S9920 Busulfan Compared With Cyclophosphamide in Patients Undergoing Total-Body Irradiation Plus Peripheral Stem Cell Transplantation for Advanced Myelodysplastic Syndrome or Related Acute Myeloid Leukemia

A Phase III Randomized Study Comparing Busulfan-Total Body Irradiation Versus Cyclophosphamide-Total Body Irradiation Preparative Regimen in Patients With Advanced Myelodysplastic Syndrome (MDS) or MDS-Related Acute Myeloid Leukemia (AML) Undergoing HLA-Identical Sibling Peripheral Blood Stem Cell Transplantation, (A BMT Study)

RATIONALE: Peripheral stem cell transplantation may be able to replace immune cells that were destroyed by chemotherapy or radiation therapy used to kill tumor cells. It is not yet known if total-body irradiation plus peripheral stem cell transplantation is more effective with busulfan or with cyclophosphamide for myelodysplastic syndrome or acute myeloid leukemia.

PURPOSE: Randomized phase III trial to compare the effectiveness of busulfan with that of cyclophosphamide in patients undergoing total-body irradiation plus peripheral stem cell transplantation for advanced myelodysplastic syndrome or related acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Procedure: allogeneic bone marrow transplantation; Drug: busulfan; Drug: cyclophosphamide; Drug: cyclosporine; Drug: methotrexate; Radiation: radiation therapy

Detailed Description

OBJECTIVES: I. Compare event free survival after total body irradiation (TBI) plus busulfan versus TBI plus cyclophosphamide followed by allogeneic peripheral blood stem cell transplantation in patients with advanced myelodysplastic syndrome (MDS) or MDS related acute myeloid leukemia. II. Determine the distribution of pharmacokinetic parameters for busulfan in those patients randomized to the busulfan treatment arm. III. Investigate the prognostic significance for event free survival of prior history of red cell transfusions, cytogenetic pattern, and of functional drug resistance at diagnosis in these patients. IV. Estimate the frequencies of cytogenetic and genetic changes during disease progression in these patients.

OUTLINE: This a randomized, multicenter study. Patients are stratified according to age (40 and under vs 41-55) and diagnosis and International Prognostic Scoring System (IPSS) risk group (myelodysplastic syndrome (MDS)/IPSS - intermediate 1 vs MDS/IPSS - intermediate 2 vs MDS/IPSS high risk vs MDS related acute myeloid leukemia). Patients are randomized to one of two treatment arms. Arm I: Patients receive busulfan IV over 2 hours every 6 hours on days -7 to -4 for a total of 16 doses. Arm II: Patients receive cyclophosphamide IV over 2 hours on days -5 and -4. Patients receive total body irradiation (TBI) twice a day on days -3 to -1; peripheral blood stem cell transplantation from genotypically HLA identical sibling on day 0; cyclosporine IV every 12 hours on days -1 to 60, and then tapering in the absence of graft versus host disease; and methotrexate IV on days 1, 3, 6, and 11. Patients are followed every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 240 patients (120 per treatment arm) will be accrued for this study over 5 years.

