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

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Alternate Title

Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted18 and underNCISJCRH-XIIIBH
NCI-T93-0101D, T93-0101


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 

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.

Entry Criteria

Disease Characteristics:

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
 - 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

Prior/Concurrent Therapy:

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)

Patient Characteristics:

  18 and under

Performance status:
  Not specified

  See Disease Characteristics

  Not specified

  Not specified

  HIV negative

Expected Enrollment

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; 

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.

Published Results

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

Ching-Hon Pui, MD, Protocol chair
Ph: 901-495-3335

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.