J.; et al. Prognostic significance of the European LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J. Clin. Oncol. 2012, 30, 4515–4523. [Google Scholar] [CrossRef] [PubMed]
- Medeiros, B.C.; Othus, M.; Fang, M.; Roulston, D.; Appelbaum, F.R. Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: The South-west Oncology Group (SWOG) experience. Blood 2010, 116, 2224–2228. [Google Scholar] [CrossRef] [PubMed]
- Sanz, M.A.; Lo Coco, F.; Martin, G.; Avvisati, G.; Rayon, C.; Barbui, T.; Diaz-Mediavilla, J.; Fioritoni, G.; Gonzalez, J.D.; Liso, V.; et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000, 96, 1247–1253. [Google Scholar] [PubMed]
- Cheson, B.D.; Bennett, J.M.; Kopecky, K.J.; Buchner, T.; Willman, C.L.; Estey, E.H.; Schiffer, C.A.; Doehner, H.; Tallman, M.S.; Lister, T.A.; et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J. Clin. Oncol. 2003, 21, 4642–4649. [Google Scholar] [CrossRef] [PubMed]
- Estey, E.; Döhner, H. Acute myeloid leukaemia. Lancet 2006, 368, 1894–1907. [Google Scholar] [CrossRef]
- Lowenberg, B.; Ossenkoppele, G.J.; van Putten, W.; Schouten, H.C.; Graux, C.; Ferrant, A.; Sonneveld, P.; Maertens, J.; Jongen-Lavrencic, M.; von Lilienfeld-Toal, M.; et al. High-dose daunorubicin in older patients with acute myeloid leukemia. N. Engl. J. Med. 2009, 361, 1235–1248. [Google Scholar] [CrossRef] [PubMed]
- Fernandez, H.F.; Sun, Z.; Yao, X.; Litzow, M.R.; Luger, S.M.; Paietta, E.M.; Racevskis, J.; Dewald, G.W.; Ketterling, R.P.; Bennett, J.M.; et al. Anthracycline Dose Intensification in Acute Myeloid Leukemia. N. Engl. J. Med. 2009, 361, 1249–1259. [Google Scholar] [CrossRef] [PubMed]
- Burnett, A.K.; Russell, N.H.; Hills, R.K.; Kell, J.; Cavenagh, J.; Kjeldsen, L.; McMullin, M.; Cahalin, P.; Dennis, M.; Friis, L.; et al. A randomized comparison of daunorubicin 90 mg/m2 vs 60 mg/m2 in AML Induction: Results from the UK NCRI AML17 Trial in 1206 Patients. Blood 2015, 125, 3878–3885. [Google Scholar] [CrossRef] [PubMed]
- Fernandez, H.F. Beyond the first glance: Anthracyclines in AML. Blood 2015, 125, 3828–3829. [Google Scholar] [CrossRef] [PubMed]
- Stone, R.M.; O’Donnell, M.R.; Sekeres, M.A. Acute myeloid leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2004, 2004, 98–117. [Google Scholar] [CrossRef] [PubMed]
- Klepin, H. Geriatric perspective: How to assess fitness for chemotherapy in acute myeloid leukemia. Hematol. Am. Soc. Hematol. Educ. Program 2014, 2014, 8–13. [Google Scholar] [CrossRef] [PubMed]
- Quintas-Cardama, A.; Ravandi, F.; Liu-Dumlao, T.; Brandt, M.; Faderl, S.; Pierce, S.; Borthakur, G.; Garcia-Manero, G.; Cortes, J.; Kantarjian, H. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012, 120, 4840–4845. [Google Scholar] [CrossRef] [PubMed]
- Blum, W.; Garzon, R.; Klisovic, R.B.; Schwind, S.; Walker, A.; Geyer, S.; Liu, S.; Havelange, V.; Becker, H.; Schaaf, L.; et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc. Natl. Acad. Sci. USA 2010, 107, 7473–7478. [Google Scholar] [CrossRef] [PubMed]
- Maurillo, L.; Venditti, A.; Spagnoli, A.; Gaidano, G.; Ferrero, D.; Oliva, E.; Lunghi, M.; D'Arco, A.M.; Levis, A.; Pastore, D.; et al. Azacitidine for the treatment of patients with acute myeloid leukemia: Report of 82 patients enrolled in an Italian Compassionate Program. Cancer 2012, 118, 1014–1022. [Google Scholar] [CrossRef] [PubMed]
- Lo-Coco, F.; Avvisati, G.; Vignetti, M.; Thiede, C.; Orlando, S.M.; Iacobelli, S.; Ferrara, F.; Fazi, P.; Cicconi, L.; Di Bona, E.; et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N. Engl. J. Med. 2013, 369, 111–121. [Google Scholar] [CrossRef] [PubMed]
