Trial document





This trial has been registered retrospectively.
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  DRKS00004313

Trial Description

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Title

Randomized comparison of two different treatment concepts in newly diagnosed acute promyelocytic leukemia (APL).
A randomized study for comparison of the effects of ATRA and intensified double induction therapy incorporating high dose ara-C followed by TAD consolidation and cyclic maintenance therapy (AMLCG concept) and induction therapy with ATRA and idarubicin (AIDA) followed by three anthracyclin/ATRA- based consloidation courses and maintenance therapy (PETHEMA conzept).



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Trial Acronym

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URL of the Trial

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Brief Summary in Lay Language

In international trials of first line therapy of acute promyelocytic leukemia (APL) was shown, that the combination of the differentiating substance ATRA (all-trans retinoic acid) with chemotherapy has doubled the cure rate in comparison to the previously used concepts with chemotherapy alone. Another important result of the studies showed, that only patients who had reached a molecular remission (no persistence of leukemic cells can be found using highly sensitive molecular tests) achieved durable remission and cure.
In the present study, patients with newly diagnosed APL are randomly (distribution by chance) assigned to two established treatment concepts, which are compared. In both concepts chemotherapy is combined with ATRA.
The available study results show, that the concept of the German AMLCG (Acute Myeloid Leukemia Cooperative Group) is highly efficient, but relatively toxic. The data further show that the patients may reach the molecular remission relatively fast. In contrast, the treatment of the Spanish Study Group (PETHEMA) seems to be less toxic, but showed more relapses, and the molecular remission seems to be reached later.
In the present study, the molecular kinetics of the leukemic cell burden and the rates of hematological (no leukemia seen by microscopy) and molecular remissions should be compared in both arms. In addition, the early death rate, and the toxicity as well as remission duration and overall survival should be compared. It is the aim of the study to optimize the treatment of this type of leukemia, that means to reach an antileukemic efficiency as high as possible in combination with side effects as low as possible.

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Brief Summary in Scientific Language

Aim of the study is the randomized comparison of two well estabished treatment startegies
with regard to antileukemic effectiveness (hematological and molecular response, kinetics of minimal residual disease) and to toxicity and early death rate




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Organizational Data

  •   DRKS00004313
  •   2012/08/20
  •   [---]*
  •   yes
  •   Approved
  •   135/04, Medizinische Ethik-Kommission II Medizinische Fakultät Mannheim der Universität Heidelberg
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Secondary IDs

  •   / 
  •   4022949 
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Health Condition or Problem studied

  •   C92.4 -  Acute promyelocytic leukaemia
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Interventions/Observational Groups

