Chemotherapy, Interferon, and Bone Marrow Transplantation in Treating Patients With Chronic Myelogenous Leukemia

PROSPECTIVE CONTROLLED STUDY FOR THE OPTIMIZATION OF THERAPY IN CHRONIC MYELOID LEUKEMIA (CML): MULTICENTRIC STUDY FOR THE EVALUATION OF INTERFERON ALPHA VS ALLOGENIC BM TRANSPLANTATION WITH CHEMOTHERAPY IN CML

RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells.

PURPOSE: Randomized phase III trial to compare the effectiveness of various combination chemotherapy regimens or bone marrow transplantation in treating patients with chronic myelogenous leukemia.

Study Overview

• Status: Unknown
• Conditions: Leukemia
• Intervention / Treatment: Biological: recombinant interferon alfa; Radiation: radiation therapy; Drug: cytarabine; Procedure: allogeneic bone marrow transplantation; Drug: busulfan; Procedure: peripheral blood stem cell transplantation; Drug: hydroxyurea; Drug: idarubicin; Procedure: autologous bone marrow transplantation

Detailed Description

OBJECTIVES:

• Compare the duration of chronic phase chronic myelogenous leukemia (CML) and survival of these patients treated with standard remission induction comprising hydroxyurea (HU) and interferon alfa (IFN-A), followed by allogeneic bone marrow transplantation and consolidation comprising HU and IFN-A vs cytarabine and idarubicin.
• Compare the frequency of hematologic and cytogenetic remission (including elimination of Philadelphia-positive and/or BCR/ABL-positive chromosome abnormalities), time to remission, and duration of remission in patients treated with these regimens.
• Correlate the quality of hematologic and cytogenetic remission with the survival of patients treated with these regimens.
• Compare the toxic effects of these regimens in these patients.
• Compare the disease progression in patients treated with these regimens.
• Correlate the duration of chronic phase CML and survival with prognostic criteria and the significance of normal vs subnormal leukocyte counts in patients treated with these regimens.
• Compare the survival of patients without a suitable allogeneic bone marrow donor treated with autologous bone marrow transplantation as consolidation therapy vs consolidation and maintenance chemotherapy regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to participating center, eligibility for allogeneic bone marrow transplantation (Allo-BMT) (yes vs no), donor availability (sibling vs unrelated vs none), and risk status (high vs low).

Induction therapy

• Patients receive induction therapy comprising oral hydroxyurea (HU) until WBC falls below 10,000/mm^3 and interferon alfa (IFN-A) subcutaneously (SC) daily beginning after WBC reduction and continuing in order to maintain WBC between 2,000-4,000/mm^3 and platelet count greater than 50,000/mm^3. If WBC is 10,000/mm^3 or greater on IFN-A alone, then HU must be restarted. Patients with disease progression and no anti-IFN antibody also receive cytarabine (ARA-C) SC for 15 days a months. Patients who develop disease progression while receiving ARA-C and IFN-A are taken off study.
• Patients who are eligible for Allo-BMT, have a sibling donor, and are age 55 and under receive induction therapy for a maximum of 1 year and then proceed to regimen B. Patients who are eligible for Allo-BMT, have an unrelated donor, and are age 45 and under receive induction therapy for 12-18 months. Those patients with cytogenetic remission receive induction therapy for up to 2 years and then proceed to regimen B. Those patients without cytogenetic remission proceed directly to regimen B. Patients who are ineligible for Allo-BMT, but are eligible for autologous BMT (AuBMT) or peripheral blood stem cell transplantation (PBSCT) receive induction therapy for a maximum of 1 year and then proceed to regimen C. Patients who are ineligible for Allo-BMT and achieve hematologic complete remission (CR) within 3 months receive induction therapy for 18 months. Those patients with cytogenetic remission proceed directly to regimen A. Those patients without cytogenetic remission proceed to randomization on regimen B. Patients who are ineligible for Allo-BMT and fail to achieve hematologic CR within 9 months proceed to randomization on regimen B. All other patients who are ineligible for Allo-BMT receive induction therapy for 1 year. Those patients with cytogenetic remission proceed to regimen A. Those patients without cytogenetic remission proceed to randomization on regimen B.

Consolidation/maintenance therapy

• Patients are assigned to 1 of 3 regimens.
• Regimen A: Patients continue to receive IFN-A as in induction therapy in the absence of disease progression.

• Regimen B: Patients receive conditioning therapy comprising busulfan for 4 days and/or total body irradiation, followed by Allo-BMT. Patients are then randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive consolidation therapy comprising HU and IFN-A as in induction therapy.
  • Arm II: Patients receive consolidation therapy comprising ARA-C SC every 12 hours on days 1-5 and idarubicin (IDA) IV on days 3 and 4 (and day 5 for patients with responding disease). Consolidation therapy continues every 2 months for a total of 3 courses. When blood counts recover, patients receive maintenance therapy comprising IFN-A and ARA-C (if needed) as in induction therapy.
• Regimen C: Patients receive IDA and ARA-C as in arm II. Patients then undergo AuBMT or PBSCT.

Patients are followed every 3-6 months for at least 4 years.

PROJECTED ACCRUAL: Approximately 750 patients will be accrued for this study within 5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 750
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Mannheim, Germany, D-68135
    • III Medizinische Klinik Mannheim

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Newly diagnosed chronic myelogenous leukemia in chronic phase

• Philadelphia chromosome- or bcr/abl-positive

  • Cytogenetic negativity (analyzed separately) allowed if at least 1 of the following criteria is met:

    • Malaise with decreased performance status
    • Weight loss of more than 10% within the past 6 months
    • Fever more than 38.5 C for 5 consecutive days
    • Symptomatic splenomegaly
    • Leukocyte count greater than 50,000/mm^3
    • Platelet count greater than 1,000,000/mm^3

PATIENT CHARACTERISTICS:

Age:

• Any age

Performance status:

• See Disease Characteristics

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Not specified

Renal:

• Not specified

Other:

• No other medical condition that would reduce life expectancy
• No other uncontrolled malignancy
• Not pregnant
• No other contraindication to study therapy

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior interferon

Chemotherapy:

• No prior cytotoxic therapy

Endocrine therapy:

• Not specified

Radiotherapy:

• No prior radiotherapy

Surgery:

• Not specified

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized

Collaborators and Investigators

• Sponsor: German CML Study Group
• Investigators: Study Chair: Ruediger Hehlmann, MD, III. Medizinische Klinik Mannheim

Study record dates

Study Major Dates

• Study Start: January 1, 1995
• Primary Completion: December 7, 2022
• Study Completion: December 7, 2022

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): August 2, 2013
• Last Update Submitted That Met QC Criteria: August 1, 2013
• Last Verified: July 1, 2000

More Information

Terms related to this study

• Keywords: chronic phase chronic myelogenous leukemia; childhood chronic myelogenous leukemia; chronic myelogenous leukemia, BCR-ABL1 positive; Philadelphia chromosome negative chronic myelogenous leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Antisickling Agents; Interferons; Interferon-alpha; Cytarabine; Idarubicin; Hydroxyurea; Busulfan
• Other Study ID Numbers: GER-CML-3; CDR0000064743 (Registry Identifier: PDQ (Physician Data Query)); EU-95042

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No