Does All-Transretinoic Acid (ATRA) Have a Role in Non-APL Acute Myeloid Leukaemia?: Results from 1666 Patients in Three MRC Trials.

ATRA has a key role in the treatment of APL where the presence of the PML-RARα protein is predictive of response. Pre-clinical data and some non-randomised clinical studies suggested that ATRA may enhance the effect of chemotherapy particularly based on its potential to reduce the Bcl2 expression which may thereby improve apoptotic responses to chemotherapy. We have evaluated this possibility in 3 randomised trials in remission induction in patients under 60 years (AML12) n=1097; in relapse (AML-HR) n=362; and as a non-intensive approach in older patients (AML14-non-intensive) n=207. In AML12 patients were randomised to receive standard induction chemotherapy options (ADE vs DAT or MAE vs DAT with Ara-C at either Ara-C 200mg/m²/day or 400mgs/m²/day). There was no significant difference in CR rate (83% vs 85%) or survival at 5 years (40% vs 36%) on ATRA or no ATRA overall or in any demographic, risk or treatment subgroup.

Patients with high risk disease (adverse cytogenetics or less than PR after course 1 of induction) or relapse were randomised to receive Fludarabine/Ara-C or ADE with or without G-CSF, with or without ATRA for 60 days. The addition of ATRA made no overall impact on remission rate (61% vs 61%) or survival at 3 years (23% vs 27%). There was no subgroup where an advantage was seen.

In AML14 patients not considered fit for intensive treatment were randomised to receive Hydroxyurea or Low Dose Ara-C with or without ATRA for 90 days. There was no evidence that patients who received ATRA derived any benefit either overall or within the treatment arms.

In this extensive assessment, no advantage of adding ATRA to chemotherapy - as a continuous daily dose during induction - could be detected in any trial or in any subgroup within each trial.