Cytarabine (Ara-C) in Children With Acute Promyelocytic Leukemia (APL)

Sponsor
Xiaofan Zhu (Other)
Overall Status
Completed
CT.gov ID
NCT01191541
Collaborator
(none)
65
2
2
81.1
32.5
0.4

Study Details

Study Description

Brief Summary

Several groups, especially the PETHEMA group (in their LPA96 and 99 trials), obtained low relapse rates in newly diagnosed Acute Promyelocytic Leukemia (APL) patients by combining ll-transretinoic acid (ATRA) and anthracyclines without Ara-C, suggesting that avoiding Ara-C in the chemotherapy of APL reduced treatment toxicity without increasing relapses. While the relapse rate for the children with white blood cell(WBC) counts greater than 10×109/L at presentation were higher than those WBC counts less than 10×109/L (31% and 3.5%,respectively) in the LPA96 and 99 trials. A recent adult randomized trial show that avoiding Ara-C leads to an increased risk of relapse in the APL patients with WBC counts less than 10×109/L. The role of the Ara-C remains controversial. And there are very limited data reported on children with APL so far.

Condition or Disease Intervention/Treatment Phase
Phase 4

Detailed Description

Some studies suggest patients with high-risk disease should be treated with intensified doses of anthracycline, or intermediate/ high-dose Ara-C or As2O3 as an early consolidation, so as to decrease the risk of relapse.However, a higher cumulative dose of anthracycline may lead to cardiac toxicity, especially for children. In addition, containing Ara-C will led to more therapy-related toxicity. The benefit to add Ara-C to the schedules is questionable and remains a matter of investigation in children.

Study Design

Study Type:
Interventional
Actual Enrollment :
65 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Treatment of Newly Diagnosed Patients With Acute Promyelocytic Leukemia in Children: Remission Induction With All-transretinoic Acid (ATRA) and Arsenic Trioxide (As2O3). Consolidation With Daunorubicin(DNR)+Ara-c or DNR Alone.
Actual Study Start Date :
May 1, 2010
Actual Primary Completion Date :
Feb 1, 2017
Actual Study Completion Date :
Feb 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: DNR+Ara-c(Ara-C group)

patients in this group were treated with DNR+Ara-C in consolidation

Drug: DNR:
DNR:45mg/m2 d1-3

Drug: Ara-c
DNR+ARA-C:DNR:45mg/m2 d1-3;Ara-C :1g/m2 d1-3

Experimental: DNR(No Ara-C group)

patients in this group were treated with DNR alone in consolidation

Drug: DNR:
DNR:45mg/m2 d1-3

Outcome Measures

Primary Outcome Measures

  1. the Overall Survival of APL Patients Treated With Retinoic Acid Receptor Alpha (ATRA) and Arsenic Trioxide (ATO) Based Trial [two years]

    We assessed the OS of APL patients when ATRA and ATO were used. The overall survival (OS) durations was calculated from the date of diagnosis to last follow-up or death.

  2. the Event-free Survival (EFS) of APL Patients Treated With Retinoic Acid Receptor Alpha (ATRA) and Arsenic Trioxide (ATO) Based Trial [2 years]

    We assessed the EFS of APL patients treated with retinoic acid receptor alpha (ATRA) and Arsenic Trioxide (ATO) based trial. Event-free survival (EFS) was defined as time from diagnosis to last follow-up or an event (relapse or death).

Secondary Outcome Measures

  1. Number of Participants With Side Effects [three years]

    Also, we compared the side effect and outcome between the two groups.To assessed whether Ara-C could be omitted when ATO and ATRA were used.

