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S. Kayser et al.
lished results on ATO/ATRA from the randomized Italian- German APL0406 trial.2,3 However, part of the difference may be explained by the fact that the Swedish report con- tained data from a population-based registry, whereas for our data, selective reporting cannot be ruled out. The under- lying patho-mechanism by which ATO in combination with ATRA exerts this effect remains elusive. The transcrip- tion factor PML-RARA behaves as an altered retinoic acid receptor with the ability to transmit oncogenic signals lead- ing to accumulation of undifferentiated promyelocytes.23 ATRA induces disease remission in APL patients by trigger- ing terminal differentiation of leukemic promyelocytes. In addition, ATO has been shown to contribute to degrada- tion of the PML-RARA oncoprotein through binding the PML moiety.23,24
Regarding post-remission outcome, results of the ran- domized North American Leukemia Intergroup Study C9710 on 481 APL patients evaluating ATO in first-line therapy during consolidation demonstrated that ATO fur- ther reduced the risk of relapse and improved survival as compared to consolidation with daunorubicin/cytarabine.25
Figure 1. Kaplan Meier plot of overall survival. Green and red curves indicate upper and lower 95% confidence intervals, respectively.
In addition, the randomized phase-III AML17 trial of the UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group showed significantly better event-free survival and relapse-free survival after ATO/ATRA than after the AIDA-based regimen.4 In line with previously published results2,3 overall survival was excellent in our cohort. In addition, the death rate in remis- sion was also very low at 4%, again arguing for the safety and efficacy of ATO/ATRA as consolidation treatment. In comparison, relatively high rates of deaths in remission, mainly due to infectious complications, were reported with AIDA treatment.20,21
Data on measurable residual disease was available for only a subgroup of patients before or after first consolida- tion (25%). Nevertheless, since no relapse was observed, our data as well as the currently up-dated APL recommen- dations of the European LeukemiaNet suggest that post- consolidation measurable residual disease monitoring can be avoided in this setting and performed only in high-risk patients (WBC count >10×109/L) in routine clinical prac- tice.18
Figure 2. Kaplan Meier plot of overall survival according to age. Red curve indi- cates age >70 years, black curve indicates age ≤70 years.
Table 2. Reported serious adverse events.
Serious adverse events N=118 %
Infection/sepsis 31 26 Hepatobiliary 21 18 Neurotoxicity/neuropathy 9 8 Differentiation syndrome 7 6
Cardiac, total 6 5 QTc prolongation 2
Pericarditis 1
Hypertension 1
Cardiac decompensation 1 Ischemic cardiomyopathy 1
Hematologic toxicity 5 4 Hemorrhage/bleeding 4 3 Thromboembolic complications 4 3
Other 31 26
Figure 3. Cumulative incidence of death according to age.
Percentages may not sum up to 100 due to rounding.
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haematologica | 2021; 106(12)