A Study for Improving the Outcome of Childhood Acute Promyeloid Leukemia

NCT02200978 | Completed Phase 4 DMC

• 1 other identifier: 2010001
• Study Type: interventional
• Target: 176
• Locations: 1 country
• Sites: 1

Brief Summary

Outcome of acute promyelocytic leukemia (APL) has greatly improved since the introduction of all-trans-retinoic acid (ATRA). Treatment with ATRA and anthracycline-based chemotherapy (ATRA + chemotherapy) decreases relapses of the disease as well as early hemorrhagic deaths. Nowadays patients with APL have an event-free survival (EFS) of up to 80%. However, there remains a subset of the patients in whom the disease relapses. Recently, a randomized prospective study showed that the addition of ATO to "ATRA + chemotherapy" treatment protocol had a significantly higher EFS in patients with APL than those treated with "ATRA + chemotherapy" protocol. The patients treated with "ATO + ATRA + chemotherapy" had a five years EFS of 89.2%. Moreover, a recent study showed that Indigo naturalis formula (RIF), a traditional Chinese medicine with tetraarsenic tetrasulfide (As4S4), indirubin, and tanshinone IIA as major active ingredients, yielded synergy in the treatment of a murine APL model in vivo and in the induction of APL cell differentiation in vitro . It is about 20 years since RIF was used to treat ALP in China. Clinical studies showed that this agent was effective against APL. Compared to ATO, RIF is relatively inexpensive and can be taken orally, resulting in reducing the number of hospital days and the treatment cost. However, there is no report comparing treatment outcomes of "ATO + ATRA + chemotherapy" and "RIF + ATRA + chemotherapy" protocols in children with APL so far. For this purpose, therefore, investigators are going to conduct a multicenter and randomized prospective study in children with APL.

Conditions

Childhood Acute Promyelocytic Leukemia

Outcome Measures

Primary Outcomes (1)

• event-free survival

  5 years

Secondary Outcomes (1)

• hospitalization cost

  2 years

Study Arms (2)

ATO and chemotherapy

ACTIVE COMPARATOR

Induction: ATRA 25mg/m2 d1-CR ≯42 days; ATO 0.16mg/kg d5-CR ≯42 days; mitoxantrone (MA) 10mg/m2 d3, or 7mg/m2 d2-4 (high risk). Consolidation 1: ATRA 25mg/m2 d1-15; MA 10mg/m2 d1-2; Intrathecal injection (IT)：Ara-C 15mg (age \< 1 year), or 20 mg (1-3 years), or 30 mg ( \> 3 years), dexamethasone 2mg. Consolidation 2: ATRA 25mg/m2 d1-15; ATO 0.16mg/kg d1-15; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Consolidation 3: ATRA 25mg/m2 d1-15; ATO 0.16mg/kg d1-15; MA 10mg/m2 d1; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Maintenance: ① ATO 0.16mg/kg.d w1-2; ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. ② ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. Rotation between ① and ② until the end of maintenance.

Drug: ATO; Drug: ATRA; Drug: mitoxantrone; Drug: Ara-C; Drug: MTX; Drug: 6MP; Other: intrathecal injection

RIF and chemotherapy

EXPERIMENTAL

Induction: ATRA 25mg/m2 d1-CR ≯42 days; RIF 0.135/kg d5-CR ≯42 days; mitoxantrone (MA) 10mg/m2 d3, or 7mg/m2 d2-4 (high risk). Consolidation 1: ATRA 25mg/m2 d1-15; MA 10mg/m2 d1-2; Intrathecal injection (IT)：Ara-C 15mg (age \< 1 year), or 20mg (age 1-3 years), or 30mg (age \> 3 years), dexamethasone 2mg. Consolidation 2: ATRA 25mg/m2 d1-15; RIF 0.135/kg d1-15; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Consolidation 3: ATRA 25mg/m2 d1-15; RIF 0.135/kg d1-15; MA 10mg/m2 d1; Ara-C 1g/m2 q12h d1-2 (high risk); IT. Maintenance: ① RIF 0.135/kg.d w1-2; ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. ② ATRA 25mg/m2.d w1-2; MTX 20mg/m2 qw w3-12; 6MP 50mg/m2 qn w3-12. Rotation between ① and ② until the end of maintenance treatment.

Drug: RIF; Drug: ATRA; Drug: mitoxantrone; Drug: Ara-C; Drug: MTX; Drug: 6MP; Other: intrathecal injection

Interventions

ATO DRUG

Given IV

Also known as: As2O3, arsenic trioxide

ATO and chemotherapy

RIF DRUG

Given orally

Also known as: Realgar-Indigo naturalis formula

RIF and chemotherapy

ATRA DRUG

Given orally

Also known as: all-trans retinoic acid

ATO and chemotherapy; RIF and chemotherapy

mitoxantrone DRUG

Given IV

Also known as: novantrone

ATO and chemotherapy; RIF and chemotherapy

Ara-C DRUG

Given IV

Also known as: cytarabine, cytosine arabinoside

ATO and chemotherapy; RIF and chemotherapy

MTX DRUG

Given orally

Also known as: methotrexate

ATO and chemotherapy; RIF and chemotherapy

6MP DRUG

Given orally

Also known as: mercaptopurine

ATO and chemotherapy; RIF and chemotherapy

intrathecal injection OTHER

Ara-C and dexamethasone

Also known as: IT

ATO and chemotherapy; RIF and chemotherapy

Eligibility Criteria

• Age: Up to 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Patients less than 16 years old with newly diagnosed PML-RARa positive acute promyelocytic leukemia.

