Stem Cell Transplantation Compared With Standard Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia in First Remission

• Sponsor: Eastern Cooperative Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00002514
• Collaborator: National Cancer Institute (NCI) (NIH), Medical Research Council (Other)

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with allogeneic or autologous stem cell transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more cancer cells. It is not yet known whether stem cell transplantation is more effective than standard chemotherapy in treating acute lymphoblastic leukemia.

PURPOSE: This randomized phase III trial is studying how well stem cell transplantation works compared to standard combination chemotherapy in treating patients with acute lymphoblastic leukemia in first remission.

Condition or Disease	Intervention/Treatment	Phase
Leukemia	Biological: sargramostim; Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: etoposide; Drug: imatinib mesylate; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Procedure: allogeneic bone marrow transplantation; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: radiation therapy	Phase 3

Detailed Description

OBJECTIVES:

• Compare the duration of complete remission (CR) and survival in patients with acute lymphoblastic leukemia in first remission treated with allogeneic or autologous stem cell transplantation (SCT) vs conventional consolidation and maintenance chemotherapy.

• Compare the overall treatment outcomes in patients treated with these regimens.

• Determine the effect of imatinib mesylate given after induction therapy in Philadelphia (Ph) chromosome-positive patients in CR.

• Determine the benefit of allogeneic or autologous SCT after imatinib mesylate in Ph chromosome-positive patients.

• Determine the benefit of additional imatinib mesylate administered after allogeneic or autologous SCT in Ph chromosome-positive patients.

• Determine the minimal residual disease in Ph chromosome-positive patients before and after treatment with imatinib mesylate.

• Determine the clinical resistance to imatinib mesylate caused by BCR-ABL gene amplification or mutation in Ph chromosome-positive patients.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to age (50 and under vs over 50), time to achieve complete remission (CR) (4 weeks or less vs more than 4 weeks), and Philadelphia (Ph) chromosome status (positive vs negative).

• First induction therapy: Patients receive daunorubicin (DNR) IV over 15-30 minutes and vincristine (VCR) IV over 3-5 minutes on days 1, 8, 15, and 22; oral prednisone (PRED) once daily on days 1-28; and asparaginase (ASP) IV over 30 minutes or intramuscularly on days 17-28. Patients with CNS leukemia at presentation also receive methotrexate (MTX) intrathecally (IT) via an Ommaya reservoir weekly until the CSF is clear. Patients without CNS leukemia at presentation receive MTX IT on day 23 only.

• Second induction therapy: Beginning immediately after first induction therapy, patients receive cyclophosphamide (CTX) IV over 30 minutes on days 1, 15, and 29; cytarabine (ARA-C) IV over 30 minutes on days 1-4, 8-11, 15-18, and 22-25; and oral mercaptopurine (MP) once daily on days 1-28. Patients with CNS leukemia at presentation also undergo concurrent craniospinal irradiation. Patients without CNS leukemia at presentation receive MTX IT on days 1, 8, 15, and 22. Patients with Ph chromosome-positive status receive oral imatinib mesylate once daily for at least 28 days (days 1-28).

Patients with Ph chromosome-positive status and CR after second induction therapy proceed to group I for autologous or allogeneic stem cell transplantation (SCT). Patients with Ph chromosome-negative status and CR after second induction therapy proceed to group II.

• Group I (Ph chromosome-positive patients):

• Autologous SCT: Patients receive high-dose consolidation/mobilization chemotherapy comprising ARA-C IV over 3 hours on days 1-3 and mitoxantrone IV immediately after ARA-C administration on days 1 and 2. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 5 and continuing until blood counts recover.

Patients then undergo peripheral blood stem cell collection or bone marrow harvesting.

Patients receive preparative therapy comprising total body irradiation twice daily (5-10 hours apart) on days -6 to -4 and high-dose etoposide (VP-16) IV over 4 hours on day -3. Male patients also undergo radiotherapy boost to the testes on day -6.

Patients undergo autologous SCT on day 0 and receive sargramostim (GM-CSF) SC once daily beginning 6 hours after the completion of SCT and continuing until blood counts recover.

• Allogeneic SCT: Patients receive the preparative regimen as in autologous SCT and then undergo allogeneic SCT on day 0. Patients receive GM-CSF as in autologous SCT.

• Post-SCT imatinib mesylate therapy: After recovery from autologous or allogeneic SCT, patients receive oral imatinib mesylate once daily. Imatinib mesylate therapy continues in the absence of disease progression or unacceptable toxicity.

• Group II (Ph chromosome-negative patients):

• Intensification therapy: Beginning 4 weeks after the completion of the second induction therapy, patients receive high-dose MTX IV over 2 hours on days 1, 8, and 22; leucovorin calcium IV every 6 hours for 4 doses and then orally every 6 hours for 12 doses beginning 22-24 hours after each MTX infusion; and ASP IV over 30 minutes on days 2, 9, and 23.

Patients who are ≤ 50 years of age with a histocompatible donor proceed to allogeneic SCT and undergo allogeneic SCT as in group I. Patients who are ≤ 50 years of age without an appropriate donor are randomized to 1 of 2 treatment arms.

• Arm I (conventional consolidation/maintenance therapy):

• Conventional consolidation therapy: During course 1, patients receive ARA-C IV over 30 minutes and VP-16 IV over 1 hour on days 1-5; VCR IV on days 1, 8, 15, and 22; and oral dexamethasone on days 1-28. During course 2 (which begins 4 weeks after initiation of course 1 or when blood counts recover), patients receive ARA-C and VP-16 as in course 1. During course 3 (which begins 4 weeks after initiation of course 2 or when blood counts recover), patients receive DNR IV on days 1, 8, 15, and 22; CTX IV over 30 minutes on day 29; ARA-C IV over 30 minutes on days 31-34 and 38-41; and oral thioguanine on days 29-42. During course 4 (which begins 8 weeks after initiation of course 3 or when blood counts recover), patients receive treatment as in course 2.

• Maintenance therapy: Beginning 4 weeks after initiation of course 4 of consolidation therapy or when blood counts recover, patients receive oral MP daily; MTX orally or IV once weekly; VCR IV once every 12 weeks; and oral PRED for 5 days every 12 weeks. Maintenance therapy continues for 2.5 years after initiation of intensification therapy.

• Arm II (autologous SCT): Patients undergo autologous SCT as in group I with the exception of high-dose consolidation/mobilization chemotherapy.

Patients are followed every 6 months for 2 years.

PROJECTED ACCRUAL: Approximately 40 patients per year will be accrued for group I (Philadelphia [Ph] chromosome-positive patients) of this study. Approximately 550 patients will be accrued for group II (Ph chromosome-negative patients) of this study within 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1929 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission
• Study Start Date: Apr 1, 1993
• Actual Primary Completion Date: Dec 1, 2006

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Transplant Allogeneic (if donor) or Autologous (if no donor) bone marrow transplant	Biological: sargramostim; Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: etoposide; Drug: imatinib mesylate; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: vincristine sulfate; Procedure: allogeneic bone marrow transplantation; Procedure: autologous bone marrow transplantation; Procedure: peripheral blood stem cell transplantation
Active Comparator: Conventional Consolidation/Maintenance Consolidation/Maintenance Therapy	Drug: asparaginase; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin hydrochloride; Drug: dexamethasone; Drug: etoposide; Drug: leucovorin calcium; Drug: mercaptopurine; Drug: methotrexate; Drug: prednisone; Drug: thioguanine; Drug: vincristine sulfate; Radiation: radiation therapy

Outcome Measures

Primary Outcome Measures

1. Overall Survival [All patients were followed for 2 years]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 15 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically confirmed acute lymphoblastic leukemia (ALL)

