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

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Alternate Title

Combination Chemotherapy in Treating Children With Acute Lymphocytic Leukemia

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IIITreatmentCompleted1 to 18NCISJCRH-XIIIBL
NCI-T93-0103D, T93-0103


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.

Entry Criteria

Disease Characteristics:

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
  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

Prior/Concurrent Therapy:

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)

Patient Characteristics:

  1 to 18

Performance status:
  Not specified

  See Disease Characteristics

  Not specified

  Not specified

  HIV negative

Expected Enrollment


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 

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 requiring dosage modification on this protocol include the 
following (see the protocol document for details):

  Acute hypersensitivity

  Exfoliative dermatitis

  Acute hemorrhagic pancreatitis

  Deficient TPMT activity

  ALT elevation
  Severe coagulopathy

  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.

Related Publications

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

John Sandlund, MD, Protocol chair
Ph: 901-595-2427

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.