Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1

Abstract

Introduction: EVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment.

Methods: In this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1.

Results: Seven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool.

Conclusion: These primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.

Keywords: Acute myeloid leukemia; All-trans-retinoic acid; EVI1; Leukemia stem cells; MECOM.

Fig. 1

Evolution on ATRA therapy in patients who did not achieve CR (a) and in patients who achieved CR (b). 6MP 6-mercaptopurine, AE adverse event, AraC low-dose cytarabine, ATRA all-trans-retinoic acid, Aza azacitidine, BM bone marrow, chemo chemotherapy, Chim chimerism, CR morphological complete remission, flow flow cytometry, GO gemtuzumab ozogamicin, GvH graft-versus-host reaction, MRD minimal residual disease, MTX methotrexate, neg negative, PegIFN peginterferon, PB peripheral blood, PD patient decision, Pt patient

Fig. 2

Strategy used for gating the blast cell population and CD34⁺CD38 cell subpopulations [red: immature CD45^low/SSC blast cells; blue: CD34⁺ cells, green: lymphocytes, blue cyan: monocytes, violet: granulocytes, black: CD45⁺ cells (erythroblasts)]; CD34⁺ cells were then separated into different stem cell fractions based on their CD38 antigen expression: a first cell population expressing a large amount of the CD34 antigen and lack of CD38 (CD34⁺CD38⁻) (yellow), a second cell population characterized by a large amount of CD34 antigen and by a low density of CD38 antigen (CD34⁺CD38^low) (green), and a third cell population characterized by a high density of CD38 antigen and of CD34 antigen (CD34⁺CD38⁺) (blue). Blast cell morphology and immunostaining in patient #7 before ATRA introduction (55% of bone marrow blasts) (a), and after 2 months of ATRA therapy (< 5% blasts on bone marrow smears and MRD at 6% detected by flow cytometry) (b)