Adjunction of a fish oil emulsion to cytarabine and daunorubicin induction chemotherapy in high-risk AML

Emmanuel Gyan, Arnaud Pigneux, Mathilde Hunault, Pierre Peterlin, Martin Carré, Jacques-Olivier Bay, Caroline Bonmati, Maria-Pilar Gallego-Hernanz, Bruno Lioure, Philippe Bertrand, Nicolas Vallet, David Ternant, François Darrouzain, Frédéric Picou, Marie-Christine Béné, Christian Récher, Olivier Hérault, Emmanuel Gyan, Arnaud Pigneux, Mathilde Hunault, Pierre Peterlin, Martin Carré, Jacques-Olivier Bay, Caroline Bonmati, Maria-Pilar Gallego-Hernanz, Bruno Lioure, Philippe Bertrand, Nicolas Vallet, David Ternant, François Darrouzain, Frédéric Picou, Marie-Christine Béné, Christian Récher, Olivier Hérault

Abstract

The treatment of acute myeloid leukemia (AML) with unfavorable cytogenetics treatment remains a 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. The FILO group launched a pilot clinical study to evaluate the feasibility, safety, and efficacy of the adjunction of a commercial FO emulsion to 3 + 7 in untreated AML with unfavorable cytogenetics. The primary objective was complete response (CR). Thirty patients were included. FO administration raised the plasma levels of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids (p < 0.001). The pharmacokinetics of cytarabine and daunorubicin were unaffected. A historical comparison to the LAM2001 trial (Lioure et al. Blood 2012) found a higher frequency of grade 3 serious adverse events, with no drug-related unexpected toxicity. The CR rate was 77%, and the partial response (PR) 10%, not significantly superior to that of the previous study (CR 72%, PR 1%). RT-qPCR analysis of Nrf2 target genes and antioxidant enzymes did not show a significant in vivo response. Overall, FO emulsion adjunction to 3 + 7 is feasible. An improvement in CR was not shown in this cohort of high-risk patients. The present data does not support the use of FO in adjunction with 3 + 7 in high-risk AML patients.ClinicalTrials.gov identifier: NCT01999413.

Conflict of interest statement

EG received honoraria from Fresenius Kabi. All other authors declare no competing interests relevant for this publication.

© 2022. The Author(s).

Figures

Figure 1
Figure 1
FAMYLY study design. Patients eligible for the study were treated with fish oil emulsion, daunorubicin and cytarabine at the indicated doses. If the baseline white blood count (WBC) was below 30 G/L, patients received 48 of fish oil before the start of chemotherapy. If the WBC was above or equal to 30 G/L, all treatments were started on the same day. An evaluation bone marrow (BM) evaluation was performed on D15. If the BM blasts were higher than 5%, a second induction was provided at the indicated doses.
Figure 2
Figure 2
PUFA plasma pharmacokinetics. Plasma samples were drawn at baseline (H0), 24 and 48 h after the start of FO infusion, after the end of infusion (D10), and at disease evaluation (D28–D35). The PUFA composition of plasma was evaluated by gas chromatography. The sum of docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) acid concentration is indicated for each individual patient (colored lines and dots). Means are indicated by a dash for each timepoint.
Figure 3
Figure 3
Historical comparison of survival data from the FAMYLY and LAM2001 trials. Overall survival (OS) was plotted from the inclusion date to the date of death or last follow up. The vertical marks indicate censored observations.

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