International Collaborative Treatment Protocol For Children And Adolescents With Acute Lymphoblastic Leukemia
Condition: Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 3

Summary: 
      Rationale/Purpose: Drugs used in chemotherapy work in different ways to stop the growth of
      cancer cells, either by killing the cells or by stopping them from dividing. Giving more than
      one drug (combination chemotherapy) may kill more cancer cells. It is not yet known which
      combination chemotherapy regimen is more effective in treating young patients with acute
      lymphoblastic leukemia (ALL).

      This trial is studying several different combination chemotherapy regimens to compare how
      well they work in treating young patients with ALL.

      Study objectives

      Primary study questions:

        -  Non high-risk (non-HR) precursor-B ALL (pB-ALL) patients with TEL/AML1-negative ALL or
           unknown TEL/AML1 status and flow cytometry minimal residual disease (MRD) in bone marrow
           on day 15 <0.1% or with TEL/AML1-positive ALL (randomized study question R1): Can the
           daunorubicin dose in Protocol IA be safely reduced by 50 % with a non-inferior EFS and a
           reduction of toxicity (treatment-related mortality and AE/SAE in Protocol I)?

        -  Patients with pB-ALL and risk group medium risk (MR) (randomized study question R2): Can
           the clinical outcome be improved by protracted asparagine depletion achieved through
           application of intensified PEG-L-asparaginase during reintensification and early
           maintenance?

        -  High-risk (HR) patients (as identified by day 33 - randomized study question RHR): Can
           the clinical outcome be improved by protracted exposure to PEG-L-asparaginase during
           Protocol IB?

      Secondary study questions:

        -  Standard risk (SR) patients identified by at least one sensitive marker: Is the clinical
           outcome comparable to that obtained in SR patients (identified with two sensitive
           markers) in AIEOP-BFM ALL 2000, or can the outcome even be improved with the use of
           PEG-L-asparaginase instead of native E. coli L-ASP?

        -  T-ALL non-HR patients: Can the high level of outcome which was obtained for these
           patients in study AIEOP-BFM ALL 2000 be preserved or even improved with the use of
           PEG-L-ASP instead of native E. coli L-ASP?

        -  HR patients with persisting high MRD levels despite the use of the HR blocks in the
           intensified consolidation phase "MRD Non-Responders": Is it possible to improve the
           outcome and to achieve a further reduction of leukemic cell burden by administration of
           an innovative treatment schedule (DNX-FLA)?

        -  Patients participating in the randomized asparaginase studies (pB-ALL/MR, HR): Are
           asparaginase activity and asparaginase antibodies associated with development of
           allergic reactions, and do they have an effect on the outcome of the patients?

        -  What is the relative value of different methods of MRD monitoring in the definition of
           alternative stratification systems within a BFM-oriented protocol?
    

Detailed description: 
      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).
    

Intervention name(s): PEG-L-asparaginase; cyclophosphamide; cytarabine; daunorubicin hydrochloride; dexamethasone; doxorubicin hydrochloride; etoposide; ifosfamide; mercaptopurine; methotrexate; prednisone; thioguanine; vincristine sulfate; vindesine; daunoxome; fludarabine; Radiation Therapy
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Radiation
Intervention description(s): see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment; see detailed protocol description; only given by patients with poor MRD-response during the high risk treatment; for eligibility for radiotherapy see detailed protocol description
Other intervention name(s): Oncaspar medac
Intervention MeSH terms: Cytarabine; Dexamethasone; Prednisone; Cyclophosphamide; Ifosfamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Fludarabine; Etoposide; Vincristine; Daunorubicin; Asparaginase; Mercaptopurine; Thioguanine; Pegaspargase; Vindesine
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment