S0333 Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

A Phase II Study of Double Induction Chemotherapy for Newly Diagnosed Non-L3 Adult Acute Lymphoblastic Leukemia With Investigation of Minimal Residual Disease and Risk of Relapse Following Maintenance Chemotherapy

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy), and giving the drugs in different combinations may kill more cancer cells.

PURPOSE: This phase II trial is studying how well combination chemotherapy works in treating patients with newly diagnosed acute lymphoblastic leukemia.

Study Overview

• Status: Completed
• Conditions: Leukemia
• Intervention / Treatment: Biological: filgrastim; Drug: cyclophosphamide; Drug: cytarabine; Drug: daunorubicin; Drug: dexamethasone; Drug: doxorubicin; Drug: leucovorin; Drug: mercaptopurine; Drug: methotrexate; Drug: mitoxantrone; Drug: Asparaginase; Drug: prednisone; Drug: thioguanine; Drug: vincristine; Radiation: radiation therapy; Drug: allopurinol; Drug: bactrim

Detailed Description

OBJECTIVES:

Primary

• Determine the probability of 1-year continuous complete remission in patients with newly diagnosed acute lymphoblastic leukemia treated with first induction chemotherapy comprising daunorubicin, vincristine, prednisone, and pegaspargase; and second induction chemotherapy comprising high-dose cytarabine and mitoxantrone.

Secondary

• Determine the frequency and severity of toxic effects of these induction regimens followed by consolidation therapy comprising cyclophosphamide, cytarabine, mercaptopurine, and methotrexate and maintenance chemotherapy comprising mercaptopurine, methotrexate, vincristine, doxorubicin, dexamethasone, cyclophosphamide, thioguanine, and cytarabine in these patients.

Other objectives (if funding allows):

• To evaluate in a preliminary manner the significance of detecting minimal residual disease as a prognostic factor for survival and relapse-free survival of patients receiving chemotherapy
• To evaluate in a preliminary manner the pattern of gene expression of patients entered onto the trial and its relationship to cytogenetics/FISH risk classification, overall survival, and relapse-free survival

OUTLINE: This is a multicenter study.

• First induction chemotherapy: Patients receive daunorubicin IV on days 1-3; vincristine IV on days 1, 8, 15, and 22; prednisone IV or orally on days 1-28, followed by a taper to day 35; and pegaspargase IV or subcutaneously (SC) on day 15. Patients with CNS leukemia also receive methotrexate intrathecally (IT) or intraventricularly twice weekly and oral leucovorin calcium four times daily for 4 doses after each administration of methotrexate. When blasts are no longer present in the spinal fluid, patients receive methotrexate IT or intraventricularly once weekly for 4 weeks and then once monthly for 1 year.

Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1 peripheral blood status or those with resistant disease proceed to second induction therapy.

• Second induction chemotherapy: Patients receive high-dose cytarabine IV on days 1-5; mitoxantrone IV on day 3; and filgrastim (G-CSF) SC or IV beginning on day 7 and continuing until blood counts recover. Patients with CNS leukemia also receive methotrexate and leucovorin calcium as in first induction chemotherapy.

Patients are reevaluated on day 28. Patients who achieve A1 bone marrow status and B1 peripheral blood status with no extramedullary disease (other than CNS involvement) proceed to consolidation chemotherapy. Patients with resistant disease OR Philadelphia chromosome- or BCR/ABL-positive disease are removed from the study after receiving double induction chemotherapy.

• Consolidation chemotherapy: Patients receive cyclophosphamide IV on days 1, 15, and 29; cytarabine IV on days 2-5 and 16-19; oral mercaptopurine on days 1-28; and methotrexate IT or intraventricularly on days 2, 9, 16, and 23. Patients with CNS leukemia also undergo cranial radiotherapy once daily, 5 days a week, for 2 weeks.

Patients in complete remission proceed to maintenance chemotherapy.

