Description:
Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML)
characterized by consistent clinical, morphologic, and genetic features. According to the FAB
classification APL is designated as"M3 leukemia" and assigned to the WHO defined type of AML
with recurrent cytogenetic abnormalities, "acute promyelocytic leukemia with
t(15;17)(q22;q12), (PML/RARα) and variants".
Despite the dramatic progress achieved in frontline therapy of APL with ATRA plus
anthracycline-based regimens, relapses still occur in approximately 20% of patients.
Moreover, these regimens are associated with significant toxicities due to severe
myelosuppression frequently associated with life-threatening infections and potentially
serious late effects including development of secondary MDS/AML. In a recent randomized
clinical trial in low/intermediate-risk APL (WBC ≤ 10 GPt/l APL0406 trial) a combination of
arsenic trioxide (ATO) and ATRA has been shown to result into better survival with
significantly lower toxicity rates compared to the standard ATRA + idarubicin (AIDA) therapy.
Inspired by the results of this trial the investigators intend to perform a randomized study
in high-risk APL (WBC at diagnosis > 10 GPt/l) comparing standard AIDA-based treatment with
ATO/ATRA combination including low-doses idarubicin during induction. The investigators
propose a modified ATO/ATRA protocol with the addition of two doses of IDA (50% compared to
standard AIDA induction) for induction because of the anticipated need of adding
anthracyclines to control hyperleukocytosis and to achieve long-term disease control in this
high-risk APL population. This is followed by 4 cycles of ATO/ATRA consolidation therapy. As
in the APL0406 study for low/intermediate-risk patients the investigators expect less severe
hematologic toxicity and treatment-related mortality resulting in an improved outcome for
patients in the experimental arm. Furthermore, from the start of consolidation, these
patients (in contrast to the standard arm) can be treated on an outpatient basis, which is
also considered to be associated with an improved quality of life. The study will be
conducted as a European intergroup study.
Title
- Brief Title: Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
- Official Title: A Randomized Phase III Study to Compare Arsenic Trioxide (ATO) Combined to ATRA and Idarubicin Versus Standard ATRA and Anthracyclines-based Chemotherapy (AIDA Regimen) for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia
Clinical Trial IDs
- ORG STUDY ID:
TUD-APOLLO-064
- NCT ID:
NCT02688140
Conditions
- Acute Promyelocytic Leukemia
Interventions
Drug | Synonyms | Arms |
---|
Arsenic trioxide | ATO, Trisenox (R), As2O3 | Arm A |
Idarubicin | IDA | Arm A |
Cytarabine | Ara-C | Arm B (standard chemotherapy) |
Tretinoin | all-trans retinoic acid, ATRA | Arm A |
Mitoxantrone | MTZ | Arm B (standard chemotherapy) |
Mercaptopurine | 6-Mercaptopurine, 6-MP | Arm B (standard chemotherapy) |
Methotrexate | MTX | Arm B (standard chemotherapy) |
Purpose
Acute promyelocytic leukemia (APL) is a rare subtype of acute myeloid leukemia (AML)
characterized by consistent clinical, morphologic, and genetic features. According to the FAB
classification APL is designated as"M3 leukemia" and assigned to the WHO defined type of AML
with recurrent cytogenetic abnormalities, "acute promyelocytic leukemia with
t(15;17)(q22;q12), (PML/RARα) and variants".
Despite the dramatic progress achieved in frontline therapy of APL with ATRA plus
anthracycline-based regimens, relapses still occur in approximately 20% of patients.
Moreover, these regimens are associated with significant toxicities due to severe
myelosuppression frequently associated with life-threatening infections and potentially
serious late effects including development of secondary MDS/AML. In a recent randomized
clinical trial in low/intermediate-risk APL (WBC ≤ 10 GPt/l APL0406 trial) a combination of
arsenic trioxide (ATO) and ATRA has been shown to result into better survival with
significantly lower toxicity rates compared to the standard ATRA + idarubicin (AIDA) therapy.
