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)
1,929
Enrollment
94
Locations
2
Arms
20.5
Patients Per Site

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 DiseaseIntervention/TreatmentPhase
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

ArmIntervention/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

SiteCityStateCountryPostal Code
1Aurora Presbyterian HospitalAuroraColoradoUnited States80012
2Boulder Community HospitalBoulderColoradoUnited States80301-9019
3Penrose Cancer Center at Penrose HospitalColorado SpringsColoradoUnited States80933
4Porter Adventist HospitalDenverColoradoUnited States80210
5Presbyterian - St. Luke's Medical CenterDenverColoradoUnited States80218
6St. Joseph HospitalDenverColoradoUnited States80218
7Rose Medical CenterDenverColoradoUnited States80220
8CCOP - Colorado Cancer Research ProgramDenverColoradoUnited States80224-2522
9Swedish Medical CenterEnglewoodColoradoUnited States80110
10St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical CenterGrand JunctionColoradoUnited States81502
11Sky Ridge Medical CenterLone TreeColoradoUnited States80124
12Hope Cancer Care Center at Longmont United HospitalLongmontColoradoUnited States80502
13St. Mary - Corwin Regional Medical CenterPuebloColoradoUnited States81004
14North Suburban Medical CenterThorntonColoradoUnited States80229
15Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health CenterFarmingtonConnecticutUnited States06360-2875
16George Bray Cancer Center at the Hospital of Central Connecticut - New Britain CampusNew BritainConnecticutUnited States06050
17Rush-Copley Cancer Care CenterAuroraIllinoisUnited States60507
18Evanston Northwestern Healthcare - Evanston HospitalEvanstonIllinoisUnited States60201-1781
19Hinsdale Hematology Oncology AssociatesHinsdaleIllinoisUnited States60521
20Joliet Oncology-Hematology Associates, Limited - WestJolietIllinoisUnited States60435
21Carle Cancer Center at Carle Foundation HospitalUrbanaIllinoisUnited States61801
22CCOP - Carle Cancer CenterUrbanaIllinoisUnited States61801
23Methodist Cancer Center at Methodist HospitalIndianapolisIndianaUnited States46202
24Saint Anthony Memorial Health CentersMichigan CityIndianaUnited States46360
25Cedar Rapids Oncology AssociatesCedar RapidsIowaUnited States52403
26Siouxland Hematology-Oncology Associates, LLPSioux CityIowaUnited States51101
27Mercy Medical Center - Sioux CitySioux CityIowaUnited States51104
28St. Luke's Regional Medical CenterSioux CityIowaUnited States51104
29Tufts-NEMC Cancer CenterBostonMassachusettsUnited States02111
30Beth Israel Deaconess Medical CenterBostonMassachusettsUnited States02215
31Baystate Regional Cancer Program at D'Amour Center for Cancer CareSpringfieldMassachusettsUnited States01199
32Saint Joseph Mercy Cancer CenterAnn ArborMichiganUnited States48106-0995
33CCOP - Michigan Cancer Research ConsortiumAnn ArborMichiganUnited States48106
34Oakwood Cancer Center at Oakwood Hospital and Medical CenterDearbornMichiganUnited States48123-2500
35Genesys Hurley Cancer InstituteFlintMichiganUnited States48503
36Hurley Medical CenterFlintMichiganUnited States48503
37Van Elslander Cancer Center at St. John Hospital and Medical CenterGrosse Pointe WoodsMichiganUnited States48236
38Foote HospitalJacksonMichiganUnited States49201
39Borgess Medical CenterKalamazooaaMichiganUnited States49001
40West Michigan Cancer CenterKalamazooMichiganUnited States49007-3731
41Bronson Methodist HospitalKalamazooMichiganUnited States49007
42Sparrow Regional Cancer CenterLansingMichiganUnited States48912-1811
43Seton Cancer Institute - SaginawSaginawMichiganUnited States48601
44St. John Macomb HospitalWarrenMichiganUnited States48093
45MeritCare BemidjiBemidjiMinnesotaUnited States56601
46Fairview Ridges HospitalBurnsvilleMinnesotaUnited States55337
47Mercy and Unity Cancer Center at Mercy HospitalCoon RapidsMinnesotaUnited States55433
