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Trial Title:
Idarubicin Overcomes MDR1 Induced Chemoresistance With Higher Induction Remission Rate and Quality Than Daunorubicin in Acute Myeloid Leukemia Patients
NCT ID:
NCT01889407
Condition:
Acute Myeloid Leukemia
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Idarubicin
Conditions: Keywords:
Acute Myeloid Leukemia
Study type:
Observational [Patient Registry]
Overall status:
Unknown status
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Drug
Intervention name:
Idarubicin
Description:
8 mg/m2, iv drip on days 1-3
Arm group label:
IA regimen
Summary:
Whether Idarubicin can overcomes multidrug resistant 1 induced chemoresistance with higher
induction remission rate than daunorubicin in de novo acute myeloid leukemia patients.Whether
induction therapy with IA regimen has a higher remission quality with AML patients than that
of DA regimen in high MDR1 expression AML patients.
Detailed description:
The long-term survival rate of acute myeloid leukemia (AML) has been significantly prolonged
due to the improvement of chemotherapeutic protocols and hemopoietic stem cell
transplantation. However, about 20%-40% of the patients with refractory AML fail to achieve
complete remission (CR) and approximately 50% of the CR patients will relapse eventually. 1-3
The refractoried and relapsed AML patients have very poor prognosis, therefore refractoriness
and relapse are the major challenges for the chemotherapy of AML.
Chemoresistance is one of the major obstacle for the success of AML treatment.4 One of the
main mediators for AML chemoresistance is the multi-drug resistance-1(MDR1) gene and MDR1
protein, also known as permeability-glycoprotein or P-gp.5,6,7 Studies on leukemic blast
cells demonstrated the association of MDR1 expression with a lower intracellular retention of
cytostatic drugs leading to cancer cell resistance to several commonly used anti-cancer drugs
in chemotherapy. Several subsequent studies indicated the influence of MDR1 expression levels
in the treatment response and survival of leukemia patients, the frequency of resistance to
the chemotherapy increased with increasing MDR1 expression.8,9,10 Previous methods for
determination of MDR1 expression have included demonstration of P-glycoprotein by flow
cytometry and/or immunohistochemistry, and molecular polymerase chain reaction (PCR)-based
assays for RNA expression. However, these assays have either proven difficult to standardize
or tedious to perform and they are mainly focused on qualitative or semi-quantitative assays.
11,12 A real-time fluorescence quantitative PCR will increase the sensitivity and also
maintain the high specificity. The false positivity caused by pollution of amplification
production can also be decreased by hermetization operation. RQ- PCR is a novel methodology
which enables sensitive and quantitative measurement of gene expression. 12We have
established RQ-PCR method for determination expression of MDR1 gene. We have performed a
pilot study with a small cohort of AML patients to determine the relationship of MDR1
expression and CR rate of AML patients. The data shows MDR1 expression has been found in most
cases of AML. However, the MDR1 expression levels vary widely from case to case. This result
indicated that RQ-PCR method would provide an accurate quantitative measurement for detection
of MDR1 expression level in different AML cases who were both positive by qualitative RT-PCR
method. 13,14 The pilot results indicated that the complete response rate to induction
therapy was compromised by the expression of high levels of MDR1. 15
Minimal residual disease (MRD) is the major cause of leukemia relapse. It has been reported
that the treatment intensity in human leukemia can be assessed by the expression status of
MRD gene. However, more than 50% of acute leukemia, especially in AMLs, lack known genetic
lesions or clonegenic markers suitable for MRD monitoring. WT1 gene is located on chromosome
11p13 coding for a zinc-finger transcription factor, has been identified in most AML
patients. It has been reported that detection of WT1 levels can effectively monitor the MRD
expression status in AML.16,17 Therefore, WT1 expression can be used to monitor the MRD and
evaluation the remission quality in AML patients. By detecting WT1 levels we can evaluate the
efficacy of different induction therapies.