- Mi, J.Q.; Li, J.M.; Shen, Z.X.; Chen, S.J.; Chen, Z. How to manage acute promyelocytic leukemia. Leukemia 2012, 26, 1743–1751. [Google Scholar] [CrossRef] [PubMed]
- Grimwade, D.; Freeman, S.D. Defining minimal residual disease in acute myeloid leukemia: Which platforms are ready for “prime time”? Blood 2014, 124, 3345–3355. [Google Scholar] [CrossRef] [PubMed]
- Kohlmann, A.; Nadarajah, N.; Alpermann, T.; Grossmann, V.; Schindela, S.; Dicker, F.; Roller, A.; Kern, W.; Haferlach, C.; Schnittger, S.; et al. Monitoring of residual disease by next-generation deep-sequencing of RUNX1 mutations can identify acute myeloid leukemia patients with resistant disease. Leukemia 2014, 28, 129–137. [Google Scholar] [CrossRef] [PubMed]
- Burnett, A.K.; Russell, N.H.; Hills, R.K.; Hunter, A.E.; Kjeldsen, L.; Yin, J.; Gibson, B.E.; Wheatley, K.; Milligan, D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: Results of the medical research council AML15 trial. J. Clin. Oncol. 2013, 31, 3360–3368. [Google Scholar] [CrossRef] [PubMed]
- Schiffer, C. Optimal dose and schedule of consolidation in AML: Is there a standard? Best Pract. Res. Clin. Haematol. 2014, 27, 259–264. [Google Scholar] [CrossRef] [PubMed]
- Appelbaum, F.R. The current status of hematopoietic cell transplantation. Annu. Rev. Med. 2003, 54, 491–512. [Google Scholar] [CrossRef] [PubMed]
- Popat, U.; de Lima, M.J.; Saliba, R.M.; Anderlini, P.; Andersson, B.S.; Alousi, A.M.; Hosing, C.; Nieto, Y.; Parmar, S.; Khouri, I.F.; et al. Long-term outcome of reduced-intensity allogeneic hematopoietic SCT in patients with AML in CR. Bone Marrow Transplant. 2012, 47, 212–216. [Google Scholar] [CrossRef] [PubMed]
- Sorror, M.L.; Maris, M.B.; Storb, R.; Baron, F.; Sandmaier, B.M.; Maloney, D.G.; Storer, B. Hematopoietic cell transplantation (HCT)-specific comorbidity index: A new tool for risk assessment before allogeneic HCT. Blood 2005, 106, 2912–2919. [Google Scholar] [CrossRef] [PubMed]
- Devine, S.M.; Owzar, K.; Blum, W.; Mulkey, F.; Stone, R.M.; Hsu, J.W.; Champlin, R.E.; Chen, Y.B.; Vij, R.; Slack, J.; et al. Phase II Study of Allogeneic Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission Using a Reduced-Intensity Conditioning Regimen: Results From Cancer and Leukemia Group B 100103 (Alliance for Clinical Trials in Oncology)/Blood and Marrow Transplant Clinical Trial Network 0502. J. Clin. Oncol. 2015, 33, 4167–4175. [Google Scholar] [PubMed]
- Breems, D.A.; Van Putten, W.L.; Huijgens, P.C.; Ossenkoppele, G.J.; Verhoef, G.E.; Verdonck, L.F.; Vellenga, E.; De Greef, G.E.; Jacky, E.; Van der Lelie, J.; et al. Prognostic index for adult patients with acute myeloid leukemia in first relapse. J. Clin. Oncol. 2005, 23, 1969–1978. [Google Scholar] [CrossRef] [PubMed]
- Soignet, S.L.; Maslak, P.; Wang, Z.G.; Jhanwar, S.; Calleja, E.; Dardashti, L.J.; Corso, D.; DeBlasio, A.; Gabrilove, J.; Scheinberg, D.A.; et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N. Engl. J. Med. 1998, 339, 1341–1348. [Google Scholar] [CrossRef] [PubMed]
- Sudhindra, A.; Smith, C.C. FLT3 inhibitors in AML: Are we there yet? Curr. Hematol. Malig. Rep. 2014, 9, 174–185. [Google Scholar] [CrossRef] [PubMed]
- Levis, M.; Ravandi, F.; Wang, E.S.; Baer, M.R.; Perl, A.; Coutre, S.; Erba, H.; Stuart, R.K.; Baccarani, M.; Cripe, L.D.; et al. Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Blood 2011, 117, 3294–3301. [Google Scholar] [CrossRef] [PubMed]