• More than 25% lymphoblasts in bone marrow

• Patients with myeloid antigen expression AND unequivocal lymphoid immunophenotype are eligible

• Philadelphia (Ph) chromosome status determined by cytogenetics, fluorescence in situ hybridization (FISH), and/or RNA analysis

• Patients determined to be Ph chromosome negative by cytogenetics, but positive for BCR-ABL by FISH or polymerase chain reaction are considered Ph chromosome positive

• Patients with Ph chromosome-positive disease may be up to age 65

• No myelodysplasia or other antecedent hematologic disorder

• Patients age 50 and under must be HLA typed during induction therapy of study treatment OR provide a written explanation for not undergoing HLA typing

• A and B typing required

• C and DR typing done if feasible

• Allogeneic stem cell transplantation patients must meet the following criteria:

• Appropriate HLA histocompatible donor available

• Ph chromosome-negative patients must have HLA identical sibling

• Ph chromosome-positive patients must have HLA identical, HLA-matched unrelated, or haploidentical related donor

• Postinduction therapy:

• CSF negative for leukemia

• No occult or overt leukemic meningitis

• Documented complete remission

PATIENT CHARACTERISTICS:

Age:

• 15 to 65

Performance status:

• Induction therapy:

• Not specified

• Postinduction therapy:

• 0-1

Life expectancy:

• Not specified

Hematopoietic:

• See Disease Characteristics

Hepatic:

• Induction therapy:

• Direct bilirubin ≤ 2.0 mg/dL

• Postinduction therapy:

• Direct bilirubin < 2.0 mg/dL

• SGPT or SGOT < 3 times normal

Renal:

• Induction therapy:

• Creatinine < 2 mg/dL

• Postinduction therapy:

• Creatinine ≤ 2 mg/dL

• Creatinine clearance ≥ 60 mL/min

Cardiovascular:

• Induction and postinduction therapy:

• No significant cardiac disease requiring digoxin and/or diuretics

• No major ventricular dysrhythmia requiring medication

• No ischemic heart disease requiring medication

• Postinduction therapy:

• Cardiac ejection fraction ≥ 50% for patients under consideration for transplantation

Pulmonary:

• Induction therapy:

• Not specified

• Postinduction therapy:

• FEV_1 ≥ 60% of predicted for patients under consideration for transplantation

• DLCO ≥ 50% of predicted for patients under consideration for transplantation

Other:

• Induction and postinduction therapy:

• HIV negative

• No concurrent organ damage or other medical problem (e.g., psychiatric disorder or drug abuse) that would preclude study therapy

• Not pregnant

• Postinduction therapy:

• No persistent infection

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No concurrent umbilical cord allogeneic transplantation

Chemotherapy:

• Not specified

Endocrine therapy:

• Prior corticosteroids for ALL allowed

Radiotherapy:

• Not specified

Surgery:

• Not specified

Other:

• Induction and postinduction therapy:

• No other prior therapy for ALL

• Postinduction therapy:

