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Role of arsenic trioxide in APL
year event-free rates were 85.5% and 92.1% (P=0.38) (Figure 3).
Excluding AraC (after the protocol amendment) from the consolidation cycles in the chemotherapy plus ATO group did not increase the 5-year cumulative incidence of relapse (4.6% in the chemotherapy arm, 5.3% in the chemothera- py plus ATO with AraC arm and 2.7% in the chemothera- py plus ATO without AraC arm, P=0.61). On the other hand, excluding AraC from consolidation cycles in the chemotherapy plus ATO arm significanty reduced myelo- suppression: the median times to an absolute neutrophil count >1x109/L after the second consolidation course were 22, 25 and 18 days in, respectively, the chemotherapy arm, the chemotherapy plus ATO with AraC arm, and the chemotherapy plus ATO without AraC arm (P<0.001), while the median times to a platelet count >50x109/L were 24, 26 and 18 days (P<0.001). Similarly, the median dura- tions of hospitalization after the first and the second consol- idation courses were 29 days, 34 days, and 33 days (P<0.0001) and 28 days, 32 days and 31 days (P=0.0005), respectively.
Discussion
The main results of this study are that, in standard-risk APL, addition of ATO to a “classical” ATRA chemotherapy regimen further reduces the incidence of relapse and that, in high-risk APL, AraC (including high-dose AraC) can be replaced by ATO without increasing the relapse risk and with more limited myelosuppression, thus potentially reducing the risk of death in complete remission.
A first finding was the very high complete remission rate obtained in the APL 2006 trial, both in standard-risk and high-risk APL (98.1% and 95.7%, respectively), even though patients could be included up to the age of 70. Recent reports have suggested that, even in the ATRA era, early death rates could be as high as 15% to 20% in “real- life” APL patients.15–19 On the other hand, we previously published that, during the 2006 to 2011 period, 75% of the patients in the 17 French largest centers participating in the APL 2006 trial could be included in the trial, while 25% could not, mainly based on age, major comorbidities or direct admission to an intensive care unit.15 The overall complete remission rate was 91.4% and the overall rate of early death was 8.6%. All studies suggest that, if APL is sus- pected and before the diagnosis is confirmed, the immedi- ate institution of ATRA treatment can reduce the risk of early death. Intensive platelet support during induction treatment can probably also contribute to reducing the risk of early death, particularly in patients with high-risk APL.
In the APL 2006 trial, in standard-risk APL patients aged less than 70 years of age, our aim was to show that by sub- stituting ATO or ATRA for AraC during consolidation cycles, we would not increase the relapse rate, but would reduce myelosuppression, thereby potentially reducing the incidence of deaths in complete remission, which was 5% in our previous experience with AraC-containing consoli- dation cycles (at a conventional dose for the first consolida- tion cycle, and intermediate dose for the second). The ATRA and chemotherapy regimen chosen appeared to be an “optimal” regimen, using in particular high cumulative doses of anthracyclines, idarubicin rather than daunoru- bicin (as the latter may lead to more relapses8), AraC during consolidation and prolonged maintenance treatment with
6-mercaptopurine, methotrexate and intermittent ATRA, which may also contribute to reducing the relapse rate.7 This reference treatment proved effective, as the incidence of relapse after 5 years was only 5.5%.
Substituting ATRA for AraC did not significantly increase the relapse rate (8.2% at 5 years, compared to 5.5% in the AraC group) , but the replacement significantly reduced the time to recovery from neutropenia after the first and second consolidation cycles, and the duration of hospitalization during those two consolidation cycles. It did not reduce the incidence of deaths in complete remission, but among the six, six and five deaths in complete remission occurring in the three consolidation groups, only two in each arm were
Figure 3. Overall survival, cumulative incidence of relapse and event-free sur- vival in patients with high-risk acute promyelocytic leukemia. Chemo: chemotherapy; ATO: arsenic trioxide; CR: complete remission.
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