Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Combination Chemotherapy in Treating Children or Adolescents With Newly Diagnosed Stage III or Stage IV Lymphoblastic Lymphoma

Basic Trial Information

Objectives

1. Compare the event-free survival and overall survival of children or adolescents with newly diagnosed disseminated stage III or IV lymphoblastic lymphoma treated with 4 chemotherapy regimens*.
2. Determine whether treatment with a regimen without methotrexate maintains the same disease-free survival as NHL/BFM 90 in these patients.
3. Determine whether intensification with anthracycline and cyclophosphamide improves disease-free survival in these patients.
4. Collect outcome data on uniformly treated patients with localized disease or CNS-positive disease.
5. Determine whether rapid reduction in tumor volume by chest radiography and CT scan is predictive of improved outcome in patients treated with these regimens.
6. Determine the prevalence of bone marrow involvement at presentation in these patients.
7. Determine whether peripheral blood can replace bone marrow in the initial staging of these patients.
8. Determine the clinical significance of bone marrow and peripheral blood involvement in these patients.

 [Note: *All patients as of 4/2006 receive treatment on Arm III regimen only]

Entry Criteria

Disease Characteristics:

• Newly diagnosed disseminated lymphoblastic lymphoma or localized lymphoblastic lymphoma*
  • Less than 25% tumor cells in the bone marrow
  • Previously untreated (prior intrathecal cytarabine allowed if protocol therapy begins within 72 hours)
  • Stage III or IV disease
   [Note: *Localized lymphblastic lymphoma is closed to accrual as of 10/2005]

Prior/Concurrent Therapy:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics

Endocrine therapy:

• Emergency steroid therapy (if required) must be started within 72 hours prior to protocol therapy

Radiotherapy:

• Emergency radiotherapy (if required) must be started within 72 hours prior to protocol therapy

Surgery:

• Not specified

Other:

• No other prior therapy except for emergency treatment of airway obstruction and/or superior vena cava syndrome

Patient Characteristics:

Age:

• 1 to 30

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• Not specified

Renal:

• Not specified

Cardiovascular:

• Adequate cardiac function

Expected Enrollment

Approximately 250-400 patients will be accrued for this study within 5 years.

Outcomes

Event-free survival as assessed by time to treatment failure, occurrence of second malignant neoplasm, or death from any cause

Survival as assessed by time to death

Outline

Patients are stratified by disease characteristics (disseminated lymphoblastic lymphoma vs localized lymphoblastic lymphoma [localized lymphoblastic lymphoma is closed to accrual as of 10/2005]) and age. Patients with CNS negative disseminated lymphoblastic lymphoma are randomized to 1 of 4 treatment arms*. Patients with testicular involvement at diagnosis are nonrandomly assigned to arm IV and do not receive testicular radiotherapy. Patients with localized lymphoblastic lymphoma (closed to accrual as of 10/2005) are not randomized.

 [Note: *All patients as of 4/2006 receive treatment on Arm III only]

• Localized lymphoblastic lymphoma (closed to accrual as of 10/2005):
  • Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over 15 minutes to 2 hours on days 0, 7, 14, and 21; oral prednisone on days 0-27; and asparaginase intramuscularly (IM) on days 3, 5, and 7 and then 3 times a week for 9 doses (during days 8-21). Patients also receive methotrexate intrathecally (IT) on days 7 and 28 and cytarabine IT on day 0.
  • Consolidation (5 weeks): Patients receive methotrexate IT on days 0, 7, 14, and 21 followed by cyclophosphamide IV over 1 hour on days 0 and 14; cytarabine IV on days 0-3, 7-10, 14-17, and 21-24; oral mercaptopurine on days 0-27; and oral prednisone over 10 days.
  • Interim maintenance (8 weeks): Patients receive methotrexate IT on days 0 and 28; oral mercaptopurine on days 0-41; and oral methotrexate on days 7, 14, 21, and 35.
  • Delayed intensification (7 weeks): Patients receive vincristine IV and doxorubicin IV over 15 minutes to 2 hours on days 0, 7, and 14; asparaginase IM on day 3 and then 3 times a week for 6 doses; oral dexamethasone on days 0-30; cyclophosphamide IV over 1 hour on day 28; and cytarabine IV or SC on days 28-31 and 35-38. Patients also receive oral thioguanine on days 28-41 and methotrexate IT on days 28 and 35.
  • Maintenance (84 day course): Patients receive vincristine IV on days 0, 28, and 56; oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; oral mercaptopurine on days 0-83; and methotrexate IT on day 0.

• Disseminated lymphoblastic lymphoma:
  • Arm I (closed to accrual as of 4/2006): Patients receive same induction, consolidation, and interim maintenance therapy schedule as localized lymphoblastic lymphoma patients.
    • Delayed intensification (7 weeks): Patients receive vincristine IV and doxorubicin IV over 15 minutes to 2 hours on days 0, 7, 14, and 21; asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days 0-28. Patients also receive cyclophosphamide IV over 1 hour on day 35; cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate IT on days 35 and 42.
    • Maintenance (84 day course): Patients receive same therapy as localized lymphoblastic lymphoma patients, except methotrexate IT is administered on day 0 and 28 (for first 4 courses).

  • Arm II (closed to accrual as of 4/2006): Patients receive consolidation, interim maintenance, and maintenance therapy as in arm I.
    • Induction (5 weeks): Patients receive vincristine IV on days 0, 7, 14, and 21; daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-27; and asparaginase IM on days 3, 5, and 7 and then 3 times a week for 9 doses (during days 8-21). Patients also receive methotrexate IT on days 7 and 28; cyclophosphamide IV over 1 hour on day 2; and cytarabine IT on day 0.
    • Delayed intensification (7 weeks): Patients receive vincristine IV on days 0, 7, 14, 21; daunorubicin IV over 48 hours on days 0-2; asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days 0-28. Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35; cytarabine IV or SC on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate IT on days 35 and 42.

  • Arm III:
    • Induction (5 weeks): Patients receive vincristine IV and daunorubicin IV over 1 hour on days 0, 7, 14, and 21 and oral prednisone on days 0-37. Patients also receive asparaginase IM on day 11 and then 3 times a week for 9 doses; methotrexate IT on days 7 and 28; and cytarabine IT on day 0.
    • Consolidation (5 weeks): Patients receive methotrexate IT and cyclophosphamide IV over 1 hour on days 0 and 14; cytarabine IV or SC on days 0-3, 7-10, 14-17, and 21-24; oral mercaptopurine on days 0-27; and oral prednisone over 10 days.
    • Interim maintenance (9 weeks): Patients receive methotrexate IT and IV on days 7, 21, 35, and 49; oral mercaptopurine on days 0-55; and leucovorin calcium IV at 42, 48, and 54 hours after methotrexate IV.
    • Delayed intensification (10 weeks): Patients receive vincristine IV and doxorubicin IV over 1 hour on days 0, 7, 14, and 21; asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days 0-29. Patients also receive cyclophosphamide IV over 1 hour on day 35; cytarabine IV on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate IT on days 35 and 42.
    • Maintenance (84 day courses): Patients receive vincristine IV on days 0, 28, and 56; oral prednisone on days 0-4, 28-32, and 56-60; oral methotrexate on days 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 77; and oral mercaptopurine on days 0-83.

  • Arm IV (closed to accrual as of 4/2006): Patients receive consolidation and interim maintenance therapy as in arm III.
    • Induction: Patients receive vincristine IV on days 0, 7, 14, and 21; daunorubicin IV over 48 hours on days 0-2; oral prednisone on days 0-37; asparaginase IM on day 11 and then 3 times a week for 9 doses; methotrexate IT on days 7, 14, 21, and 28; cyclophosphamide IV on day 2; and cytarabine IT on day 0.
    • Delayed intensification (10 weeks): Patients receive vincristine IV on days 7, 14, 21, and 28; daunorubicin IV over 48 hours on days 0-2; asparaginase IM on day 3 and then 3 times a week for 6 doses; and oral dexamethasone on days 0-29. Patients also receive cyclophosphamide IV over 1 hour on days 2 and 35; cytarabine IV on days 35-38 and 42-45; oral thioguanine on days 35-48; and methotrexate IT on days 35 and 42.
    • Maintenance (84 day courses): Patients receive therapy as in arm III. Patients who are over 1 year of age and have CNS disease at diagnosis undergo cranial radiotherapy once daily 5 days a week beginning on day 0. Patients over 2 years of age undergo radiotherapy over 11-14 days (6-9 days for 1-2 years of age).

Patients are followed monthly for one year, every 3 months for 1 year, every 6 months for 1.5 years, and then annually thereafter.

Coustan-Smith E, Sandlund JT, Perkins SL, et al.: Minimal disseminated disease in childhood T-cell lymphoblastic lymphoma: a report from the children's oncology group. J Clin Oncol 27 (21): 3533-9, 2009.[PUBMED Abstract]

Abromowitch M, Termuhlen A, Chang M, et al.: High-dose methotrexate and early intensification of therapy do not improve 3 year EFS in children and adolescents with disseminated lymphoblastic lymphoma: results of the randomized arms of COG A5971. [Abstract] Blood 112 (11): A-3610, 2008.

Smock KJ, Nelson M, Tripp SR, et al.: Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: a report from the Children's Oncology Group. Pediatr Blood Cancer 51 (4): 489-94, 2008.[PUBMED Abstract]

Coustan-Smith E, Abromowitz M, Sandlund JT, et al.: A novel approach for minimal residual disease detection in childhood T-cell lymphoblastic lymphoma (T-LL): a Children’s Oncology Group report. [Abstract] Blood 110 (11): A-3564, 2007.

Trial Contact Information

Trial Lead Organizations

Children's Oncology Group

Minnie Abromowitch, MD, Protocol chair		Ph: 402-955-3949; 800-437-0272 Email: mabromowitch@chsomaha.org

Registry Information
Official Title		Randomized Phase III Study for the Treatment of Newly Diagnosed Disseminated Lymphoblastic Lymphoma or Localized Lymphoblastic Lymphoma
Trial Start Date		2000-06-15
Trial Completion Date		2008-08-25
Registered in ClinicalTrials.gov		NCT00004228
Date Submitted to PDQ		1999-12-10
Information Last Verified		2010-11-18
NCI Grant/Contract Number		CA13539

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