Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure, with an Investigational Window of MP vs MP/HD-MTX vs MP/LD-MTX
Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia
Basic Trial Information
|Phase III||Treatment||Completed||1 to 18||NCI||SJCRH-XIIIBL|
I. Estimate the complete response rate and event-free survival of pediatric patients with acute lymphocytic leukemia (ALL) at low risk of treatment failure following antimetabolite-based multiagent induction chemotherapy intensified with high-dose methotrexate (HD-MTX). II. Determine whether this regimen can be safely given on an outpatient basis (i.e., more than 90% of therapy given in an outpatient setting). III. Assess the in vivo intracellular disposition and interaction of mercaptopurine vs. HD-MTX vs. low-dose MTX in an upfront "window" therapy by comparing blast cell 6-thioguanine nucleotides and MTX polyglutamate concentrations, inhibition of de novo purine and thymidylate synthesis, and influence of patient characteristics (age at diagnosis, WBC, percent cells in S-phase, leukemia lineage, cytogenetics, systemic drug clearance, and activities of folylpolyglutamate synthetase, hypoxanthine guanine phosphoribosyltransferase, thiopurine methyltransferase, and xanthine oxidase). IV. Compare plasma and cerebrospinal fluid concentrations of etoposide (VP-16) 1 hour after completion of infusion. V. Estimate the frequency of urate oxidase antibody development. VI. Assess whether the frequency of specific hypoxanthine phosphoribosyltransferase (HPRT) gene mutations in lymphocytes increases after VP-16 treatment and whether HPRT mutations are related to the cumulative dose or area under the curve of VP-16, VP-16 catechol, or both. VII. Estimate the frequency of minimal residual disease (MRD) in patients with ALL in clinical remission using serial immunologic and molecular measures. VIII. Assess the clinical relevance of MRD in bone marrow or cerebrospinal fluid by correlating findings with subsequent clinical course (e.g., duration of complete remission). IX. Study whether patients who relapse have leukemia resistant to MTX via mutation in the dihydrofolate reductase (DHFR) gene, and determine whether children with DHFR mutation at relapse also had mutant DHFR at diagnosis and/or after "window" therapy with MTX. X. Study the nature of the mutation in DHFR and the mechanism by which it confers MTX insensitivity.
Non-B-cell acute lymphocytic leukemia (ALL) diagnosed by immunophenotyping, morphology, and cytochemistry, i.e.: Greater than 30% marrow blasts in peripheral blood No Auer rods Negative for myeloperoxidase, Sudan black B (myeloid pattern), and alpha naphthyl butyrate esterase (myeloid pattern) Acute undifferentiated leukemia also eligible provided criteria for M0, M1, and M7 acute myeloid leukemia are absent as determined by ultrastructural peroxidase reactivity and immunophenotyping At low risk of relapse as determined by the presence of all the following characteristics: Age 1-9 years (inclusive) and white blood cells less than 50,000 or DNA index of 1.16-1.60 No T-cell phenotype CNS status 1 or 2 Status 1: no detectable leukemic blasts in cerebrospinal fluid Status 2: less than 5 WBC with detectable blasts on cytospin No testicular involvement with leukemia Absence of t(9;22), t(4;11), MLL rearrangement, and, in pre-B ALL, t(1;19) Concurrent registration on LEUCEL III protocol for leukemic cell classification required Patients who do not meet the criteria for low relapse risk are referred to protocol SJCRH-XIIIBH
No prior therapy other than 1 week or less of steroids, vinca alkaloids, or emergency radiotherapy to the mediastinum (in patients with severe respiratory compromise secondary to a mediastinal mass)
Age: 1 to 18 Performance status: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified Other: HIV negative
A total of 189 patients will be entered on both studies over approximately 3.5 years. All patients receive oral fluids and urate oxidase (100 units/kg/day iv for 5 days); those with large tumor burden (e.g., hepatosplenomegaly and markedly elevated WBC or serum LDH) receive additional iv hydration (3 liters/sqm/day) and urine alkalinization (4 g NaHCO3/sqm/day), and urate oxidase is continued until serum uric acid levels normalize. Patients presenting with WBC >/= 50,000 or uric acid >/= 8 mg/dL and either creatinine or LDH >/= twice normal may receive recombinant urate oxidase (SR 29142), provided they meet the eligibility criteria for protocol SJCRH-URIOXI. TIT is administered in age-adjusted doses of IT MTX/IT HC/IT ARA-C (in mg), as follows: 12-23 months - 8/16/24; 24-35 months - 10/20/30; and > 35 months - 12/24/36. Window Therapy. Arm I: MP - 200 mg/sqm iv over 20 minutes followed by 800 mg/sqm iv over 5 hours and 40 minutes. Arm II: HD-MTX - 200 mg/sqm iv push followed by 800 mg/sqm in 2,400 mL/sqm D5 0.25 NS containing NaHCO3 (40 mEq/liter) iv over 24 hours, with adequate pre- and posthydration and urine alkalinization; MP - dose as in Arm I administered immediately following HD-MTX infusion; CF - 10 mg/sqm po (or iv) q 6 hours x 5, beginning 48 hours after initiation of HD-MTX. Hydration/alkalinization consists of D5 0.25 NS containing NaHCO3 (40 mEq/liter) administered at a rate of 200 mL/sqm/hour prior to MTX until the urine pH is at least 6.5 and continued po or iv post-MTX until the plasma MTX level is < 0.1 microM; during MTX, additional fluids or iv NaHCO3 may be used to maintain urine specific gravity < 1.015 and pH at least 6.5. Arm III: LD-MTX - 30 mg/sqm po (12 mg/sqm iv if unable to take oral medication) q 6 hours x 6; MP - dose as in Arm I administered 24 hours after the first LD-MTX dose; CF - as in Arm II. Patients who experience progressive disease during Window Therapy proceed to Induction within the first 48 hours; otherwise, Induction therapy begins 72 hours after the start of Window Therapy. Induction (days 1 through 43): PRED - 40 mg/sqm/day po in 3 divided doses on days 1 through 28; VCR - 1.5 mg/sqm (maximum dose 2.0 mg) iv on days 1, 8, 15, and 22; DNR - 25 mg/sqm iv on days 1 and 8; ASP - 10,000 IU/sqm im on days 2, 4, 6, 8, 10, and 12; VP-16 - 300 mg/sqm (150 mg/sqm in patients with bilirubin > 3.0 mg/dL or albumin < 2.5 g/dL) iv over 1-2 hours on days 22, 25, and 29; ARA-C - 300 mg/sqm iv over 1-2 hours on days 22, 25, and 29. VP-16/ARA-C may be delayed 3-7 days in patients with ANC < 300 if day 22 marrow is very hypoplastic. Starting on day 15, all patients receive Pneumocystis prophylaxis with trimethoprim/sulfamethoxazole (TMP/SMX - 150/750 mg/sqm/day in 2 divided doses daily until CR, then 3 x weekly until 1 month after cessation of therapy). TIT - age-adjusted doses on days 1, 22, and 43 (and on days 8 and 15 for patients who entered with CNS status 2). Patients with greater than or equal to 5% lymphoblasts in the day 15 bone marrow exam are crossed to protocol SJCRH-XIIIBH for high-risk patients; all others have CR status reassessed on day 43 and proceed to Consolidation. Consolidation (ideally, days 44 through 57): HD-MTX - 500 mg/sqm iv push followed immediately by 1,500 mg/sqm iv over 2 hours on days 44 and 51, with hydration and urine alkalinization; MP - 75 mg/sqm/day po on days 44 through 57; CF - 10 mg/sqm po (or iv) q 6 hours x 5 or until the plasma MTX level is < 0.1 microM, beginning 44 hours after the start of HD-MTX and with dose adjusted according to serum MTX levels; TIT - age-adjusted doses on day 51. Hydration/alkalinization consists of NaHCO3 (12 mEq/sqm) in 50 mL D5W administered iv over 15 minutes at the start of prehydration, then 200 mL/sqm/hour of D5 0.25 NS with NaHCO3 (40 mEq/liter) iv over 1 hour prior to HD-MTX or until the urine pH is at least 6.5, during HD-MTX, and for 5 hours following HD-MTX, with additional NaHCO3 as needed to maintain urine pH. Patients not in CR after Consolidation are removed from study; all others begin Continuation 7 days after the completion of Consolidation, toxicity permitting. Continuation (ideally, begins on day 58): WEEKS 1-3: MP - 75 mg/sqm/day po on days 1 through 7; MTX - 40 mg/sqm im or iv on day 1; WEEK 4: DM - 8 mg/sqm/day po in 3 divided doses on days 1 through 7; VCR - 1.5 mg/sqm (maximum dose 2.0 mg) iv on day 1. This cycle repeats for a total of 120 weeks with the HD-MTX/CF (doses as in Consolidation) replacing MTX on weeks 7, 15, 29, 37, 45, and 53. The cycle is interrupted from weeks 16 through 21 for re-induction/re-consolidation except the second and third doses of VP-16/ARA-C are omitted as is the day 22 TIT. During Continuation, TIT is administered on weeks 1, 2, 7, and 15, at the end of re-induction/re-consolidation, then q 8 weeks to week 53 (q 4 weeks in patients who entered with CNS 2 status). Patients who experience hematologic or extramedullary relapse are removed from study and considered for relapse protocols; those who experience unacceptable toxicity at any time are also removed from study. All patients are followed for survival. --Toxicities-- Toxicities requiring dosage modification on this protocol include the following (see the protocol document for details): Allergic/Immunologic: Acute hypersensitivity Anaphylaxis Dermatologic: Rash Exfoliative dermatitis Gastrointestinal: Acute hemorrhagic pancreatitis Hematologic: Anemia Neutropenia Thrombocytopenia Deficient TPMT activity Hepatic: Jaundice Hepatomegaly ALT elevation Hyperbilirubinemia Hypoalbuminemia Severe coagulopathy Neurologic: Stroke-like syndrome Motor paralysis Severe abdominal cramps Gait impairment Additional toxicities may occur. Consult one of the investigators associated with this protocol for information. This study is conducted in conjunction with protocol SJCRH-XIIIBH.
Randomized study. Patients are initially randomized to Arms I, II, and III for "window" therapy, then proceed to Induction. Patients with 5% or more leukemic blasts in the bone marrow on day 15 of Induction are crossed to protocol SJCRH-XIIIBH for high-risk patients; all others enter Consolidation. Patients in CR at the end of Consolidation proceed to Continuation. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase (E. coli), NSC-109229 CF Leucovorin calcium, NSC-3590 DM Dexamethasone, NSC-34521 DNR Daunorubicin, NSC-82151 HC Hydrocortisone, NSC-10483 HD High-Dose LD Low-Dose MP Mercaptopurine, NSC-755 MTX Methotrexate, NSC-740 PRED Prednisone, NSC-10023 TIT Triple Intrathecal Therapy (IT MTX/IT HC/IT ARA-C) VCR Vincristine, NSC-67574 VP-16 Etoposide, NSC-141540 Window Therapy. Arm I: Single-Agent Chemotherapy. MP. Arm II: 2-Drug Combination Chemotherapy. HD-MTX/CF; MP. Arm III: 2-Drug Combination Chemotherapy. LD-MTX/CF; MP. Induction: 4-Drug Combination Systemic Chemotherapy followed by 2-Drug Combination Systemic Chemotherapy plus Triple Intrathecal Therapy. PRED; VCR; DNR; ASP; followed by VP-16; ARA-C; plus TIT. Consolidation: 2-Drug Combination Systemic Chemotherapy plus Triple Intrathecal Therapy. HD-MTX/CF; MP; plus TIT. Continuation: Alternating Regimens of 2-Drug Combination Systemic Chemotherapy plus Re-Induction/Re-Consolidation (4-Drug Combination Systemic Chemotherapy followed by 2-Drug Combination Systemic Chemotherapy followed by 2-Drug Combination Systemic Chemotherapy) plus Triple Intrathecal Therapy. MP; MTX (or HD-MTX); alternating with DM; VCR; plus Re-Induction/Re-Consolidation: PRED; VCR; DNR; ASP; followed by VP-16; ARA-C; followed by HD-MTX/CF; MP; plus TIT.
Yang JJ, Cheng C, Yang W, et al.: Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301 (4): 393-403, 2009.[PUBMED Abstract]
Synold TW, Relling MV, Boyett JM, et al.: In vivo leukemic lymphoblast concentrations of methotrexate polyglutamates (MTX-PG) differ by lineage and ploidy. [Abstract] Proceedings of the American Society of Clinical Oncology 13: A-355, 140, 1994.
Trial Contact Information
Trial Lead Organizations
St. Jude Children's Research Hospital
Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.