Combination Chemotherapy in Treating Patients With Acute Lymphoblastic Leukemia or Advanced Lymphoblastic Non-Hodgkin's Lymphoma (T-Cell #4)

Intensive Treatment For T-CELL Acute Lymphoblastic Leukemia and Advanced Stage Lymphoblastic Non-Hodgkin's Lymphoma: A Pediatric Oncology Group Phase III Study

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells. Dexrazoxane may lessen the side effects of chemotherapy.

PURPOSE: Randomized phase III trial to compare combination chemotherapy with or without dexrazoxane and with or without high-dose methotrexate in patients with acute lymphoblastic leukemia or advanced lymphoblastic non-Hodgkin's lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Leukemia; Cardiac Toxicity
• Intervention / Treatment: Drug: leucovorin calcium; Drug: methotrexate; Drug: cytarabine; Drug: doxorubicin hydrochloride; Drug: vincristine sulfate; Drug: prednisone; Drug: dexrazoxane hydrochloride; Drug: asparaginase; Drug: therapeutic hydrocortisone; Drug: mercaptopurine; Radiation: radiation therapy

Detailed Description

OBJECTIVES: I. Determine, in a randomized trial, the effectiveness of high-dose methotrexate when added to a multiagent chemotherapy backbone (the Dana Farber Cancer Institute regimen, protocol DFCI-87001) proven effective in T-cell acute lymphoblastic leukemia (T-ALL) and advanced lymphoblastic non-Hodgkin's lymphoma (NHL). II. Determine the role of dexrazoxane in preventing cardiotoxicity in children with T-ALL and advanced lymphoblastic NHL treated with an anthracycline-based regimen. III. Study the biology of T-cell lymphoid malignancies by accumulating data on the concurrent ALL classification study (POG-9400) and analyzing the data relative to outcome. IV. Evaluate the correlation of minimal residual disease (using the TAL 1 proto-oncogene) with event-free survival. V. Determine the role of p53 and p16 tumor suppressor genes in T-ALL. VI. Determine whether drug sensitivity profiles of blast cells to doxorubicin, methotrexate, and cytarabine correlate with initial response and subsequent relapse.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to disease category (acute lymphoblastic leukemia (ALL) with no CNS disease vs. ALL with CNS disease vs. non-Hodgkin's lymphoma (NHL) with no CNS disease vs. NHL with CNS disease), gender, race (Caucasian vs. African American vs. Hispanic). Patients are randomized to one of four treatment arms. ARM I: During induction therapy, patients receive vincristine IV once daily on days 1, 8, 15, and 22, oral prednisone three times a day on days 1-21, doxorubicin IV daily on days 1, 2, and 22, methotrexate IV once, at least 8 hours after doxorubicin on day 2, and oral mercaptopurine daily on days 22-35. Patients receive triple intrathecal therapy (TIT) consisting of methotrexate, cytarabine, and hydrocortisone on weeks 1, 3, 4, 5, and 6. Patients with CNS 2 or 3 disease receive TIT on week 2. During weeks 7-33, patients receive consolidation therapy consisting of vincristine IV once every 3 weeks, oral prednisone three times a day over 5 days, every 3 weeks, doxorubicin IV once every 3 weeks, oral mercaptopurine daily for 14 days, every 3 weeks, and asparaginase intramuscularly (IM) weekly on weeks 7-26. Patients receive TIT on week 10 and 22 (on week 16 for patients with CNS 2 or 3 disease). Patients receive radiotherapy beginning on week 22. During weeks 34-108, patients receive continuation therapy consisting of vincristine IV once every 3 weeks, oral prednisone three times a day over 5 days, every 3 weeks, methotrexate IV or IM weekly (omitted during TIT) and oral mercaptopurine daily for 14 days, every 3 weeks. Patients receive TIT on weeks 40, 58, 76, and 94. Arm II: Patients receive induction therapy as in Arm I with an addition of dexrazoxane IV given prior to doxorubicin on days 1, 2, and 22. Patients receive consolidation therapy as in Arm I with an addition of dexrazoxane IV given prior to doxorubicin once every 3 weeks. Patients receive continuation therapy as in Arm I. Arm III: Patients receive induction therapy as in Arm I in addition to high dose methotrexate IV on week 4 and leucovorin calcium IV or orally every 6 hours for 7 doses beginning 36 hours after high dose methotrexate. Patients receive consolidation therapy as in Arm I in addition to high dose methotrexate IV on weeks 7, 10, and 13 followed by leucovorin calcium as in induction therapy. Patients receive continuation therapy as in Arm I. Arm IV: Patients receive induction therapy and consolidation therapy as in Arms I, II, and III. Patients receive continuation therapy as in Arm I. Treatment continues for up to 108 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 2 months for 1 year, every 4 months for 3 years, then every 6 months for 2 years.

PROJECTED ACCRUAL: A total of 494 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 573
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 21 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

DISEASE CHARACTERISTICS: T-cell acute lymphoblastic leukemia (ALL) Registration on current ALL classification study (POG-9400) required within 6 working days prior to entry DR-, T+ DR-, T- or DR+, T+ eligible if T-cell ALL confirmed at the Johns Hopkins Reference Laboratory Biopsy-proven diffuse lymphoblastic lymphoma Murphy stage III/IV disease Registered on ALL classification study (POG-9400)

PATIENT CHARACTERISTICS: Age: Over 12 months to under 22 years for T-ALL Under 22 years for lymphoma

PRIOR CONCURRENT THERAPY: No prior therapy other than steroids or emergency mediastinal irradiation in patients with severe respiratory distress from mediastinal disease Steroid treatment allowed provided that physical examination and complete blood count with differential were performed immediately prior to beginning steroids and results of both are known

Study Plan

How is the study designed?

Design Details

• Primary Purpose: SUPPORTIVE_CARE
• Allocation: NON_RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: DOUBLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Treatment 1: (No HD MTX / No Zinecard); Closed 09/2000 Induction (Vincristine sulfate, Prednisone, doxorubicin hydrochloride, Methotrexate (MTX), mercaptopurine (6-MP), methotrexate/cytarabine), Consolidation (Vincristine sulfate), Prednisone, doxorubicin hydrochloride, mercaptopurine (6-MP), asparaginase, IT methotrexate /cytarabine radiation therapy (XRT)). Continuation (Vincristine sulfate, Prednisone, IT methotrexate/Ara-C,mercaptopurine (6-MP), IT methotrexate/cytarabine)	Drug: methotrexate; Given IV; Other Names: amethopterin; MTX; NSC #000740; Drug: cytarabine; Given IV; Other Names: Cytosar; Cytosine Arabinoside; AraC; NSC #06387; Drug: doxorubicin hydrochloride; Given IV; Other Names: Doxorubicin; NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #067574; Drug: prednisone; Given orally; Other Names: Deltasone; Meticorten; Liquid Pred; NSC #010023; Drug: asparaginase; Given IV; Other Names: E. coli; Elspar; NSC #10922; Drug: therapeutic hydrocortisone; Given IT; Other Names: Solu-cortef; NSC #010483; hydrocortisone sodium succinate; Drug: mercaptopurine; Given orally; Other Names: 6-MP; Purinethol; NSC #000755; Radiation: radiation therapy; Radiation to cranium; Other Names: XRT
ACTIVE_COMPARATOR: Treatment 2: (No HD MTX / Zinecard); Closed 09/2000 Induction (Vincristine sulfate, Prednisone, doxorubicin hydrochloride, Methotrexate (MTX), mercaptopurine (6-MP), methotrexate/cytarabine, dexrazoxane hydrochloride (Zinecard or DZR)), Consolidation (Vincristine sulfate), Prednisone, doxorubicin hydrochloride, mercaptopurine (6-MP), asparaginase, dexrazoxane hydrochloride (Zinecard or DZR), IT methotrexate /cytarabine, radiation therapy (XRT)). Continuation (Vincristine sulfate, Prednisone, IT methotrexate/Ara-C,mercaptopurine (6-MP), IT methotrexate/cytarabine)	Drug: methotrexate; Given IV; Other Names: amethopterin; MTX; NSC #000740; Drug: cytarabine; Given IV; Other Names: Cytosar; Cytosine Arabinoside; AraC; NSC #06387; Drug: doxorubicin hydrochloride; Given IV; Other Names: Doxorubicin; NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #067574; Drug: prednisone; Given orally; Other Names: Deltasone; Meticorten; Liquid Pred; NSC #010023; Drug: dexrazoxane hydrochloride; Given IV; Other Names: ADR-529; ICRF-187; DZR; ZINECARD; NSC #169780; Drug: asparaginase; Given IV; Other Names: E. coli; Elspar; NSC #10922; Drug: therapeutic hydrocortisone; Given IT; Other Names: Solu-cortef; NSC #010483; hydrocortisone sodium succinate; Drug: mercaptopurine; Given orally; Other Names: 6-MP; Purinethol; NSC #000755; Radiation: radiation therapy; Radiation to cranium; Other Names: XRT
ACTIVE_COMPARATOR: Treatment 3: (HD MTX / No Zinecard); Closed 09/2001 Induction (Vincristine sulfate, Prednisone, doxorubicin hydrochloride, Methotrexate (MTX), mercaptopurine (6-MP), leucovorin calcium (LCV), HD methotrexate/cytarabine), Consolidation (Vincristine sulfate), Prednisone, doxorubicin hydrochloride, mercaptopurine (6-MP), asparaginase, leucovorin calcium (LCV), HD methotrexate /cytarabine radiation therapy (XRT)). Continuation (Vincristine sulfate, Prednisone, IT methotrexate/Ara-C,mercaptopurine (6-MP), HD methotrexate/cytarabine)	Drug: leucovorin calcium; Given IV; Other Names: LCV; Wellcovorin; citrovorum factor; folinic acid; NSC #003590; Drug: methotrexate; Given IV; Other Names: amethopterin; MTX; NSC #000740; Drug: cytarabine; Given IV; Other Names: Cytosar; Cytosine Arabinoside; AraC; NSC #06387; Drug: doxorubicin hydrochloride; Given IV; Other Names: Doxorubicin; NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #067574; Drug: prednisone; Given orally; Other Names: Deltasone; Meticorten; Liquid Pred; NSC #010023; Drug: asparaginase; Given IV; Other Names: E. coli; Elspar; NSC #10922; Drug: therapeutic hydrocortisone; Given IT; Other Names: Solu-cortef; NSC #010483; hydrocortisone sodium succinate; Drug: mercaptopurine; Given orally; Other Names: 6-MP; Purinethol; NSC #000755; Radiation: radiation therapy; Radiation to cranium; Other Names: XRT
ACTIVE_COMPARATOR: Treatment 4: (HD MTX / Zinecard); Closed 09/2001 Induction (Vincristine sulfate, Prednisone, doxorubicin hydrochloride, Methotrexate (MTX), mercaptopurine (6-MP), leucovorin calcium (LCV), HD methotrexate/cytarabine, dexrazoxane hydrochloride (Zinecard or DZR)), Consolidation (Vincristine sulfate), Prednisone, doxorubicin hydrochloride, mercaptopurine (6-MP), asparaginase, HD methotrexate /cytarabine, dexrazoxane hydrochloride (Zinecard or DZR), radiation therapy (XRT)). Continuation (Vincristine sulfate, Prednisone, IT methotrexate/Ara-C,mercaptopurine (6-MP), HD methotrexate/cytarabine)	Drug: leucovorin calcium; Given IV; Other Names: LCV; Wellcovorin; citrovorum factor; folinic acid; NSC #003590; Drug: methotrexate; Given IV; Other Names: amethopterin; MTX; NSC #000740; Drug: cytarabine; Given IV; Other Names: Cytosar; Cytosine Arabinoside; AraC; NSC #06387; Drug: doxorubicin hydrochloride; Given IV; Other Names: Doxorubicin; NSC #123127; Drug: vincristine sulfate; Given IV; Other Names: VCR; Oncovin; NSC #067574; Drug: prednisone; Given orally; Other Names: Deltasone; Meticorten; Liquid Pred; NSC #010023; Drug: dexrazoxane hydrochloride; Given IV; Other Names: ADR-529; ICRF-187; DZR; ZINECARD; NSC #169780; Drug: asparaginase; Given IV; Other Names: E. coli; Elspar; NSC #10922; Drug: therapeutic hydrocortisone; Given IT; Other Names: Solu-cortef; NSC #010483; hydrocortisone sodium succinate; Drug: mercaptopurine; Given orally; Other Names: 6-MP; Purinethol; NSC #000755; Radiation: radiation therapy; Radiation to cranium; Other Names: XRT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete Continuous Remission	Since all patients receive the same induction, the endpoint will be CCR , i.e. complete continuous remission (the time to failure for any cause among patients achieving a complete response)	Time to failure for any cause among patients achieving a complete response

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Abnormalities in the 31 week and the year 3 echocardiograms	Endpoint will be abnormalities in the 31 week and the year 3 echocardiograms (i.e. year 1 off therapy). Secondarily, we shall compare the CCR rates for the two treatment regimens, in a two sided fashion.	1 year off therapy

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Barbara L. Asselin, MD, James P. Wilmot Cancer Center

Publications and helpful links

General Publications

• Seibel NL, Asselin BL, Nachman JB, et al.: Treatment of high risk T-cell acute lymphoblastic leukemia (T-ALL): comparison of recent experience of the Children's Cancer Group (CCG) and Pediatric Oncology Group (POG). [Abstract] Blood 104 (11): A-681, 2004.
• Cleaver AL, Beesley AH, Firth MJ, Sturges NC, O'Leary RA, Hunger SP, Baker DL, Kees UR. Gene-based outcome prediction in multiple cohorts of pediatric T-cell acute lymphoblastic leukemia: a Children's Oncology Group study. Mol Cancer. 2010 May 12;9:105. doi: 10.1186/1476-4598-9-105.
• Salzer WL, Devidas M, Carroll WL, Winick N, Pullen J, Hunger SP, Camitta BA. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children's oncology group. Leukemia. 2010 Feb;24(2):355-70. doi: 10.1038/leu.2009.261. Epub 2009 Dec 17.
• Matloub Y, Asselin BL, Stork LC, et al.: Outcome of children with T-Cell acute lymphoblastic leukemia (T-ALL) and standard risk (SR) features: results of CCG-1952, CCG-1991 and POG 9404. [Abstract] Blood 104 (11): A-680, 195a, 2004.

Study record dates

Study Major Dates

• Study Start: June 1, 1996
• Primary Completion (ACTUAL): September 1, 2001
• Study Completion (ACTUAL): October 1, 2004

Study Registration Dates

• First Submitted: October 28, 2010
• First Submitted That Met QC Criteria: October 28, 2010
• First Posted (ESTIMATE): October 29, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): June 6, 2013
• Last Update Submitted That Met QC Criteria: June 4, 2013
• Last Verified: June 1, 2013

More Information

Terms related to this study

• Keywords: untreated childhood acute lymphoblastic leukemia; stage III childhood lymphoblastic lymphoma; stage IV childhood lymphoblastic lymphoma; cardiac toxicity; T-cell childhood acute lymphoblastic leukemia
• Additional Relevant MeSH Terms: Chemically-Induced Disorders; Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Wounds and Injuries; Drug-Related Side Effects and Adverse Reactions; Radiation Injuries; Lymphoma; Leukemia; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Cardiotoxicity; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cardiotonic Agents; Dermatologic Agents; Micronutrients; Antibiotics, Antineoplastic; Vitamins; Reproductive Control Agents; Antidotes; Vitamin B Complex; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Leucovorin; Levoleucovorin; Prednisone; Doxorubicin; Liposomal doxorubicin; Cytarabine; Methotrexate; Vincristine; Asparaginase; Mercaptopurine; Hydrocortisone; Hydrocortisone 17-butyrate 21-propionate; Hydrocortisone acetate; Hydrocortisone hemisuccinate; Dexrazoxane; Razoxane
• Other Study ID Numbers: 9404; U10CA030969 (U.S. NIH Grant/Contract); POG-9404 (OTHER: Pediatric Oncology Group); CDR0000064664 (OTHER: Clinical Trials.gov)