Trial Information

A Randomized Trial of the I-BFM-SG for the Management of Childhood Non-B Acute Lymphoblastic Leukemia

OBJECTIVES:

- To test in a randomized way the type and intensity of reintensification therapy for
pediatric patients with acute lymphoblastic leukemia in each risk group: standard-risk
(SR), intermediate-risk (IR), and high-risk (HR) group.

- To compare two shorter elements of reintensification (protocol III x 2 courses) to one
(protocol II x 1 course) in terms of effectiveness when cumulative dose of most drugs
are the same in both regimen in patients in the standard-risk group.

- To determine if the increased risk of failure in patients in the intermediate-risk
group can be curtailed by a third reintensification element (protocol III x 3 courses
vs protocol II x 1 course).

- To determine if the three reintensification elements (protocol III x 3 courses) achieve
the same or better results in high-risk group patients, as compared with current
applied HR approach in Berlin-Frankfurt-Münster Group (BFM) or Italian Association of
Pediatric Hematology and Oncology (AIEOP).

OUTLINE: This is a partially randomized, multicenter study. Patients are stratified
according to risk group (standard risk [SR] vs intermediate risk [IR] vs high risk [HR]).
Patients are randomized in reinduction part of the treatment.

- Induction therapy:

- Protocol I' (SR B-cell precursor [BCP] ALL ): Patients receive methotrexate
intrathecally (IT) on days 1, 12, and 33 (and possibly on days 18 and 27);
prednisone or prednisolone orally or IV on days 1-28 followed by a taper;
vincristine sulfate IV on days 1, 8, 15, 22, and 29; daunorubicin hydrochloride IV
over 1 hour on days 8 and 15; and asparaginase IV over 1 hour on days 12, 15, 18,
21, 24, 27, 30, and 33. Patients then receive cyclophosphamide IV over 1 hour on
days 36 and 64; oral mercaptopurine once daily on days 36-63; cytarabine IV
continuously on days 38-41, 45-48, 52-55, and 59-62; and methotrexate IT on days
45 and 59.

- Protocol I (SR T-cell ALL, IR, or HR): Patients receive therapy as in Protocol I'
except that they also receive daunorubicin hydrochloride on days 22 and 29.

Approximately 2 weeks after completion of induction therapy, patients proceed to
consolidation therapy.

- Consolidation: Patients who have achieved complete cytomorphologic remission proceed to
protocol mM or protocol M. Patients in HR group proceed to 3-block consolidation
regimen.

- Protocol mM (BCP-ALL) (SR or IR): Patients receive oral mercaptopurine once daily
on days 1-56; medium-dose methotrexate IV over 24 hours and methotrexate IT on
days 8, 22, 36, and 50; and leucovorin calcium IV every 6 hours on days 9, 23, 37,
and 51.

- Protocol M (T-cell ALL) (SR or IR): Patients receive mercaptopurine, methotrexate
IT, and leucovorin calcium as in protocol mM, and they also receive high-dose (HD)
methotrexate IV over 24 hours on days 8, 22, 36, and 50.

- 3-block consolidation regimen (HR): Patients receive 3 regimen blocks with 2 weeks
between blocks. Treatment continues in the absence of unacceptable toxicity.

- Block HR-1': Patients receive dexamethasone orally or IV 3 times daily on
days 1-5; vincristine sulfate IV on days 1-6; HD methotrexate IV over 24
hours on day 1; leucovorin calcium IV every 6 hours, beginning 42 hours after
the start of HD methotrexate, for 3 doses; cyclophosphamide IV over 1 hour,
every 12 hours, on days 2-4; HD cytarabine IV over 3 hours, every 12 hours,
on day 5 (2 doses); asparaginase IV over 2 hours on days 6 and 11; and triple
intrathecal therapy (TIT) comprising methotrexate, cytarabine, and
prednisone, 3 times on day 1.

- Block HR-2': Patients receive dexamethasone, HD methotrexate, leucovorin
calcium, and asparaginase as in block HR-1'. Patients receive TIT once on day
1 (CNS-negative patients) or twice on days 1 and 5 (CNS-positive patients).
Patients also receive vindesine IV on days 1 and 6; ifosfamide IV over 1
hour, every 12 hours, on days 2-4; and daunorubicin hydrochloride IV over 24
hours on day 5.

- Block HR-3': Patients receive dexamethasone and asparaginase as in block
HR-1'; TIT 3 times on day 5; HD cytarabine IV over 3 hours, every 12 hours,
on days 1 and 2; and etoposide IV over 1 hour, every 12 hours, on days 3-5.

Approximately 2 weeks after completion of consolidation therapy, patients proceed to
reinduction therapy.