Inspired by the results of this trial the investigators intend to perform a randomized study
in high-risk APL (WBC at diagnosis > 10 GPt/l) comparing standard AIDA-based treatment with
ATO/ATRA combination including low-doses idarubicin during induction. The investigators
propose a modified ATO/ATRA protocol with the addition of two doses of IDA (50% compared to
standard AIDA induction) for induction because of the anticipated need of adding
anthracyclines to control hyperleukocytosis and to achieve long-term disease control in this
high-risk APL population. This is followed by 4 cycles of ATO/ATRA consolidation therapy. As
in the APL0406 study for low/intermediate-risk patients the investigators expect less severe
hematologic toxicity and treatment-related mortality resulting in an improved outcome for
patients in the experimental arm. Furthermore, from the start of consolidation, these
patients (in contrast to the standard arm) can be treated on an outpatient basis, which is
also considered to be associated with an improved quality of life. The study will be
conducted as a European intergroup study.
Trial Arms
Name | Type | Description | Interventions |
---|
Arm A | Experimental | Induction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1 and 3, oral tretinoin twice daily on day 1-28 (max. up to day 60) and arsenic trioxide i.v. over 2 hours on day 5-28 (max. up to day 60).
In case of morphological CR and regenerated blood counts, consolidation therapy should be started within 2-4 weeks after documented CR.
Consolidation therapy: Patients receive oral tretinoin twice daily on day 1-14. Treatment with tretinoin repeats every 4 weeks for up to 7 courses. Patients also receive arsenic trioxide i.v. over 2 hours on days 1-5 in week 1-4. Treatment with arsenic trioxide repeats every 8 weeks for up to 4 courses. | - Arsenic trioxide
- Idarubicin
- Tretinoin
|
Arm B (standard chemotherapy) | Active Comparator | Induction therapy: Patients receive idarubicin i.v. over 20 minutes on day 1,3,5 and 7, oral tretinoin twice daily on day 1-28 (max. up to day 60).
In case of morphological CR and regenerated blood counts, consolidation therapy should be started within 2-4 weeks after documented CR.
Consolidation I:
IDA 5 mg/m2 i.v. day 1-4 Ara-C 1000 mg/m2/3h i.v. day 1-4 ATRA 45 mg/m2 p.o. day 1-15
Consolidation II:
MTZ 10 mg/m2 i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15
Consolidation III:
IDA 12 mg/m2 i.v. day 1 Ara-C 150 mg/m2 every 8h i.v. day 1-5 ATRA 45 mg/m2 p.o. day 1-15
Maintenance (duration 7 cycles = 2 years; one cycle lasts 106 days):
6-MP 50 mg/m2 p.o. Cycle 1-7: day 1-91 (followed by 15 days of ATRA on days 92-106)
MTX 15mg/m2 i.m./p.o. Cycle 1-7: once weekly for 91 days (followed by 15 days of ATRA on days 92-106)
ATRA 45 mg/m2 p.o. Cycle 1-6: day 92-106 Cycle 7: without ATRA Administration
(treatment break of 6-MP and MTX during ATRA administration) | - Idarubicin
- Cytarabine
- Tretinoin
- Mitoxantrone
- Mercaptopurine
- Methotrexate
|
Eligibility Criteria
Inclusion Criteria:
- Informed consent
- Women or men with a newly diagnosed APL by cytomorphology, confirmed by molecular
analysis*
- Age ≥ 18 and ≤ 65 years
- ECOG performance status 0-3
- WBC at diagnosis > 10 GPt/l
- Serum total bilirubin ≤ 3.0 mg/dl (≤ 51 µmol/l)
- Serum creatinine ≤ 3.0 mg/dl (≤ 260 µmol/l)
- Women must fulfill at least one of the following criteria in order to be eligible for
trial inclusion:
- Post-menopausal (12 months of natural amenorrhea or 6 months of amenorrhea with Serum
FSH > 40 U/ml)
- Postoperative (i.e. 6 weeks) after bilateral ovariectomy with or without hysterectomy
- Continuous and correct application of a contraception method with a Pearl Index of <1%
(e.g. implants, depots, oral contraceptives, -intrauterine device - IUD)
- Sexual abstinence
- Vasectomy of the sexual partner
- The confirmation of diagnosis at genetic level (microspeckled PML nuclear
distribution by PGM3 monoclonal antibody and/or PML/RARa fusion by RT-PCR or
fluorescence in situ hybridization (FISH) and/or demonstration of t(15;17) at
karyotyping) will be mandatory for patient eligibility. However, in order to
