Treatment of Acute Myeloid Leukemia With Arsenic and All-trans Retinoid Acid

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Treatment of Acute Myeloid Leukemia With Arsenic and All-trans Retinoid Acid (ATRA)

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: All-trans retinoic acid
* Drug: Arsenic Trioxide
* Drug: Realgar-Indigo naturalis formula


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed or relapsed AML.Diagnosis based on Chinese guidelines for diagnosis and treatment of adult acute myeloid leukemia(not APL)(2018) Older than 18 years old Patients or their families signed written informed consent Exclusion Criteria: Be allergic to the drug ingredient, the supplementary material or the allergic constitution person Cardiac insufficiency, renal insufficiency, significant arrhythmias, EKG abnormalities or other important organ dysfunction Combined with other malignant tumors Pregnant and lactating women Participants in other drug trials in the last 3 months Suffering from mental illness or other circumstances which unable to carry out the plan Other patients who were not suitable for the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ATRA/arsenic Group<br>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. | Drug: All-trans retinoic acid<br>* All-trans retinoic acid (ATRA) 20mg 3 times a day for 8 weeks.<br>* Other names: ATRA;Drug: Arsenic Trioxide<br>* ATO 0.15mg/kg/d for 8 weeks (If the total daily amount is greater than 10mg, only 10mg/d can be given)<br>* Other names: ATO;Drug: Realgar-Indigo naturalis formula<br>* 60 mg/kg/d for 8 weeks<br>* Other names: RIF;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 |  | From the date of enrollment to the date of relpase proved by bone marrow test, assessed up to 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute myeloid leukemia, All-trans Retinoic Acid, Arsenic