Trial Information

A Randomized Study on CNS Prophylaxis With Liposome-Encapsulated Cytarabine in Association With a Lineage-Targeted and MRD-Oriented Postremission Strategy in Adult ALL

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.