Eligibility Criteria

Criteria

Ages Eligible for Study:
1 Year to 14 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Acute Promyelocytic Leukemia (APL)
Exclusion Criteria:
  • 14

Contacts and Locations

Locations

Site City State Country Postal Code
1 Institute of Hematology & Blood Diseases Hospital Tianjin Tianjin China 300020
2 Department of Pediatrics, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, PR China Tianjin China 300020

Sponsors and Collaborators

  • Xiaofan Zhu

Investigators

  • Principal Investigator: Xiaofan Zhu, MD, Department of Pediatrics, CAMS&PUMC

Study Documents (Full-Text)

More Information

Publications

Responsible Party:
Xiaofan Zhu, chief physician, Chinese Academy of Medical Sciences
ClinicalTrials.gov Identifier:
NCT01191541
Other Study ID Numbers:
  • CCAPL2010
First Posted:
Aug 31, 2010
Last Update Posted:
Aug 10, 2021
Last Verified:
Aug 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Xiaofan Zhu, chief physician, Chinese Academy of Medical Sciences
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details Eligible patients were those who were less than 14 years old, were newly diagnosed with APL, and had not previously received chemotherapy. Sixty-five patients were included in the study.
Pre-assignment Detail The demonstration of PML-RARA transcripts, was required for inclusion in the analysis.
Arm/Group Title Daunorubicin(DNR)+Ara-c (Ara-C Group) DNR (No Ara-c Group)
Arm/Group Description one group treated with daunorubicin(DNR)+Ara-C in consolidation Only DNR was used in consolidation
Period Title: All the Patients
STARTED 30 35
COMPLETED 30 35
NOT COMPLETED 0 0
Period Title: All the Patients
STARTED 30 35
COMPLETED 30 35
NOT COMPLETED 0 0

Baseline Characteristics

Arm/Group Title DNR+Ara-c DNR( no Ara-C) Total
Arm/Group Description one group treated with DNR+Ara-C one group treated with DNR Total of all reporting groups
Overall Participants 30 35 65
Age (Count of Participants)
<=18 years
30
100%
35
100%
65
100%
Between 18 and 65 years
0
0%
0
0%
0
0%
>=65 years
0
0%
0
0%
0
0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]
8
7
8
Sex: Female, Male (Count of Participants)
Female
10
33.3%
13
37.1%
23
35.4%
Male
20
66.7%
22
62.9%
42
64.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
30
100%
35
100%
65
100%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
White
0
0%
0
0%
0
0%
More than one race
0
0%
0
0%
0
0%
Unknown or Not Reported
0
0%
0
0%
0
0%
Region of Enrollment (participants) [Number]
China
30
100%
35
100%
65
100%
white blood cell count (cells x 10^9/L) [Median (Full Range) ]
Median (Full Range) [cells x 10^9/L]
4.23
5.47
4.71
Haemoglobin (g/L) [Median (Full Range) ]
Median (Full Range) [g/L]
78
81.0
78
Platelet count (cells x 10^9/L) [Median (Full Range) ]
Median (Full Range) [cells x 10^9/L]
24.5
32.0
30.5

Outcome Measures

1. Primary Outcome
Title the Overall Survival of APL Patients Treated With Retinoic Acid Receptor Alpha (ATRA) and Arsenic Trioxide (ATO) Based Trial
Description We assessed the OS of APL patients when ATRA and ATO were used. The overall survival (OS) durations was calculated from the date of diagnosis to last follow-up or death.
Time Frame two years

