Clinical trial NCT00055874: Imatinib Mesylate With or Without Interferon Alfa or Cytarabine Compared With Interferon Alfa Followed by Donor Stem Cell Transplant in Treating Patients With Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia
Official title: Treatment Optimization Trial in Chronic Myeloid Leukemia (CML) - Randomized Controlled Comparison of Imatinib vs. Imatinib/Interferon-alpha vs. Imatinib/Low-Dose AraC vs. Interferon-alpha Standard Therapy and Determination of the Role of Allografting in Newly Diagnosed Chronic Phase
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leukemia
Keywords: chronic phase chronic myelogenous leukemia
childhood chronic myelogenous leukemia
chronic myelogenous leukemia, BCR-ABL1 positive
Lead sponsor: Heidelberg University
Sponsor class: OTHER
First posted: 2003-03-07
Enrollment: 1551
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Giving chemotherapy before a donor bone marrow transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. Also, imatinib mesylate may stop the growth of cancer cells by blocking the enzymes needed for cancer cell growth. 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 which treatment regimen is most effective in treating chronic phase chronic myelogenous leukemia.

PURPOSE: This randomized phase III trial is studying imatinib mesylate with or without interferon alfa or cytarabine to see how well it works compared with interferon alfa followed by donor stem cell transplant in treating patients with newly diagnosed chronic phase chronic myelogenous leukemia.

Detailed description: OBJECTIVES:

* Compare the hematologic, cytogenetic, and molecular response rates in patients with newly diagnosed chronic phase chronic myelogenous leukemia treated with imatinib mesylate alone or with interferon alfa or low-dose cytarabine vs interferon alfa standard therapy.
* Compare the group-dependent, progression-free and overall survival and time to progression in patients treated with these regimens.
* Compare the efficacy of allogeneic stem cell transplantation vs imatinib mesylate-based therapy in patients eligible for transplantation.
* Compare the efficacy of reduced-intensity conditioning vs standard conditioning in patients over 45 years of age.
* Determine the time to and duration of hematologic, cytogenetic, and molecular responses and correlate these factors in patients treated with these regimens.
* Compare the short- and long-term adverse effects of these regimens in these patients.
* Compare the presentation, duration, and responses to therapy of accelerated and blastic phases in patients treated with these regimens.
* Determine the survival of high-risk patients after early allografting.
* Determine the influence of pre-transplantation therapies on the outcome of allogeneic stem cell transplantation in these patients.

OUTLINE: This is a randomized, multicenter, pilot study. Patients are stratified according to participating center. Patients with low- to intermediate-risk disease are randomized to 1 of 4 treatment arms. Patients with high-risk disease are randomized to 1 of 3 treatment arms with imatinib mesylate-based regimens.

* Arm I: Patients receive oral imatinib mesylate once daily for up to 12 months in the absence of disease progression or unacceptable toxicity.
* Arm II: Patients receive oral imatinib mesylate as in arm I. Patients also receive interferon alfa subcutaneously (SC) 3 times a week beginning at least 3 months after the start of imatinib mesylate.
* Arm III: Patients receive oral imatinib mesylate as in arm I. Patients also receive cytarabine SC up to twice daily for 5 days monthly beginning at least 3 months after the start of imatinib mesylate.
* Arm IV: After initial cytoreduction with hydroxyurea, patients receive interferon alfa SC daily with or without hydroxyurea. In the absence of a complete response after 3 months, patients may also receive low-dose cytarabine SC once daily. Treatment continues for up to 21 months.

Patients who fail interferon alfa therapy are crossed over to receive imatinib mesylate.

Patients who fail therapy with imatinib mesylate and are eligible for an allogeneic transplantation are stratified according to availability of donor (HLA-identical related vs unrelated), status, and participating center. Patients are randomized to receive an allogeneic transplantation or continue any salvage therapy.

Patients who are not eligible for allogeneic transplantation receive hydroxyurea and cytarabine or high-dose chemotherapy with autologous stem cell rescue followed by interferon- or imatinib mesylate-based therapy.

Patients over 45 years of age are further randomized to receive an age-adjusted standard conditioning regimen or reduced intensity preparative regimen (mini transplantation) prior to allogeneic transplantation.

