In vivo biological effects of ATRA in the treatment of AML

All-trans retinoic acid (ATRA) is mandatory in the treatment of acute promyelocytic leukaemia (APL). Experimental studies suggest that ATRA can induce differentiation and apoptosis in leukaemia cells also for other acute myelogenous leukaemia (AML) subtypes, but the clinical observations are conflicting.

Twenty-two AML patients with non-APL disease received oral ATRA alone (22.5 mg/m2 twice daily) for two days, the patients thereafter continued ATRA together with valproic acid and theophylline. We investigated the biological effects of the initial 2 days treatment with ATRA alone. Serum/plasma samples were collected before and after 2 days of ATRA, peripheral blood AML cells were collected from all 12 patients with circulating leukaemia cells (ClinicalTrials.gov NCT00175812; EudraCT no. 2004-001663-22).

AML cells collected during therapy had altered flow cytometric forward and right angle light scatters but no morphological signs of differentiation. ATRA increased the percentage of circulating AML cells in G0/G1 phase for 9 out of 12 patients (p = 0.043). Circulating leukaemia cells derived during therapy had increased intracellular levels of P21 (mean increase in mean fluorescence intensity (MFI) being 18.2%, p = 0.017), and decreased levels of Gata-2 (mean decrease in MFI 19%, p = 0.026), NF-kappaB p65 (mean decrease in MFI 15.4%, p = 0.033) and Bcl-2 (mean decrease in MFI 7.2%, p = 0.005). In addition, increased systemic levels of the endothelial marker endocan (plasma) and the angioregulatory mediator angiopoietin-2 (serum) were observed.

In vivo ATRA treatment in AML affects leukaemic cell morphology, regulation of cell cycle progression and apoptosis, and possibly also microvascular endothelial cell functions.