Clinical trial NCT00025402: Chemotherapy and Biological Therapy With or Without Bone Marrow or Peripheral Stem Cell Transplant in Treating Patients With Chronic Myelogenous Leukemia
Official title: Randomized Multicenter Treatment Optimization Study In Chronic Myeloid Leukemia (CML) Interferon-a Vs. Allogeneic Stem Cell Transplantation Vs. High-Dose Chemotherapy Followed By Autografting And Interferon-a Maintainance In Early Chronic Phase
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Leukemia
Keywords: chronic phase chronic myelogenous leukemia
chronic myelogenous leukemia, BCR-ABL1 positive
Philadelphia chromosome negative chronic myelogenous leukemia
childhood chronic myelogenous leukemia
atypical chronic myeloid leukemia, BCR-ABL1 negative
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-01-27
Enrollment: 1000
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy, such as hydroxyurea, cytarabine, idarubicin, and etoposide before a donor bone marrow transplant or stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Interferon alfa may interfere with the growth of cancer cells and slow the growth of cancer. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. It is not yet known whether chemotherapy is more effective with or without interferon alfa and/or bone marrow or stem cell transplant in treating patients with chronic myelogenous leukemia.

PURPOSE: This randomized phase III trial is studying chemotherapy and biological therapy to see how well it works compared with chemotherapy, biological therapy, and donor bone marrow transplant or autologous stem cell transplant in treating patients with chronic phase chronic myelogenous leukemia.

Detailed description: OBJECTIVES:

* Compare survival in patients with chronic myelogenous leukemia in early chronic phase treated with allogeneic bone marrow transplantation vs drug treatment with or without autologous peripheral blood stem cell transplantation.
* Compare survival of patients with late-phase disease treated with high-dose cytarabine vs low-dose cytarabine followed by autografting and interferon alfa maintenance.
* Compare survival of patients not responding cytogenetically to treatment with continued interferon alfa vs hydroxyurea.
* Determine frequency, time-point, and duration of hematological and cytogenetic remissions and of Philadelphia chromosome-negative and/or BCR-ABL-positive cells on the various treatments.
* Correlate the quality of hematological and cytogenetic remissions with survival time in patients treated with these regimens.
* Compare the course of the terminal phase in patients treated with these regimens.
* Compare the toxic effects of these regimens in these patients.
* Determine the effect of prognostic criteria and normal or subnormal WBC on chronic phase duration and survival time in patients treated with these regimens.
* Compare the effect of early vs late high-dose therapy plus autografting on feasibility, toxicity, and survival times in these patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to eligibility for transplantation (yes vs no).

All patients undergo cytoreduction comprising hydroxyurea (HU) IV daily.

Patients who are ineligible for or refuse transplantation are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive interferon alfa (IFN) subcutaneously (SC) daily. After 2 weeks of IFN therapy, patients also receive low-dose cytarabine (ARA-C) SC once daily for 10-15 days each month. Patients who do not achieve cytogenetic remission within 12 months continue to receive HU.
* Arm II: Patients receive IFN SC daily. After 2 weeks of IFN therapy, patients also receive low-dose ARA-C SC daily for 10-15 days each month. Patients who do not achieve cytogenetic remission within 12 months continue to receive IFN therapy SC daily.

Patients who are eligible for transplantation with a related donor undergo allogeneic bone marrow transplantation. Patients may receive HU or IFN prior to transplantation. Patients may also receive oral high-dose busulfan daily for 4 days with or without cyclophosphamide or cyclophosphamide with total body irradiation.

Patients who are eligible for transplantation but do not have a related donor undergo peripheral blood stem cell (PBSC) harvest and are randomized to 1 of 2 treatment arms.

* Arm III: Patients receive IFN and low-dose ARA-C as in arm I. Patients who accelerate on treatment may undergo autologous PBSC transplantation.
* Arm IV: Patients receive idarubicin IV, ARA-C IV over 2 hours, and etoposide IV on days 1-3. Patients then undergo leukapheresis. Beginning on day 8, patients receive filgrastim (G-CSF) SC daily until end of leukapheresis. Patients then receive oral high-dose busulfan daily for 4 consecutive days. The following day, patients undergo reinfusion of autologous PBSC. After blood count recovery, patients receive maintenance IFN 3 times weekly for 8 weeks and then daily.

