All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia.
Both all-trans retinoic acid (ATRA) and arsenic trioxide (As(2)O(3)) 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, As(2)O(3), 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 alpha (promyelocytic leukemia-retinoic acid receptor alpha) 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 (> or =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 alpha transcripts at CR decreased more significantly in combined therapy as compared with ATRA or As(2)O(3) 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 As(2)O(3) on apoptosis and degradation of PML-RAR alpha oncoprotein might provide a plausible explanation for superior efficacy of combination therapy in clinic. In conclusion, the ATRA/As(2)O(3) 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.
Shen
Zhi-Xiang
ZX
Shanghai Institute of Hematology, State Key Lab of Medical Genomics, Rui Jin Hospital, Shanghai Second Medical University, 197 Rui Jin Road II, Shanghai 200025, China.
Shi
Zhan-Zhong
ZZ
Fang
Jing
J
Gu
Bai-Wei
BW
Li
Jun-Min
JM
Zhu
Yong-Mei
YM
Shi
Jing-Yi
JY
Zheng
Pei-Zheng
PZ
Yan
Hua
H
Liu
Yuan-Fang
YF
Chen
Yu
Y
Shen
Yang
Y
Wu
Wen
W
Tang
Wei
W
Waxman
Samuel
S
De Thé
Hugues
H
Wang
Zhen-Yi
ZY
Chen
Sai-Juan
SJ
Chen
Zhu
Z
D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D015473:Leukemia, Promyelocytic, Acute / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis; D010087:Oxides / Q000008:administration & dosage* / Q000009:adverse effects; D011446:Prospective Studies; D012074:Remission Induction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects; D014407:Tumor Cells, Cultured
D001152:Arsenicals; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D000077237:Arsenic Trioxide