Cytarabine (Ara-C) in Children With Acute Promyelocytic Leukemia (APL)
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
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
- 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.
- 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
- 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
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
- CCAPL2010
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
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 |
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%
|
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
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 |
xfzhu@ihcams.ac.cn |
- CCAPL2010