  •   AMLCG arm:
    The treatment concept consists of induction therapy (double induction), consolidation therapy and maintenance therapy. The treatment intensification is stratified according to the age of the patient. The induction therapy consists of all-trans-retinoic acid (Vesanoid®) 45 mg/m²/day and simultaneous chemotherapy with TAD. The second induction cycle, HAM with high dose cytarabine (ara-C) is scheduled at day 21 after the start of TAD, independent of the recovery of peripheral blood counts. In elderly patients aged over 60 years the second induction cycle (HAM with reduced ara-C-dose) is at the discretion of the treating physician. ATRA is continued until complete hematological remission or for a maximum of 90 days. Details of therapy: TAD: 6-thioguanine (6-TG) 100 mg/m² orally every 12 hours (h), days 3-9, ara-C 100 mg/m² by continuous intravenous (i.v.) infusion, days 1-2, thereafter 100 mg/m² as i.v. infusion every 12h, days 3-8, daunorubicin (DNR) 60 mg/m² i.v. infusion, days 3-5. HAM: ara-C 3g/m² (in patients over 60 years 1g/m² instead of 3g/m²) i.v. infusion every 12h, days 1-3, mitoxantrone 10 mg/m² i.v. infusion, days 3-5. Consolidation therapy with one cycle TAD starts two to four weeks after CR followed by two-years monthly maintenance therapy consisting of ara-C 200 mg/m²/day s.c. over 5 days combined with either DNR 45 mg/m² i.v., days 3 and 4 (course 1), or 6-TG 200 mg/m²/day orally over 5 days (course 2 and 4), or cyclophosphamide 1g/m2 i.v., day 3 (course 3). The sequence is restarted with DNR (course 5). After a cumulative DNR dose of 540 mg/m², DNR is replaced by 6-TG. In each course ATRA 45 mg/m² is given from day1 to 7.
  •   PETHEMA arm:
    The treatment regimen consists of induction therapy, consolidation and maintenance therapy.
    The intensity of the therapy is stratified according to the relapse risk Score (Sanz Score), which was established on the basis of the Spanish and Italian protocols. Low risk: initial white blood cell (WBC) count <10000/µl and platelet count >40000/µl, intermediate risk: initial WBC count <10000/µl and platelet count <40000/µl, high risk: initial WBC count >10000/µl.
    The induction therapy consist of all-trans retinoic acid (ATRA, Vesanoid®) 45 mg/m2/day orally and Idarubicin 12 mg/m² intravenously (i.v.) at days 2,4,6,8. ATRA is given until complete hematological remission or for a maximum of 90 days. The consolidation therapy comprises three cycles.
    Consolidation course 1: low risk patients: idarubicin 5 mg/m²/day i.v., days 1-4; intermediate and high risk patients: idarubicin 7 mg/m²/day, days 1-4, ATRA 45 mg/m² orally at days 1-15, in all risk groups. Consolidation course 2 (uniform therapy for all risk groups): Mitoxantrone 10 mg/m² i.v. at days 1-15, ATRA 45 mg/m² orally at days 1-15. Consolidation course 3: low risk patients: idarubicin 12 mg/m² i.v. at day 1; intermediate and high risk patients idarubicin 12 mg/m² at days 1 and 2, ATRA 45 mg/m² orally at days 1-15 in all risk groups. The maintenance therapy is prospected for two years and consist of s 6-Mercaptopurin (Purinethol®), methotrexate and ATRA (6-mercaptopurin 50 mg/m²/day orally, methotrexate 15 mg/m²/week orally, ATRA 45 mg/m²/day orally for 15 days every three months.
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Active control (effective treament of control group)
  •   Treatment
  •   Parallel
  •   III
  •   No
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Primary Outcome

Assessment of the molecular and hematological remission rate, early death rate, toxicity, description of the kinetics of the minimal residual disease.



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Secondary Outcome

Relapse free survival, event free survival, overall survival, cumulative incidence of relapse after 2 years.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

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Recruitment

  •   Actual
  •   2005/11/24
  •   100
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   16   Years
  •   no maximum age
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Additional Inclusion Criteria

Newly diagnosed APL (AML FAB M3 or M3v), molecularly or cytogeneticall confirmed,
Age 16 years or older, no upper age limit,
written informed consent

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Exclusion Criteria

Cardiac failure NYHA-Stadium III und IV,
Chronic pulmonary disease with hypoxemia,
severe treatment resistant hypertension,
renal disease (serum creatinine 2 mg/100 ml or more, if not caused by leukemic infiltration, sever liver disease, if not caused by leukemia, severe pneumonia in particular with hypoxemia, uncontrolled sepsis, uncontrolled life-threatening bleeding, psychiatric disorder, frailty before onset of leukemia, cachexia, pregnancy, active secondary malignancy, no informed consent.



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Addresses

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    • Universitätsklinikum Mannheim
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • Universitätsklinikum Mannheim
    • Ms.  Prof. Dr. med.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    • III. Medizinische Klinik Universitätsmedizin Mannnheim
    • Ms.  Prof. Dr. med.  Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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    •   0049 621 383-4131 oder 383-4115
    •   0049 621 383-2128
    •   eva.lengfelder at umm.de
    •   [---]*
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Sources of Monetary or Material Support

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    • III. Medizinische Klinik, Universitätsmedizin Mannheim
    • Ms.  Prof. Dr. med.   Eva  Lengfelder 
    • Theodor-Kutzer-Ufer 1-3
    • 68167  Mannheim
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2015/12/31
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Trial Publications, Results and other Documents

  •   Lengfelder E, Görlich D, Nowak D, et al. Frontline therapy of acute promyelocytic leukemia: Randomized comparison of ATRA and intensified chemotherapy versus ATRA and anthracyclines. Eur J Haematol. 2018;100:154–162. https://doi.org/10.1111/ejh.12994
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* This entry means the parameter is not applicable or has not been set.