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

PROJECTED ACCRUAL: A total of 1,600 patients (400 per treatment arm) will be accrued for this study within 4-5 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Newly diagnosed chronic phase chronic myelogenous leukemia (CML)

  * bcr-abl positive
  * No blasts, promyelocytes, myelocytes, or metamyelocytes in the peripheral blood
* Availability of a HLA-identical sibling or unrelated donor

PATIENT CHARACTERISTICS:

Age

* Any age

Performance status

* Not specified

Life expectancy

* Not specified

Hematopoietic

* Not specified

Hepatic

* Not specified

Renal

* Not specified

Other

* Not pregnant or nursing
* Fertile patients must use effective contraception
* No second malignancy requiring therapy
* No evidence of disease-related symptoms or extramedullary disease (including hepatosplenomegaly)
* No serious diseases that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

* No prior interferon

Chemotherapy

* No prior chemotherapy other than hydroxyurea

Endocrine therapy

* Not specified

Radiotherapy

* No prior radiotherapy

Surgery

* Not specified

Other

* Prior anagrelide allowed
* No participation in another clinical trial

Primary outcomes:
measure: Overall survival
measure: Risk group-dependent survival
measure: Progression-free survival
measure: Hematologic, cytogenetic, and molecular response rates
Secondary outcomes:
measure: Adverse drug effects
measure: Quality of life
Other outcomes:
Locations:
city: Aachen
country: Germany
facility: Krankenhaus / Klinikum Krefeld
city: Aurich
country: Germany
facility: Kreiskrankenhaus Aurich
city: Bad Hersfeld
country: Germany
facility: Kreiskrankenhaus
city: Berlin
country: Germany
facility: St. Hedwig Krankenhaus
city: Berlin
country: Germany
facility: Haematologisch-Onkologische Schwerpunktpraxis
city: Berlin
country: Germany
facility: Schwerpunktpraxis fuer Haematologie und Internistische Onkologie
city: Berlin
country: Germany
facility: Gemeinschaftspraxis fuer Haematologie und Internistische Onkologie
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis Bielefeld
city: Bonn
country: Germany
facility: Augustinum
city: Brandenburg
country: Germany
facility: Hamatologische Sprechstunde
city: Bremen
country: Germany
facility: Praxis Dres. F.& G. Doering
city: Delmenhorst
country: Germany
facility: Staedtisches Kliniken Delmenhorst
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Essen
country: Germany
facility: Evangelisches Krankenhaus Essen Werden
city: Frankfurt
country: Germany
facility: Klinikum der J.W. Goethe Universitaet
city: Germering
country: Germany
facility: Internistische Praxisgemeinschaft
city: Goslar
country: Germany
facility: DR Herbert - Nieper Krankenhaus Goslar
city: Gottingen
country: Germany
facility: Universitaetsklinikum Goettingen
city: Hagen
country: Germany
facility: St. Marien Hospital - Katholisches Krankenhaus Hagen gGmbH
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Hamburg
country: Germany
facility: University Medical Center Hamburg - Eppendorf
city: Hamm
country: Germany
facility: Evangelische Krankenhaus Hamm
city: Heidelberg
country: Germany
facility: Medizinische Universitaetsklinik und Poliklinik
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Heidelberg
country: Germany
facility: Ruprecht - Karls - Universitaet Heidelberg
city: Homburg
country: Germany
facility: Medical University Hospital Homburg
city: Homburg
country: Germany
facility: Universitaetsklinikum des Saarlandes
city: Kaiserslautern
country: Germany
facility: Westpfalz-Klinikum GmbH
city: Karlsruhe
country: Germany
facility: Staedtisches Klinikum Karlsruhe gGmbH
city: Karlsruhe
country: Germany
facility: St. Vincentius - Kliniken
city: Kempten
country: Germany
facility: Klinikum Kempten Oberallgaeu
city: Kiel
country: Germany
facility: University Hospital Schleswig-Holstein - Kiel Campus
city: Krefeld
country: Germany
facility: Klinikum Krefeld GmbH
city: Langen
country: Germany
facility: Internistisches Fachaerzte Zentrum Langen
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: Ludwigshafen am Rhein
country: Germany
facility: Klinikum der Stadt Ludwigshafen am Rhein
city: Mannheim
country: Germany
facility: III Medizinische Klinik Mannheim
city: Monchengladbach
country: Germany
facility: Hospital Maria-Hilf II
city: Muenchen
country: Germany
facility: Krankenhaus Muenchen Schwabing
city: Muenster
country: Germany
facility: Haematologisch - Onkologische Gemeinschaftspraxis - Muenster
city: Munich
country: Germany
facility: Klinikum der Universitaet Muenchen - Grosshadern Campus
city: Munich
country: Germany
facility: Haematologische Schwerpunktpraxis
city: Regensburg
