Daunorubicin and cytarabine for certain types of poor-prognosis acute myeloid leukemia: a systematic literature review

ABSTRACT

Introduction

Induction chemotherapy based on anthracyclines and cytarabine (Ara-C) combination remains the standard of care for acute myeloid leukemia (AML) patients who are considered candidate for intensive and curative approaches. However, the toxicity of this regimen is high, with disappointing clinical outcomes among the so-called poor-prognosis AML subsets, which generally refer to patients with adverse cytogenetic risk, secondary AML including therapy-related AML, poor-prognosis mutations, especially FLT3-ITD, and relapse/refractory AML.

Areas covered

To the best of our knowledge, the role and efficacy of 7 + 3 schedules containing daunorubicin (DNR) and Ara-C for certain types of poor-prognosis AML has not been systematically assessed. A critical approach to the role of DNR and Ara-C induction could be relevant to establish which patients should be enrolled in clinical trials using novel therapies.

Expert commentary

In this regard, a recent randomized clinical trial (RCT) showed improved results in older patients with sAML or high-risk cytogenetics who received CPX-351 compared with standard 7 + 3 combination. We perform a systematic literature review to analyze the clinical outcomes reported with DNR plus Ara-C regimens in adult patients with poor-prognosis AML, the use of liposomal formulations of DNR and Ara-C and the RCTs which compared standard 7 + 3 with the addition of a third drug.

KEYWORDS:

• Acute myeloid leukemia
• daunorubicin
• cytarabine
• adverse cytogenetics
• secondary AML
• therapy related AML
• FLT3 mutated
• poor-prognosis

Article highlights

• The standard AML induction schedule 7 + 3 of DNR + Ara-C achieved approximately a weighted mean CR of 62.1% in 79 studies including near to 20,000 AML untreated patients.

• The outcomes in poor-prognosis AML were worse and very heterogenous, obtaining a median CR rate of 44%. The poor-risk subgroups should be analyzed separately, because a great variability in wmCR was estimated: 38.5% in sAML after MDS, 47.1% in adverse cytogenetic risk, 51.2% in tAML, and 53.1% in FLT3 mutations.

• OS data were limited and did not show differences between subgroups, with the exception of higher survival rates in patients with positive FLT3 mutation and patients younger than 60 years old.

• The influence of high doses of DNR and/or Ara C in OS and CR has been established in overall population. However, in poor-prognosis subsets, only patients with adverse cytogenetics or FLT3 positive mutation showed an incremental benefit in wmCR with the increase of DNR or Ara-C dose.

• The impact of patient´s age in poor-prognosis subsets has not been studied. Our review suggested that patients with <60 years obtained higher wmCR rate than patients with ≥60 years old, especially in adverse AML and positive FLT3 mutation subsets.

• The addition of a third agent to ‘7 + 3’ only showed a significant improvement with GO or midostaurin, which demonstrated higher OS and CR in patients with positive FLT3 mutation.

• CPX-351 obtained an increase in OS in all the subsets of poor-risk AML, especially in sAML, in which recently obtained the FDA and EMA approval in elderly patients with tAML or AML-MRC. Besides, this liposomal formulation could be an alternative therapy in R/R AML, in which standard salvage chemotherapy is not defined.

Declaration of interest

P Montesinos conflict of interest: advisory board for Celgene, Jazz, Janssen, and Novartis; and research funding from Pfizer and Celgene. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was not funded.