By employing multiple fluorescence quantitative PCR, several target genes can be
simultaneously and quantitatively amplified. Therefore multiple fluorescence quantitative PCR
is more suitable for clinical application. This technology will not only provide higher
accuracy, specificity and reproducibility but also simplify procedure and reduce measurement
cost. The recombinant plasmids of MDR1 and WT1 gene have been constructed and the methodology
of multiple fluorescence quantitative PCR has also been developed in our group .14
High MDR1 gene expression is a common feature of AML resistance to conventional
chemotherapeutic regimen.18,19 One of the strategies that overcome MDR is to increase the
pharmacal liposolubility and elevate the intracellular drug concentration, so as to
counteract drug efflux pumped by P-glycoprotein. Idarubicin (IDA), a new anthracycline, has
more strengthened liposolubility and can easily permeate the cell membrane in comparison with
traditional marcellomycin. Also, the in vivo metabolite of IDA (4-IDA) has the same
antineoplastic activity as IDA and a longer half-life in vivo. It can also permeate blood
brain barrier. As a result, IDA has a stronger antileukemia activity than other marcellomycin
and can partially overcome P-glycoprotein-mediated drug resistance.20, 21 In our recently
pilot study, we have detected the expression of MDR1 in pre-treated bone marrow samples from
160 de novo AML patients and the median value of MDR1/GAPDH ratio in the de novo AML cases
was 0.016(0-81.865). The median value of MDR1 gene expression was taken as the cut-off point
of high or low MDR1 gene expression levels. For high MDR1 expression patients, a lower CR
rate (61.3%) was observed compared with low-MDR1 expression patients (80.0%, P =0.009). In
this retrospective pilot study, 123 patients were received daunorubicin (DNR 35~45mg/m2/d,3
days) or idarubicin (IDA 6~8 mg/m2/d, 3 days) in combination with cytarabine (Ara-c100~200
mg/m2/d, 7 days) for remission induction and significant difference were also observed after
2 courses of chemotherapy between those who receive IA regimen (57 cases) and DA regimen (66
cases) regarding to CR rate (80.7% vs 57.6%, P=0.006). Significant difference could also be
discovered between two treatment arm with regard to CR rate (75.9% vs 43.6%, P=0.011) in
those who had high MDR1 expression AML patients. Our data shows that IDA may overcome MDR1
induced chemoresistance with a higher CR rate than DNR in de novo high MDR1 expresser AML
patients.These results provide rationale for development of randomized, prospective trial to
compare the CR rate of IA regimen and DA regimen in de novo AML patients with high MDR1
expression and to identify whether Idarubicin can overcomes MDR1 induced chemoresistance with
higher induction remission rate than daunorubicin in de novo acute myeloid leukemia patients.
We speculated that the more favorable outcome in high-MDR1 patient group with IA regimen may
be associated with a higher remission rate.
It had been reported that AML patients achieved lower MRD level had an extremely lower
relapse rate. It had also been reported that patients treated with IA regimen had a
significant higher long-term survival than those with DA regimen .22-24 Therefore, we
speculated that the more favorable outcome in IA group may be associated with a lower MRD
level and higher remission quality. This study is also to conduct a prospective analysis on
the alteration of WT1 and MDR1 gene expression level after induction therapy with IA or DA
separately to identify whether induction therapy with IA regimen has a lower MRD level and a
higher remission quality than that of DA regimen.
Criteria for eligibility:
Study pop:
• Patients aged 16 to 60 years are eligible. Patients must be chemo-naïve, i.e. not have
received any prior chemotherapy (except hydrea) for AML. They could have received
transfusion, hematopoietic growth factors or vitamins. Temporary measures such as pheresis
or hydrea (0.5 to 5g daily or more for up to 3 days) are allowed
Sampling method:
Probability Sample
Criteria:
Inclusion Criteria:
- • Diagnosis of AML (WHO classification definition of >/= 20% blasts).
- Patients aged 16 to 60 years are eligible. Patients must be chemo-naïve, i.e. not
have received any prior chemotherapy (except hydrea) for AML. They could have
received transfusion, hematopoietic growth factors or vitamins. Temporary
measures such as pheresis or hydrea (0.5 to 5g daily or more for up to 3 days)
are allowed.
- The relative expression level of MDR1 mRNA (MDR1/GAPDH ratio using the
quantitative real-time PCR) in pre-treated bone marrow samples should over 0.016
(cut-off point from our results of preliminary experiment data )
- ECOG PS of 0, 1, 2 at screening.
- Serum biochemical values with the following limits: - creatinine = 2.0 mg/dl -
total bilirubin = 2.0 mg/dL, unless increase is due to hemolysis -
transaminases (SG PT) = 3x ULN
- Ability to understand and provide signed informed consent.
Exclusion Criteria:
- • Subjects with Acute Promyelocytic Leukemia (APL).
- Presence of active systemic infection.
- Any coexisting medical condition that in the judgment of the treating physician
is likely to interfere with study procedures or results.
- Nursing women, women of childbearing potential with positive urine pregnancy
test, or women of childbearing potential who are not willing to maintain adequate
contraception (such as birth control pills, IUD, diaphragm, abstinence, or
condoms by their partner) over the entire course of the study.
Gender:
All
Minimum age:
14 Years
Maximum age:
60 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
Bing Xu
Address:
City:
GuangZhou
Zip:
510515
Country:
China
Status:
Recruiting
Contact:
Last name:
Bing Xu, M.D
Phone:
13189096353
Email:
xubingzhangjian@126.com
Contact backup:
Last name:
Xutao Guo, M.D
Phone:
13802426709
Email:
gxt827@126.com
Investigator:
Last name:
Bing Xu, M.D
Email:
Principal Investigator
Start date:
August 2013
Completion date:
July 2016
Lead sponsor:
Agency:
Nanfang Hospital, Southern Medical University
Agency class:
Other
Collaborator:
Agency:
Pfizer
Agency class:
Industry
Source:
Nanfang Hospital, Southern Medical University
Record processing date:
ClinicalTrials.gov processed this data on April 10, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01889407
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