Patients are followed every 3 months for 3 years and then every 6 months thereafter.

PROJECTED ACCRUAL: A total of 1,000 patients will be accrued for this study within 5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of chronic myelogenous leukemia in chronic phase

  * Previously untreated
* Patients negative for Philadelphia chromosome and BCR-ABL translocation must fulfill at least 1 of the following criteria:

  * Impaired health status with reduced exercise tolerance
  * Spleen-related symptoms in cases of splenomegaly
  * Weight loss greater than 10% in 6 months
  * Fever greater than 38.5 degrees C on 5 consecutive days
  * Clinically relevant bone pain
  * Leukocytosis greater than 5,000/mm\^3
  * Thrombocytosis greater than 100,000/mm\^3

PATIENT CHARACTERISTICS:

Age:

* Any age

Performance status:

* Not specified

Life expectancy:

* Not specified

Hematopoietic:

* See Disease Characteristics

Hepatic:

* Not specified

Renal:

* Not specified

Other:

* No other concurrent malignancy that is likely to require treatment during study or that is likely to reduce life expectancy
* No severe concurrent disease or other cause that would preclude study
* Not pregnant

PRIOR CONCURRENT THERAPY:

Biologic therapy:

* No prior interferon

Chemotherapy:

* No prior chemotherapy

Endocrine therapy:

* Not specified

Radiotherapy:

* No prior radiotherapy

Surgery:

