Trial Information

Treatment of Adult Acute Lymphoblastic Leukemia Using a Post-remission Programme Whose Intensity Varies Depending on the Risk Class Defined on the Basis of Minimal Residual Disease.

Improved outcome of adult ALL through the application of:

- Risk-adapted induction (cycle no. 1: IVAP i.e
idarubicin-vincristine-asparaginase-prednisone, plus fractionated cyclophosphamide in
T-ALL,and imatinib in Ph/BCR-ABL+ ALL)

- Risk stratification (clinical) according to morphology, immunophenotype, cytogentics
and molecular biology results. Standard risk (SR) is defined by pre-B CD10+ phenotype,
Ph/BCR-ABL- status, and a blast count <10x10e9/L. All other subgroups are HR
(high-risk) except for Ph/BCR-ABL+ and t(4;11)+ ALL (VHR, very high-risk)

- Homogeneous early consolidation programme including both conventional therapy with
idarubicin-vincristine-cyclophosphamide-dexamethasone/prednisone(cycles no. 2,3,5,6,8)
and high-dose treatemt with MTX/Ara-C (cycles no. 4,7) and meningeal prophylaxis
(triple intrathecal therapy x8-12, skull irradiation), plus imatinib in Ph+ ALL (Phase
A). Autologous bllo stem cells are mobilized and cryopreserved after cycle no. 4.

- Serial evaluation of minimal residual disease (MRD) with RQ-PCT technology, aiming to
define in individual patients the rate of reduction during early consolidation. The
molecular study was centralized and aimed at obtaining one or more patient-specific
probe(s)with a sensitivity of at least 10e-3. Patient bone marrow was sampled for MRD
analysis at timepoints 13 i.e. after cycles no.3,5, and 7. Only patients with a
negative result at timepoint 3 and a negative/low positive (<10e-4) result at timepoint
3 are considered MRD-, all other combinations being regarded MRD+.

- Phase B therapy according to MRD results and ALL subset:

- MRD- nonPh/t(4;11): standard maintenance

- MRD+ nonPh/t(4;11): allogeneic stem cell transplantation (from sibling/MUD) or,
alternatively, intensified high-dose therapy (2-4 "hypercycles")with autologous
stem cell support and anti CD20 MoAb (if CD20+), followed by maintenance. Each
"hypercycle" consists of high-dose mercaptopurine-etoposide-melphalan (cycles no.
1,3) or methotrexate-cytarabine (cycles no. 2,4)

- MRD unknown nonPh/t(4;11): treatment by clinical risk (SR: maintenance; HR, as per
MRD+)

- Ph/t(4;11)+: allogeneic stem cell transplantation as soon as possible into
complete remission; if a transplant is not possible, consolidation is as for HR
patients. each cycle is supplemented by imatinib in Ph+ ALL

The illustrated strategy aims to optimize postremission consolidation therapy by offering
standard treatment "only" to patients at lowest risk of relapse (MRD-), thereby reducing the
risks of high dose treatments (expected TRM from allogeneic SCT 20-30%), while maintaining
the latter approach in MRD+ cases and very HR subsets.

The prognostic role of MRD evaluation in unselected patients will be evaluated.