Trial Information

International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia

Risk Stratification

- T/non-HR: T-ALL in absence of any HR criteria (see below)

- pB/non-HR: pB-ALL in absence of any HR criteria (see below).

- SR (polymerase chain reaction(PCR)-MRD-SR (MRD-negative on day 33 and 78) or, if
no PCR-MRD result available, FCM d15 < 0.1%)

- MR (no SR)

- HR: Prednisone poor-response (≥1000 blast cells/µl in peripheral blood on day 8), blast
cells ≥10% in bone marrow on day 15 as measured by FCM, non-remission on day 33,
positivity for MLL/AF4 or t(4;11), hypodiploidy (< 45 chromosomes), PCR-MRD-HR (MRD
≥10E-3 on day 78) or PCR-MRD-MR SER (only in pB-ALL, MRD ≥ 10-3 on day 33 and MRD
positive at a level of < 10E-3 on day 78)

Chemotherapy

According to the risk group, patients receive the following chemotherapy elements:

T/non-HR: Protocol I, Protocol M, Protocol II and Maintenance pB/non-HR: Protocol I,
Protocol M, Protocol II and Maintenance HR: Protocol I, HR-1', HR-2', HR-3', 3x Protocol
III, Maintenance Patients of the HR group with PCR-MRD ≥10E-3 after element HR-3' are
eligible for treatment with element DNX-FLA.

Protocol I Cytoreductive prephase: Prednisone (PDN) on days 1-7 and one dose of methotrexate
(MTX) intrathecal (IT) on day 1 Protocol IA: Prednisone (PDN) on days 8 to 28 (21 days);
vincristine (VCR) on days 8, 15, 22, 29 (4 doses); daunorubicin (DNR) on days 8, 15, 22 and
29 (4 doses); pegylated L-asparaginase (PEG-L-ASP) on days 12 and 26; MTX IT on days 12 and
33 and in case of blast cells in cerebrospinal fluid at diagnosis additional IT MTX is given
on days 19 and 26.

Protocol IA': Only two doses of DNR on days 8 and 15 given to patients eligible for
randomization R1 and randomized into the experimental arm Protocol IA-CPM: additional
cyclophosphamide (CPM) on day 10 only in T-ALL patients with prednisone poor-response
Protocol IA-Dexa (IAD): Dexamethasone (DXM) instead of PDN is given to all patients with
T-ALL without any high-risk criteria as identified by day 8.

Protocol IB: CPM on days 36 and 64; cytarabine (ARA-C) on days 38-41, 45-48, 52-55 and
59-62; 6-mercaptopurine (6-MP) on days 36 to 63 (28 days); MTX IT on day 45 and 59 Protocol
IB-ASP+: additional PEG-L-ASP on days 40, 47, 54, and 61 (4 doses) are given to the patients
eligible for randomization RHR and randomized into the experimental arm.

Protocol M 6-MP on days 1- 56, high-dose MTX (HD-MTX) on days 8, 22, 36, 50 and MTX IT on
days 8, 22, 36 and 50 Protocol II Protocol IIA: DXM on days 1 to 21 (21 days); VCR on days
8, 15, 22, 29 (4 doses); doxorubicine (DOX) on days 8, 15, 22 and 29 (4 doses); PEG-L-ASP on
day 8 (1 dose); MTX IT on days 1 and 18 only in patients with initial CNS involvement.

Protocol IIA-ASP+: additional PEG-L-ASP on day 22 for patients eligible for randomization R2
and randomized into the experimental arm.

Protocol IIB: CPM on day 36; ARA-C on days 38-41 and 45-48; thioguanine (TG) on days 36 to
49 (14 days) and MTX IT on days 38 and 45.

Protocol IIB-ASP+: additional PEG-L-ASP on days 36 and 50 for eligible for randomization R2
and randomized into the experimental arm.

Protocol III DXM on days 1-15; VCR on days 1 and 8; DOX on days 1 and 8; PEG-L-ASP on day 1;
CPM on day 15; ARA-C on days 17-20 and 24-27; TG on days 15 - 28 and MTX IT on days 17 and
24, also on day 1 in patients with initial CNS involvement HR-1' DXM on days 1-5; VCR on
days 1 and 6; HD-MTX on day 1; CPM every 12 hours on days 2-4 (5 doses); HD-ARA-C every 12
hours on day 5 (2 doses); PEG-L-ASP on day 6, MTX IT on day 1 HR-2' DXM on days 1 to 5; VDS
on days 1 and 6; HD-MTX on day 1; IFO every 12 hours on days 2-4 (5 doses); DNR on day 5;
PEG-L-ASP on day 6; MTX IT on day 1 and 1 in patients with initial CNS involvement also day
5 HR-3' DXM on days 1-5; ARA-C 4 x on days 1-2 in 12 h intervals; etoposide (VP-16) every
12 hours on days 3-5 (5 doses); PEG-L-ASP on day 6; MTX IT on day 1 DNX-FLA Flucytosine
(FLU) on days 1-5 (5 doses); HD-ARA-C on days 1 to 5 (5 doses); liposomal daunorubicin (DNX)
on days 1, 3 and 5 (3 doses); MTX IT on day 1

Interim/Maintenance (until week 104):

6-MP p.o. daily; MTX p.o. once a week, doses adjusted to white blood cell count; PEG-L-ASP:
every second week (6 doses), only for patients eligible for randomization R2 and randomized
into the experimental arm; MTX IT every 6 weeks up to a total of 6 doses for the following
subgroups (all CNS-negative):

- T-ALL (HR or non-HR) with < 2 years of age at start of maintenance,

- T-ALL, non-HR and initial WBC < 100 000/μl

- pB-ALL with PPR and/or FCM-MRD day 15 ≥ 10 % and/or PCR-MRDMR SER as only HR criteria

Radiotherapy Patients without CNS involvement and

- T-ALL/non-HR, WBC ≥ 100 000/μl, and age ≥ 2 years at start of pCRT or

- with risk group HR and age ≥ 2 years at start of pCRT except pB-ALL with PPR and/or
FCM-MRD day 15 ≥ 10 % and/or PCR-MRD-MR SER as only HR criteria receive preventive
cranial radiotherapy with 12 Gy

Patients with CNS involvement receive therapeutic cranial radiotherapy with 18 Gy (age 1 to
<2 years 12 Gy).