country: Germany
facility: Hematologische Onkologische Praxis
city: Regensburg
country: Germany
facility: Klinikum der Universitaet Regensburg
city: Remscheid
country: Germany
facility: Klinikum Remscheid GmbH
city: Russelsheim
country: Germany
facility: Internistische Schwerpunktpraxis
city: Schwaebisch Hall
country: Germany
facility: Diakonie - Krankenhaus
city: Siegen
country: Germany
facility: St. Marien - Krankenhaus Siegen GMBH
city: Siegen
country: Germany
facility: Kreiskrankenhaus Siegen
city: Stralsund
country: Germany
facility: Hanse-Klinikum Stralsund - Krankenhaus West
city: Straubing
country: Germany
facility: Onkologische Schwerpunktpraxis - Straubing
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
city: Tuebingen
country: Germany
facility: Schwerpunktpraxis fuer Rheumatologie und Haematologie/Internistische Onkologie
city: Tuebingen
country: Germany
facility: Southwest German Cancer Center at Eberhard-Karls-University
city: Weiden
country: Germany
facility: Haematologische Praxis
city: Wuppertal
country: Germany
facility: Praxis Fuer Haemotologie Und Internistischer Onkologie
city: Wuppertal
country: Germany
facility: Helios Kliniken Wuppertal University Hospital
city: Wurzburg
country: Germany
facility: Hamatologisch - Onkologische Praxis Wurzburg
city: Wurzburg
country: Germany
facility: University Wurzburg
city: Basel
country: Switzerland
Study officials:
affiliation: III. Medizinische Klinik Mannheim
name: Ruediger Hehlmann, MD
role: STUDY_CHAIR
References:
citation: Hehlmann R, Lauseker M, Jung-Munkwitz S, Leitner A, Muller MC, Pletsch N, Proetel U, Haferlach C, Schlegelberger B, Balleisen L, Hanel M, Pfirrmann M, Krause SW, Nerl C, Pralle H, Gratwohl A, Hossfeld DK, Hasford J, Hochhaus A, Saussele S. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol. 2011 Apr 20;29(12):1634-42. doi: 10.1200/JCO.2010.32.0598. Epub 2011 Mar 21.
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citation: Saussele S, Hehlmann R, Fabarius A, Jeromin S, Proetel U, Rinaldetti S, Kohlbrenner K, Einsele H, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Oppliger Leibundgut E, Heim D, Krause SW, Hofmann WK, Hasford J, Pfirrmann M, Muller MC, Hochhaus A, Lauseker M. Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV. Leukemia. 2018 May;32(5):1222-1228. doi: 10.1038/s41375-018-0055-7. Epub 2018 Feb 26.
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citation: Lauseker M, Hasford J, Hoffmann VS, Muller MC, Hehlmann R, Pfirrmann M; German CML Study Group. A multi-state model approach for prediction in chronic myeloid leukaemia. Ann Hematol. 2015 Jun;94(6):919-27. doi: 10.1007/s00277-014-2246-2. Epub 2014 Dec 3.
citation: Hanfstein B, Lauseker M, Hehlmann R, Saussele S, Erben P, Dietz C, Fabarius A, Proetel U, Schnittger S, Haferlach C, Krause SW, Schubert J, Einsele H, Hanel M, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Pfirrmann M, Hasford J, Hofmann WK, Hochhaus A, Muller MC; SAKK and the German CML Study Group. Distinct characteristics of e13a2 versus e14a2 BCR-ABL1 driven chronic myeloid leukemia under first-line therapy with imatinib. Haematologica. 2014 Sep;99(9):1441-7. doi: 10.3324/haematol.2013.096537. Epub 2014 May 16.
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citation: Lauseker M, Hasford J, Pfirrmann M, Hehlmann R; German CML Study Group. The impact of health care settings on survival time of patients with chronic myeloid leukemia. Blood. 2014 Apr 17;123(16):2494-6. doi: 10.1182/blood-2013-11-539742. Epub 2014 Mar 12.
citation: Hehlmann R, Muller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, Proetel U, Pletsch N, Pfirrmann M, Haferlach C, Schnittger S, Einsele H, Dengler J, Falge C, Kanz L, Neubauer A, Kneba M, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Baerlocher GM, Ehninger G, Heim D, Heimpel H, Nerl C, Krause SW, Hossfeld DK, Kolb HJ, Hasford J, Saussele S, Hochhaus A. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014 Feb 10;32(5):415-23. doi: 10.1200/JCO.2013.49.9020. Epub 2013 Dec 2.
citation: Kalmanti L, Saussele S, Lauseker M, Proetel U, Muller MC, Hanfstein B, Schreiber A, Fabarius A, Pfirrmann M, Schnittger S, Dengler J, Falge C, Kanz L, Neubauer A, Stegelmann F, Pfreundschuh M, Waller CF, Spiekermann K, Krause SW, Heim D, Nerl C, Hossfeld DK, Kolb HJ, Hochhaus A, Hasford J, Hehlmann R; German Chronic Myeloid Leukemia Study Group; Schweizerische Arbeitsgemeinschaft fur Klinische Krebsforschung (SAKK). Younger patients with chronic myeloid leukemia do well in spite of poor prognostic indicators: results from the randomized CML study IV. Ann Hematol. 2014 Jan;93(1):71-80. doi: 10.1007/s00277-013-1937-4. Epub 2013 Oct 27.