Study for Patients With Newly Diagnosed, High-risk Acute Promyelocytic Leukemia

NCT02688140 | Completed Phase 3 DMC

• 1 other identifier: TUD-APOLLO-064
• Study Type: interventional
• Target: 135
• Locations: 5 countries
• Sites: 8

Brief Summary

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.

Conditions

Acute Promyelocytic Leukemia

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

Outcome Measures

Primary Outcomes (1)

• Event-free survival

  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

  From date of randomization until the date of first documented event, assessed up to 66 months

Secondary Outcomes (11)

• Rate of hematological complete remission

  up to 60 days, from date of randomization until end of induction therapy

• Rate of early death within 30 days after randomization

  up to 30 days after randomization

• Rate of overall survival (OS)

  at 2 years

• Rate of cumulative incidence of secondary MDS or AML

  assessed up to 66 months, from date of randomization until occurance of secondary AML or MDS

• Rate of cumulative incidence of relapse (CIR)

  at 2 years

Study Arms (2)

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.

Drug: Arsenic trioxide; Drug: Idarubicin; Drug: 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)

Drug: Idarubicin; Drug: Cytarabine; Drug: Tretinoin; Drug: Mitoxantrone; Drug: Mercaptopurine; Drug: Methotrexate

Interventions

Arsenic trioxide DRUG

Also known as: ATO, Trisenox (R), As2O3

Arm A

Idarubicin DRUG

Also known as: IDA

Arm A; Arm B (standard chemotherapy)

Cytarabine DRUG

Also known as: Ara-C

Arm B (standard chemotherapy)

Tretinoin DRUG

Also known as: all-trans retinoic acid, ATRA

Arm A; Arm B (standard chemotherapy)

Mitoxantrone DRUG

Also known as: MTZ

Arm B (standard chemotherapy)

Mercaptopurine DRUG

Also known as: 6-Mercaptopurine, 6-MP

Arm B (standard chemotherapy)

Methotrexate DRUG

Also known as: MTX

Arm B (standard chemotherapy)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Technische Universität Dresden: lead
• Gruppo Italiano Malattie EMatologiche dell'Adulto: collaborator
• Groupe Francophone des Myelodysplasies: collaborator
• HOVON - Dutch Haemato-Oncology Association: collaborator
• Programa para el Tratamiento de Hemopatías Malignas: collaborator
• German Federal Ministry of Education and Research: collaborator
• Teva Pharmaceuticals Europe: collaborator

Study Sites (8)

French-Belgian-Swiss APL study group

Multiple Locations, France

Location

AML-CG study group

Multiple Locations, Germany

Location

AML-SG study group

Multiple Locations, Germany

Location

OSHO study group

Multiple Locations, Germany

Location

SAL study group

Multiple Locations, Germany

Location

GIMEMA study group

Multiple Locations, Italy

Location

HOVON study group

Multiple Locations, Netherlands

Location

PETHEMA study group

Multiple Locations, Spain

Location

Related Publications (1)

• Platzbecker U, Ades L, Montesinos P, Ammatuna E, Fenaux P, Baldus C, Bernardi M, Berthon C, Bocchia M, Bonmati C, Borlenghi E, Bornhauser M, Carp D, Chantepie S, Crea E, Divona M, Dohner H, Ehninger G, Esteve Reyner J, Frayfer J, Garrido Diaz A, Gil C, Guarnera L, Hamm AF, Heiblig M, Heidenreich D, Kramer AJ, Ledoux MP, Lunghi M, Mancini V, Metzeler K, Miggiano MC, Muller-Tidow C, Peterlin P, Piciocchi A, Rieger K, Rollig C, Rossi G, Sanz MA, Serve H, Sohne M, Spiekermann K, Tavernier-Tardy E, Thiede C, Vives Polo S, Vogel W, Zappasodi P, Ziller-Walter P, Voso MT; SAL, AMCL-CG, AML-SG, OSHO, PETHEMA, HOVON and GIMEMA study groups. Arsenic Trioxide and All-Trans Retinoic Acid Combination Therapy for the Treatment of High-Risk Acute Promyelocytic Leukemia: Results From the APOLLO Trial. J Clin Oncol. 2025 Oct 10;43(29):3160-3169. doi: 10.1200/JCO-25-00535. Epub 2025 Aug 18.

  PMID: 40825164 DERIVED

MeSH Terms

Conditions

Leukemia, Promyelocytic, Acute

Interventions

Arsenic Trioxide; Idarubicin; Cytarabine; Tretinoin; Mitoxantrone; Mercaptopurine; Methotrexate

Condition Hierarchy (Ancestors)

Leukemia, Myeloid, Acute; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Uwe Platzbecker, Prof. Dr.

  Technische Universität Dresden (TUD)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 11, 2016
• First Posted: February 23, 2016
• Study Start: June 1, 2016
• Primary Completion: January 20, 2025
• Study Completion: January 20, 2025
• Last Updated: February 26, 2025

Record last verified: 2025-02

Locations

FR (1); NL (1); ES (1); DE (4); IT (1)