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The clinical trial was designed to prove that Arsenic plus ATRA possibly had an effect on improving the symptoms, reducing the early mortality rate and prolonging the total survival time of patients with newly diagnosed or relapsed AML.
Acute myeloid leukemia (AML) is a genetically heterogeneous disease with a highly variable prognosis and an overall high mortality rate. The 5-year overall survival of adult AML patients is less than 50%, and only 20% of elderly patients survive over 2 years. Acute promyelocytic leukemia (APL) accounts for 10% - 15% of acute myeloid leukemia. Arsenic and ATRA are very effective treatments for APL, a distinct AML subtype characterized by the expression of the PML/RARA fusion protein. PML/RARA expression disrupts PML NBs and blunts p53 signaling, which contributes to increased self-renewal of myeloid progenitors. The application of all-trans retinoic acid (ATRA) and arsenic modifies APL from highly fatal to highly curable. Both RA and arsenic induce degradation of PML/RARA through distinct pathways. Nucleophosmin-1(NPM1) is the most frequently mutated gene in acute myeloid leukemia (AML). According to El Hajj's research, RA or arsenic trioxide synergistically induces proteasomal degradation of mutant NPM1 in AML cell lines or primary samples, leading to differentiation and apoptosis. Combined ATRA/arsenic treatment significantly reduced bone marrow blasts in 3 AML patients and restored the subnuclear localization of both NPM1 and PML. Overall, there is no consensus yet as to whether the addition of ATRA/arsenic improves the outcome of patients with NPM1 mutant AML. However, it still needs clinical research to confirm. The investigators design a clinical trial to prove that arsenic plus ATRA is possibly improving the symptoms of AML patients, reduce early mortality, and extending overall survival time.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ATRA/arsenic Group | Experimental | ATRA 20mg 3 times a day for 8 weeks Arsenic can be given intravenously (ATO) or oral Realgar-Indigo naturalis formula(RIF) ATO 0.15mg/kg/d for 8 weeks (If the total daily amount is greater than 10mg, only 10mg/d can be given) RIF 60 mg/kg/d for 8 weeks The total dose can be appropriately adjusted according to the side-effects of the drug. 4 weeks for 1 course. If the patient has obvious side effects, the treatment should stop for 2 weeks. Each patient will be received at least two courses. Quality of life assessments are performed every 2 months. After the end of the course of treatment, the condition is mainly evaluated based on the platelet count and bone marrow smear. If the treatment is effective, the above regimen can be continued; if not, the study is withdrawn. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| All-trans retinoic acid | Drug | All-trans retinoic acid (ATRA) 20mg 3 times a day for 8 weeks. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Early death rate (ED) | Death reported within the first month of diagnosis | 30 days |
| Overall survival (OS) | the time from enrolled to death from any cause | From date of enrollment until the date of death from any cause, assessed up to 3 years |
| Measure | Description | Time Frame |
|---|---|---|
| Hematologic complete remission (HCR) | Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0×10^9 /L; platelet count >100× 10^9 /L. | 30 days |
| Cumulative relapse rate |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Huaiyu Wang, Dr. | Contact | 008615809207527 | whymed@126.com |
| Name | Affiliation | Role |
|---|---|---|
| Huaiyu Wang, Dr. | First Affiliated Hospital Xi'an Jiaotong University | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| First Affiliated Hospital of Xi'an Jiaotong University | Recruiting | Xi'an | Shaanxi | 710016 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11688629 | Background | Bennett DA. How can I deal with missing data in my study? Aust N Z J Public Health. 2001 Oct;25(5):464-9. | |
| 24344243 | Background | Dos Santos GA, Kats L, Pandolfi PP. Synergy against PML-RARa: targeting transcription, proteolysis, differentiation, and self-renewal in acute promyelocytic leukemia. J Exp Med. 2013 Dec 16;210(13):2793-802. doi: 10.1084/jem.20131121. |
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| ID | Term |
|---|---|
| D015470 | Leukemia, Myeloid, Acute |
| ID | Term |
|---|---|
| D007951 | Leukemia, Myeloid |
| D007938 | Leukemia |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D014212 | Tretinoin |
| D000077237 | Arsenic Trioxide |
| ID | Term |
|---|---|
| D014801 | Vitamin A |
| D012176 | Retinoids |
| D002338 | Carotenoids |
| D011090 | Polyenes |
| D000475 |
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| Arsenic Trioxide | Drug | ATO 0.15mg/kg/d for 8 weeks (If the total daily amount is greater than 10mg, only 10mg/d can be given) |
|
|
| Realgar-Indigo naturalis formula | Drug | 60 mg/kg/d for 8 weeks |
|
|
| From the date of enrollment to the date of relpase proved by bone marrow test, assessed up to 3 years |
| 20966922 | Background | de The H, Chen Z. Acute promyelocytic leukaemia: novel insights into the mechanisms of cure. Nat Rev Cancer. 2010 Nov;10(11):775-83. doi: 10.1038/nrc2943. Epub 2010 Oct 22. |
| 20595231 | Background | Zhao Z, Zuber J, Diaz-Flores E, Lintault L, Kogan SC, Shannon K, Lowe SW. p53 loss promotes acute myeloid leukemia by enabling aberrant self-renewal. Genes Dev. 2010 Jul 1;24(13):1389-402. doi: 10.1101/gad.1940710. |
| 25800051 | Background | El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O, Hleihel R, Sahin U, Tawil N, Salameh A, Zibara K, Darwiche N, Mohty M, Dombret H, Fenaux P, de The H, Bazarbachi A. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood. 2015 May 28;125(22):3447-54. doi: 10.1182/blood-2014-11-612416. Epub 2015 Mar 23. |
| D006402 |
| Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| Alkenes |
| D006839 | Hydrocarbons, Acyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D053138 | Cyclohexenes |
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
| D013729 | Terpenes |
| D004224 | Diterpenes |
| D010860 | Pigments, Biological |
| D001685 | Biological Factors |
| D001152 | Arsenicals |
| D007287 | Inorganic Chemicals |
| D010087 | Oxides |
| D017601 | Oxygen Compounds |