Intrathecal DepoCyte and Lineage-targeted Minimal Residual Disease-oriented Therapy of Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The aim of this clinical study in adult ALL is to compare by risk category (1) the
      feasibility of two different CNS prophylaxis regimens and (2) the overall disease-free
      survival in relation to the achievement of an early MRD negative status and following
      consolidation with lineage-targeted methotrexate infusions and other disease-specific
      therapeutic elements, with or without the application of allogeneic or autologous SCT
      depending on risk class and MRD study results.

      In this multicentric prospective pilot randomized phase II trial on CNS prophylaxis, all
      patients receive induction/consolidation therapy incorporating lineage-targeted high-dose
      methotrexate plus other drugs (with additional imatinib in Ph/BCR-ABL+ ALL), for the
      achievement of an early negative MRD status. The MRD study supports a risk/MRD-oriented final
      consolidation phase.
    

Detailed description: 
      A) Risk Classification

      Newly diagnosed patients are hierarchically clustered into very high, high and standard risk
      cases (VHR, HR, SR) using international risk criteria modified according to NILG:

      A1) VHR (any criterium): B-precursor: WBC count >100x109/L; adverse cytogenetics/molecular
      biology such as t(9;22)/BCR-ABL, t(4;11)/MLL rearrangement at 11q23, +8, -7, del6q, t(8;14),
      low hypodiploidy with 30-39 chromosomes, near triploidy with 60-78 chromosomes, complex with
      >5 unrelated anomalies. T-precursor: WBC count >100x109/L; early/late non-cortical
      immunophenotype (CD1a-); adverse cytogenetics/molecular biology (as above).

      A2) HR (any criterium, VHR excluded): B-precursor: WBC count >30x109/L; pro-B
      immunophenotype; complete remission after cycle 2. T-precursor: complete remission after
      cycle 2.

      A3) SR (all criteria, VHR/HR excluded): B-precursor: WBC count <30x109/L; T-precursor: WBC
      count <100x109/L; cortical immunophenotype (CD1a+).

      B) CNS Prophylaxis Stratification before randomisation

        1. by immunophenotype, i.e. B-precursor vs. T-precursor

        2. by risk class, i.e. SR vs. non-SR (using only known factors) Randomisation: intrathecal
           (IT) CNS prophylaxis with standard triple therapy (TIT, 12 total injections) vs.
           DepoCyte (6-8 total injections by disease subset). Cranial irradiation is omitted in
           both arms, and all patients receive the same chemotherapy program including CNS-crossing
           agents.

      C)Induction/Early Consolidation and MRD Study

      Randomised patients receive homogeneous induction/early consolidation chemotherapy, including
      subset-specific elements for B-precursor ALL (3x targeted-infusion methotrexate 2.5 g/m2),
      T-precursor ALL (3x targeted-infusion methotrexate 5 g/m2), age >55 years (methotrexate
      reduced to 1.5 g/m2), Ph/BCR-ABL+ ALL (imatinib, reduced-intensity chemotherapy), radiation
      therapy (LL). Patients not in CR after cycles 1-2 are off study. For CR evaluation bone
      marrow is checked on days 28 and/or 56. Consolidation cycles are administered at 21-28 day
      intervals Concurrent MRD analysis is performed at four timepoints (weeks 4, 10, 16 and 22 of
      induction/consolidation), to optimize risk classification and support risk/MRD-oriented
      therapy:

      C1) MRD negative (M-NEG): negative MRD study (<10-4 at timepoints #2 and #3, and negative at
      timepoint #4) C2) MRD positive (M-POS): positive MRD study (>10-4 at timepoints #2 or #3, or
      positive at timepoint #4)

      D)MRD/Risk-Oriented Final Therapy D1) VHR patients are candidate to an early allogeneic SCT
      (related/unrelated donor/cord blood; ablative/non-ablative conditioning according to current
      protocols/guidelines) after CR, regardless MRD study results.

      D2) M-POS as well as HR patients with unknown MRD are allocated to allogeneic SCT after MRD
      timepoint 2 (M-POS >10-4) or MRD timepoint 4 (others). When an allogeneic SCT is not
      possible, patients complete consolidation and receive autologous-type SCT followed by
      maintenance.

      D3) M-NEG as well as SR patients with unknown MRD are allocated to maintenance therapy.

      Age-limited therapeutic procedures: Patients aged >55 years are treated with age-adapted
      therapy, and when indicated will be included in SCT programs whenever possible and according
      to performance status and comorbidity.
    

Intervention name(s): liposome-encapsulated cytarabine (DepoCyte); Triple intrathecal therapy (TIT)
Intervention type(s): Drug; Drug
Intervention description(s): DepoCyte 50 mg injected intrathecally x6-8 (6: B-lineage, 8: T-lineage) during induction/consolidation phases; Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg. injected intrathecally x12 during induction/consolidation therapy
Other intervention name(s): DepoCyte; DepoCyt; Methotrexate; Cytosine arabinoside; Cytosar
Intervention MeSH terms: Cytarabine; Methotrexate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Adults; Central nervous system prophylaxis; Minimal residual disease