[ATRA/As2O3 combination for remission/maintenance therapy of APL]
>>Published online before print March 24, 2004
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0400053101
Inaugural Article
Medical Sciences
All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia
Zhi-Xiang Shen *, Zhan-Zhong Shi *, Jing Fang *, Bai-Wei Gu *, Jun-Min Li *, Yong-Mei Zhu *, Jing-Yi Shi *, Pei-Zheng Zheng *, Hua Yan *, Yuan-Fang Liu *, Yu Chen *, Yang Shen *, Wen Wu *, Wei Tang *, Samuel Waxman , Hugues de Thé , Zhen-Yi Wang *, Sai-Juan Chen *¶, and Zhu Chen *¶
*Shanghai Institute of Hematology, State Key Lab of Medical Genomics, Rui Jin Hospital affiliated with Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China; Centre National de la Recherche Scientifique, Unité Propre de Recherche 9051, Laboratoire Associé du Comité de Paris de la Ligue Contre le Cancer, Affilié à l'Université de Paris VII, Hôpital St. Louis, 1 Avenue C. Vellefaux, 75475 Paris Cedex 10, France; and Division of Neoplastic Diseases, Department of Medicine, Mount Sinai Medical Center, New York, NY 10029-6547
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 29, 2003.
Contributed by Zhu Chen, January 5, 2004
Both all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have proven to be very effective in obtaining high clinical complete remission (CR) rates in acute promyelocytic leukemia (APL), but they had not been used jointly in an integrated treatment protocol for remission induction or maintenance among newly diagnosed APL patients. In this study, 61 newly diagnosed APL subjects were randomized into three treatment groups, namely by ATRA, As2O3, and the combination of the two drugs. CR was determined by hematological analysis, tumor burden was examined with real-time quantitative RT-PCR of the PML-RAR (promyelocytic leukemia-retinoic acid receptor ) fusion transcripts, and side effects were evaluated by means of clinical examinations. Mechanisms possibly involved were also investigated with cellular and molecular biology methods. Although CR rates in three groups were all high (90%), the time to achieve CR differed significantly, with that of the combination group being the shortest one. Earlier recovery of platelet count was also found in this group. The disease burden as reflected by fold change of PML-RAR transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As2O3 mono-therapy (P < 0.01). This difference persisted after consolidation (P < 0.05). Importantly, all 20 cases in the combination group remained in CR whereas 7 of 37 cases treated with mono-therapy relapsed (P < 0.05) after a follow-up of 8-30 months (median: 18 months). Synergism of ATRA and As2O3 on apoptosis and degradation of PML-RAR oncoprotein might provide a plausible explanation for superior efficacy of combinative therapy in clinic. In conclusion, the ATRA/As2O3 combination for remission/maintenance therapy of APL brings much better results than either of the two drugs used alone in terms of the quality of CR and the status of the disease-free survival.<<
Cheers, Tuck |
