Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial

Zhu, Hong‐Hu; Wu, Depei; Du, Xin; Zhang, Xi; Liu, Lin; Ma, Jun; Shao, Zonghong; Ren, Hanyun; Hu, Jianda; Xu, Kailin; Wang, Jingwen; Song, Yongping; Fang, Meiyun; Li, Juan; Yan, Xiaoyan; Huang, Xiao‐Jun

doi:10.1016/s1470-2045(18)30295-x

Cited by 113 publications

(107 citation statements)

References 31 publications

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“…13,17 In another study that recruited patients of all risk categories, ATRA and iv As 2 O 3 were administered to low-and intermediate-risk patients, whereas high-risk patients received gemtuzumab ozogamicin in addition. 24 We did not have any relapses in our oral As 2 O 3 induction cohort. In our arsenic induction cohort, 12 patients did not receive chemotherapy, with 4 of them belonging to the highrisk category.…”

Section: Discussionmentioning

confidence: 75%

“…Another oral arsenic formulation, oral arsenic realgar-indigo naturalis, was shown in combination with ATRA without chemotherapy to be noninferior to iv As 2 O 3 in non-high-risk patients with newly diagnosed APL. 24 We did not have any relapses in our oral As 2 O 3 induction cohort. This contrasts with relapse rates of 1% to 4% in studies of frontline iv As 2 O 3 , 12-17 with relapses occurring mostly in high-risk patients.…”

Section: Discussionmentioning

confidence: 75%

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Oral arsenic trioxide incorporation into frontline treatment with all‐trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5‐year prospective study

Gill

Kumana

Yim

et al. 2019

Cancer

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BACKGROUND: Strategies using oral arsenic trioxide (As 2 O 3 ) are efficacious in relapsed acute promyelocytic leukemia (APL), but they have not been examined in newly diagnosed cases. METHODS: Sixty-two consecutive patients (24 men and 38 women) with a median age of 52 years (range, 22-85 years), 36% of whom had high-risk features, underwent induction with all-trans retinoic acid at 45 mg/m 2 /d, oral As 2 O 3 at 10 mg/d, and ascorbic acid at 1 g/d (the all-trans retinoic acid-arsenic trioxide-ascorbic acid [AAA] regimen) for 6 weeks (with patients younger than 70 years additionally receiving daunorubicin at 50 mg/m 2 /d × 3); they then underwent consolidation with 2 monthly cycles of daunorubicin (50 mg/m 2 /d × 2) and cytarabine (100 mg/m 2 /d × 5) and received AAA maintenance (2 weeks every 8 weeks) for 2 years. A contemporaneous cohort of 37 newly diagnosed patients (15 men and 22 women) with a median age of 51 years (range, 23-78 years), not consenting to oral As 2 O 3 induction but receiving similar induction, consolidation, and AAA maintenance, served as a comparator group; 46% of these patients had high-risk features. RESULTS: The oral As 2 O 3 induction cohort showed a complete remission (CR) rate of 100%. After a median of 37 months (range, 13-82 months), there were no relapses, so conventional risks (age, leukocyte and platelet counts, and Fms-like tyrosine kinase 3 [FLT3] mutations) were not relevant. The leukemia-free survival (LFS) and overall survival (OS) rates were 100% at 3 years and 94.1% at 5 years. The non-As 2 O 3 induction cohort showed a CR rate of 100%. After a median of 52 months (range, 14-77 months), there were 3 relapses (8%). Comparable patients in the oral As 2 O 3 induction and non-As 2 O 3 induction cohorts showed similar OS, but LFS was significantly superior in the oral As 2 O 3 induction cohort. CONCLUSIONS: The incorporation of oral As 2 O 3 into induction for newly diagnosed APL was safe and decreased relapses. Cancer 2019;125:3001-3012.