- Stone, R.M.; DeAngelo, D.J.; Klimek, V.; Galinsky, I.; Estey, E.; Nimer, S.D.; Grandin, W.; Lebwohl, D.; Wang, Y.; Cohen, P.; 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, 54–60. [Google Scholar] [CrossRef] [PubMed]
- Smith, B.D.; Levis, M.; Beran, M.; Giles, F.; Kantarjian, H.; Berg, K.; Murphy, K.M.; Dauses, T.; Allebach, J.; Small, D. 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, 3669–3676. [Google Scholar] [CrossRef] [PubMed]
- Pratz, K.W.; Cortes, J.; Roboz, G.J.; Rao, N.; Arowojolu, O.; Stine, A.; Shiotsu, Y.; Shudo, A.; Akinaga, S.; Small, D.; et al. A pharmacodynamic study of the FLT3 inhibitor KW-2449 yields insight into the basis for clinical response. Blood 2009, 113, 3938–3946. [Google Scholar] [CrossRef] [PubMed]
- Serve, H.; Krug, U.; Wagner, R.; Sauerland, M.C.; Heinecke, A.; Brunnberg, U.; Schaich, M.; Ottmann, O.; Duyster, J.; Wandt, H.; et al. Sorafenib in combination with intensive chemotherapy in elderly patients with acute myeloid leukemia: Results from a randomized, placebo-controlled trial. J. Clin. Oncol. 2013, 31, 3110–3118. [Google Scholar] [CrossRef] [PubMed]
- Ravandi, F.; Alattar, M.L.; Grunwald, M.R.; Rudek, M.A.; Rajkhowa, T.; Richie, M.A.; Pierce, S.; Daver, N.; Garcia-Manero, G.; Faderl, S.; 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, 4655–4662. [Google Scholar] [CrossRef] [PubMed]
- Fiedler, W.; Kayser, S.; Kebenko, M.; Krauter, J.; Salih, H.R.; Götze, K.; Späth, D.; Göhring, G.; Teleanu, V.; Döhner, K.; et al. Sunitinib and intensive chemotherapy in patients with acute myeloid leukemia and activating flt3 mutations: Results of the amlsg 10-07 study (clinicaltrials.Gov no. Nct00783653). In Procedings of the 56th ASH Annual Meeting and Exposition, Atlanta, GA, USA, 8–11 December 2012.
- Stone, R.M.; Mandrekar, S.; Sanford, B.L.; Geyer, S.; Bloomfield, C.D.; Dohner, K.; Thiede, C.; Marcucci, G.; Lo-CoCo, F.; Klisovic, R.B.; et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose c consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18–60 with FLT3 mutations (muts): An international prospective randomized (rand) p-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). In Proceedings of the American Society of Hematology Annual Meeting, Orlando, FL, USA, 5–8 December 2015.
- Smith, C.C.; Wang, Q.; Chin, C.S.; Salerno, S.; Damon, L.E.; Levis, M.J.; Perl, A.E.; Travers, K.J.; Wang, S.; Hunt, J.P.; et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukemia. Nature 2012, 485, 260–263. [Google Scholar] [CrossRef] [PubMed]
- Lee, H.K.; Kim, H.W.; Lee, I.Y.; Lee, J.; Lee, J.; Jung, D.S.; Lee, S.Y.; Park, S.H.; Hwang, H.; Choi, J.S.; et al. G-749, a novel FLT3 kinase inhibitor, can overcome drug resistance for the treatment of acute myeloid leukemia. Blood 2014, 123, 2209–2219. [Google Scholar] [CrossRef] [PubMed]
- Altman, J.K.; Perl, A.E.; Cortes, J.E.; Levis, M.J.; Smith, C.S.; Litzow, M.R.; Baer, M.R.; Claxton, D.F.; Erba, H.P.; Gill, S.C.; et al. Antileukemic Activity and Tolerability of ASP2215 80mg and Greater in FLT3 Mutation-Positive Subjects with Relapsed or Refractory Acute Myeloid Leukemia: Results from a Phase 1/2, Open-Label, Dose-Escalation/Dose-Response Study. In Proceedings of the American Society of Hematology Annual Meeting, Orlando, FL, USA, 5–8 December 2015.
- Stein, E.M.; Altman, J.K.; Collins, R.; DeAngelo, D.J.; Fathi, A.T.; Flinn, I.; Frankel, A.; Levine, R.L.; Medeiros, B.C.; Patel, M.; et al. AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies. In Procedings of 56th ASH Annual Meeting and Exposition, San Francisco, CA, USA, 6–9 December 2014; p. 115.
