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. The APL0406 trialrr was a phase 3 noninferiority study which examined removing chemotherapy altogether from an ATO/ATRA backbone in low to intermediate-risk APML patients (white cell count ≤ 10x109/L). The rationale was that removing chemotherapy may reduce rates of haematological toxicity and infections when compared to a “standard” chemotherapy-containing regimen. Induction in the “no chemotherapy arm” utilised ATRA and ATO in combination until achievement of haematological complete remission (hCR) or a maximum of 60 days (patients were taken off study if hCR not achieved at this time point). For responders, this was followed by consolidation with overlapping blocks of ATRA and ATO, where notably, ATO was given on weekdays (which facilitates outpatient administration). Notable inclusion criteria included an age range of 18-71 and a WHO performance status of 0-2.
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 263 evaluable patients for response to induction (127 in the ATRA/ATO arm and 136 in the ATRA-chemotherapy arm). CR was achieved in 100% (127/127) of the ATRA/ATO arm compared to 97% (132/136) for ATRA-chemotherapy (P=0.12). 4/136 ATRA-chemotherapy patients died during induction (2 differentiation syndrome, 1 stroke, 1 infection). All deaths were recorded in the initial series, and no further deaths occurred in the second cohort of 110 patients enrolled in the post-amendment period. After a median follow-up of 40.6 months (range 0.1 to 83.6 months), outcome estimates calculated at 50 months was EFS 97.3% (95% CI 94.3 to 100) in ATRA/ATO group compared with 80% (95% CI 72.9 to 88) in the ATRA-chemotherapy group (p<0.001 for non-inferiority).Overall survival (OS) was 99.2% (95% CI 97.7 to 100) for ATRA/ATO versus 92.6% (95% CI 87.9 to 97.5) for ATRA-chemotherapy group (P = 0.0073). Cumulative incidence of relapse was 1.9% (95% CI 1 to 4.5) in ATRA/ATO group versus 13.9% (95% CI 7.1 to 20.6) for ATRA-chemotherapy group (p=0.0013, gray test).r
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. Outcome estimatesr
© JCO 2017
Toxicity
A total of 95 serious adverse effects (43 ATRA/ATO therapy, and 52 ATRA-chemotherapy) were reported in 65 patients.r
Tables. Haematologic and non-haematologic toxicityr
© JCO 2017