• No concurrent antibiotics

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aurora Presbyterian Hospital	Aurora	Colorado	United States	80012
2	Boulder Community Hospital	Boulder	Colorado	United States	80301-9019
3	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
4	Porter Adventist Hospital	Denver	Colorado	United States	80210
5	Presbyterian - St. Luke's Medical Center	Denver	Colorado	United States	80218
6	St. Joseph Hospital	Denver	Colorado	United States	80218
7	Rose Medical Center	Denver	Colorado	United States	80220
8	CCOP - Colorado Cancer Research Program	Denver	Colorado	United States	80224-2522
9	Swedish Medical Center	Englewood	Colorado	United States	80110
10	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado	United States	81502
11	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
12	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado	United States	80502
13	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
14	North Suburban Medical Center	Thornton	Colorado	United States	80229
15	Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health Center	Farmington	Connecticut	United States	06360-2875
16	George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus	New Britain	Connecticut	United States	06050
17	Rush-Copley Cancer Care Center	Aurora	Illinois	United States	60507
18	Evanston Northwestern Healthcare - Evanston Hospital	Evanston	Illinois	United States	60201-1781
19	Hinsdale Hematology Oncology Associates	Hinsdale	Illinois	United States	60521
20	Joliet Oncology-Hematology Associates, Limited - West	Joliet	Illinois	United States	60435
21	Carle Cancer Center at Carle Foundation Hospital	Urbana	Illinois	United States	61801
22	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
23	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana	United States	46202
24	Saint Anthony Memorial Health Centers	Michigan City	Indiana	United States	46360
25	Cedar Rapids Oncology Associates	Cedar Rapids	Iowa	United States	52403
26	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa	United States	51101
27	Mercy Medical Center - Sioux City	Sioux City	Iowa	United States	51104
28	St. Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
29	Tufts-NEMC Cancer Center	Boston	Massachusetts	United States	02111
30	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
31	Baystate Regional Cancer Program at D'Amour Center for Cancer Care	Springfield	Massachusetts	United States	01199
32	Saint Joseph Mercy Cancer Center	Ann Arbor	Michigan	United States	48106-0995
33	CCOP - Michigan Cancer Research Consortium	Ann Arbor	Michigan	United States	48106
34	Oakwood Cancer Center at Oakwood Hospital and Medical Center	Dearborn	Michigan	United States	48123-2500
35	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
36	Hurley Medical Center	Flint	Michigan	United States	48503
37	Van Elslander Cancer Center at St. John Hospital and Medical Center	Grosse Pointe Woods	Michigan	United States	48236
38	Foote Hospital	Jackson	Michigan	United States	49201
39	Borgess Medical Center	Kalamazooaa	Michigan	United States	49001
40	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
41	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
42	Sparrow Regional Cancer Center	Lansing	Michigan	United States	48912-1811
43	Seton Cancer Institute - Saginaw	Saginaw	Michigan	United States	48601
44	St. John Macomb Hospital	Warren	Michigan	United States	48093
45	MeritCare Bemidji	Bemidji	Minnesota	United States	56601
46	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
47	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota	United States	55433
48	Duluth Clinic Cancer Center - Duluth	Duluth	Minnesota	United States	55805-1983
49	CCOP - Duluth	Duluth	Minnesota	United States	55805
50	Miller - Dwan Medical Center	Duluth	Minnesota	United States	55805
51	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
52	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota	United States	55432
53	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
54	Meeker County Memorial Hospital	Lichfield	Minnesota	United States	55355
55	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota	United States	55109
56	Minnesota Oncology Hematology, PA - Maplewood	Maplewood	Minnesota	United States	55109
57	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
58	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota	United States	55415
59	Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota	United States	55422-2900
60	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
61	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota	United States	55379
62	HealthEast Cancer Care at St. Joseph's Hospital	St Paul	Minnesota	United States	55102
63	Park Nicollet Cancer Center	St. Louis Park	Minnesota	United States	55416
64	Regions Hospital Cancer Care Center	St. Paul	Minnesota	United States	55101
65	United Hospital	St. Paul	Minnesota	United States	55102
66	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
67	HealthEast Cancer Care at Woodwinds Health Campus	Woodbury	Minnesota	United States	55125
68	Minnesota Oncology Hematology, PA - Woodbury	Woodbury	Minnesota	United States	55125
69	CCOP - MeritCare Hospital	Fargo	North Dakota	United States	58122
70	MeritCare Broadway	Fargo	North Dakota	United States	58122
71	Mercy Cancer Center at Mercy Medical Center	Canton	Ohio	United States	44708
72	Aultman Cancer Center at Aultman Hospital	Canton	Ohio	United States	44710-1799
73	Jewish Hospital Cancer Center	Cincinnati	Ohio	United States	45236
74	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
75	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio	United States	44109
76	St. Rita's Medical Center	Lima	Ohio	United States	45801
77	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
78	Geisinger Medical Center	Danville	Pennsylvania	United States	17822-0001
79	Penn State Cancer Institute at Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
80	Drexel University College of Medicine - Center City Hahnemann Campus	Philadelphia	Pennsylvania	United States	19102
81	Abramson Cancer Center of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283
82	Geisinger Medical Group - Scenery Park	State College	Pennsylvania	United States	16801
83	Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center	Wilkes-Barre	Pennsylvania	United States	18711
84	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
85	Medical X-Ray Center, PC	Sioux Falls	South Dakota	United States	57105
86	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota	United States	57117-5039
87	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee	United States	37232-6838
88	Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
89	Dean Medical Center - Madison	Madison	Wisconsin	United States	53717
90	University of Wisconsin Paul P. Carbone Comprehensive Cancer Center	Madison	Wisconsin	United States	53792-6164
91	Marshfield Clinic - Marshfield Center	Marshfield	Wisconsin	United States	54449
92	Froedtert Hospital and Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226-3596
93	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
94	Marshfield Clinic - Indianhead Center	Rice Lake	Wisconsin	United States	54868

