Adjunction of a Fish Oil Emulsion to Cytarabine and Daunorubicin Induction Chemotherapy in High-Risk AML. the Famyly Pilot Study from the French Innovative Leukemia Organization (FILO)
Authors: Gyan Emmanuel , Pigneux Arnaud , Hunault-Berger Mathilde , Peterlin Pierre , Carre Martin , Bay Jacques-Olivier , Bonmati Caroline , Gallego Hernanz Maria Pilar , Lioure Bruno , Bertrand Philippe , Vallet Nicolas , Ternant David , Darrouzain François , Picou Frederic , Bene Marie C , Recher Christian , Herault Olivier 
Published: November 2020

Background. Acute myeloid leukemia (AML) with unfavorable cytogenetics remains a therapeutic challenge. We previously established that ex vivo exposure of AML blasts to eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or fish oil emulsion (FO) induces Nrf2 pathway activation, metabolic switch and cell death (Picou et al., Pharmacol Res 2018;136:45-55).
Objectives. The FILO group launched a pilot clinical study to evaluate the feasibility, safety and efficacy of the adjunction of a commercial FO emulsion (OMEGAVEN) to 3+7 in untreated AML with unfavorable cytogenetics.
Patients and methods. The FAMYLY trial was a multicenter single-arm phase II study. Eligible patients had a diagnosis of untreated AML with unfavorable cytogenetics, 18 years old or above. For patients with WBC &lt; 30 G/L, FO was administered at 2 mL/kg/d IV 2 days before 3+7 induction chemotherapy (daunorubicin 60 mg/m² days 1-3 and cytarabine 200 mg/m²/d as a continuous infusion days 1-7), until day 7 of induction. For patients with WBC &gt;= 30 G/L, FO and 3+7 were started concomitantly, and FO was administered until day 9. The primary objective was complete response (CR) on the BM aspirate at the end of induction. Data from 75 patients with adverse cytogenetics and treated with daunorubicin and cytarabine in LAM2001 study (Lioure et al., Blood 2012) was used as a historical control. Serial blood samples were collected before treatment, and on days 1 and 3 after start of treatment, to evaluate the expression of NRF-2 target genes and antioxidant enzymes by RT-qPCR.
Results. Thirty patients were included. The median age was 54 years (range: 30-64 years), and only 3 patients were hyperleukocytic. FO administration raised the plasma levels of EPA and DHA (p&lt;0.05). The Cmax of daunorubicin was 92.2 µg/L (Q1; Q3: 44.8; 105.1), and the AUCꚙ 414.9 ng.h, representing a mean clearance Cl=358.5 mL/h and a half-life T1/2=3.5h. The cytarabine clearance was highly variable with a mean of 1.628 L/h. A historical comparison to the LAM2001 trial found no unexpected toxicity. The CR rate was 76%, similar to the daunorubicin arm of the previous study in patients with unfavorable cytogenetics (72%). No survival improvement was observed in a historical comparison. RT-qPCR analysis of NRF-2 target genes and antioxidant enzymes (particularly HMOX1 and NQO1) in sequential blood samples did not show a significant in vivo response.
Conclusions. Altogether, FO emulsion adjunction to 3+7 is feasible and safe. Although CR rate improvement was not shown in this cohort of high-risk patients, further research aiming at finding the sufficient dose to trigger an NRF-2 response in vivo should be considered.
ClinicalTrials.gov identifier: NCT01999413.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
OMEGAVEN (fish oil emulsion) in Acute Myeloid Leukemia