A Phase II Study of Elacytarabine/Idarubicin As Second Course Remission-Induction in Patients with Acute Myeloid Leukemia Who Failed Cytarabine/Anthracycline
Authors: Rizzieri David A. , Vey Norbert , Thomas Xavier , Huguet Françoise , Schlenk Richard F , Krauter Jürgen , Kindler Thomas , Gjertsen Bjorn , Blau Igor W. , Johansen Malin , Bergeland Trygve , Gianella-Borradori Athos , Jacobsen Tove Flem , Rao Jianyu , Krug Utz 
Published: October 2019

Abstract
Abstract 46

Background
Elacytarabine, a fatty acid derivative (elaidic acid ester) of cytarabine, has pharmacokinetic and pharmacodynamic properties that may lead to improved clinical outcomes (Adema et al., 2011) compared to cytarabine. A phase I study had established 1000 mg/m2/d continuous infusion on d 1 – 5 as a safe and effective dose of elacytarabine given in combination with idarubicin at 12 mg/m2/d IV d 1 – 3 (Giles et al., 2012).

Mechanism of Action
The mechanism of action is similar to cytarabine, but unlike cytarabine, plasma elimination half-life is long, intracellular distribution is prolonged and activity is independent of membrane nucleoside transporters. Resistance to cytarabine has been associated with decreased expression of the human equilibrative nucleoside transporter 1 (hENT1) (Hubeek et al., 2005).

Aims
The aim of the study is to determine the efficacy and safety of elacytarabine given in combination with idarubicin; to explore the relationship between the hENT1 status in AML cells and response to cytarabine and to elacytarabine; to evaluate the safety and toxicity of the combination therapy.

Methods
Adult patients with AML who have not attained blast clearance after the first induction course with a standard dose cytarabine based regimen, assessed from day 12 on, were enrolled in the study. Patients received a combination of elacytarabine and idarubicin scheduled as described above, as second induction course. Patients treated with further courses received either the combination therapy or elacytarabine monotherapy at 2000 mg/m2/d on d 1 – 5, at the investigator‘s discretion.
hENT1 expression level was analysed retrospectively by immunocytochemistry at time of initial AML diagnosis (pre-therapeutic) and/or before elacytarabine/idarubicin treatment (baseline).

Results
In the on-going study which will recruit up to 50 evaluable patients, 47 patients [27 male, 20 female, median age 60 years (range 18–78), ECOG 0–2] have currently been treated. 40 patients have been evaluated for response, of whom 35% suffered from secondary leukemia. Median time from start of first induction course to start of elacytarabine treatment was 36 days (range 13 – 189).
After treatment with elacytarabine and idarubicin, 18/40 evaluable patients attained a CR/CRi. Median time to remission was 36 days (range 25 – 60).
Incidence of low hENT1 expression was approximately 50%. Preliminary data shows a higher response rate of elacytarabine compared to cytarabine in this low hENT1 population (47% versus 37%).
The most frequently reported non haematological adverse events grades 3 and 4 were fatigue, infections/sepsis, hypoalbuminaemia, hypokalaemia and hypoxia.
Three deaths occurred within 30 days after start of treatment, all due to sepsis. Additional two patients died from progressive AML within 60 days after start of treatment. All these five patients suffered from secondary leukaemia.

Summary/Conclusion
At the time of this abstract (August 2012) elacytarabine in combination with idarubicin shows a promising clinical activity with a CR/CRi rate of approximately 45% in patients failing a first induction course. Low expression of the hENT1 transporter is associated with a lower probability of achieving remissions following cytarabine treatment. Preliminary data indicates that assessment of hENT1 expression in blast cells could be used to identify patients less likely to benefit from cytarabine and for whom elacytarabine could be an effective therapy. The emerging safety profile is as expected for these groups of cytotoxic therapies. Results of the completed study will be presented at the meeting.

Disclosures:
Kindler: Novartis: Honoraria. Johansen:Clavis Pharma: Employment. Bergeland:Clavis Pharma: Employment. Gianella-Borradori:Clavis Pharma: Employment. Flem Jacobsen:Clavis Pharma: Employment. Rao:Clavis Pharma: Honoraria.