Outcome Measure Data

Analysis Population Description
There were 65 patients included in our study, including 35 in the DNR group and 30 in the DNR+Ara-C group.
Arm/Group Title DNR Group DNR+Ara-C Group
Arm/Group Description the patients in this group were treated with DNR alone in consolidation the patients in this group were treated with DNR +Ara-C in consolidation
Measure Participants 35 30
relapse
1
3.3%
0
0%
died
0
0%
0
0%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection DNR Group, DNR+Ara-C Group
Comments The characteristics of all of the included patients were summarized using cross-tabulations (for categorical variables) and quantiles. Nonparametric tests were used to analyse comparisons between groups .EFS、disease-free survival (DFS) and OS were estimated using the Kaplan -Meier method, and log-rank tests were used. All P values were two-sided, and those with values of 0.05 or less were considered to be statistically significant.
Type of Statistical Test Non-Inferiority
Comments The primary objective was to demonstrate the noninferiority of DNR alone to DNR+ARA-C in the rate of DFS at 2 years. Assuming a 95% rate of DFS in the two groups, a margin of -15% , 5% type 1 error, 80% power, 30 evaluable patients per group were required to draw a noninferiority conclusion.
Statistical Test of Hypothesis p-Value <0.05
Comments the p-value is not adjusted
Method Log Rank
Comments
2. Primary Outcome
Title the Event-free Survival (EFS) of APL Patients Treated With Retinoic Acid Receptor Alpha (ATRA) and Arsenic Trioxide (ATO) Based Trial
Description We assessed the EFS of APL patients treated with retinoic acid receptor alpha (ATRA) and Arsenic Trioxide (ATO) based trial. Event-free survival (EFS) was defined as time from diagnosis to last follow-up or an event (relapse or death).
Time Frame 2 years

Outcome Measure Data

Analysis Population Description
There were 65 patients included in our study, including 35 in the DNR group and 30 in the DNR+Ara-C group.
Arm/Group Title DNR+Ara-c(Ara-C Group) DNR(No Ara-C Group)
Arm/Group Description patients in this group were treated with DNR+Ara-C in consolidation DNR:: DNR:45mg/m2 d1-3 Ara-c: DNR+ARA-C:DNR:45mg/m2 d1-3;Ara-C :1g/m2 d1-3 patients in this group were treated with DNR alone in consolidation DNR:: DNR:45mg/m2 d1-3
Measure Participants 30 35
relapse
0
0%
1
2.9%
die
0
0%
0
0%
3. Secondary Outcome
Title Number of Participants With Side Effects
Description Also, we compared the side effect and outcome between the two groups.To assessed whether Ara-C could be omitted when ATO and ATRA were used.
Time Frame three years

Outcome Measure Data

Analysis Population Description
There were 66 patients included in our study. One patient gave up treatment due to the economic reasons. Then the number of the patients were 65, including 35 in the DNR group and 30 in the DNR+Ara-C group.
Arm/Group Title DNR+Ara-c (Ara-C Group) DNR (No Ara-c Group)
Arm/Group Description one group treated with DNR+Ara-C in consolidation Only DNR was used in consolidation
Measure Participants 30 35
sepsis
5
16.7%
1
2.9%
platelet transfusion
26
86.7%
0
0%
red blood cell transfusion
7
23.3%
7
20%
relapse
0
0%
1
2.9%