- Reinduction (randomized): Patients in continuous complete remission proceed to protocol
II or III. Patients from SR and IR group are randomized to arms I and II; patients from
HR group are randomized to arms II and III.

- Arm I (protocol II x 1 course) (SR-1 or IR-1): Patients receive dexamethasone
orally or IV on days 1-21 followed by a taper; vincristine sulfate IV and
doxorubicin hydrochloride IV over 1 hour on days 8, 15, 22, and 29; asparaginase
IV over 1 hour on days 8, 11, 15, and 18; and methotrexate IT on days 1 and 18.
Patients then receive cyclophosphamide IV over 1 hour on day 36; oral thioguanine
once daily on days 36-49; cytarabine IV continuously on days 38-41 and 45-48; and
methotrexate IT on days 38 and 45.

- Arm II (protocol III x 2 or 3 courses and interim maintenance therapy [IMT])
(SR-2, IR-2, or HR-1): Patients receive dexamethasone orally or IV three times
daily on days 1-14 followed by a taper; vincristine sulfate IV and doxorubicin
hydrochloride IV over 1 hour on days 1 and 8; and asparaginase IV over 1 hour on
days 1, 4, 8, and 11. Patients then receive cyclophosphamide IV over 1 hour on day
15; oral thioguanine once daily on days 15-28; cytarabine IV continuously on days
17-20 and 24-27; and methotrexate IT on days 17 and 21 (and day 1 if there is
initial CNS involvement). Approximately 1 week after completion of protocol III
(course 1), patients receive IMT for 10 weeks (SR group) or 4 weeks (IR and HR
groups) as described below. Approximately 1 week after completion of IMT, patients
receive protocol III as above (course 2). Approximately 1 week after completion of
protocol III (course 2), patients in IR and HR group receive IMT for another 4
weeks followed by another course of protocol III (course 3) 1 week later.

- IMT: Patients receive oral methotrexate once weekly and oral mercaptopurine
daily.

- Arm III (HR-2): Patients receive 1 of the following regimens according to local
practices:

- Regimen HR-2A: Patients receive protocol II as in arm I, rest 1 week and
receive IMT for 4 weeks. Approximately 1 week later, patients receive another
course of protocol II.

- Regimen HR-2B: Patients receive treatment as in 3-block consolidation regimen
with 3 weeks between each block. Approximately 3 weeks later, patients
receive protocol II as in arm I.

- Cranial radiotherapy (CRT) during reinduction: CNS positive patients (CNS status
3) receive CRT after completion of protocol II (SR, IR, HR-2B) or during the first
1.5-2.5 weeks of IMT (SR, IR, HR-2A). SR and IR patients with T-cell ALL and HR
patients receive prophylactic CRT at these same time periods.

Beginning 2 weeks after completion of reinduction (some patients in HR group also undergo
allogeneic stem cell transplantation, as described below), patients proceed to maintenance
therapy.

- Maintenance therapy (MT): Patients receive oral mercaptopurine once daily and
methotrexate IV once weekly. Each patient subgroup (except HR patients undergoing
transplantation) receives MT for a period that brings the total weeks of treatment to
104 weeks, as follows:

- SR: Patients receive MT for 74 weeks (SR-1) or 61 weeks (SR-2).

- IR: Patients receive MT for 74 weeks (IR-1) or 57 weeks (IR-2).

- HR: Patients receive MT for 58 weeks (HR-1), 62 weeks (HR-2A), or 63 weeks
(HR-2B).

Patients with BCP-ALL and in group SR-1 or IR-1 also receive methotrexate IT once in weeks
4, 8, 12, and 16 of MT. Patients with BCP-ALL and in group SR-2 receive methotrexate IT in
weeks 4 and 8 of MT.

- Allogeneic stem cell transplantation (ASCT): Some patients in HR group may undergo ASCT
(usually bone marrow, but may be peripheral blood or umbilical cord stem cells), (at
the time of reinduction therapy) beginning 3-4 weeks after the completion of second
protocol III (HR-1), the first protocol II (HR-2A), or completion of the 3-block
consolidation regimen (HR-2B).

- Under 2 years old: Patients receive oral busulfan every 6 hours on days -8 to -5,
etoposide IV over 4 hours on day -4, and cyclophosphamide IV over 1 hour on days
-3 and -2, and then undergo ASCT on day 0.

- At least 2 years old: Patients undergo total body irradiation twice daily on days
-6 to -4 and receive etoposide IV over 4 hours on day -3, and then undergo ASCT on
day 0. Fractionated local radiotherapy, if required, is administered on days -14
to -7.