Treatment of Adult ALL With an MRD-directed Programme.

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia, Adult patients, Minimal residual disease, Risk-oriented therapy

The study aims to optimize the concept of risk-oriented postremission consolidation therapy, by offering (i) standard consolidation-maintenance to patients at lowest risk of relapse as defined by MRD(Minimal Residual Disease) negative status, and (ii) allogeneic stem cell transplantation (related/unrelated donor available) or multicycle high-dose therapy with autologous blood stem cell transplant (no donor) to patients at highest risk of relapse as defined by MRD+ status. The prognostic role of MRD evaluation in unselected patients will be evaluated.

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.

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