You may not qualify if:

• Patients who have coma, convulsion or paralysis due to intracranial hemorrhage or central nervous system leukemia at diagnosis.

Sponsors & Collaborators

• South China Children's Leukemia Group: lead

Study Sites (1)

The First Affiliated Hospital of Sun Yat-Sen University

Guangzhou, Guangdong, 510080, China

Location

Related Publications (7)

• Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM, Shi JY, Zheng PZ, Yan H, Liu YF, Chen Y, Shen Y, Wu W, Tang W, Waxman S, De The H, Wang ZY, Chen SJ, Chen Z. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5328-35. doi: 10.1073/pnas.0400053101. Epub 2004 Mar 24.

  PMID: 15044693 BACKGROUND

• Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, Li JM, Tang W, Zhao WL, Wu W, Sun HP, Chen QS, Chen B, Zhou GB, Zelent A, Waxman S, Wang ZY, Chen SJ, Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3342-7. doi: 10.1073/pnas.0813280106. Epub 2009 Feb 18.

  PMID: 19225113 BACKGROUND

• Wang L, Zhou GB, Liu P, Song JH, Liang Y, Yan XJ, Xu F, Wang BS, Mao JH, Shen ZX, Chen SJ, Chen Z. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci U S A. 2008 Mar 25;105(12):4826-31. doi: 10.1073/pnas.0712365105. Epub 2008 Mar 14.

  PMID: 18344322 BACKGROUND

• Xiang Y, Wang XB, Sun SJ, Guo AX, Wei AH, Cheng YB, Huang SL. [Compound huangdai tablet as induction therapy for 193 patients with acute promyelocytic leukemia]. Zhonghua Xue Ye Xue Za Zhi. 2009 Jul;30(7):440-2. Chinese.

  PMID: 19954593 BACKGROUND

• Luo XQ, Ke ZY, Huang LB, Guan XQ, Zhang YC, Zhang XL. Improved outcome for Chinese children with acute promyelocytic leukemia: a comparison of two protocols. Pediatr Blood Cancer. 2009 Sep;53(3):325-8. doi: 10.1002/pbc.22042.

  PMID: 19422024 BACKGROUND

• Fan Z, Yang LC, Chen YQ, Wan WQ, Zhou DH, Mai HR, Li WL, Yang LH, Lan HK, Chen HQ, Guo BY, Zhen ZJ, Liu RY, Chen GH, Feng XQ, Liang C, Wang LN, Yu-Li, Luo JS, Huang DP, Luo XQ, Li B, Huang LB, Zhang XL, Tang YL. Prognostic significance of MRD and its correlation with arsenic concentration in pediatric acute promyelocytic leukemia: a retrospective study by SCCLG-APL group. Ther Adv Hematol. 2025 Jan 7;16:20406207241311774. doi: 10.1177/20406207241311774. eCollection 2025.

  PMID: 39781038 DERIVED

• Liao LH, Chen YQ, Huang DP, Wang LN, Ye ZL, Yang LH, Mai HR, Li Y, Liang C, Luo JS, Wang LN, Luo XQ, Tang YL, Zhang XL, Huang LB. The comparison of plasma arsenic concentration and urinary arsenic excretion during treatment with Realgar-Indigo naturalis formula and arsenic trioxide in children with acute promyelocytic leukemia. Cancer Chemother Pharmacol. 2022 Jul;90(1):45-52. doi: 10.1007/s00280-022-04449-9. Epub 2022 Jun 27.

  PMID: 35760920 DERIVED

MeSH Terms

Interventions

Arsenic Trioxide; Tretinoin; Mitoxantrone; Cytarabine; Methotrexate; Mercaptopurine; Injections, Spinal

Intervention Hierarchy (Ancestors)

Arsenicals; Inorganic Chemicals; Oxides; Oxygen Compounds; Vitamin A; Retinoids; Carotenoids; Polyenes; Alkenes; Hydrocarbons, Acyclic; Hydrocarbons; Organic Chemicals; Cyclohexenes; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Diterpenes; Pigments, Biological; Biological Factors; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Quinones; Polycyclic Compounds; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Sulfhydryl Compounds; Sulfur Compounds; Purines; Injections; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Xue-Qun Luo, professor

  First Affiliated Hospital, Sun Yat-Sen University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2014
• First Posted: July 25, 2014
• Study Start: September 1, 2011
• Primary Completion: October 1, 2021
• Study Completion: October 1, 2021
• Last Updated: May 10, 2022

Record last verified: 2022-05

Locations

CN (1)