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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: All-trans retinoic acid; Drug: Arsenic Trioxide; Drug: Realgar-Indigo naturalis formula

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Huaiyu Wang, Dr.; Phone Number: 008615809207527; Email: whymed@126.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710016
      • Recruiting
      • First Affiliated Hospital of Xi'an Jiaotong University
      • Contact: Huaiyu Wang, Dr.; Phone Number: 15809207527; Email: whymed@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: First Affiliated Hospital Xi'an Jiaotong University
• Investigators: Study Chair: Huaiyu Wang, Dr., First Affiliated Hospital Xi'an Jiaotong University

Publications and helpful links

General Publications

• Bennett DA. How can I deal with missing data in my study? Aust N Z J Public Health. 2001 Oct;25(5):464-9.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 3, 2019
• Primary Completion (Anticipated): December 3, 2023
• Study Completion (Anticipated): December 31, 2023

Study Registration Dates

• First Submitted: October 8, 2021
• First Submitted That Met QC Criteria: March 23, 2022
• First Posted (Actual): March 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 28, 2022
• Last Update Submitted That Met QC Criteria: March 23, 2022
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Keywords: Acute myeloid leukemia; Arsenic; All-trans Retinoic Acid
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Antineoplastic Agents; Dermatologic Agents; Keratolytic Agents; Arsenic Trioxide; Tretinoin
• Other Study ID Numbers: XJTU1AF2019LSK-077

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No