• Maintenance chemotherapy:

  • Course 1: Patients receive oral mercaptopurine on days 1-63 and oral methotrexate on days 1, 8, 15, 22, 29, 36, 43, 50, and 57. Patients proceed to course 2 after blood counts recover.
  • Course 2: Patients receive vincristine IV and doxorubicin IV on days 1, 8, 15, and 22 and oral dexamethasone on days 1-28. Patients proceed to course 3 after blood counts recover.
  • Course 3: Patients receive cyclophosphamide IV on day 1; oral thioguanine on days 1-14; and cytarabine IV on days 3-6 and 10-13. Patients proceed to course 4 after blood counts recover.
  • Course 4: Patients receive oral mercaptopurine once daily for 2 years and oral methotrexate once weekly for 2 years.

Treatment continues in the absence of disease relapse or unacceptable toxicity.

After completion of study therapy, patients are followed every 3 months for 1 year, every 6 months for 1 year, and then annually for 3 years.

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Burbank, California, United States, 91505
      • Providence Saint Joseph Medical Center - Burbank
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas, PA - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas, PA - Dodge City
    • El Dorado, Kansas, United States, 67042
      • Cancer Center of Kansas, PA - El Dorado
    • Independence, Kansas, United States, 67301
      • Cancer Center of Kansas-Independence
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas, PA - Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Liberal, Kansas, United States, 67901
      • Southwest Medical Center
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas, PA - Newton
    • Overland Park, Kansas, United States, 66209
      • Menorah Medical Center
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas, PA - Parsons
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas, PA - Pratt
    • Salina, Kansas, United States, 67042
      • Cancer Center of Kansas, PA - Salina
    • Shawnee Mission, Kansas, United States, 66204
      • Shawnee Mission Medical Center
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas, PA - Wellington
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas, PA - Medical Arts Tower
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas, PA - Wichita
    • Wichita, Kansas, United States, 67214
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Cancer Center at Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67208
      • Associates in Womens Health, PA - North Review
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas, PA - Winfield
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
  • Missouri
    • Independence, Missouri, United States, 64050
      • Independence Regional Health Center
    • Kansas City, Missouri, United States, 64131
      • CCOP - Kansas City
    • Kansas City, Missouri, United States, 64116
      • North Kansas City Hospital
    • Kansas City, Missouri, United States, 64132
      • Research Medical Center
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Center - Hospital Hill
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Cancer Institute at Saint Luke's Hospital
    • Kansas City, Missouri, United States, 64114
      • St. Joseph Medical Center
    • Kansas City, Missouri, United States, 64116
      • Parvin Radiation Oncology
    • Lee's Summit, Missouri, United States, 64086
      • Saint Luke's East - Lee's Summit
    • Liberty, Missouri, United States, 64068
      • Liberty Hospital
    • Saint Joseph, Missouri, United States, 64506
      • Heartland Regional Medical Center
  • Montana
    • Billings, Montana, United States, 59101
      • CCOP - Montana Cancer Consortium
    • Billings, Montana, United States, 59101
      • Hematology-Oncology Centers of the Northern Rockies - Billings
    • Billings, Montana, United States, 59101
      • Northern Rockies Radiation Oncology Center
    • Billings, Montana, United States, 59101
      • St. Vincent Healthcare Cancer Care Services
    • Billings, Montana, United States, 59107-7000
      • Billings Clinic - Downtown
    • Bozeman, Montana, United States, 59715
      • Bozeman Deaconess Cancer Center
    • Butte, Montana, United States, 59701
      • St. James Healthcare Cancer Care
    • Great Falls, Montana, United States, 59405
      • Great Falls Clinic - Main Facility
    • Great Falls, Montana, United States, 59405-5309
      • Big Sky Oncology
    • Great Falls, Montana, United States, 59405
      • Sletten Cancer Institute at Benefis Healthcare
    • Great Falls, Montana, United States, 59405
      • Frontier Cancer Center
    • Havre, Montana, United States, 59501
      • Northern Montana Hospital
    • Helena, Montana, United States, 59601
      • St. Peter's Hospital
    • Kalispell, Montana, United States, 59901
      • Kalispell Regional Medical Center
    • Kalispell, Montana, United States, 59901
      • Glacier Oncology, PLLC
    • Kalispell, Montana, United States, 59901
      • Kalispell Medical Oncology at KRMC
    • Missoula, Montana, United States, 59801
      • Community Medical Center
    • Missoula, Montana, United States, 59804
      • Guardian Oncology and Center for Wellness
    • Missoula, Montana, United States, 59807-7877
      • Montana Cancer Specialists at Montana Cancer Center
    • Missoula, Montana, United States, 59807
      • Montana Cancer Center at St. Patrick Hospital and Health Sciences Center
  • North Carolina
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital, Incorporated
    • Rutherfordton, North Carolina, United States, 28139
      • Rutherford Hospital
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Cancer Center
    • Charleston, South Carolina, United States, 29425
      • Hollings Cancer Center at Medical University of South Carolina
    • Florence, South Carolina, United States, 29501
      • McLeod Regional Medical Center
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Huntsman Cancer Institute at University of Utah
  • Washington
    • Bellingham, Washington, United States, 98225
      • St. Joseph Cancer Center
    • Bremerton, Washington, United States, 98310
      • Olympic Hematology and Oncology
    • Kennewick, Washington, United States, 99336
      • Columbia Basin Hematology
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98104
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98104
      • Minor and James Medical, PLLC
    • Seattle, Washington, United States, 98112
      • Group Health Central Hospital
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Seattle, Washington, United States, 98122
      • Polyclinic First Hill
    • Seattle, Washington, United States, 98195-6043
      • University Cancer Center at University of Washington Medical Center
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest - Spokane South
  • Wyoming
    • Casper, Wyoming, United States, 82609
      • Rocky Mountain Oncology
    • Sheridan, Wyoming, United States, 82801
      • Welch Cancer Center at Sheridan Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS:

