Treatment of Childhood Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to reduce the side-effects and discomfort of anti-leukemia therapy, to attain long-term control of the disease and to hopefully eradicate it.

Detailed Description
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Children with acute lymphoblastic leukemia (ALL) are treated somewhat differently depending upon on the relative risk of the leukemia recurring. For this study they are classified into Standard Risk, High Risk and Infant/High Risk. The treatment for patients in the Standard Risk and High Risk groups consists of three phases of therapy: induction treatment; prevention of brain and spinal cord leukemia (CNS treatment); and intensification/continuation chemotherapy. The treatment for patients in the Infant/High Risk group consists of four phases of therapy: induction treatment; infant intensification therapy; intensification/continuation chemotherapy; and CNS treatment. The induction treatment consists of a combination of chemotherapy drugs whose purpose is to kill all detectable leukemia cells. This process usually requires a least one month and includes six anti-leukemia drugs. These drugs are: vincristine, doxorubicin, methotrexate, cytosine arabinoside, asparaginase and steroids (methylprednisolone or prednisone). After the induction phase, Infant/High Risk patients will receive a highly intensive month of treatment (infant intensification) . Drugs used during this month include high-dose methotrexate, asparaginase, 6-mercaptopurine and high dose cytosine arabinoside (ARA-C). CNS treatment begins during induction therapy but is intensified during the second and third month after diagnosis. Treatment for all patients will include a series of spinal taps with the instillation of anti-leukemia drugs, including cytosine arabinoside and methotrexate and with or without hydrocortisone (depending upon randomization). All high risk patients (those in both High Risk and Infant/High Risk) as well as some standard risk patients will receive radiation treatment to the brain. Radiation therapy will either be given in either conventional treatments (once daily for 10 days), or hyperfractionated treatments (twice daily at half doses for 10 days). Total dose of radiation is 1800 cGy. Intensification and continuation therapy, begins 4-5 weeks after diagnosis for Standard Risk and High Risk groups and 4-5 weeks after infant intensification in Infant/High Risk group. This phase of treatment continues until the completion of two years of treatment. Patients in the Standard Risk group will receive five anti-leukemia drugs (vincristine, prednisone, methotrexate, asparaginase, and 6-mercaptopurine). Patients in High Risk and Infant/High Risk will receive six anti-leukemia drugs (vincristine, prednisone, doxorubicin, methotrexate, asparaginase and 6-mercaptopurine). All patients will be able to participate in a randomization comparing two types of asparaginase, E.coli and Erwinia. Patients will be randomized to receive either once weekly E.coli or once-weekly Erwinia during the Intensification phase, each given for a total of 20 weeks. Patients in the Standard Risk group are able to participate in an additional randomization. Standard risk patients will be randomized to receive one of two different regimens designed to prevent central nervous system leukemia, either 1)radiation therapy (given twice daily) with chemotherapy in the spinal fluid every 18 weeks, or 2) intensive chemotherapy in the spinal fluid alone without radiation. Patients in the High Risk and Infant/High Risk groups are able to participate in two randomizations in addition to the asparaginase randomization. The first will be to assess whether the drug dexrazoxane prevents heart damage caused by doxorubicin without affecting risk of relapse. Patients will be randomized to receive either doxorubicin alone or doxorubicin with dexrazoxane during the induction, CNS and intensification phases. The second randomization will compare the relative efficacy and toxicity of different cranial radiation schedules. Patients will be randomized to receive radiation in either once daily or twice daily fractions. Blood and bone marrow samples will be collected to learn more about the biology of leukemia. These samples will also be used to test minimal residual disease levels to learn if these levels help predict risk of relapse. Quality of life questionnaires will also be performed by the parents of patients, by children over eight, and by the child's clinician.

Official Title
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Treatment of Childhood Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: asparaginase (E. Coli)
* Drug: asparaginase (Erwina)
* Drug: dexrazoxane
* Drug: doxorubicin
* Procedure: cranial radiation (once daily fractionation)
* Procedure: cranial radiation (twice-daily fractionation)
* Procedure: Intrathecal chemotherapy without radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute lymphoblastic leukemia, excluding known mature B-cell ALL < 18 years of age Patients who are leukopheresed or exchanged are eligible for study only after completion of the pheresis or exchange transfusion Absence of a t(8,14) (q24; q32), t (8,22), t(2,8) Total bilirubin < 1.4mg/dl Exclusion Criteria: Known HIV positive Prior steroid therapy within 30 days of diagnosis Septic shock Ongoing intracranial hemorrhage Clinical evidence of CNS or lung leukostasis

Ages Eligible for Study
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Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: asparaginase (E. Coli)|nan|
|Drug: asparaginase (Erwina)|nan|
|Drug: dexrazoxane|nan|
|Drug: doxorubicin|nan|
|Procedure: cranial radiation (once daily fractionation)|nan|
|Procedure: cranial radiation (twice-daily fractionation)|nan|
|Procedure: Intrathecal chemotherapy without radiation|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| -To evaluate the efficacy and safety of doxorubicin with or without dexrazoxane |  |  | 
| -To determine the efficacy of hyperfractionated radiation plus standard intrathecal chemotherapy compared with intensive intrathecal chemotherapy alone in standard risk patients. |  |  | 
| -To compare the relative efficacy and toxicity of E.coli and Erwinia asparaginase |  |  | 
| -To compare the relative efficacy and toxicity of cranial radiation delivered in once-daily versus twice-daily fractions in high risk patinets. |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| -To compare randomized treatment groups using health-related quality of life analyses. |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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infant/high risk, childhood ALL, standard risk, high risk