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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Leukemia

Intervention / Treatment
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* Biological: recombinant interferon alfa
* Drug: cytarabine
* Drug: hydroxyurea
* Drug: imatinib mesylate
* Procedure: allogeneic bone marrow transplantation
* Procedure: autologous bone marrow transplantation
* Procedure: peripheral blood stem cell transplantation


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: recombinant interferon alfa|nan|
|Drug: cytarabine|nan|
|Drug: hydroxyurea|nan|
|Drug: imatinib mesylate|nan|
|Procedure: allogeneic bone marrow transplantation|nan|
|Procedure: autologous bone marrow transplantation|nan|
|Procedure: peripheral blood stem cell transplantation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  |  | 
| Risk group-dependent survival |  |  | 
| Progression-free survival |  |  | 
| Hematologic, cytogenetic, and molecular response rates |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse drug effects |  |  | 
| Quality of life |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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chronic phase chronic myelogenous leukemia, childhood chronic myelogenous leukemia, chronic myelogenous leukemia, BCR-ABL1 positive