An editorial commentary based on a review of relevant medical literature and published in Leukemia examined the influence of cumulative dose, dose rate, and dosing schedule on the efficacy of cytarabine in acute myeloid leukemia (AML).
Cytarabine is a deoxycytidine nucleoside analog used both in the induction and consolidation settings in AML. Before it can be incorporated into growing chains of DNA and RNA, cytarabine requires enzymatic conversion to its active tri-phosphorylated form (ara-CTP).
Although cytarabine has often been administered as a continuous infusion over a period of days (standard doses, 100-200 mg/m2), strategies to boost its efficacy have included bolus administration of high doses of cytarabine (HiDAC; >2000 mg/m2). Nevertheless, there is uncertainty regarding the relative effectiveness of the 2 approaches, and bolus HiDAC has been associated with increased toxicity.
When highlighting this lack of clinical clarity, the authors posed the following questions: “might dose rate matter, ie, can 2 g/m2 over [4 hours] as bolus or over [24 hours] as [continuous infusion] be regarded as equivalent? In addition, is cumulative cytarabine dose as important as individual doses, dose rates, or addition of other drugs?”
Following a review of the medical literature regarding use of cytarabine in the consolidation setting, the authors concluded that “recent data increase our confidence that there is no reason to use cumulative doses [greater than] 20g/m2 or individual doses [greater than] 2g/m2 in post-remission therapy.”
With respect to cytarabine administration scheduling in the consolidation setting, Walter et al concluded, “while not derived from prospective, randomized trials—and acknowledging it is unknown whether these results apply to lower cytarabine doses—we believe HiDAC-123 [ie, 3 g/m2 twice daily on days 1, 2, and 3] should be the preferred means to administer post-remission, higher-dose cytarabine after standard induction therapy.”
Although cytarabine in the induction setting is traditionally given as part of a 7 + 3 regimen where standard-dose cytarabine (ie, 100 mg/m2 daily for 7 days via continuous infusion) is coadministered with another agent such as daunorubicin, idarubicin, or mitoxantrone, the authors remarked that “while HiDAC appears to have a role as consolidation after standard induction, whether HiDAC should be used as induction, or as consolidation in those who are induced using HiDAC [remain] open questions.”
In their concluding remarks, the authors of this article stated that “many unsettled questions and confounding issues remain surrounding cytarabine.”
Walter RB, Appelbaum FR, Estey EH. Optimal dosing of cytarabine in induction and post-remission therapy of acute myeloid leukemia. Leukemia Published online December 16, 2020. doi:10.1038/s41375-020-01110-3