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Section: Discussionmentioning

confidence: 75%

Section: Discussionmentioning

confidence: 75%

Oral arsenic trioxide incorporation into frontline treatment with all‐trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5‐year prospective study

Gill

Kumana

Yim

et al. 2019

Cancer

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“…So far, more than 5,000 patients have been treated with RIF-based regimens with excellent results and very favorable toxicity profiles, especially when considering the potential of a completely chemo-free regimen [55]. An important milestone has been the demonstration of non-inferiority of ATRA/ ATO versus ATRA/RIF treatment in terms of 2-year EFS in newly diagnosed patients with APL (94 vs. 97%, respectively) [58]. These results were confirmed by the use of RIF/ATRA in standard-risk and later in high-risk patients [59,60].…”

Section: Oral Ato Formulationsmentioning

confidence: 99%

“…If up to 16% of patients with APL experience a QTc prolongation of any grade after ATO administration [38], no cardiac toxicity has been reported using RIF [59,60]. On the other hand, liver toxicity still occurs with ATRA/ RIF, at a milder degree than with ATRA/ATO [58]. A further advantage of the ATRA/RIF combination is the applicability of this entirely chemotherapy-free, outpatient-based post-remission strategy, attractive in terms of quality of life and health system-related costs, in particular for children or elderly patients [61].…”

Section: Oral Ato Formulationsmentioning

confidence: 99%

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Gurnari¹,

Bellis²,

Divona³

et al. 2019

Chemotherapy

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Arsenic has been known for centuries for its double-edged potential: a poison and at the same time a therapeutic agent. The name "arsenikon," meaning "potent," speaks itself for the pharmaceutical properties of this compound, questioned and analyzed for at least 2000 years. In the last decades, acute promyelocytic leukemia (APL) has evolved from a highly fatal to a curable disease, due to the use of all-transretinoic acid and, more recently, arsenic trioxide combinations. The success of these entirely chemo-free regimens increased the awareness of APL and reduced the prevalence of early deaths, which was an impending issue in this disease. Further improvements are expected with the next use of oral arsenic formulations, which will allow a complete outpatient approach, at least in the post-induction settings, further improving patients' quality of life. The wide use of standardized approaches in APL will also help unravel long-standing open questions, including the pathogenesis, prevention, and treatment of the differentiation syndrome and of short-term organ toxicities. In the long term, the study of survivorship issues, such as fertility and organ-related and psychological damages, in the increasing number of survivors will help further improve their life after APL.

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“…Arsenic sulfide is a kind of mineral drug that can be orally administered and has shown certain therapeutic effects of the treatment on several types of leukemia . However, As 4 S 4 leads to low bioavailability due to its poor water solubility.…”

Section: Introductionmentioning

confidence: 99%

Arsenic Sulfide Nanoformulation Induces Megakaryocytic Differentiation through Histone Deacetylase Inhibition

Jia

Wang

et al. 2019

Advanced Therapeutics

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Arsenic sulfide (As 4 S 4 ) is a mineral drug that can be administrated orally and has been applied in several Chinese medicine formulations for the treatment on some kinds of myeloid leukemia. However, mechanisms of As 4 S 4 are not demonstrated adequately due to the poor water solubility of As 4 S 4 in its original crystal form. The authors previously fabricated water dissolvable arsenic sulfide nanoformulation (ee-As 4 S 4 ), which downregulated intracellular reactive oxygen species (ROS). As ROS is closely associated with the histone deacetylase (HDAC), in this study the effect of ee-As 4 S 4 on the HDAC activity in chronic myeloid leukemia (CML) cells and whether the effect can induce subsequent megakaryocytic differentiation and underlying mechanisms are investigated. Results show that ee-As 4 S 4 inhibits HDAC activity in CML cells, resulting in the suppression of cellular respiration. The inhibition of HDAC activity also leads to the transcriptional activation of RUNX1, which induces megakaryocytic differentiation in CML cell lines, evidenced by the significantly multiple nuclei and giant nuclear structure, upregulation of CD41a and the increased phosphorylation of ERK1/2. In conclusion, ee-As 4 S 4 is able to inhibit HDAC activity, and therefore induce significant megakaryocytic differentiation in CML cells through RUNX1-dependent pathways, which suggests its clinical potential as a complementary drug option for CML patients.

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Oral arsenic plus retinoic acid versus intravenous arsenic plus retinoic acid for non-high-risk acute promyelocytic leukaemia: a non-inferiority, randomised phase 3 trial

Cited by 113 publications

References 31 publications

Oral arsenic trioxide incorporation into frontline treatment with all‐trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5‐year prospective study

Oral arsenic trioxide incorporation into frontline treatment with all‐trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5‐year prospective study

When Poisons Cure: The Case of Arsenic in Acute Promyelocytic Leukemia

Arsenic Sulfide Nanoformulation Induces Megakaryocytic Differentiation through Histone Deacetylase Inhibition

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