Acute promyelocytic leukemia (APML) is a biologically and clinically distinct variant of acute myeloid leukaemia characterised by t(15;17) translocation resulting in a PML-RAR fusion protein. The impaired myeloid differentiation resulting from the translocation may be restored by pharmacologic doses of all-trans-retinoic acid (ATRA).
Arsenic trioxide (ATO) acts synergistically with ATRA to degrade PML-RARA. APML4 was a phase 2 study which aimed to exploit ATO/ATRA synergy in order to minimize exposure to anthracycline (idarubicin) which is only given on days 2,4,6 and 8 of induction along with ATO/ATRA. Two “chemotherapy free” ATO/ATRA-only consolidation cycles were followed by 2 years of oral maintenance (ATRA, weekly methotrexate and 6-mercaptopurine).
Notable inclusion criteria included age >1 year (but no upper limit; age range was 19-73), ECOG performance status 0-3, normal left ventricular ejection fraction and Q-Tc interval <500 milliseconds. Idarubicin dosing was age adjusted. Molecular monitoring of bone marrow was mandated for assessment of treatment efficacy.r
There were 124 evaluable patients with 4 deaths during induction (1 myocardial ischaemia, 2 intracerebral haemorrhage, 1 cerebral oedema), while 2 withdrew from study during induction. The remaining 118/124 (95%) entered haematological complete remission (hCR). 112/118 hCR patients proceeded to consolidation, each of whom attained molecular remission. 2/112 patients relapsed after completion of consolidation, one with initial molecular relapse after 166 days (followed by CNS relapse and death) and one with molecular relapse after 189 (dying from sepsis during salvage therapy).
This equates to a freedom from relapse (FFR) of 97.5% and overall survival (OS) of 93.2%. Age did not correlate with FFR or OS. The failure free survival (FFS) of 88.1% was a composite measure of time from commencement of ATRA therapy to the earliest of treatment failure (failure to achieve molecular CR or withdrawal of protocol therapy for any reason), relapse, or death. The results compared favorably with the group’s prior APML3 study which used ATRA and idarubicin (but no arsenic) in induction and consolidation.r
Comparison of APML4 with APML3 (historic control). (C) FFS.
© Blood 2012
Most patients received at least 80% of maximum specified dosing of idarubicin, ATRA and ATO. During either of the 2 cycles of consolidation there was no case of differentiation syndrome and there were no deaths. During induction 14% experienced Q-Tc prolongation greater than 500ms, 44% developed grade 3/4 hepatic changes and 76% developed grade 3/4 infections.r
Grade 3/4 differentiation syndrome developed in 14%, with no resulting deaths. During either of the 2 cycles of consolidation there was no case of differentiation syndrome and there were no deaths.
© Blood 2012