• Morphologically confirmed acute lymphoblastic leukemia (ALL), meeting any of the following criteria:

  • FAB class L1 or L2 disease
  • Mixed lineage ALL
• Ph-negative/BCR/ABL-negative
• Newly diagnosed disease

• Patients with the following diagnoses are not eligible:

  • FAB class L3 ALL
  • Non-Hodgkin's lymphoma
  • Chronic myelogenous leukemia in lymphoid blast crisis
  • Mixed lineage acute myeloid leukemia
  • Acute minimally differentiated myeloid leukemia (M0)
• Must be registered on protocols SWOG-9007 AND SWOG-S9910

PATIENT CHARACTERISTICS:

Age

• 18 to 64

Performance status

• Zubrod 0-3

Life expectancy

• Not specified

Hematopoietic

• Not specified

Hepatic

• No chronic liver disease

• Hepatitis panel, including hepatitis B and C, negative

  • History of hepatitis A with positive antibody allowed

Renal

• Creatinine ≤ 1.5 times upper limit of normal OR
• Creatinine clearance > 60 mL/min

Cardiovascular

• Left ventricular function normal

  • Ejection fraction ≥ 50% by MUGA or 2-dimensional echocardiogram
• No symptomatic congestive heart failure
• No coronary artery disease
• No cardiomyopathy
• No uncontrolled arrhythmia

Other

• Not pregnant or nursing
• Fertile patients must use effective contraception
• HIV negative
• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or adequately treated stage I or II cancer in complete remission

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior remission induction chemotherapy for ALL

  • Prior hydroxyurea to control WBC count allowed

Endocrine therapy

• Not specified

Radiotherapy

• Not specified

Surgery

• Not specified

Other

• No other prior treatment for ALL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Induc x2, Consol, Maint; Induc 1: Allopurinol; Daunorubicin; Vincristine; Prednisone; asparaginase; Bactrim Induc 2: Allopurinol; cytarabine; Dexamethasone; filgrastim; mitoxantrone; Methotrexate; leucovorin Consol: Cyclophosphamide; cytarabine; 6-mercaptopurine; Methotrexate; filgrastim Maint:Course 1: 6-mercaptopurine; Methotrexate Course 2: Vincristine; doxorubicin; Dexamethasone Course 3: Cyclophosphamidee; thioguanine; cytarabine Course 4: 6-mercaptopurine; methotrexate

