Trial Information

Intensified PEG-Asparaginase in High Risk Acute Lymphoblastic Leukemia (ALL): A Pilot Study

OBJECTIVES:

Primary

- To demonstrate that biweekly intravenous pegaspargase in combination with
consolidation, interim maintenance, delayed intensification, and maintenance therapies
is feasible and safe in younger patients with newly diagnosed high-risk acute
lymphoblastic leukemia. (closed to accrual 4-22-2011)

OUTLINE: This is a multicenter study (closed to accrual 4-22-2011). Patients are stratified
according to risk assignment (high-risk [HR]-average [day 29 minimal residual disease (MRD)
< 0.01%] vs HR-high [MRD ≥ 0.01%, presence of CNS3 leukemia, testicular disease, MLL
rearrangement, hypodiploidy, or steroid therapy within the past month]). Patients are
assigned to 1 of 2 treatment groups.*

NOTE: *Amendment 2 (4-22-2011) requires changes in the regimens. See the changes below,
after Maintenance therapy.

- Induction therapy: All patients receive cytarabine intrathecally (IT) on day 1;
vincristine sulfate IV on days 1, 8, 15, and 22; prednisone IV or orally twice daily on
days 1-28; daunorubicin hydrochloride IV over 15 minutes on days 1, 8, 15, and 22;
methotrexate IT on days 8 and 29*; and pegaspargase IV over 1-2 hours on day 4.

Patients with M3 (< 25% lymphoblasts) or Philadelphia chromosome-positive (Ph+) disease at
day 29 are removed from study.

NOTE: *Patients with CNS3 disease (WBC ≥ 5/μL and positive for blasts on cytospin) also
receive methotrexate IT on days 15 and 22.

- Consolidation therapy (begins on day 36 of induction therapy):

- Group A (HR-average): Patients receive cyclophosphamide IV over 1 hour on days 1
and 29; cytarabine IV over 15 minutes or subcutaneously (SC) on days 1-4, 8-11,
29-32, and 36-39; oral mercaptopurine once daily on days 1-14 and 29-42;
vincristine sulfate IV on days 15, 22, 43, and 50; methotrexate IT on days 1, 8,
15*, and 22*; and pegaspargase IV over 1-2 hours on days 15 and 43.

- Group B (HR-high): Patients receive cyclophosphamide, cytarabine, mercaptopurine,
vincristine sulfate, and methotrexate as in group A. Beginning on day 1, patients
also receive pegaspargase IV over 1-2 hours every 2 weeks. Patients with CNS3
disease undergo cranial radiotherapy once daily for 10 days and patients with
testicular disease undergo testicular radiotherapy once daily for 12 days,
beginning on day 1 of consolidation.

NOTE: *Patients with CNS3 disease (WBC ≥ 5/μL and positive for blasts on cytospin) do not
receive methotrexate IT on days 15 and 22.

- Interim maintenance (IM) therapy (begins on day 57 of consolidation):

- Group A: Patients receive vincristine sulfate IV on days 1, 11, 21, 31, and 41;
methotrexate IV over 10-15 minutes on days 1, 11, 21, 31, and 41; methotrexate IT
on days 1 and 31; and pegaspargase IV over 1-2 hours on days 2 and 22.

- Group B: Patients receive vincristine sulfate and methotrexate as in group A.
Beginning on day 1, patients also receive pegaspargase IV over 1-2 hours every 2
weeks.

- Delayed intensification (DI) therapy (begins on day 57 of IM):

- Group A: Patients receive vincristine sulfate IV on days 1, 8, 15, 43, and 50;
dexamethasone IV or orally twice daily on days 1-7 and 15-21; doxorubicin
hydrochloride IV over 15 minutes on days 1, 8, and 15; cyclophosphamide IV over 1
hour on day 29; cytarabine IV over 15 minutes or SC on days 29-32 and 36-39; oral
thioguanine on days 29-42; methotrexate IT on days 1, 29, and 36; and pegaspargase
IV over 1-2 hours on days 4 and 43.

- Group B: Patients receive vincristine sulfate, dexamethasone, doxorubicin
hydrochloride, cyclophosphamide, cytarabine, thioguanine, and methotrexate as in
group A. Beginning on day 1, patients also receive pegaspargase IV over 1-2 hours
every 2 weeks.

- Maintenance therapy (MT; begins on day 57 of DI): All patients receive vincristine
sulfate IV on days 1, 29, and 57; oral prednisone on days 1-5, 29-33, and 57-61; oral
mercaptopurine on days 1-84; methotrexate IT on day 1; and oral methotrexate on days 8,
15, 22, 29*, 36, 43, 50, 57, 64, 71, and 78.

In both groups, MT repeats every 12 weeks until total duration of therapy is 2 years from
the start of IM for female patients and 3 years from the start of IM for male patients.
Patients in group B who did not undergo radiotherapy to the brain during consolidation
therapy undergo prophylactic cranial radiotherapy (CR) daily for 8 days.

NOTE: *Patients in group A also receive methotrexate IT on day 29 of courses 1-4 (no oral
methotrexate).

- Revised MT (RMT): The regimen is the same as standard MT, but 2 of the doses of IT
methotrexate are omitted (day 29 of courses 3 and 4).

Amendment 2 (4-22-2011) requires changes to the regimens as follows:

- Group A (HR-Avg):

- Patients who have not started IM therapy receive high-dose (HD) methotrexate
instead of Capizzi methotrexate. The rest of the IM therapy remains the same.

- Patients currently in IM or DI therapy receive the same regimens, but also receive
and additional block of therapy (IM-HD) and then proceed to RMT.

- If patient is currently receiving MT, then stop the regimen. After 1 week,
patients receive IM-HD therapy, then RMT.

- Group B (HR-high):

- Patients who have not started IM therapy (except those who are CNS3) receive
IM-HD, then revised DI (pegaspargase IV resumes every other week on days 4, 18,
32, and 46 of DI), and then receive standard MT.

- Patients who are currently in IM or DI (except those who are CNS3) complete the
standard regimens, then receive IM-HD and MT.

- Patients who are currently receiving the first course of MT (except those who are
CNS3) stop MT therapy. After 1 week, patients receive IM-HD therapy. MT then
begins with course 1 starting with the next prednisoe pulse (day 1, 29, or 57) and
undergo CR in the first 4 weeks of that course.

- Patients with CNS3 disease:

- Patients who have received CR continue protocol with no modifications.

- Patients in consolidation therapy who have NOT undergone CR finish the
consolidation therapy and then receive IM-HD, revised DI, and then CR during the
first 4 weeks of MT.

- Patients less than 10 years old who have not received day 8 of IM therapy stop
receiving prednisone and receive a 14-day course of dexamethasone instead.

- The total number of lumbar punctures performed with IT chemotherapy is capped at 23 for
females and 27 for men in group A and 19 for females and 23 for males in group B.

After completion of study treatment, patients are followed periodically for 5 years.