- Hansen, E.; Quivoron, C.; Straley, K.; Lemieux, R.M.; Popovici-Muller, J.; Sadrzadeh, H.; Fathi, A.T.; Gliser, C.; David, M.; Saada, V.; et al. AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient Samples Treated Ex Vivo. In Procedings of 56th ASH Annual Meeting and Exposition, San Francisco, CA, USA, 6–9 December 2014; Volume 124, p. 3734.
- Fukuda, M.; Asano, S.; Nakamura, T.; Adachi, M.; Yoshida, M.; Yanagida, M.; Nishida, E. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. Nature 1997, 390, 308–311. [Google Scholar] [PubMed]
- Kojima, K.; Kornblau, S.M.; Ruvolo, V.; Dilip, A.; Duvvuri, S.; Davis, R.E.; Zhang, M.; Wang, Z.; Coombes, K.R.; Zhang, N.; et al. Prognostic impact and targeting of CRM1 in acute myeloid leukemia. Blood 2013, 121, 4166–4174. [Google Scholar] [CrossRef] [PubMed]
- Turner, J.G.; Sullivan, D.M. CRM1-mediated nuclear export of proteins and drug resistance in cancer. Curr. Med. Chem. 2008, 15, 2648–2655. [Google Scholar] [CrossRef] [PubMed]
- Ranganathan, P.; Yu, X.; Na, C.; Santhanam, R.; Shacham, S.; Kauffman, M.; Walker, A.; Klisovic, R.; Blum, W.; Caligiuri, M.; et al. Preclinical activity of a novel CRM1 inhibitor in acute myeloid leukemia. Blood 2012, 120, 1765–1773. [Google Scholar] [CrossRef] [PubMed]
- Etchin, J.; Sun, Q.; Kentsis, A.; Farmer, A.; Zhang, Z.C.; Sanda, T.; Mansour, M.R.; Barcelo, C.; McCauley, D.; Kauffman, M.; et al. Antileukemic activity of nuclear export inhibitors that spare normal hematopoietic cells. Leukemia 2013, 27, 66–74. [Google Scholar] [CrossRef] [PubMed]
- Castaigne, S.; Pautas, C.; Terré, C.; Raffoux, E.; Bordessoule, D.; Bastie, J.-N.; Legrand, O.; Thomas, X.; Turlure, P.; Reman, O.; et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): A randomised, open-label, phase 3 study. Lancet 2012, 379, 1508–1516. [Google Scholar] [CrossRef]
- Gasiorowski, R.E.; Clark, G.J.; Bradstock, K.; Hart, D.N.J. Antibody therapy for acute myeloid leukaemia. Br. J. Haematol. 2014, 164, 481–495. [Google Scholar] [CrossRef] [PubMed]
- Gill, S.; Tasian, S.K.; Ruella, M.; Shestova, O.; Li, Y.; Porter, D.L.; Carroll, M.; Danet-Desnoyers, G.; Scholler, J.; Grupp, S.A.; et al. Preclinical targeting of human acute myeloid leukemia and myeloablation using chimeric antigen receptor-modified T cells. Blood 2014, 123, 2343–2354. [Google Scholar] [CrossRef] [PubMed]
Risk Group | Subsets |
---|---|
Favorable | t(8;21)(q22;q22); RUNX1-RUNX1T1 |
inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 | |
Mutated NPM1 without FLT3-ITD (normal karyotype) | |
Biallelic mutated CEBPA (normal karyotype) | |
Intermediate-I | Mutated NPM1 and FLT3-ITD (normal karyotype) |
Wild-type NPM1 and FLT3-ITD (normal karyotype) | |
Wild-type NPM1 without FLT3-ITD (normal karyotype) | |
Intermediate-II | t(9;11)(p22;q23); MLLT3-KMT2A |
Cytogenetic abnormalities not classified as favorable | |
or adverse | |
Adverse | inv(3)(q21q26.2) or t(3;3)(q21;q26.2); GATA2-MECO (EVI1) |
t(6;9)(p23;q34); DEK-NUP214 | |
t(v;11)(v;q23); KMT2A rearranged | |
–5 or del(5q); –7; abnl(17p); complex karyotype * |
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Saultz, J.N.; Garzon, R. Acute Myeloid Leukemia: A Concise Review. J. Clin. Med. 2016, 5, 33. https://doi.org/10.3390/jcm5030033
Saultz JN, Garzon R. Acute Myeloid Leukemia: A Concise Review. Journal of Clinical Medicine. 2016; 5(3):33. https://doi.org/10.3390/jcm5030033
Chicago/Turabian StyleSaultz, Jennifer N., and Ramiro Garzon. 2016. "Acute Myeloid Leukemia: A Concise Review" Journal of Clinical Medicine 5, no. 3: 33. https://doi.org/10.3390/jcm5030033