Hong-Hu Zhu1, De-Pei Wu2, Xin Du3, Xi Zhang4, Lin Liu5, Jun Ma6, Zong-Hong Shao7, Han-Yun Ren8, Jian-Da Hu9, Kai-Lin Xu10, Jing-Wen Wang11, Yong-Ping Song12, Mei-Yun Fang13, Juan Li14, Xiao-Yan Yan15, Xiao-Jun Huang16. 1. Department of Hematology, Peking University People's Hospital, Beijing, China. 2. Department of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China. 3. Department of Hematology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 4. Department of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China. 5. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 6. Harbin Institute of Hematology and Oncology, Harbin, China. 7. Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China. 8. Department of Hematology, Peking University First Hospital, Beijing, China. 9. Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China. 10. Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China. 11. Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, China. 12. The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China. 13. Department of Hematology, The First Affiliated Hospital of Dalian Medical University, Dalian, China. 14. Department of Hematology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. 15. Department of Biostatistics, Peking University Clinical Research Institute, Beijing, China. 16. Department of Hematology, Peking University People's Hospital, Beijing, China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China; Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China. Electronic address: xjhrm@medmail.com.cn.
Abstract
BACKGROUND:Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 109 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. METHODS: We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. FINDINGS:Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) orarsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27-36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3-4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3-4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). INTERPRETATION:Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. FUNDING: Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China.
RCT Entities:
BACKGROUND: Intravenous arsenic trioxide plus all-trans retinoic acid (ATRA) without chemotherapy is the standard of care for non-high-risk acute promyelocytic leukaemia (white blood cell count ≤10 × 109 per L), resulting in cure in more than 95% of cases. However, a pilot study of treatment with oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA without chemotherapy, which has a more convenient route of administration than the standard intravenous regimen, showed high efficacy. In this study, we compare an oral RIF plus ATRA treatment regimen with the standard intravenous arsenic trioxide plus ATRA treatment regimen in patients with non-high-risk acute promyelocytic leukaemia. METHODS: We did a multicentre, non-inferiority, open-label, randomised, controlled phase 3 trial at 14 centres in China. Patients aged 18-70 years with newly diagnosed (within 7 days) non-high-risk acute promyelocytic leukaemia, and a WHO performance status of 2 or less were eligible. Patients were randomly assigned (2:1) to receive treatment with RIF-ATRA or arsenic trioxide-ATRA as the induction and consolidation therapy. Randomisation was done centrally with permuted blocks and stratification according to trial centre and was implemented through an interactive web response system. RIF (60 mg/kg bodyweight daily in an oral divided dose) or arsenic trioxide (0·15 mg/kg daily in an intravenous dose) and ATRA (25 mg/m2 daily in an oral divided dose) were used until complete remission was achieved. The home-based consolidation therapy was RIF (60 mg/kg daily in an oral divided dose) or intravenous arsenic trioxide (0·15 mg/kg daily in an intravenous dose) in a 4-week on 4-week off regimen for four cycles and ATRA (25 mg/m2 daily in an oral divided dose) in a 2-week on 2-week off regimen for seven cycles. Patients and treating physicians were not masked to treatment allocation. The primary outcome was event-free survival at 2 years. A non-inferiority margin of -10% was used to assess non-inferiority. Primary analyses were done in a modified intention-to-treat population of all patients who received at least one dose of their assigned treatment and the per-protocol population. This study was registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-13004054), and the trial is complete. FINDINGS: Between Feb 13, 2014, and Aug 31, 2015, 109 patients were enrolled and assigned to RIF-ATRA (n=72) or arsenic trioxide-ATRA (n=37). Three patients in the RIF-ATRA and one in the arsenic trioxide-ATRA did not receive their assigned treatment. After a median follow-up of 32 months (IQR 27-36), 67 (97%) of 69 patients in the RIF-ATRA group and 34 (94%) of 36 in the arsenic trioxide-ATRA group had achieved 2-year event-free survival in the modified intention-to-treat population. The percentage difference in event-free survival was 2·7% (95% CI, -5·8 to 11·1). The lower limit of the 95% CI for the difference in event-free survival was greater than the -10% non-inferiority margin, confirming non-inferiority (p=0·0017). Non-inferiority was also confirmed in the per-protocol population. During induction therapy, grade 3-4 hepatic toxic effects (ie, increased liver aspartate aminotransferase or alanine transaminase concentrations) were reported in six (9%) of 69 patients in the RIF-ATRA group versus five (14%) of 36 patients in the arsenic trioxide-ATRA group; grade 3-4 infection was reported in 15 (23%) of 64 versus 15 (42%) of 36 patients. Two patients in the arsenic trioxide-ATRA group died during induction therapy (one from haemorrhage and one from thrombocytopenia). INTERPRETATION: Oral RIF plus ATRA is not inferior to intravenous arsenic trioxide plus ATRA for the treatment of patients with non-high-risk acute promyelocytic leukaemia. This study suggests that a completely oral, chemotherapy-free model might be an alternative to the standard intravenous treatment for patients with non-high-risk acute promyelocytic leukaemia. FUNDING: Foundation for innovative research group of the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the National Key R&D Program of China, and the National Natural Science Foundation of China.
Authors: Miguel A Sanz; Pierre Fenaux; Martin S Tallman; Elihu H Estey; Bob Löwenberg; Tomoki Naoe; Eva Lengfelder; Hartmut Döhner; Alan K Burnett; Sai-Juan Chen; Vikram Mathews; Harry Iland; Eduardo Rego; Hagop Kantarjian; Lionel Adès; Giuseppe Avvisati; Pau Montesinos; Uwe Platzbecker; Farhad Ravandi; Nigel H Russell; Francesco Lo-Coco Journal: Blood Date: 2019-02-25 Impact factor: 22.113
Authors: Anand P Jillella; Martha L Arellano; Manila Gaddh; Amy A Langston; Leonard T Heffner; Elliott F Winton; Morgan L McLemore; Chao Zhang; Catherine R Caprara; Kathryn S Simon; Sheldon L Bolds; Stephanie DeBragga; Prachi Karkhanis; Shruthi H Krishnamurthy; Jose Tongol; Mohamed M El Geneidy; Asim Pati; Jonathan M Gerber; Michael R Grunwald; Jorge Cortes; Asad Bashey; Robert K Stuart; Vamsi K Kota Journal: JCO Oncol Pract Date: 2020-10-30