• Study Type: Interventional
• Enrollment (Anticipated): 240
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85062-2989
      • Good Samaritan Medical Center
    • Tucson, Arizona, United States, 85724
      • Arizona Cancer Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • University of Arkansas for Medical Sciences
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Comprehensive Cancer Center
    • Duarte, California, United States, 91010-3000
      • Cancer Center and Beckman Research Institute, City of Hope
    • La Jolla, California, United States, 92037
      • Scripps Clinic
    • Los Angeles, California, United States, 90095-1781
      • Jonsson Comprehensive Cancer Center, UCLA
    • Los Angeles, California, United States, 90033-0804
      • USC/Norris Comprehensive Cancer Center and Hospital
    • Orange, California, United States, 92868
      • Chao Family Comprehensive Cancer Center
    • Orange, California, United States, 92613-5600
      • St. Joseph Hospital - Orange
    • Sacramento, California, United States, 95816
      • Sutter Cancer center
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center
    • Stanford, California, United States, 94305-5408
      • Stanford University Medical Center
    • Walnut Creek, California, United States, 94598
      • Northern California Cancer Specialists Medical Clinic
  • Colorado
    • Denver, Colorado, United States, 80010
      • University of Colorado Cancer Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Medical Center
    • Honolulu, Hawaii, United States, 96813
      • Cancer Research Center of Hawaii
    • Honolulu, Hawaii, United States, 96817
      • St. Francis Medical Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • Mountain States Tumor Institute
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160-7357
      • University of Kansas Medical Center
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas - Wichita
    • Wichita, Kansas, United States, 67214-3882
      • CCOP - Wichita
  • Kentucky
    • Lexington, Kentucky, United States, 40536-0084
      • Albert B. Chandler Medical Center, University of Kentucky
    • Lexington, Kentucky, United States, 40536-0093
      • Lucille Parker Markey Cancer Center, University of Kentucky
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Tulane University School of Medicine
    • New Orleans, Louisiana, United States, 70112
      • MBCCOP - LSU Health Sciences Center
    • New Orleans, Louisiana, United States, 70112-2822
      • Louisiana State University School of Medicine
    • New Orleans, Louisiana, United States, 70115
      • Memorial Medical Center
    • Shreveport, Louisiana, United States, 71130-3932
      • Louisiana State University Health Sciences Center - Shreveport
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02118
      • Cancer Research Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0752
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110-0250
      • St. Louis University Health Sciences Center
    • Springfield, Missouri, United States, 65807
      • CCOP - Cancer Research for the Ozarks
    • Springfield, Missouri, United States, 65804
      • St. John's Health System
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center
  • Ohio
    • Cincinnati, Ohio, United States, 45236
      • Jewish Hospital of Cincinnati, Inc.
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
    • Dayton, Ohio, United States, 45409
      • Miami Valley Hospital
    • Kettering, Ohio, United States, 45429
      • CCOP - Dayton
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73190
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97213
      • CCOP - Columbia River Program
    • Portland, Oregon, United States, 97201-3098
      • Oregon Cancer Center
    • Portland, Oregon, United States, 97225
      • Providence St. Vincent Medical Center
    • Portland, Oregon, United States, 97210
      • Legacy Cancer Services
  • Texas
    • Fort Sam Houston, Texas, United States, 78234
      • Brooke Army Medical Center
    • Lackland Air Force Base, Texas, United States, 78236-5300
      • Wilford Hall - 59th Medical Wing
    • Lubbock, Texas, United States, 79423
      • Texas Tech University Health Science Center
    • Lubbock, Texas, United States, 79430
      • Health Science Center
    • San Antonio, Texas, United States, 78284-7811
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78229
      • Methodist Health Care System
    • Temple, Texas, United States, 76508
      • Scott and White Clinic
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Seattle, Washington, United States, 98101
      • CCOP - Virginia Mason Research Center
    • Seattle, Washington, United States, 98104
      • Swedish Cancer Institute
    • Seattle, Washington, United States, 98109-1024
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98195-6043
      • University of Washington Medical Center
    • Tacoma, Washington, United States, 98405-0986
      • CCOP - Northwest
    • Tacoma, Washington, United States, 98401-2197
      • Franciscan Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: Cytologically confirmed myelodysplastic syndrome (MDS) Increased blasts (i.e., greater than 1 to 30% peripheral blood blasts and/or 5 to 30% bone marrow blasts) AND International Prognostic Score intermediate 1, intermediate 2, or high risk Refractory anemia with excess blasts OR Refractory anemia with excess blasts in transformation (no presence of auer rods as sole criteria) OR Chronic myelomonocytic leukemia Greater than 1% blasts in the peripheral blood and/or at least 5% blasts in the bone marrow OR MDS related acute myeloid leukemia Arising after documented MDS of at least 60 days Absolute peripheral blast count no greater than 5,000/mm3 Must have genotypically HLA identical sibling donor Must also be enrolled on SWOG-S9910 and SWOG-9007

PATIENT CHARACTERISTICS: Age: 16 to 55 Performance status: Zubrod 0-2 Life expectancy: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified Other: No prior malignancy within past 5 years except: Adequately treated basal cell or squamous cell skin cancer Carcinoma in situ of the cervix Adequately treated stage I or II cancer in complete remission HIV negative Not pregnant or nursing Fertile patients must use effective contraception

PRIOR CONCURRENT THERAPY: Biologic therapy: No autologous peripheral stem cell transplantation prior to diagnosis of myelodysplastic syndrome (MDS) or MDS related acute myeloid leukemia Chemotherapy: No prior chemotherapy for MDS or MDS related acute myeloid leukemia except oral chemotherapy to control leukocytosis or thrombocytosis (e.g., hydroxyurea or etoposide) Endocrine therapy: Not specified Radiotherapy: No radiotherapy prior to diagnosis of MDS or MDS related acute myeloid leukemia Surgery: Not specified

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: treatment

Procedure: allogeneic bone marrow transplantation; day 0; Drug: busulfan; arm 1: 0.44 mg/kg every 6 hours, IV over 2 hours, day -7 to -4; Drug: cyclophosphamide; arm 2: 60 mg/kg every 24 hrs for 2 doses, IV over 2 hrs, days -5 and -4; Drug: cyclosporine; both arms per published schedule; Drug: methotrexate; GVHD: 15 mg/m2 day 1, 10 mg/m2 day 3, 6 and 11 by IV; Radiation: radiation therapy; both arms: 1200 cGy total dose (6 x 200 fractions)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event-free survival	every 6 months after stem cell infusion until death or 5 years

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Jeanne E. Anderson, MD, Katmai Oncology Group

Study record dates

Study Major Dates

• Study Start: February 1, 2000
• Primary Completion (Actual): March 1, 2004
• Study Completion (Actual): March 1, 2006

Study Registration Dates

• First Submitted: June 2, 2000
• First Submitted That Met QC Criteria: March 15, 2004
• First Posted (Estimate): March 16, 2004

Study Record Updates

• Last Update Posted (Estimate): March 6, 2015
• Last Update Submitted That Met QC Criteria: March 5, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: refractory anemia with excess blasts; refractory anemia with excess blasts in transformation; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; secondary myelodysplastic syndromes; secondary acute myeloid leukemia; childhood myelodysplastic syndromes; untreated adult acute myeloid leukemia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dermatologic Agents; Antifungal Agents; Reproductive Control Agents; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Calcineurin Inhibitors; Cyclophosphamide; Methotrexate; Busulfan; Cyclosporine; Cyclosporins
• Other Study ID Numbers: S9920 (Other Identifier: SWOG); U10CA032102 (U.S. NIH Grant/Contract)