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Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission


Phase 3
15 Years
65 Years
Not Enrolling
Both
Leukemia

Thank you

Trial Information

Phase III Randomized Trial of Autologous and Allogeneic Stem Cell Transplantation Versus Intensive Conventional Chemotherapy in Acute Lymphoblastic Leukemia in First Remission


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.

Inclusion Criteria


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

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall Survival

Outcome Time Frame:

All patients were followed for 2 years

Safety Issue:

No

Principal Investigator

Jacob M. Rowe, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Rambam Health Care Campus

Authority:

United States: Federal Government

Study ID:

CDR0000078099

NCT ID:

NCT00002514

Start Date:

April 1993

Completion Date:

Related Keywords:

  • Leukemia
  • adult acute lymphoblastic leukemia in remission
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma

Name

Location

Hurley Medical CenterFlint, Michigan  48503
CCOP - Carle Cancer CenterUrbana, Illinois  61801
Beth Israel Deaconess Medical CenterBoston, Massachusetts  02215
CCOP - Metro-MinnesotaSaint Louis Park, Minnesota  55416
Aurora Presbyterian HospitalAurora, Colorado  80012
Boulder Community HospitalBoulder, Colorado  80301-9019
Penrose Cancer Center at Penrose HospitalColorado Springs, Colorado  80933
CCOP - Colorado Cancer Research ProgramDenver, Colorado  80224-2522
Porter Adventist HospitalDenver, Colorado  80210
Presbyterian - St. Luke's Medical CenterDenver, Colorado  80218
St. Joseph HospitalDenver, Colorado  80218
Rose Medical CenterDenver, Colorado  80220
Swedish Medical CenterEnglewood, Colorado  80110
St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical CenterGrand Junction, Colorado  81502
Sky Ridge Medical CenterLone Tree, Colorado  80124
Hope Cancer Care Center at Longmont United HospitalLongmont, Colorado  80502
St. Mary - Corwin Regional Medical CenterPueblo, Colorado  81004
North Suburban Medical CenterThornton, Colorado  80229
Carole and Ray Neag Comprehensive Cancer Center at the University of Connecticut Health CenterFarmington, Connecticut  06360-2875
George Bray Cancer Center at the Hospital of Central Connecticut - New Britain CampusNew Britain, Connecticut  06050
Rush-Copley Cancer Care CenterAurora, Illinois  60507
Evanston Northwestern Healthcare - Evanston HospitalEvanston, Illinois  60201-1781
Hinsdale Hematology Oncology AssociatesHinsdale, Illinois  60521
Joliet Oncology-Hematology Associates, Limited - WestJoliet, Illinois  60435
Carle Cancer Center at Carle Foundation HospitalUrbana, Illinois  61801
Methodist Cancer Center at Methodist HospitalIndianapolis, Indiana  46202
Saint Anthony Memorial Health CentersMichigan City, Indiana  46360
Cedar Rapids Oncology AssociatesCedar Rapids, Iowa  52403
Mercy Medical Center - Sioux CitySioux City, Iowa  51104
Siouxland Hematology-Oncology Associates, LLPSioux City, Iowa  51101
St. Luke's Regional Medical CenterSioux City, Iowa  51104
Tufts-NEMC Cancer CenterBoston, Massachusetts  02111
Baystate Regional Cancer Program at D'Amour Center for Cancer CareSpringfield, Massachusetts  01199
CCOP - Michigan Cancer Research ConsortiumAnn Arbor, Michigan  48106
Saint Joseph Mercy Cancer CenterAnn Arbor, Michigan  48106-0995
Oakwood Cancer Center at Oakwood Hospital and Medical CenterDearborn, Michigan  48123-2500
Genesys Hurley Cancer InstituteFlint, Michigan  48503
Van Elslander Cancer Center at St. John Hospital and Medical CenterGrosse Pointe Woods, Michigan  48236
Foote HospitalJackson, Michigan  49201
