Azacitidine in adult patients with acute myeloid leukemia
Introduction
Acute myeloid leukemia (AML) is an aggressive malignancy of hematopoietic progenitor cells that carries a poor prognosis (Klepin, 2015). Primarily a disease of older patients, the majority of patients with AML are aged ≥65 years, with the estimated overall median age being about 70 years (Juliusson et al., 2009, Klepin, 2015, National Cancer Institute, 2016, Ossenkoppele and Lowenberg, 2015). There is currently no standard approach to AML treatment in older patients due to a variety of factors, including heterogeneity of disease biology, age-related comorbidities and potential toxicities, patient choice, and physician preference (Juliusson et al., 2009, Klepin, 2015, Ossenkoppele and Lowenberg, 2015). In clinical practice, treatment decisions are based on careful consideration of disease- and patient-related factors. For example, while an elderly patient may be deemed fit to tolerate intensive treatment by the treating physician, disease features may render the likelihood of durable benefit so low, that a non-intensive alternative therapy might be the preferred option (Erba, 2015, Kantarjian et al., 2010, Michaelis and Erba, 2015, Ossenkoppele and Lowenberg, 2015, Thepot et al., 2014).
Age-related differences in tumor biology and a diminished ability to tolerate intensive therapy influence survival outcomes for older patients. While the overall 5-year survival rates for AML have improved over the past four decades, they remain unsatisfactory, declining from 39% for those younger than age 65 years, to 8.5% for patients aged 65–74 years, and less than 2% for patients age 75 or older (Klepin, 2015). In the United States (US), less than 50% of aged ≥65 years with newly-diagnosed patients AML currently receive active anti-leukemic treatment (Walter and Estey, 2015), and the frequently chosen best supportive care (BSC) option is associated with a median survival of only about 2–3 months (Oran and Weisdorf, 2012, Wang et al., 2014). Accumulating evidence suggests, however, that older patients precluded from intensive chemotherapy (IC) should be offered alternative treatment strategies that can prolong OS without undue toxicity (Michaelis and Erba, 2015, Oran and Weisdorf, 2012, Shah et al., 2013, Thein et al., 2013, Walter and Estey, 2015). Hence, there is a continuing need for low-intensity AML treatments for patients who are not candidates for IC or allogeneic hematopoietic stem cell transplant (alloHSCT).
By virtue of lying on a biological continuum (Deschler et al., 2006), advances in treatment of myelodysplastic syndromes (MDS) have led to advances in treatment of AML (Estey, 2013b, Walter, 2015, Wong and Juneja, 2015). Until 2004, BSC with transfusions and symptomatic treatment were the mainstay of MDS therapy. In that year, azacitidine (Vidaza®; Celgene Corporation, Summit, NJ) became the first drug approved by the US Food and Drug Administration (FDA) for the treatment of MDS (Kaminskas et al., 2005b). Azacitidine studies in MDS used the French-American-British (FAB) classification scheme and included patients with 20–30% bone marrow (BM) blasts who are now classified by the World Health Organization (WHO) as having AML (see Section 3a). Thus, the azacitidine phase 3 MDS study results included a subset of patients with WHO-defined AML (Fenaux et al., 2010c). Currently, azacitidine has regulatory approval for the treatment of MDS and AML with 20–30% BM blasts in the US, Canada, and the European Union (EU). Azacitidine is also approved in the EU, and in several other countries, for the treatment of patients with AML with >30% BM blasts. As described here, encouraging data from clinical trials, azacitidine treatment registries, and retrospective analyses, suggest that azacitidine has wide therapeutic application in AML.
Section snippets
Early use of azacitidine
Azacitidine is a cytidine analog DNA methyltransferase inhibitor and hypomethylating agent (HMA) (Jones, 1985a, Jones, 1985b, Jones et al., 1983). Azacitidine is phosphorylated by uridine-cytidine kinase to a monophosphate derivative and then further to diphosphate and triphosphate forms. The triphosphate form is incorporated predominantly into RNA (∼80–90%), but also some into DNA (10–20%) (Li et al., 1970). Originally, it was thought that the primary antineoplastic activity of azacitidine was
AZA-MDS-001: azacitidine in low-blast-count AML (20–30% BM blasts)
Early clinical trial experience with azacitidine in WHO-defined AML emerged from the large international, randomized, phase 3 AZA-MDS-001 study which inlcuded patients with higher-risk MDS (HR-MDS) defined according to the FAB MDS classification system with up to 30% BM blasts, and with an International Prognostic Scoring System (IPSS) (Greenberg et al., 1997)] Intermediate-2 or High risk MDS risk score (Fenaux et al., 2009). As there was no standard treatment for patients with HR-MDS at the
Experience with azacitidine in community practice
An inherent limitation of clinical trials is that patients are often excluded from study entry due to comorbidities, poor performance status, prior treatment, and other disease-related factors, with the result that study populations may not reflect typical patients seen in clinical practice. It is thus essential to determine outcomes in unselected patients treated in routine clinical practice. Accordingly, a number of large community-based registry studies (Itzykson et al., 2015, Maurillo et
Azacitidine vs. standard induction chemotherapy
Although there is a trend toward considering “physiological age” over chronological age when making AML treatment decisions, clinicians typically exercise greater caution when recommending IC to patients aged ≥75 years (Kantarjian et al., 2010, Klepin, 2015, Oran and Weisdorf, 2012, Ossenkoppele and Lowenberg, 2015). While age per se is not a contraindication to intensive AML treatment, (Juliusson et al., 2009, Oran and Weisdorf, 2012), elderly patients considered unfit for IC are at high risk
Oral azacitidine (CC-486)
An oral formulation of azacitidine, CC-486, is in clinical development and preliminary outcomes for AML patients in a phase 1/2 trial have been reported (Garcia-Manero et al., 2016b, Garcia-Manero et al., 2011). Methylation reduction with HMAs is transient. Extending azacitidine dosing over more of the treatment cycle – which is more practical with an oral formulation – may increase azacitidine exposure to cycling malignant cells. When CC-486 is administered in extended dosing schedules (ie,
Summary/Discussion
The prevalence of AML is projected to continue to increase for the foreseeable future due to population aging and the increasing availability of better treatments for MDS and myeloproliferative neoplasms (MPNs), which prolong patient survival but unfortunately do not always prevent transformation to AML (Fenaux et al., 2009). Ongoing changes in clinical practice have resulted in treatment of more, and of older, patients. However, improvements in AML outcomes over recent decades have not been
Conflict of interests
Dr. Schuh: nothing to disclose
Dr. Döhner: Consultation with honoraria: Agios, Amgen, Astex Pharmaceuticals, Celator, Celgene, Novartis, Roche, Seattle Genetics, Sunesis, Tolero
Dr. Pleyer: has been a consultant for Agios, Celgene, Janssen-Cilag, Bristol-Myers Squibb, and Novartis, and reports receiving honoraria and travel support from Agios, Celgene, Bristol-Myers Squibb, Novartis, and AOP Orphan Pharmaceuticals
Dr. Seymour: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of
Acknowledgments
All authors equally contributed to, revised, and approved manuscript content, and approved submission to the journal. The authors received editorial support during manuscript development from Sheila Truten and Kelly Dittmore of MC2 Inc., Wynnewood, PA, who were funded by Celgene Corporation. Celgene did not contribute to content or participate in the development of this paper. The authors are fully responsible for all content and editorial decisions.
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