Sponsors and Collaborators

• Eastern Cooperative Oncology Group
• National Cancer Institute (NCI)
• Medical Research Council

Investigators

• Study Chair: Jacob M. Rowe, MD, Rambam Health Care Campus
• Principal Investigator: Mark R. Litzow, MD, Mayo Clinic
• Study Chair: Antony H. Goldstone, FRCP, University College London Hospitals

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ferrando AA, Neuberg D, Dodge RK, et al.: Adult T-cell ALL patients whose lymphoblasts express the HOX11 oncogene have an excellent prognosis when treated with chemotherapy and are not candidates for allogeneic bone marrow transplantaton in first remission. [Abstract] Blood 100 (11 pt 1): A-578, 2002.
• Goldstone AH. Transplants in Adult ALL--? Allo for everyone. Biol Blood Marrow Transplant. 2009 Jan;15(1 Suppl):7-10. doi: 10.1016/j.bbmt.2008.11.017. Review.
• Paietta E, Ferrando AA, Neuberg D, Bennett JM, Racevskis J, Lazarus H, Dewald G, Rowe JM, Wiernik PH, Tallman MS, Look AT. Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias. Blood. 2004 Jul 15;104(2):558-60. Epub 2004 Mar 25.
• Ramanujachar R, Richards S, Hann I, Goldstone A, Mitchell C, Vora A, Rowe J, Webb D. Adolescents with acute lymphoblastic leukaemia: outcome on UK national paediatric (ALL97) and adult (UKALLXII/E2993) trials. Pediatr Blood Cancer. 2007 Mar;48(3):254-61.
• Wang H, Chen XQ, Geng QR, Liu PP, Lin GN, Xia ZJ, Lu Y. Induction therapy using the MRC UKALLXII/ECOG E2993 protocol in Chinese adults with acute lymphoblastic leukemia. Int J Hematol. 2011 Aug;94(2):163-168. doi: 10.1007/s12185-011-0891-y. Epub 2011 Jul 6.

• Responsible Party: Eastern Cooperative Oncology Group
• ClinicalTrials.gov Identifier: NCT00002514
• Other Study ID Numbers: CDR0000078099; E2993; MRC-LEUK-UKALL-XII; EST-4491; NCT00222586
• First Posted: Jan 27, 2003
• Last Update Posted: Nov 22, 2012
• Last Verified: Aug 1, 2007

• Keywords provided by Eastern Cooperative Oncology Group: adult acute lymphoblastic leukemia in remission
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Leucovorin; Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Methotrexate; Etoposide; Vincristine; Imatinib Mesylate; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Sargramostim; Levoleucovorin

Study Results

No Results Posted as of Nov 22, 2012