Risk-Directed Therapy in Treating Younger Patients with Newly Diagnosed Acute Lymphoblastic Leukemia

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIITreatment18 and underTOTXVI
NCI-2011-01254, NCT00549848

Trial Description


This randomized phase III trial studies how well risk-directed therapy works in treating younger patients with newly diagnosed acute lymphoblastic leukemia and the best dose of a chemotherapy drug called pegaspargase. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Risk-directed therapy gives more intensive chemotherapy to patients whose cancer has a higher risk of coming back. It is not yet known whether risk-directed chemotherapy is more effective than standard chemotherapy, and whether giving higher doses of pegaspargase during risk-directed therapy is more effective than standard doses in treating acute lymphoblastic leukemia.

Further Study Information


I. To compare the distributions of continuous complete remission of patients randomized on the first day of the continuation phase to receive a higher dose of PEG-asparaginase (pegaspargase) or to receive the conventional dose (2,500 units/m^2).


I. To estimate the event-free survival and overall survival of children with acute lymphoblastic leukemia (ALL) who are treated with risk-directed therapy.

II. To study whether intensifying induction, including fractionated cyclophosphamide and thioguanine, in patients with day 15 minimal residual disease (MRD) >= 5%, will result in improved leukemia cytoreduction in this subgroup compared to Total Therapy Study XV (TOTXV).

III. To assess whether intensification of central nervous system (CNS)-directed intrathecal and systemic chemotherapy will improve outcome in patients at high risk of CNS relapse.


I. To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for treatment-related outcomes in the context of the systemic therapy used in the protocol.

II. To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose (3,500 or 3,000 units/m^2) versus those of PEG-asparaginase given in conventional dose (2,500 units/m^2) in the continuation phase.

III. To determine the prognostic value of levels of minimal residual disease in peripheral blood at day 8 of remission induction.

IV. To validate new markers and methods for MRD detection.

V. To genotype natural killer (NK) cell receptors and measure their expressions at diagnosis and before reinduction, and to associate these features with treatment outcome.

VI. To identify new prognostic factors by applying new technologies to study patient material (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells).

VII. To use quantitative magnetic resonance (MR) measures (Diffusion Tensor Imaging and high resolution volumetric imaging) to assess differences in myelin and cortical thickness development in patients treated for ALL relative to healthy controls matched for age and gender.

VIII. To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness development and neurocognitive performance.

IX. To assess the impact of frontal-parietal lobe myelin and cortical thickness development on neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning and processing speed with both neurocognitive testing and functional magnetic resonance imaging.

X. To perform a comprehensive analysis of the intestinal microflora in patients with ALL prior to and subsequent to chemotherapy using next generation sequencing technologies as an exploratory approach.

XI. To study any alteration in the composition and population dynamics of the resident intestinal microflora in patients with ALL after exposure to chemotherapy compared to prior to exposure to chemotherapy.

XII. To describe the frequency and severity of gastrointestinal illnesses during induction chemotherapy and over the 6 month period after completion of induction in patients who did and those who did not have changes in intestinal microbiota.

XIII. To detect the presence of pathogens found to be abundant by the microbiome analysis in subsequent stool samples collected over the 6 month period after completion of induction chemotherapy.


REMISSION INDUCTION: Patients receive 6-7 weeks of remission induction comprising prednisone or dexamethasone, vincristine sulfate, daunorubicin hydrochloride, pegaspargase, and triple intrathecal therapy (methotrexate, hydrocortisone, and cytarabine [ITMHA]) followed by cyclophosphamide, cytarabine, and thioguanine or mercaptopurine. Some patients also receive dasatinib, clofarabine, or etoposide.

CONSOLIDATION TREATMENT: Patients then receive 8 weeks of consolidation comprising high-dose methotrexate, mercaptopurine, and triple ITMHA. Some patients may receive reintensification therapy comprising dexamethasone, cytarabine, etoposide, ITMHA, and pegaspargase and are then offered the option of transplant. Other patients may receive 1-2 courses of clofarabine, etoposide, cyclophosphamide, and dexamethasone.

CONTINUATION TREATMENT: Patients are then randomized to 1 of 2 treatment arms and receive 120 weeks of continuation chemotherapy (according to risk classification) comprising dexamethasone, doxorubicin hydrochloride, vincristine sulfate, mercaptopurine, methotrexate, ITMHA, high-dose cytarabine, clofarabine, etoposide, triple ITMHA, cyclophosphamide, and/or dasatinib. Some patients may undergo allogeneic stem cell transplant.

ARM I: Patients also receive high-dose pegaspargase.

ARM II: Patients also receive standard-dose pegaspargase.

Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 4 months for 1 year, every 6 months for 1 year, and then annually until patient is in remission for 10 years.

Eligibility Criteria

Inclusion Criteria:

Diagnosis of precursor B-cell or precursor T-cell ALL by immunophenotyping

Limited prior therapy, including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy; other circumstances must be cleared by principal investigator (PI) or co-PI

Written, informed consent and assent following Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office for Human Research Protections (OHRP) Guidelines

Exclusion Criteria:

Inability or unwillingness of research participant or legal guardian/representative to give written informed consent

Participants with prior therapy, other than therapy including systemic glucocorticoids for one week or less, one dose of vincristine, emergency radiation therapy to the mediastinum and one dose of intrathecal chemotherapy

Participants who are pregnant or lactating

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

St. Jude Children's Research Hospital

  • National Cancer Institute
Sima C. Jeha, Principal Investigator

Trial Sites



St. Jude Children's Research Hospital

Sima C. Jeha
Ph: 901-595-3901
Email: sima.jeha@stjude.org

Sima C. Jeha
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00549848

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.