Bronson Methodist HospitalKalamazoo, Michigan  49007
West Michigan Cancer CenterKalamazoo, Michigan  49007-3731
Borgess Medical CenterKalamazooaa, Michigan  49001
Sparrow Regional Cancer CenterLansing, Michigan  48912-1811
Seton Cancer Institute - SaginawSaginaw, Michigan  48601
St. John Macomb HospitalWarren, Michigan  48093
MeritCare BemidjiBemidji, Minnesota  56601
Fairview Ridges HospitalBurnsville, Minnesota  55337
Mercy and Unity Cancer Center at Mercy HospitalCoon Rapids, Minnesota  55433
Duluth Clinic Cancer Center - DuluthDuluth, Minnesota  55805-1983
CCOP - DuluthDuluth, Minnesota  55805
Miller - Dwan Medical CenterDuluth, Minnesota  55805
Fairview Southdale HospitalEdina, Minnesota  55435
Mercy and Unity Cancer Center at Unity HospitalFridley, Minnesota  55432
Hutchinson Area Health CareHutchinson, Minnesota  55350
Meeker County Memorial HospitalLichfield, Minnesota  55355
Minnesota Oncology Hematology, PA - MaplewoodMaplewood, Minnesota  55109
HealthEast Cancer Care at St. John's HospitalMaplewood, Minnesota  55109
Hennepin County Medical Center - MinneapolisMinneapolis, Minnesota  55415
Virginia Piper Cancer Institute at Abbott - Northwestern HospitalMinneapolis, Minnesota  55407
Hubert H. Humphrey Cancer Center at North Memorial Outpatient CenterRobbinsdale, Minnesota  55422-2900
St. Francis Cancer Center at St. Francis Medical CenterShakopee, Minnesota  55379
HealthEast Cancer Care at St. Joseph's HospitalSt Paul, Minnesota  55102
Park Nicollet Cancer CenterSt. Louis Park, Minnesota  55416
Regions Hospital Cancer Care CenterSt. Paul, Minnesota  55101
United HospitalSt. Paul, Minnesota  55102
Ridgeview Medical CenterWaconia, Minnesota  55387
Minnesota Oncology Hematology, PA - WoodburyWoodbury, Minnesota  55125
HealthEast Cancer Care at Woodwinds Health CampusWoodbury, Minnesota  55125
MeritCare BroadwayFargo, North Dakota  58122
CCOP - MeritCare HospitalFargo, North Dakota  58122
Aultman Cancer Center at Aultman HospitalCanton, Ohio  44710-1799
Mercy Cancer Center at Mercy Medical CenterCanton, Ohio  44708
Jewish Hospital Cancer CenterCincinnati, Ohio  45236
Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065
MetroHealth Cancer Care Center at MetroHealth Medical CenterCleveland, Ohio  44109
St. Rita's Medical CenterLima, Ohio  45801
Natalie Warren Bryant Cancer Center at St. Francis HospitalTulsa, Oklahoma  74136
Geisinger Medical CenterDanville, Pennsylvania  17822-0001
Penn State Cancer Institute at Milton S. Hershey Medical CenterHershey, Pennsylvania  17033-0850
Abramson Cancer Center of the University of PennsylvaniaPhiladelphia, Pennsylvania  19104-4283
Drexel University College of Medicine - Center City Hahnemann CampusPhiladelphia, Pennsylvania  19102
Geisinger Medical Group - Scenery ParkState College, Pennsylvania  16801
Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical CenterWilkes-Barre, Pennsylvania  18711
Sanford Cancer Center at Sanford USD Medical CenterSioux Falls, South Dakota  57117-5039
Medical X-Ray Center, PCSioux Falls, South Dakota  57105
Avera Cancer InstituteSioux Falls, South Dakota  57105
Vanderbilt-Ingram Cancer CenterNashville, Tennessee  37232-6838
Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical CenterLa Crosse, Wisconsin  54601
Dean Medical Center - MadisonMadison, Wisconsin  53717
University of Wisconsin Paul P. Carbone Comprehensive Cancer CenterMadison, Wisconsin  53792-6164
Marshfield Clinic - Marshfield CenterMarshfield, Wisconsin  54449
Medical College of Wisconsin Cancer CenterMilwaukee, Wisconsin  53226
Froedtert Hospital and Medical College of WisconsinMilwaukee, Wisconsin  53226-3596
Marshfield Clinic - Indianhead CenterRice Lake, Wisconsin  54868