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Nat Rev Clin Oncol. Author manuscript; available in PMC 2017 July 25. Published in final edited form as: Nat Rev Clin Oncol. 2016 May ; 13(5): 305–318. doi:10.1038/nrclinonc.2015.210.
Molecular therapy for acute myeloid leukaemia Catherine C. Coombs1, Martin S. Tallman1,2, and Ross L. Levine1,3 1Leukemia
Service, Department of Medicine, Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
2Weill
Cornell Medical Center, 1300 York Avenue, New York, New York 10065, USA
Author Manuscript
3Human
Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Abstract
Author Manuscript
Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.
Author Manuscript
Acute myeloid leukaemia (AML) is the most-common acute leukaemia in adults, and is primarily a disease of older adults (defined in this Review as those aged ≥60 years, unless otherwise stated), with a median age at diagnosis of 67 years1,2. The survival rates for younger adults with AML (aged 75 years, for whom no improvement in outcome has been demonstrated over the past three decades4.
Author Manuscript Author Manuscript
The use of different therapies in the postremission treatment of AML is largely determined by prognostic risk stratification, which has classically been based on cytogenetic findings. The largest subset of patients with AML falls into the ‘intermediate-risk’ group, which includes those with normal-karyotype AML (NK-AML), as well as patients without either adverse or favourable cytogenetic abnormalities5,6. Considerable efforts have been made to refine risk stratification among this large and diverse subset of patients, with the emergence of multiple molecular abnormalities, including FLT3-ITD (FLT3 internal tandem duplication), and mutations in NPM1, KIT, and/or CEBPA, which have been shown to predict outcome and have been incorporated into modern prognostic and treatment guidelines7,8, although, in addition to cytogenetic and molecular findings, clinical factors can also predict outcomes9. Advances in next-generation sequencing (NGS) technology have led to the discovery of novel somatic mutations in patients with AML, providing greater insight into the mutational landscape of the disease. The majority of patients with AML (>97%) demonstrate at least one clonal somatic abnormality on mutational profiling10–12. Through genomic analysis of samples from 200 patients with de novo AML, The Cancer Genome Atlas (TCGA) investigators demonstrated that the distribution of genomic aberrations includes mutations in signalling-pathway genes in 59%, DNA-methylationrelated genes in 44%, chromatin-modifying genes in 30%, NPM1 in 27%, myeloidtranscription-factor genes in 22%, transcription-factor-gene fusions in 18%, tumoursuppressor genes in 16%, spliceosome-complex genes in 14%, and cohesin-complex genes in 13% of patients12 (TABLE 1), with findings from several other studies corroborating a similar distribution of mutations13–15. The use of mutation profiling in the clinic continues to evolve, and a substantial degree of variance remains among oncologists on how to apply genomic findings to clinical practice16. Consequently, evidence-based approaches are urgently required for the application of genetic data in molecular medicine for patients with AML.
Author Manuscript
In this Review, we propose that the lack of progress in improving the outcomes of patients with AML over the past four decades calls for consideration of a major paradigm shift regarding the present clinical treatment algorithms; for example, consideration of the use of upfront targeted therapy in elderly or unfit patients who are not candidates for standard intensive induction regimens, and addition of targeted agents to induction chemotherapy for younger patients, all in the setting of clinical trials (FIGS 1,2). We hypothesize that the integration of mutational profiling into the care of patients with AML will improve the outcomes associated with this characteristically devastating disorder. To accommodate the integration of mutational profiling into daily practice, more-high-throughput and morecomprehensive sequencing assays need to be used, in order to inform not only the approach to therapy for relapsed or refractory disease, but also decisions on upfront treatments.
Genetic profiling and induction therapy Karyotype and molecular alterations are powerful prognostic markers in AML; however, at present, these data are often unavailable at the initiation of induction therapy, particularly
Nat Rev Clin Oncol. Author manuscript; available in PMC 2017 July 25.
Coombs et al.
Page 3
Author Manuscript
outside of a clinical trial. As such, patients with AML generally receive induction therapy independent of their subsequent risk stratification; the choice of induction regimen is based on the patient’s age and comorbidities, with ‘fit’ younger patients typically receiving standard induction therapy with cytarabine and an anthracycline7. Daunorubicin and idarubicin are the anthracyclines used most commonly in induction regimens, and neither agent is clearly superior to the other17,18. The findings of studies performed in the past decade, which are outlined in the following sections, indicate that molecular subtypes of AML correlate with improved responses to induction therapy in various subsets of patients, stressing the importance of integrating upfront comprehensive mutational profiling into initial treatment decisions. Candidates for intensive induction therapy
Author Manuscript Author Manuscript
In the large, randomized, phase III Eastern Cooperative Oncology Group (ECOG) E1900 trial in which patients
Nat Rev Clin Oncol. Author manuscript; available in PMC 2017 July 25. Published in final edited form as: Nat Rev Clin Oncol. 2016 May ; 13(5): 305–318. doi:10.1038/nrclinonc.2015.210.
Molecular therapy for acute myeloid leukaemia Catherine C. Coombs1, Martin S. Tallman1,2, and Ross L. Levine1,3 1Leukemia
Service, Department of Medicine, Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
2Weill
Cornell Medical Center, 1300 York Avenue, New York, New York 10065, USA
Author Manuscript
3Human
Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
Abstract
Author Manuscript
Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine.
Author Manuscript
Acute myeloid leukaemia (AML) is the most-common acute leukaemia in adults, and is primarily a disease of older adults (defined in this Review as those aged ≥60 years, unless otherwise stated), with a median age at diagnosis of 67 years1,2. The survival rates for younger adults with AML (aged 75 years, for whom no improvement in outcome has been demonstrated over the past three decades4.
Author Manuscript Author Manuscript
The use of different therapies in the postremission treatment of AML is largely determined by prognostic risk stratification, which has classically been based on cytogenetic findings. The largest subset of patients with AML falls into the ‘intermediate-risk’ group, which includes those with normal-karyotype AML (NK-AML), as well as patients without either adverse or favourable cytogenetic abnormalities5,6. Considerable efforts have been made to refine risk stratification among this large and diverse subset of patients, with the emergence of multiple molecular abnormalities, including FLT3-ITD (FLT3 internal tandem duplication), and mutations in NPM1, KIT, and/or CEBPA, which have been shown to predict outcome and have been incorporated into modern prognostic and treatment guidelines7,8, although, in addition to cytogenetic and molecular findings, clinical factors can also predict outcomes9. Advances in next-generation sequencing (NGS) technology have led to the discovery of novel somatic mutations in patients with AML, providing greater insight into the mutational landscape of the disease. The majority of patients with AML (>97%) demonstrate at least one clonal somatic abnormality on mutational profiling10–12. Through genomic analysis of samples from 200 patients with de novo AML, The Cancer Genome Atlas (TCGA) investigators demonstrated that the distribution of genomic aberrations includes mutations in signalling-pathway genes in 59%, DNA-methylationrelated genes in 44%, chromatin-modifying genes in 30%, NPM1 in 27%, myeloidtranscription-factor genes in 22%, transcription-factor-gene fusions in 18%, tumoursuppressor genes in 16%, spliceosome-complex genes in 14%, and cohesin-complex genes in 13% of patients12 (TABLE 1), with findings from several other studies corroborating a similar distribution of mutations13–15. The use of mutation profiling in the clinic continues to evolve, and a substantial degree of variance remains among oncologists on how to apply genomic findings to clinical practice16. Consequently, evidence-based approaches are urgently required for the application of genetic data in molecular medicine for patients with AML.
Author Manuscript
In this Review, we propose that the lack of progress in improving the outcomes of patients with AML over the past four decades calls for consideration of a major paradigm shift regarding the present clinical treatment algorithms; for example, consideration of the use of upfront targeted therapy in elderly or unfit patients who are not candidates for standard intensive induction regimens, and addition of targeted agents to induction chemotherapy for younger patients, all in the setting of clinical trials (FIGS 1,2). We hypothesize that the integration of mutational profiling into the care of patients with AML will improve the outcomes associated with this characteristically devastating disorder. To accommodate the integration of mutational profiling into daily practice, more-high-throughput and morecomprehensive sequencing assays need to be used, in order to inform not only the approach to therapy for relapsed or refractory disease, but also decisions on upfront treatments.
Genetic profiling and induction therapy Karyotype and molecular alterations are powerful prognostic markers in AML; however, at present, these data are often unavailable at the initiation of induction therapy, particularly
Nat Rev Clin Oncol. Author manuscript; available in PMC 2017 July 25.
Coombs et al.
Page 3
Author Manuscript
outside of a clinical trial. As such, patients with AML generally receive induction therapy independent of their subsequent risk stratification; the choice of induction regimen is based on the patient’s age and comorbidities, with ‘fit’ younger patients typically receiving standard induction therapy with cytarabine and an anthracycline7. Daunorubicin and idarubicin are the anthracyclines used most commonly in induction regimens, and neither agent is clearly superior to the other17,18. The findings of studies performed in the past decade, which are outlined in the following sections, indicate that molecular subtypes of AML correlate with improved responses to induction therapy in various subsets of patients, stressing the importance of integrating upfront comprehensive mutational profiling into initial treatment decisions. Candidates for intensive induction therapy
Author Manuscript Author Manuscript
In the large, randomized, phase III Eastern Cooperative Oncology Group (ECOG) E1900 trial in which patients
