Treatment of Adult ALL With an MRD-directed Programme.
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Postremission consolidation based on MRD status
Intervention type(s): Behavioral
Intervention description(s): Application of combination chemotherapy aimed to reduce MRD burden in unselected patients, followed by MRD-adjusted therapy that range from maintenance chemotherapy (MRD-negative patients) to allogeneic SCT (MRD-positive patients) or high-dose therapy with autologous blood stem cell support (MRD-positive patients without compatible donor for allogeneic SCT)
Other intervention name(s): MRD-guided therapy
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Acute lymphoblastic leukemia; Adult patients; Minimal residual disease; Risk-oriented therapy