* Not specified

Primary outcomes:
measure: Survival
measure: Frequency, time-point, and duration of hematologic and cytogenetic remissions and of Philadelphia chromosome-negative and/or BCL-ABL-positive cells
measure: Correlation of quality of hematological and cytogenetic remission with survival time
measure: Course of the terminal phase
measure: Toxicity
measure: Effect of prognostic criteria and normal or subnormal WBC on chronic phase duration and survival time
measure: Effect of early vs late high-dose therapy and autografting on feasibility, toxicity and survival times
Secondary outcomes:
Other outcomes:
Locations:
city: Brno
country: Czech Republic
facility: Masaryk University Hospital
city: Aachen
country: Germany
facility: Haematologisch Onkologische Praxis
city: Aachen
country: Germany
facility: Kinderklinik - Universitaetsklinikum Aachen
city: Aachen
country: Germany
facility: Urologische Klinik - Universitaetsklinikum Aachen
city: Aalen
country: Germany
facility: Kreiskrankenhaus
city: Amberg
country: Germany
facility: Klinikum St. Marien
city: Ansbach
country: Germany
facility: Gemeinschaftspraxis Fuer Innere Medizin, Haematologie Und Internistische Onkologie
city: Aschaffenburg
country: Germany
facility: II. Medizinische Klinik
city: Augsburg
country: Germany
facility: Haematologische Praxis
city: Augsburg
country: Germany
facility: Klinikum Augsburg
city: Bad Hersfeld
country: Germany
facility: Kreiskrankenhaus
city: Bayreuth
country: Germany
facility: Krankenhaus Hohe Warte Mediziniche Klinik
city: Berlin
country: Germany
facility: St. Hedwig Kranken Haus
city: Berlin
country: Germany
facility: Tumorzentrum Berlin-Moabit
city: Berlin
country: Germany
facility: Wenckebach - Krankenhaus
city: Berlin
country: Germany
facility: Helios Klinikum Berlin
city: Berlin
country: Germany
facility: Haematologisch-Onkologische Schwerpunktpraxis
city: Berlin
country: Germany
facility: Charite - Campus Charite Mitte
city: Berlin
country: Germany
facility: Onkolog - Haematolog Schwerpunktpraxis
city: Berlin
country: Germany
facility: Krankenhaus Neukoelln
city: Berlin
country: Germany
facility: Charite - Campus Virchow Klinikum
city: Berlin
country: Germany
facility: Kinderklinik der Freier Universitaet Berlin
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
city: Bietigheim
country: Germany
facility: Franziskus Hospital
city: Bietigheim
country: Germany
facility: Krankenhaus Bietigheim
city: Bochum
country: Germany
facility: Europahochhaus
city: Boeblingen
country: Germany
facility: Kreiskrankenhaus Boeblingen
city: Bonn
country: Germany
facility: Universitaetsklinikum Bonn
city: Bonn
country: Germany
facility: Medizinische Poliklinik
city: Bottrop
country: Germany
facility: Marienhospital Bottrop gGmbH
city: Braunschweig
country: Germany
facility: Staedtisches Klinikum Braunschweig
city: Bremen
country: Germany
facility: Klinikum Bremen-Mitte
city: Bremerhaven
country: Germany
facility: St. Joseph Hospital
city: Bremerhaven
country: Germany
facility: Zentralkrankenhaus
city: Buende
country: Germany
facility: Medizinische Klinik Am Lukas - Krankenhaus
city: Coburg
country: Germany
facility: Klinikum Coburg
city: Cologne
country: Germany
facility: Praxis Gemeinschaft
city: Cologne
country: Germany
facility: Praxis Fuer Haematologie Internistische Onkologie
city: Cologne
country: Germany
facility: Medizinische Universitaetsklinik I at the University of Cologne
city: Cottbus
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Dresden
country: Germany
facility: Stadt. KH Dresden - Neustadt
city: Dresden
country: Germany
facility: Medizinische Klinik I
city: Dueren
country: Germany
facility: Krankenhaus Dueren
city: Duesseldorf
country: Germany
facility: Universitaetsklinikum Duesseldorf
city: Duisburg
country: Germany
facility: Michael Schaefers und Partner
city: Duisburg
country: Germany
facility: St. Johannes Hospital - Medical Klinik II
city: Emden
country: Germany
facility: Hans - Susemihl - Krankenhaus
city: Erfurt
country: Germany
facility: Internistiche Praxis
city: Erfurt
country: Germany
facility: Klinikum Erfurt
city: Erfurt
country: Germany
facility: Praxis DR. J. Weniger
city: Erlangen
country: Germany
facility: Onkologische Schwerpunkt Praxis
city: Erlangen
country: Germany
facility: Medizinische Klinik III - Universitaetsklinikum Erlangen
city: Eschweiler
country: Germany
facility: St. Antonius Hospital
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Essen
country: Germany
facility: Evangelisches Krankenhaus Essen Werden
city: Flensburg
country: Germany
facility: Malteser Krankenhaus
city: Frankfurt
country: Germany
