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

Sponsor

Southwest Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00005866

Collaborator

National Cancer Institute (NCI) (NIH)

240

Enrollment

Locations

Arm

72.9

Duration (Months)

3.6

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia Myelodysplastic Syndromes	Drug: busulfan Drug: cyclophosphamide Drug: cyclosporine Drug: methotrexate Procedure: allogeneic bone marrow transplantation Radiation: radiation therapy	Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

240 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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)

Study Start Date :

Feb 1, 2000

Actual Primary Completion Date :

Mar 1, 2004

Actual Study Completion Date :

Mar 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: treatment	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 Procedure: allogeneic bone marrow transplantation day 0 Radiation: radiation therapy both arms: 1200 cGy total dose (6 x 200 fractions)

Arm

Intervention/Treatment

Experimental: treatment

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

Procedure: allogeneic bone marrow transplantation

day 0

Radiation: radiation therapy

both arms: 1200 cGy total dose (6 x 200 fractions)

Outcome Measures

Primary Outcome Measures

Event-free survival [every 6 months after stem cell infusion until death or 5 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years to 55 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Good Samaritan Medical Center	Phoenix	Arizona	United States	85062-2989
2	Arizona Cancer Center	Tucson	Arizona	United States	85724
3	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
4	Alta Bates Comprehensive Cancer Center	Berkeley	California	United States	94704
5	Cancer Center and Beckman Research Institute, City of Hope	Duarte	California	United States	91010-3000
6	Scripps Clinic	La Jolla	California	United States	92037
7	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90033-0804
8	Jonsson Comprehensive Cancer Center, UCLA	Los Angeles	California	United States	90095-1781
9	St. Joseph Hospital - Orange	Orange	California	United States	92613-5600
10	Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
11	Sutter Cancer Center	Sacramento	California	United States	95816
12	University of California Davis Cancer Center	Sacramento	California	United States	95817
13	Stanford University Medical Center	Stanford	California	United States	94305-5408
14	Northern California Cancer Specialists Medical Clinic	Walnut Creek	California	United States	94598
15	University of Colorado Cancer Center	Denver	Colorado	United States	80010
16	Cancer Research Center of Hawaii	Honolulu	Hawaii	United States	96813
17	Queen's Medical Center	Honolulu	Hawaii	United States	96813
18	St. Francis Medical Center	Honolulu	Hawaii	United States	96817
19	Mountain States Tumor Institute	Boise	Idaho	United States	83712
20	Loyola University Medical Center	Maywood	Illinois	United States	60153
21	University of Kansas Medical Center	Kansas City	Kansas	United States	66160-7357
22	CCOP - Wichita	Wichita	Kansas	United States	67214-3882
23	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
24	Albert B. Chandler Medical Center, University of Kentucky	Lexington	Kentucky	United States	40536-0084
25	Lucille Parker Markey Cancer Center, University of Kentucky	Lexington	Kentucky	United States	40536-0093
26	Louisiana State University School of Medicine	New Orleans	Louisiana	United States	70112-2822
27	MBCCOP - LSU Health Sciences Center	New Orleans	Louisiana	United States	70112
28	Tulane University School of Medicine	New Orleans	Louisiana	United States	70112
29	Memorial Medical Center	New Orleans	Louisiana	United States	70115
30	Louisiana State University Health Sciences Center - Shreveport	Shreveport	Louisiana	United States	71130-3932
31	Boston Medical Center	Boston	Massachusetts	United States	02118
32	Cancer Research Center	Boston	Massachusetts	United States	02118
33	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0752
34	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
35	Henry Ford Hospital	Detroit	Michigan	United States	48202
36	University of Mississippi Medical Center	Jackson	Mississippi	United States	39216-4505
37	St. Louis University Health Sciences Center	Saint Louis	Missouri	United States	63110-0250
38	St. John's Health System	Springfield	Missouri	United States	65804
39	CCOP - Cancer Research for the Ozarks	Springfield	Missouri	United States	65807
40	Herbert Irving Comprehensive Cancer Center	New York	New York	United States	10032
41	Jewish Hospital of Cincinnati, Inc.	Cincinnati	Ohio	United States	45236
42	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
43	Miami Valley Hospital	Dayton	Ohio	United States	45409
44	CCOP - Dayton	Kettering	Ohio	United States	45429
45	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73190
46	Oregon Cancer Center	Portland	Oregon	United States	97201-3098
47	Legacy Cancer Services	Portland	Oregon	United States	97210
48	CCOP - Columbia River Program	Portland	Oregon	United States	97213
49	Providence St. Vincent Medical Center	Portland	Oregon	United States	97225
50	Brooke Army Medical Center	Fort Sam Houston	Texas	United States	78234
51	Wilford Hall - 59th Medical Wing	Lackland Air Force Base	Texas	United States	78236-5300
52	Texas Tech University Health Science Center	Lubbock	Texas	United States	79423
53	Health Science Center	Lubbock	Texas	United States	79430
54	Methodist Health Care System	San Antonio	Texas	United States	78229
55	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78284-7811
56	CCOP - Scott and White Hospital	Temple	Texas	United States	76508
57	Scott and White Clinic	Temple	Texas	United States	76508
58	Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
59	LDS Hospital	Salt Lake City	Utah	United States	84143
60	CCOP - Virginia Mason Research Center	Seattle	Washington	United States	98101
61	Swedish Cancer Institute	Seattle	Washington	United States	98104
62	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024
63	University of Washington Medical Center	Seattle	Washington	United States	98195-6043
64	Franciscan Health System	Tacoma	Washington	United States	98401-2197
65	CCOP - Northwest	Tacoma	Washington	United States	98405-0986
66	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9