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Optimal dose and schedule of consolidation in AML: Is there a standard?

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Approximately 35%–40% of younger adults with acute myeloid leukemia (AML) can be cured using higher doses of cytosine arabinoside (ara-C) as post remission consolidation. Earlier studies focused on higher doses of 3 gms/m2, but since then numerous studies evaluating differences in dose, schedule, number of courses, and the addition of other agents, suggest that an intermediate-dose of ara-C may offer the greatest benefit to most patients with less toxicity than with higher dose regimens. In retrospect, this was predictable by the cellular pharmacology of ara-C. Perhaps most importantly, the overall outcome has not changed in the past 2-3 decades, indicating that the limits of available chemotherapy have been defined for AML. This review examines studies that have established the various dosing options and considers whether there is a true standard for post remission therapy for patients with AML.

Introduction

Cytosine arabinoside (1β-arabinofuranosylcytosine), or ara-C, represents the backbone of induction and consolidation therapy for acute myeloid leukemia (AML). It was initially approved by the U.S. Food and Drug Administration in 1969. It is a prodrug that has to overcome a number of metabolic hurdles in order to exert its cytotoxic effect. It must first escape neutralization by plasma cytidine deaminases followed by active transport across cell membranes. Ara-C must then be triphosphorylated, competing with a number of normal cellular substrates, before eventual incorporation into DNA during cell division [1]. The cell in which ara-C has been incorporated is unable to process this “false” nucleotide and ultimately dies.

Based on sometimes compelling in vitro experiments, a number of attempts have been made to manipulate these metabolic pathways to enhance the activity of ara-C, including, but not limited to, pretreatment with or co-administration of thymidine, granulocyte colony stimulating factor (G-CSF), l-asparaginase [2], and purine nucleotides such as fludarabine [3]. Unfortunately, except for the dose intensification of ara-C described below, there is no clear evidence from clinical trials that these maneuvers were successful.

Section snippets

High-dose ara-C

In an attempt to overcome these multiple mechanisms of resistance, clinical trials using much higher doses of ara-C were done, initially in patients in relapse. A variety of doses and schedules were explored and remissions were seen in patient refractory to conventional dose ara-C, albeit with higher rates of mucositis and a unique syndrome of neurotoxicity frequently characterized by cerebellar dysfunction, which was usually but not always, reversible. A randomized trial conducted by The

Improving on high-dose ara-C

Numerous study groups have added other drug combinations to a high-dose ara-C backbone including:

  • CALGB protocol 9222 added non-cross-resistant drugs, with a course of high-dose ara-C, a second course with cyclophosphamide and etoposide, and a third course with diaziquone and mitoxantrone [12]. The addition of the new drugs did not improve outcomes vs high-dose cytarabine alone, and toxicity was increased with the multiagent therapy.

  • The German AML96 study compared cytarabine total doses of 36 g/m

“Olderly” patients with AML

Older individuals (historically and arbitrarily defined as >60 years of age), or sometimes pejoratively termed “elderly,” comprise the large majority of AML patients. This is a very heterogeneous group, however, and using contemporary supportive care, induction mortality is <10% in patients >60 years of age entered on clinical trials [20]. Hence, I propose the term “olderly” to encompass the spectrum of disease biology, performance status, and presence of co-morbidities found in this patient

Autologous transplantation as consolidation

Multiple randomized trials have failed to show an overall advantage from autologous transplantation for patients with AML in first remission compared to consolidation chemotherapy. However, we can assume that many, if not most, patients mobilized in morphologic remission in these older trials actually had minimal residual disease (MRD) that could have been detected by flow or molecular studies if collected now. This suggests that these patients had more resistant disease, as well as the

Conclusion

Although anthracyclines and ara-C have been administered in multiple doses and schedules to patients with AML, the overall outcome is consistently disappointing in olderly patients and stagnant in younger adults. Most correlative studies have focused on cellular mechanisms of drug resistance with the goal of bypassing these pharmacologically. Despite many efforts to address the mult-drug resistance phenotype and the clinical experiments to enhance ara-C incorporation into DNA described above,

Conflict of interest

None.

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