facility: Onkolog Gemeinschaftspraxis
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Fuerth
country: Germany
facility: II Medizinische Klinik - Klinikum Fuerth
city: Fuessen
country: Germany
facility: Kreiskrankenhaus Fuessen
city: Garmisch-Partenkirchen
country: Germany
facility: Klinikum Garmisch - Partenkirchen GmbH
city: Giessen
country: Germany
facility: Gemeinschaftspraxis Fuer Innere Medizin, Hematologie Und Onkologie
city: Giessen
country: Germany
facility: Klinik und Poliklinik fuer Urologie und Kinderurologie
city: Goeppingen
country: Germany
facility: Klinik fuer Radioonkologie und Strahlentherapie
city: Goettingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Goslar
country: Germany
facility: DR Herbert - Nieper Krankenhaus Goslar
city: Hagen
country: Germany
facility: Allgemeines Krankenhaus Hagen
city: Hagen
country: Germany
facility: St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
city: Hamburg
country: Germany
facility: Allgemeines Krankenhaus Altona
city: Hamburg
country: Germany
facility: Hermann - Holthusen Institute for Radiotherapy
city: Hamburg
country: Germany
facility: Universitaetsklinikum Hamburg-Eppendorf
city: Hamburg
country: Germany
facility: Onkologischer Schwerpunkt Lerchenfeld
city: Hamburg
country: Germany
facility: Asklepios Klinik Barmbek
city: Hamburg
country: Germany
facility: Haematologisch-Onkologische Praxis Altona
city: Hamm
country: Germany
facility: Evangelische Krankenhaus Hamm
city: Hamm
country: Germany
facility: St. Marien-Hospital Hamm - Klinik Knappenstrasse
city: Hanau
country: Germany
facility: Haematologie Und Internistische Onkologie
city: Hannover
country: Germany
facility: Krankenhaus Siloah - Medizinische Klinik II
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
city: Heidelberg
country: Germany
facility: Medizinische Universitaetsklinik und Poliklinik
city: Herford
country: Germany
facility: Klinikum Herford
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Idar-Oberstein
country: Germany
facility: Clinic for Bone Marrow Transplantation and Hematology and Oncology
city: Iserlohn
country: Germany
facility: Praxis am Evangelischen Krankenhaus Bethanien
city: Jena
country: Germany
facility: Klinikum der Friedrich-Schiller Universitaet Jena
city: Karlsruhe-Rueppur
country: Germany
facility: Diakonissen - Krankenhaus
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Karlsruhe
country: Germany
facility: Gemeinschaftspraxis Brunoehler
city: Karlsruhe
country: Germany
facility: St. Vincentius-Kliniken
city: Kassel
country: Germany
facility: Klinikum Kassel
city: Kempten
country: Germany
facility: Klinikum Kempten Oberallgaeu
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Konstanz
country: Germany
facility: Klinik Konstanz
city: Krefeld
country: Germany
facility: Haematologische / Onkologische Schwerpunktpraxis
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Landau
country: Germany
facility: Vinzentiuskrankenhaus
city: Lebach
country: Germany
facility: Caritas - Krakenhaus Lebach
city: Leer
country: Germany
facility: Onkologische Schwerpunktpraxis - Leer
city: Lemgo
country: Germany
facility: Klinikum Lippe - Lemgo
city: Lindenfels
country: Germany
facility: Luisenkrankenhaus
city: Ludwigshafen am Rhein
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein
city: Ludwigshafen, Rhein
country: Germany
facility: St Marienkrankenhaus
city: Luebeck
country: Germany
facility: Praxis Fuer Haematologie/Onkologie
city: Lueneburg
country: Germany
facility: Onkologische Schwerpunktpraxis Lueneburg
city: Mannheim
country: Germany
facility: Gemeinschaftspraxis
city: Mannheim
country: Germany
facility: III Medizinische Klinik Mannheim
city: Marburg
country: Germany
facility: Philipps-Universitaet Marburg Klinikum
city: Mellrichstad
country: Germany
facility: Kreiskrankenhaus Mellrichstadt
city: Minden
country: Germany
facility: Klinikum Minden
city: Moenchengladbach
country: Germany
facility: Krankenhaus Maria Hilf GmbH
city: Muenchen
country: Germany
facility: Universitaets - Kinderpoliklinik
city: Muenster
country: Germany
facility: Klinik und Poliklinik fuer Kinder und Jugendmedizin - Universitaetsklinikum Muenster
city: Munich
country: Germany
facility: Gemeinschaftspraxis
city: Munich
country: Germany
city: Munich
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Munich
country: Germany
facility: Medizinische Kl. Klinikum Innenstadt Universitaet Muenchen
city: Munich
country: Germany
facility: Praxis fuer Innere Medizin und Haematologie
city: Munich
country: Germany
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Munich
country: Germany
facility: Staedtisches Krankenhaus Muenchen - Harlaching
