PML–RARα kinetics and impact of FLT3–ITD mutations in newly diagnosed acute promyelocytic leukaemia treated with ATRA and ATO or ATRA and chemotherapy

Abstract

The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) are not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediaterisk acute promyelocytic leukaemia (APL). We analysed the kinetics of promyelocytic leukaemia-retinoic acid receptor-α (PML-RARα) transcripts by real-time quantitative PCR (RQ-PCR) in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT as compared with those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation, a greater log reduction of PML-RARα transcripts was detected in the ATRA-ATO as compared with the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse in patients receiving ATRA-ATO, whereas a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior antileukaemic efficacy compared with ATRA-CHT in low-intermediaterisk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.

Clinical impact of BAALC expression in high-risk acute promyelocytic leukemia

“…These results suggested that ATRA-ATO treatment abrogates the negative prognostic impact of fms-related tyrosine kinase 3-internal tandem duplication mutations. 33 In agreement, Powell et al showed that the addition of ATO on consolidation therapy significantly improved the prognosis (event-free, DFS. and OS) of adults with newly diagnosed APL and negated all previously identified prognostic factors, including initial leukocyte count.…”

Akute Promyelozytenleukämie (APL). Niedrig-/Intermediärrisiko-Erkrankung heilbar ohne Chemotherapie

“…Mit ATO wird PML-RARα-Transkript freiheit erreicht Molekulare Untersuchungen des Knochenmarks von 184 Patienten der APL0406-Studie zeigten im Therapieverlauf bei Therapie mit ATRA-ATO eine im Vergleich zur Chemotherapie langsamere Abnahme der Promyelozytenleukä-mie-Retinsäure-α-Transkripte (PML-RARα) [4]. Nach Konsolidierung fand sich aber mit dem ATO-ATRA-Regime kein Transkript-Nachweis mehr, im Chemotherapie-Arm noch bei 2% der Patienten.…”

Clinical implications of molecular markers in acute myeloid leukemia

“…To date, data on the impact of additional chromosomal or genetic aberrations including FLT3 mutations on outcome in APL patients are still conflicting. [43][44][45][46][47][48][49][50][51][52] In addition, there seems to be an association of higher WBC at diagnosis and FLT3-ITD mutations in patients with APL as compared to FLT3 wild-type patients, 48…”