avoid delay in treatment initiation, patients can be randomized on the basis of
morphologic diagnosis only and before the results of genetic tests are available
Exclusion Criteria:
- Patients who are not eligible for chemotherapy as per discretion of the treating
physician
- APL secondary to previous radio- or chemotherapy for non-APL disease
- Other active malignancy at time of study entry (exception: basal-cell carcinoma)
- Lack of diagnostic confirmation at genetic level
- Significant arrhythmias, ECG abnormalities:
- Congenital long QT syndrome;
- History or presence of significant ventricular or atrial tachyarrhythmia;
- Clinically significant resting bradycardia (<50 beats per minute)
- QTc >500msec on screening ECG for both genders (using the QTcF formula detailed on
protocol)
- Right bundle branch block plus left anterior hemiblock, bifascicular block
- Other cardiac contraindications for intensive chemotherapy (L-VEF <50%)
- Uncontrolled, life-threatening infections
- Severe non controlled pulmonary or cardiac disease
- Severe hepatic or renal dysfunction
- HIV and/or active hepatitis C infection
- Pregnant or breast-feeding patients
- Allergy to trial medication or excipients in study medication
- Substance abuse; medical, psychological or social conditions that may interfere with
the patients participation in the study or evaluation of the study results
- Use of other investigational drugs at the time of enrolment or within 30 days before
study entry
Maximum Eligible Age: | 65 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Event-free survival |
Time Frame: | From date of randomization until the date of first documented event, assessed up to 66 months |
Safety Issue: | |
Description: | events are: no achievement of haematological complete remission after induction therapy; no achievement of molecular remission after the last consolidation course; relapse; death including early death or development of secondary AML or MDS |
Secondary Outcome Measures
Measure: | Rate of hematological complete remission |
Time Frame: | up to 60 days, from date of randomization until end of induction therapy |
Safety Issue: | |
Description: | |
Measure: | Rate of early death within 30 days after randomization |
Time Frame: | up to 30 days after randomization |
Safety Issue: | |
Description: | |
Measure: | Rate of overall survival (OS) |
Time Frame: | at 2 years |
Safety Issue: | |
Description: | |
Measure: | Rate of cumulative incidence of secondary MDS or AML |
Time Frame: | assessed up to 66 months, from date of randomization until occurance of secondary AML or MDS |
Safety Issue: | |
Description: | |
Measure: | Rate of cumulative incidence of relapse (CIR) |
Time Frame: | at 2 years |
Safety Issue: | |
Description: | |
Measure: | Incidence of hematological and non-hematological toxicity |
Time Frame: | assessed up to 30 months after randomization |
Safety Issue: | |
Description: | |
Measure: | Rate of molecular remission after the last consolidation cycle |
Time Frame: | up to 256 days after randomization |
Safety Issue: | |
Description: | |
Measure: | Assessment of acute promyelocytic leukemia/RARa transcript level reduction after induction therapy until end of study |
Time Frame: | assessed up to 30 months after randomization |
Safety Issue: | |
Description: | |
Measure: | Quality of Life at the end of induction therapy until the end of study |
Time Frame: | assessed up to 30 months after randomization |
Safety Issue: | |
Description: | |
Measure: | To investigate differences in the immune reconstitution between the two arms |
Time Frame: | assessed up to 30 months after randomization |
Safety Issue: | |
Description: | |
Measure: | Total hospitalization days during therapy |
Time Frame: | assessed up to 30 months after randomization |
Safety Issue: | |
Description: | |
Details
Phase: | Phase 3 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | Technische Universität Dresden |
Trial Keywords
- APL
- acute promyelocytic leukemia (M3)
- high-risk acute promyelocytic leukemia (APL/AML M3)
- acute myeloid leukemia with t(15;17)(q22;q12)
- newly diagnosed
- high-risk
Last Updated
August 19, 2021