48Duluth Clinic Cancer Center - DuluthDuluthMinnesotaUnited States55805-1983
49CCOP - DuluthDuluthMinnesotaUnited States55805
50Miller - Dwan Medical CenterDuluthMinnesotaUnited States55805
51Fairview Southdale HospitalEdinaMinnesotaUnited States55435
52Mercy and Unity Cancer Center at Unity HospitalFridleyMinnesotaUnited States55432
53Hutchinson Area Health CareHutchinsonMinnesotaUnited States55350
54Meeker County Memorial HospitalLichfieldMinnesotaUnited States55355
55HealthEast Cancer Care at St. John's HospitalMaplewoodMinnesotaUnited States55109
56Minnesota Oncology Hematology, PA - MaplewoodMaplewoodMinnesotaUnited States55109
57Virginia Piper Cancer Institute at Abbott - Northwestern HospitalMinneapolisMinnesotaUnited States55407
58Hennepin County Medical Center - MinneapolisMinneapolisMinnesotaUnited States55415
59Hubert H. Humphrey Cancer Center at North Memorial Outpatient CenterRobbinsdaleMinnesotaUnited States55422-2900
60CCOP - Metro-MinnesotaSaint Louis ParkMinnesotaUnited States55416
61St. Francis Cancer Center at St. Francis Medical CenterShakopeeMinnesotaUnited States55379
62HealthEast Cancer Care at St. Joseph's HospitalSt PaulMinnesotaUnited States55102
63Park Nicollet Cancer CenterSt. Louis ParkMinnesotaUnited States55416
64Regions Hospital Cancer Care CenterSt. PaulMinnesotaUnited States55101
65United HospitalSt. PaulMinnesotaUnited States55102
66Ridgeview Medical CenterWaconiaMinnesotaUnited States55387
67HealthEast Cancer Care at Woodwinds Health CampusWoodburyMinnesotaUnited States55125
68Minnesota Oncology Hematology, PA - WoodburyWoodburyMinnesotaUnited States55125
69CCOP - MeritCare HospitalFargoNorth DakotaUnited States58122
70MeritCare BroadwayFargoNorth DakotaUnited States58122
71Mercy Cancer Center at Mercy Medical CenterCantonOhioUnited States44708
72Aultman Cancer Center at Aultman HospitalCantonOhioUnited States44710-1799
73Jewish Hospital Cancer CenterCincinnatiOhioUnited States45236
74Case Comprehensive Cancer CenterClevelandOhioUnited States44106-5065
75MetroHealth Cancer Care Center at MetroHealth Medical CenterClevelandOhioUnited States44109
76St. Rita's Medical CenterLimaOhioUnited States45801
77Natalie Warren Bryant Cancer Center at St. Francis HospitalTulsaOklahomaUnited States74136
78Geisinger Medical CenterDanvillePennsylvaniaUnited States17822-0001
79Penn State Cancer Institute at Milton S. Hershey Medical CenterHersheyPennsylvaniaUnited States17033-0850
80Drexel University College of Medicine - Center City Hahnemann CampusPhiladelphiaPennsylvaniaUnited States19102
81Abramson Cancer Center of the University of PennsylvaniaPhiladelphiaPennsylvaniaUnited States19104-4283
82Geisinger Medical Group - Scenery ParkState CollegePennsylvaniaUnited States16801
83Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical CenterWilkes-BarrePennsylvaniaUnited States18711
84Avera Cancer InstituteSioux FallsSouth DakotaUnited States57105
85Medical X-Ray Center, PCSioux FallsSouth DakotaUnited States57105
86Sanford Cancer Center at Sanford USD Medical CenterSioux FallsSouth DakotaUnited States57117-5039
87Vanderbilt-Ingram Cancer CenterNashvilleTennesseeUnited States37232-6838
88Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical CenterLa CrosseWisconsinUnited States54601
89Dean Medical Center - MadisonMadisonWisconsinUnited States53717
90University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadisonWisconsinUnited States53792-6164
91Marshfield Clinic - Marshfield CenterMarshfieldWisconsinUnited States54449
92Froedtert Hospital and Medical College of WisconsinMilwaukeeWisconsinUnited States53226-3596
93Medical College of Wisconsin Cancer CenterMilwaukeeWisconsinUnited States53226
94Marshfield Clinic - Indianhead CenterRice LakeWisconsinUnited States54868

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

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

Study Results

No Results Posted as of Nov 22, 2012