Trial Information

Treatment of Childhood Acute Lymphoblastic Leukemia: Grant Application Title: Erwinia Asparaginase in Childhood Acute Leukemia

OBJECTIVES: I. Compare the efficacy and toxicity of doxorubicin with or without the
cardioprotectant drug dexrazoxane in children with high risk acute lymphoblastic leukemia.
II. Compare the efficacy and toxicity of hyperfractionated cranial radiation plus standard
vs intensive intrathecal chemotherapy in preventing CNS leukemia in standard risk patients.
III. Compare the efficacy and toxicity of hyperfractionated vs conventionally fractionated
cranial radiation plus standard intrathecal chemotherapy in high risk patients. IV. Compare
quality of life of these patients. V. Determine whether molecular evidence of leukemia is
present in the bone marrow and peripheral blood at the time of remission induction and
during intensification and continuation therapy and whether it disappears, changes over
time, and is predictive of relapse.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to risk
group (standard risk AND 2 to 8 years AND highest pretreatment WBC less than 20,000/mm3 vs
all other standard risk vs high risk). The high risk stratum is further stratified according
to dexrazoxane administration (yes vs no). Doxorubicin Investigational Window: Standard risk
patients: Patients receive doxorubicin IV on days 0 and 1. High risk patients are randomized
to one of two treatment arms: Arm I: Patients receive doxorubicin IV on days 0 and 1. Arm
II: Patients receive dexrazoxane IV over 15 minutes immediately followed by doxorubicin IV
on days 0 and 1. Induction Therapy for Patients Eligible for Investigational Window:
Patients receive oral prednisone or prednisolone or methylprednisolone IV every 6 hours on
days 2-30. Patients also receive vincristine IV on days 2, 9, 16, and 23; methotrexate IV
over 1 hour on day 2; leucovorin calcium orally or IV every 6 hours beginning 36 hours after
methotrexate; and E. coli asparaginase IM on day 4. Intrathecal methotrexate, cytarabine,
and hydrocortisone are administered on days 16 and 30. Induction Therapy for Patients
Ineligible for Investigational Window: Patients receive the same chemotherapy but at
different timing intervals, which are determined by bilirubin levels. Patients who are in
hematologic remission on day 30 proceed to CNS treatment. Patients who do not achieve
remission by day 30 continue vincristine IV weekly for 3 weeks or until complete remission.
Patients who do not achieve remission by day 51 are taken off study. Patients who are in
hematologic remission but have CNS blasts on day 30 continue intrathecal chemotherapy,
vincristine IV, and asparaginase IM weekly for 3 weeks (days 30, 37, and 44), and
doxorubicin IV (with or without dexrazoxane, depending on earlier randomization) on day 30.
Cranial radiation is delayed until CSF is clear. CNS Treatment for Standard Risk Patients:
Patients receive chemotherapy consisting of vincristine IV for one dose and oral
mercaptopurine for 14 days. Patients are then randomized to one of two treatment arms: Arm
I: Patients undergo cranial radiotherapy twice a day for 10 days and receive intrathecal
methotrexate and cytarabine twice weekly for 2 weeks. Arm II: Patients receive intrathecal
methotrexate, cytarabine, and hydrocortisone twice weekly for 2 weeks. Girls with
pretreatment WBC less than 20,000/mm3 are nonrandomly assigned to this arm. Patients who
refuse randomization undergo conventional radiotherapy daily for 10 days plus receive
intrathecal methotrexate and cytarabine twice weekly for 2 weeks. CNS Treatment for High
Risk Patients At Least 365 Days Old: Patients receive the same chemotherapy regimen as
standard risk patients, plus they receive intrathecal methotrexate and cytarabine twice
weekly for 2 weeks. Patients receive doxorubicin with or without dexrazoxane as in the
earlier randomization, then are randomized to one of two radiotherapy arms: Arm I: Patients
undergo cranial radiotherapy daily for 10 days. Arm II: Patients undergo cranial
radiotherapy twice daily for 10 days. Patients who refuse randomization receive therapy as
in arm I. Intensification and Continuation Therapy for Patients At Least 365 Days Old:
Therapy begins after CNS treatment and at least 3 weeks after complete remission is
documented. Standard Risk: Patients receive vincristine IV every 3 weeks, oral prednisone or
prednisolone twice a day for five days every 3 weeks, and oral mercaptopurine for 14 days
every 3 weeks. E. coli asparaginase IM followed by methotrexate IV or IM are administered
weekly for 18 weeks. Treatment is repeated as a 3 week sequence until continuous complete
remission has been achieved for 24 months. Patients who had radiotherapy now receive
intrathecal methotrexate and cytarabine every 18 weeks, while those patients who did not
undergo radiotherapy receive intrathecal methotrexate, cytarabine, and hydrocortisone every
9 weeks for 6 doses, then every 18 weeks. High Risk: Patients receive vincristine,
prednisone or prednisolone, mercaptopurine, asparaginase, and methotrexate as for standard
risk patients. According to prior randomization, patients also receive doxorubicin IV every
3 weeks or dexrazoxane IV over 15 minutes and doxorubicin IV every 3 weeks. Doxorubicin is
continued for 9 months or until the total cumulative dose is reached, then methotrexate IV
is administered weekly. Treatment continues as for standard risk patients. Quality of life
is assessed on induction day 23, during the second week of CNS therapy or at the start of
intensification therapy, during the third week of intensification, during the first week of
maintenance therapy (18 months after diagnosis), then every 2 years thereafter. Patients are
followed every month for 6 months, every 2 months for 1 year, every 4 months for 2 years,
and then annually thereafter.

PROJECTED ACCRUAL: A total of 420 patients will be accrued for this study within 4 years.