Acute promyelocytic leukaemia (APML) is a biologically and clinically distinct variant of acute myeloid leukaemia characterised by t(15;17) translocation resulting in a PML-RARA 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 that aimed to exploit ATO/ATRA synergy in order to minimise exposure to anthracyclines. Idarubicin is given on days 2, 4, 6, and 8 of induction along with prednisolone and ATO/ATRA, followed by two “chemotherapy-free” ATO/ATRA-only consolidation cycles and 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
Chemotherapy-free consolidation without maintenance has been found to be beneficial in standard-risk patients, it has been utilised to a limited extent in the National Cancer Research Institute (NCRI) AML17 trialr and by the MD Anderson groupr for high-risk adult patients following induction with ATO/ATRA, combined with gemtuzumab ozogamicin (GO). However, GO is currently not TGA-approved for use in APML. The Children’s Oncology Group (COG) AAML1331 studyr is a nonrandomised, noninferiority trial that looked at survival outcomes in 154 paediatric patients with APML. The patients, aged between 1 and 21 years, received ATRA and arsenic throughout induction and intermittently throughout 4 cycles of consolidation. The high-risk patients (56/154) received 4 doses of idarubicin (similar to APML4). The duration of treatment was approximately 9 months without any maintenance. Shah et al.r reported a retrospective analysis of 10 high-risk APML patients, median age 44.5 years, with 7 patients receiving induction as per APML4 with idarubicin and all patients receiving consolidation with ATO/ATRA without maintenance, as per the APL0406 studyr. The TUD-APOLLO-64 study (NCT02688140) is currently underway, a randomised phase 3 study of high-risk APML patients, comparing standard ATRA and anthracycline-based chemotherapy regimens with ATO/ATRA in combination with low-doses of idarubicin during induction, followed by 4 cycles of ATO/ATRA consolidation therapy. However, there are no results of this study published to date. Despite the absence of published trials for high-risk adults with APML, which involve standard of care induction combined with chemotherapy-free consolidation without maintenance, it is the consensus of the reference committee that based on the above studies, high-risk patients may receive chemotherapy-free consolidation as per ID 1943 Acute promyelocytic leukaemia standard risk (chemotherapy free) consolidation.
Efficacy
There were 124 evaluable patients with 4 deaths (1 myocardial ischaemia, 2 intracerebral haemorrhage, and 1 cerebral oedema), and 2 withdrawals from the 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.r
In the final analysis, there had been a total of 5 relapses and there was one off-study death. The 5-year outcome data showed 95% freedom from relapse (FFR) and disease-free survival (DFS), 90% event-free survival (EFS), and 94% overall survival (OS).r The FFR, DFS, EFS, and OS results were all statistically significantly superior to the ALLG's prior APML3 study which used ATRA and idarubicin (but no arsenic) in induction and consolidation.
In the Children’s Oncology Group (COG) AAML1331 study the median follow-up duration was 24.7 months for patients with standard-risk APML and 22.8 months for patients with high-risk APML. The 2-year EFS and OS for standard-risk patients was 98% and 99% respectively, and for high-risk patients 2-year EFS was 96.4% and OS 100%.r
Figure 1. Kaplan-Meier DFS and OS curves from the APML4 (purple) and APML3 (green) treatment protocolsr
© Lancet Haematology 2015
Toxicity
Most patients received at least 80% of the maximum specified dosing of idarubicin, ATRA, and ATO. During induction, 14% experienced Q-Tc prolongation greater than 500 ms, 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. No case of differentiation syndrome or deaths were reported during either consolidation cycle.
In comparison with the 2-year interim APML4 data, there were no major differences in grade 3–4 non-haematologic toxic effects during induction and consolidation.r Toxic effects declined with successive treatment cycles, being the highest in induction and lowest in the second cycle of consolidation. Myelotoxic effects in consolidation were dependent on the arsenic trioxide schedule, with grade 3–4 neutropenia seen in 69 (62%) of 112 patients in the first consolidation cycle compared with 30 (27%) of 112 patients in the second cycle. No grade 3–4 thrombocytopenia occurred in either cycle of consolidation. During the maintenance period, the most frequent grade 3–4 adverse events were increased concentrations of alanine or aspartate aminotransferase and neutropenia.
Table 1. Number of patients experiencing grade 3-4 non-haematologic adverse events during induction and consolidationr
© Blood 2012