Page 114 - 2018_12-Haematologica-web

L. Adès et al.
due to myelosuppression (the remaining being due to inter- current disease or secondary AML/MDS).
However, the main result in this standard-risk APL group was that no relapses were seen in the ATO arm, and that this relapse rate was significantly lower than in the AraC and ATRA consolidation arms. These results suggest that adding ATO to an already highly effective ATRA chemotherapy regimen may further improve the regimen’s anti-leukemic effect, and that ATO may not be dispensable in the treatment of standard-risk APL. On the other hand, substituting ATO for AraC did not reduce the duration of neutropenia after consolidation cycles, and neutropenia was longer with ATO and idarubicin than with ATRA and idarubicin consolidation cycles. This finding suggests that ATO, a non-myelosuppressive drug when used alone or combined with ATRA, may worsen myelosuppression when used concomitantly with chemotherapy. The dura- tion of hospitalization was, however, shorter after ATO and idarubicin than after AraC and idarubicin consolida- tion cycles. The incidence of deaths in complete remission was not reduced in the ATO group, but only two deaths in complete remission were attributable to myelosuppression in the three consolidation arms. Finally, the incidence of secondary AML/MDS was similar in the three treatment arms, and similar to that reported in APL patients treated with ATRA chemotherapy regimens, i.e., between 1% and 2%.20–22 By contrast, in the follow up of the two main clini- cal trials that used ATRA-ATO regimens without chemotherapy in newly diagnosed APL, no case of second- ary AML/MDS has been reported so far (Lo Coco and Russell, personal communications).
Thus, in standard-risk APL, and in spite of very high com- plete remission and very low relapse rates obtained with ATRA chemotherapy combinations, our results confirm that the rates can be further improved by using ATO during the consolidation regimen. ATO in this situation did indeed reduce the relapse risk in standard-risk APL, confirming results of two recent, large studies.10,11 Long-term results of one of them, the Italian German study, show in particular that an ATRA-ATO regimen is not just equivalent but supe- rior to ATRA chemotherapy regimens in terms of relapse rate and overall survival. Thus, ATRA-ATO (chemotherapy free) regimens are becoming reference treatments for stan- dard-risk APL.
With regards to high-risk APL, only limited studies of ATO-ATRA regimens without chemotherapy have been published, and in those studies patients often also received
myelosuppressive drugs, mainly gentuzumab.10,12 In the British study, this approach was found to give results equiv- alent to those of an ATRA chemotherapy regimen, but the overall number of patients included in the randomized study was only 56.10 A US intergroup study showed that addition of ATO to a classical ATRA chemotherapy regimen signifi- cantly reduced the relapse rate. The ATRA chemotherapy regimen was, however based on daunorubicin instead of idarubicin (with a total scheduled dose of 500 mg/m2), which may have contributed to higher relapse rates.
In the present study, among the patients with high-risk APL there was a very high complete remission rate (97.4%) and, contrary to the US intergroup study, a very low relapse rate (2.5%) was seen in the chemotherapy consoli- dation arm (without ATO), confirming our previous results.23
The fact that substituting ATO for AraC was not associ- ated with an increased incidence of relapse (5.3% versus 2.7%), but with a reduced incidence of deaths in complete remission (from 7.8% to 0%) was, therefore, an important finding. This substitution also lead to less myelosuppres- sion and less hospitalization for consolidation cycles.
By contrast, the chemotherapy plus ATO consolidation therapy, combining AraC and ATO, used during the first part of the trial, did not further reduce the relapse rate (which was, it should be noted, already very low in the con- ventional AraC arm) but was associated with increased myelosuppression and a 5% rate of deaths in complete remission. This finding supports the fact that ATO worsens myelosuppression when used concomitantly with chemotherapy, as in the standard-risk group.
Our results therefore support the addition of ATO during consolidation cycles, in high-risk APL, at least in order to reduce the amount of chemotherapy administered and, therefore, the rate of deaths in complete remission (as in our study) but also the relapse rate (according to other stud- ies, including the US intergroup study). While ATO-ATRA regimens without chemotherapy can now probably be sub- stituted for ATRA chemotherapy regimens in standard-risk APL, ongoing clinical trials will show to what extent chemotherapy can also be reduced or even avoided in high- risk APL.
Funding
This study was supported by the programme Hospitalier de Recherche Clinique and the Association pour la Recherche sur le Cancer (ARC).
References
1. Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009;113(9):1875– 1891.
2. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA- 2000 trial of the GIMEMA group. Blood.
2010;116(17):3171–3179.
3. Adès L, Chevret S, Raffoux E, et al. Long-
term follow-up of European APL 2000 trial, evaluating the role of cytarabine combined with ATRA and daunorubicin in the treat- ment of nonelderly APL patients. Am J Hematol. 2013;88(7):556–559.
4. Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelo- cytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high- risk patients: further improvements in treat- ment outcome. Blood. 2010;115(25): 5137– 5146.
5. Fenaux P, Chastang C, Chevret S, et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL group. Blood. 1999;94(4): 1192–1200.
6. Adès L, Guerci A, Raffoux E, et al. Very long- term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL group experience. Blood. 2010;115(9):1690–1696.
7. Muchtar E, Vidal L, Ram R, Gafter-Gvili A,
2038
haematologica | 2018; 103(12)