Novel therapeutic options in Acute Myeloid Leukemia

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Abstract

Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease, and its incidence is increasing as the population ages. Cytogenetic anomalies and mutation testing remain important prognostic tools for tailoring treatment after induction therapy. Despite major advances in understanding the genetic landscape of AML and its impact on the pathophysiology and biology of the disease, as well as the rapid development of new drugs, standard treatment options have not experienced major changes during the past three decades. Especially for patients with intermediate or high-risk AML, which often show relapse. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the best chance for cure. Here we review the state of the art therapy of AML, with special focus on new developments in immunotherapies and cellular therapies including HSCT and particularly discuss the impact of new conditioning and haplo-identical donor regimens for HSCT, post-transplant strategies for preventing and treating relapse, and emerging novel therapeutic options.

Highlights

•

Acute myeloid leukemia (AML) is a biologically complex and molecularly and clinically heterogeneous disease.
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The therapy intensity depends on AML risk group and the fitness of the patient.
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Allogeneic hematopoietic stem cell transplantation (HSCT) remains the best chance for cure.
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Novel therapeutic options include “targeted therapies” and immunotherapy.

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Most cited references 68

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The blockade of immune checkpoints in cancer immunotherapy.

Drew M Pardoll (2012)

Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.

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Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

Pierre Fenaux, Ghulam J Mufti, Eva Hellstrom-Lindberg … (2009)

Drug treatments for patients with high-risk myelodysplastic syndromes provide no survival advantage. In this trial, we aimed to assess the effect of azacitidine on overall survival compared with the three commonest conventional care regimens. In a phase III, international, multicentre, controlled, parallel-group, open-label trial, patients with higher-risk myelodysplastic syndromes were randomly assigned one-to-one to receive azacitidine (75 mg/m(2) per day for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomisation). Patients were stratified by French-American-British and international prognostic scoring system classifications; randomisation was done with a block size of four. The primary endpoint was overall survival. Efficacy analyses were by intention to treat for all patients assigned to receive treatment. This study is registered with ClinicalTrials.gov, number NCT00071799. Between Feb 13, 2004, and Aug 7, 2006, 358 patients were randomly assigned to receive azacitidine (n=179) or conventional care regimens (n=179). Four patients in the azacitidine and 14 in the conventional care groups received no study drugs but were included in the intention-to-treat efficacy analysis. After a median follow-up of 21.1 months (IQR 15.1-26.9), median overall survival was 24.5 months (9.9-not reached) for the azacitidine group versus 15.0 months (5.6-24.1) for the conventional care group (hazard ratio 0.58; 95% CI 0.43-0.77; stratified log-rank p=0.0001). At last follow-up, 82 patients in the azacitidine group had died compared with 113 in the conventional care group. At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI 42.1-58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7-34.3) in the conventional care group (p<0.0001). Peripheral cytopenias were the most common grade 3-4 adverse events for all treatments. Treatment with azacitidine increases overall survival in patients with higher-risk myelodysplastic syndromes relative to conventional care.

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Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

Jay Patel, Mithat Gonen, María Figueroa … (2012)

Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).

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Author and article information

Contributors

Michael Medinger

Journal

Journal ID (nlm-ta): Leuk Res Rep

Journal ID (iso-abbrev): Leuk Res Rep

Title: Leukemia Research Reports

Publisher: Elsevier

ISSN (Electronic): 2213-0489

Publication date PMC-release: 01 October 2016

Publication date Collection: 2016

Publication date (Electronic): 01 October 2016

Volume: 6

Pages: 39-49

Affiliations

[a ]Divisions of Hematology, Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland

[b ]Divisions of Internal Medicine, Department of Medicine, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland

Author notes

[* ]Correspondence to: Divisions of Hematology and Internal Medicine, Department of Medicine University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland. medingerm@ 123456uhbs.ch

Article

Publisher ID: S2213-0489(16)30023-1

DOI: 10.1016/j.lrr.2016.09.001

PMC ID: 5061308

PubMed ID: 27752467

SO-VID: a4592779-9e85-4c8f-ac7d-bfab6314305f

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 20 July 2016

Date accepted : 30 September 2016

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Novel therapeutic options in Acute Myeloid Leukemia

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Cancer Immunotherapy

Most cited references 68

The blockade of immune checkpoints in cancer immunotherapy.

Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study.

Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

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Cited by 14

Most referenced authors 2,530