Biological: filgrastim; As needed per physician discretion; Drug: cyclophosphamide; Cyclophosphamide Consolidation: 650 mg/m2; IV; days 1, 15, 29 Post-consolidation course 3: 650 mg/m2; IV; day 1; Drug: cytarabine; Induction 2: 3 g/m2; IV over 3 hrs; days 1-5 Consolidation: 75 mg/m2/d; IV push; days 2-5 and 16-19 Post-consolidation course 3: 75 mg/m2/d; IV push; days 3-6 and 10-13; Drug: daunorubicin; Induction: 60 mg/m2/d; IV; days 1, 2, and 3; Drug: dexamethasone; Induction 2: 0.1% QID; eye drops; days 1-6 Post consolidation course 2: 10 mg/m2/d; PO; days 1-28; Drug: doxorubicin; Post consolidation: 25 mg/m2; IV; days 1, 8, 15, and 22; Drug: leucovorin; For CNS during induction: 5 mg every 6 hrs for 4 doses; PO; days 1, 4, 8, 11, etx.; after methotrexate if WBC < 3,000; Drug: mercaptopurine; Consolidation: 60 mg/m2; PO; days 1-28 Post-consolidation course 1: 60 mg/m2/d; PO; days 1-63 Post-consolidation course 4: 60 mg/m2/d; PO; daily for 2 yrs; Drug: methotrexate; Consolidation: 12 mg; intrathecal or intraventricularly; days 2, 9, 16, and 23 Post-consolidation course 1: 20 mg/m2/wk; PO; days 1, 8 15, 22, 29, 36, 43, 50, 57 Post-consolidation course 4: 20 mg/m2; PO; weekly for 2 yrs; Drug: mitoxantrone; Induction 2: 80 mg/m2; IV; day 3; Drug: Asparaginase; Induction: 2,000 IU/m2; IM or IV; day 15; Drug: prednisone; Induction: 60 mg/m2/d; PO or IV; days 1-35; Drug: thioguanine; Post-consolidation course 3: 60 mg/m2/d; PO; days 1-14; Drug: vincristine; Induction: 1.4 mg/m2/d (2 mg max); IV; days 1, 8, 15, 22; Radiation: radiation therapy; For CNS during consolidation: cranial radiation after blasts are no longer present in spinal fluid. Total dose of 1800 cGy over 2 wks in 10 fractions of 180 cGy 5 days/wk.; Drug: allopurinol; 300 mg/d PO Days 1-7; Drug: bactrim; 1 double strenth tablet 2x/d, 2x/wk, PO, begin with prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Continuous Complete Remission at 1 Year	A patient has a continuous complete remission at 1 year if they achieve a CR and are alive 365 days after registering to the study.	After induction, after consolidation, every 3 months during maintenance, and every three months after off treatment for up to a year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity	Number of patients with Grade 3-5 adverse events that are related to study drug by given type of adverse event	Patients were assessed for adverse events after the induction cycle

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Frederick R. Appelbaum, MD, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2005
• Primary Completion (ACTUAL): November 1, 2010
• Study Completion (ACTUAL): November 1, 2014

Study Registration Dates

• First Submitted: May 3, 2005
• First Submitted That Met QC Criteria: May 3, 2005
• First Posted (ESTIMATE): May 4, 2005

Study Record Updates

• Last Update Posted (ESTIMATE): March 25, 2015
• Last Update Submitted That Met QC Criteria: March 5, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: L1 adult acute lymphoblastic leukemia; L2 adult acute lymphoblastic leukemia; untreated adult acute lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Micronutrients; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Vitamins; Reproductive Control Agents; Antiprotozoal Agents; Antiparasitic Agents; Antioxidants; Antidotes; Vitamin B Complex; Free Radical Scavengers; Antimalarials; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Gout Suppressants; Anti-Infective Agents, Urinary; Renal Agents; Dexamethasone; Cyclophosphamide; Leucovorin; Prednisone; Doxorubicin; Cytarabine; Methotrexate; Vincristine; Daunorubicin; Asparaginase; Mitoxantrone; Mercaptopurine; Allopurinol; Thioguanine; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: S0333 (OTHER: SWOG); U10CA032102 (U.S. NIH Grant/Contract)