city: Munich
country: Germany
facility: Klinikum Rechts Der Isar - Technische Universitaet Muenchen
city: Munich
country: Germany
facility: Krankenhaus Muenchen Neuperlach
city: Neuruppin
country: Germany
facility: Ruppiner Klinikum GMBH
city: Niddatel-IIbenstadt
country: Germany
facility: Gemeinschaftspraxis
city: Norderstedt
country: Germany
facility: Praxis fuer Haematologie und Interne Onkologie
city: Nuernberg
country: Germany
facility: Gemeinschaftspraxis
city: Nuernberg
country: Germany
facility: Klinikum Nuernberg - Klinikum Nord
city: Nuernberg
country: Germany
facility: Klinikum Nuernberg - Klinikum Sued
city: Oldenburg
country: Germany
facility: Hematologische Praxis
city: Oldenburg
country: Germany
facility: Klinikum Oldenburg
city: Osnabrueck
country: Germany
facility: Paracelsus - Klinik Osnabrueck
city: Pforzheim
country: Germany
facility: Staedtisches Krankenhaus
city: Radebeul
country: Germany
facility: Kreiskrankenhaus Radebeul
city: Ravensburg
country: Germany
facility: St. Elisabeth Krankenhaus
city: Recklinghausen
country: Germany
facility: Prosper-Hospital Recklinghausen
city: Regensburg
country: Germany
facility: Hematologische Onkologische Praxis
city: Regensburg
country: Germany
facility: Krankenhaus Barmherzige Brueder Regensburg
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Remscheid
country: Germany
facility: Klinikum Remscheid GmbH
city: Rheine
country: Germany
facility: Jakobi Krankenhaus
city: Saarbrucken
country: Germany
facility: Caritasklinik St. Theresia
city: Saarbruecken
country: Germany
facility: Schwerpunktpraxis fuer Haematologie und Onkologie
city: Sebnitz
country: Germany
facility: Saechsische Schweiz Klinik
city: Sebnitz
country: Germany
facility: Staedt Krankenhaus
city: Siegen
country: Germany
facility: St. Marien - Krankenhaus Siegen GMBH
city: Siegen
country: Germany
facility: Kreiskrankenhaus Siegen
city: Stralsund
country: Germany
facility: Klinikum Der Hansestadt Stralsund - Klin. West
city: Stuttgart
country: Germany
facility: Robert-Bosch-Krankenhaus
city: Stuttgart
country: Germany
facility: Haematologische Praxis
city: Stuttgart
country: Germany
facility: Klinik fuer Onkologie - Katharinenhospital Stuttgart
city: Stuttgart
country: Germany
facility: Diakonie Klinikum Stuttgart
city: Trier
country: Germany
facility: Krankenanstalt Mutterhaus der Borromaerinnen
city: Trier
country: Germany
city: Troisdorf
country: Germany
facility: Praxis Fuer Internistische Haematologie / Onkologie
city: Tuebingen
country: Germany
facility: Schwerpunktpraxis für Rheumatologie und Haematologie/Internistische Onkologie
city: Tuebingen
country: Germany
facility: Southwest German Cancer Center at Eberhard-Karls-University
city: Ulm
country: Germany
facility: Bundeswehr Krakenhaus
city: Ulm
country: Germany
facility: Universitaetsklinikum Ulm
city: Viersen-Suechteln
country: Germany
facility: St. Irmgardis Krankenhaus
city: Villingen-Schwenningen
country: Germany
facility: Klinikum Der Stadt Villingen - Schwenningen
city: Voeklingen
country: Germany
facility: Krankenhaus St. Michael
city: Waldroel
country: Germany
facility: Kreiskrankenhaus
city: Wiesbaden
country: Germany
facility: Deutsche Klinik fuer Diagnostik
city: Wilhelmshaven
country: Germany
facility: St. Willehad Hospital
city: Wuppertal 2
country: Germany
facility: Kliniken St. Antonius
city: Wuppertal
country: Germany
facility: Praxis Fuer Haemotologie Und Internistischer Onkologie
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Katowice
country: Poland
facility: Silesian Medical Academy
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Baar
country: Switzerland
facility: Facharzt FMH Fuer Innere Medizin and Oncology
city: Basel
country: Switzerland
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland
city: Bern
country: Switzerland
facility: Facharzt Fuer Onkologie-Hematologie
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Breitenbach
country: Switzerland
facility: Inneremedizin FMH
city: Dornach
country: Switzerland
facility: Bezirksspital Dornach
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Grosshochstetten
country: Switzerland
facility: FMH f. Innere Medizin and Hematologie
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Luzerne
country: Switzerland
facility: Kantonsspital, Luzerne
city: Sion
country: Switzerland
facility: Institut Central des Hopitaux Valaisans
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Zurich
country: Switzerland
facility: Klinik Hirslanden
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: III. Medizinische Klinik Mannheim
name: Ruediger Hehlmann, MD
role: STUDY_CHAIR
References: