Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High 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||18 and under||NCI||SJCRH-XIIIBH|
I. Estimate the complete response rate and event-free survival of children with acute lymphocytic leukemia (ALL) at intermediate or high risk of treatment failure following treatment with multiagent chemotherapy intensified with high-dose methotrexate (HD-MTX) with or without cranial radiation. II. Determine whether this regimen can be safely given on an outpatient basis (i.e., more than 80% 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 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 etoposide (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. IX. Estimate the frequency of minimal residual disease (MRD) in patients with ALL in clinical remission using serial immunologic and molecular measures. X. Assess the clinical relevance of MRD in bone marrow or CSF by correlating findings with subsequent clinical course (e.g., duration of complete remission). XI. 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. XII. 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 25% marrow blasts 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 intermediate or high risk of relapse as defined by any of the following characteristics: - Age less than 1 or 10 or more years OR WBC greater than 50,000 and DNA index less than 1.16 or greater than 1.60 - CNS leukemia grade 3 (at least 5 WBC/microliter and detectable blasts in CSF or cranial nerve palsies) - Testicular involvement with leukemia - Presence of t(9;22), t(4;11), MLL rearrangement, t(1;19) in association with pre-B-ALL, or near haploidy - T-cell ALL - At least 5% leukemic blasts in Induction day 15 bone marrow - At least 0.01% leukemic blasts in bone marrow aspirate upon completion of remission induction on day 42 Patients who do not meet the criteria for intermediate or high relapse risk are referred to protocol SJCRH-XIIIBL
No prior therapy except no more than 1 week of steroids, vinca alkaloids, or emergency radiotherapy to the mediastinum (in patients with severe respiratory compromise secondary to a mediastinal mass)
Age: 18 and under Performance status: Not specified Hematopoietic: See Disease Characteristics Hepatic: Not specified Renal: Not specified Other: HIV negative
This study is conducted in conjunction with protocol SJCRH-XIIIBL. A total of 247 patients will be entered on both studies over approximately 3.5 years.
Randomized study. Patients are initially randomized to Arm I, II, or III for "window" therapy, then proceed to Induction. All patients enter Consolidation. Patients with Ph+ ALL and WBC greater than 25,000 who achieve CR, infants under 12 months of age with MLL rearrangement, adolescents 10 years of age and older with the t(4;11), and Induction failures at day 43 are offered allogeneic bone marrow transplant; all others who achieve CR during Induction/Consolidation proceed to Continuation (4-week rotations of combination chemotherapy interrupted by a shortened course of Induction). Patients who enter with testicular involvement or who subsequently relapse in the testes receive gonadal irradiation. The following acronyms are used: ARA-C Cytarabine, NSC-63878 ASP Asparaginase (E. coli), NSC-109229, or (Erwinia), NSC-106977 CF Leucovorin calcium, NSC-3590 CTX Cyclophosphamide, NSC-26271 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 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 TIT plus, as indicated, Radiotherapy. PRED; VCR; DNR; ASP; followed by VP-16; ARA-C; plus IT MTX; IT HC; IT ARA-C; plus, for patients with cranial nerve palsies, local irradiation using photons with energies of 4-15 MV. Consolidation: 2-Drug Combination Systemic Chemotherapy plus TIT. HD-MTX/CF; MP; plus IT MTX; IT HC; IT ARA-C. Continuation: Sequential Regimens of 2-Drug Combination Systemic Chemotherapy plus Re-Induction plus TIT and, as indicated, Radiotherapy. VP-16/CTX; MP/MTX (or MP/HD-MTX in alternating sequences); MTX/ARA-C (or VP-16/ARA-C in alternating sequences); DM/VCR; plus Re-Induction: PRED/VCR/DNR/ASP/VP-16/ARA-C followed by MP/HD-MTX; plus IT MTX; IT HC; IT ARA-C; plus, in patients at risk for CNS relapse, cranial irradiation using equipment as in Induction. Gonadal Irradiation: Testicular irradiation using electrons for patients with testicular leukemia at diagnosis or with isolated relapse.
Pui CH, Sandlund JT, Pei D, et al.: Improved outcome for children with acute lymphoblastic leukemia: results of Total Therapy Study XIIIB at St Jude Children's Research Hospital. Blood 104 (9): 2690-6, 2004.[PUBMED Abstract]
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.