Adverse Events

Time Frame Between May 2010 and December 2016, 65 consecutive paediatric (≤14years old) patients who were genetically confirmed with a new diagnosis of APL were admitted in our hospital.The follow-up of the patients was updated on Jan 2017 and included a median of 32 months (range, 1 to 79). The adverse event data were collected from the patient enrolled in our trials.The median period of time were 32 months (range, 1 to 79).
Adverse Event Reporting Description All adverse events described were founded during the course of induction therapy.
Arm/Group Title All the Patients at Presentation the Adverse Events Associated With ATRA the Adverse Events Associated With ATO Consolidation: IDA Consolidation: ATO Consolidation: DNR (No Ara-c Group) Consolidation: DNR+Ara-c (Ara-C Group) Maintenance: ATRA+MTX+6-MP
Arm/Group Description Between May 2010 and December 2016, 65 consecutive paediatric (≤14 years of age) patients who were genetically confirmed with a new diagnosis of APL were admitted in our hospital. There were 65 patients were treated with ATRA and ATO in induction. There were 65 patients were treated with ATRA and ATO in induction. There were 65 patients were treated with IDA in consolidation. . There were 65 patients were treated with ATO in consolidation. There were 35 patients were treated with DNR in consolidation. There were 30 patients were treated with DNR+ARA-C in consolidation. There were 65 patients were treated with maintenance.
All Cause Mortality
All the Patients at Presentation the Adverse Events Associated With ATRA the Adverse Events Associated With ATO Consolidation: IDA Consolidation: ATO Consolidation: DNR (No Ara-c Group) Consolidation: DNR+Ara-c (Ara-C Group) Maintenance: ATRA+MTX+6-MP
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/65 (0%) 0/65 (0%) 0/65 (0%) 0/65 (0%) 0/65 (0%) 0/35 (0%) 0/30 (0%) 0/65 (0%)
Serious Adverse Events
All the Patients at Presentation the Adverse Events Associated With ATRA the Adverse Events Associated With ATO Consolidation: IDA Consolidation: ATO Consolidation: DNR (No Ara-c Group) Consolidation: DNR+Ara-c (Ara-C Group) Maintenance: ATRA+MTX+6-MP
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 12/65 (18.5%) 2/65 (3.1%) 1/65 (1.5%) 0/65 (0%) 0/65 (0%) 0/35 (0%) 0/30 (0%) 0/65 (0%)
Blood and lymphatic system disorders
retinoic acid syndrome 0/65 (0%) 0 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Cardiac disorders
cardiac arrhythmia 0/65 (0%) 0 0/65 (0%) 0 1/65 (1.5%) 1 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Eye disorders
intraocular bleeding 6/65 (9.2%) 6 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Nervous system disorders
intracranial bleeding 4/65 (6.2%) 4 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/30 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Vascular disorders
mild partial splenic embolization 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Other (Not Including Serious) Adverse Events
All the Patients at Presentation the Adverse Events Associated With ATRA the Adverse Events Associated With ATO Consolidation: IDA Consolidation: ATO Consolidation: DNR (No Ara-c Group) Consolidation: DNR+Ara-c (Ara-C Group) Maintenance: ATRA+MTX+6-MP
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/65 (0%) 55/65 (84.6%) 21/65 (32.3%) 3/65 (4.6%) 0/65 (0%) 0/35 (0%) 0/30 (0%) 0/65 (0%)
Blood and lymphatic system disorders
retinoic acid syndrome 0/65 (0%) 0 7/65 (10.8%) 7 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Cardiac disorders
asymptomatic QTc prolongation 0/65 (0%) 0 0/65 (0%) 0 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Gastrointestinal disorders
nausea 0/65 (0%) 0 7/65 (10.8%) 7 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
abdominal pain 0/65 (0%) 0 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
General disorders
extremity oedema 0/65 (0%) 0 0/65 (0%) 0 9/65 (13.8%) 9 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
headache 0/65 (0%) 0 24/65 (36.9%) 24 0/65 (0%) 0 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Hepatobiliary disorders
hepatotoxicity 0/65 (0%) 0 0/65 (0%) 0 4/65 (6.2%) 4 3/65 (4.6%) 3 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Musculoskeletal and connective tissue disorders
bone ache 0/65 (0%) 0 8/65 (12.3%) 8 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0
Skin and subcutaneous tissue disorders
skin pigmentation 0/65 (0%) 0 7/65 (10.8%) 7 2/65 (3.1%) 2 0/65 (0%) 0 0/65 (0%) 0 0/35 (0%) 0 0/30 (0%) 0 0/65 (0%) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title xiaofan Zhu
Organization Department of pediatrics, Institute of Hematology and Blood Diseases Hospital.
Phone +86 22 23909001
Email xfzhu@ihcams.ac.cn
Responsible Party:
Xiaofan Zhu, chief physician, Chinese Academy of Medical Sciences
ClinicalTrials.gov Identifier:
NCT01191541
Other Study ID Numbers:
  • CCAPL2010
First Posted:
Aug 31, 2010
Last Update Posted:
Aug 10, 2021
Last Verified:
Aug 1, 2021