Treatment of Adult ALL With an MRD-directed Programme.

Northern Italy Leukemia Group

Status and phase: Completed; Phase 2

Conditions: Acute Lymphoblastic Leukemia

Treatments: Behavioral: Postremission consolidation based on MRD status

Study type: Interventional

Funder types: Other

Identifiers

NCT00358072

NILG-ALL 09/00

Details and patient eligibility

About

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.

Full 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.

Enrollment: 280 patients

Sex: All

Ages: 15 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Untreated Acute lymphoblastic leukemia or lymphoblastic lymphoma (T-cell, precursor B-cell)
• Age 15-65 years (older patients if biologically fit according to responsible physician)
• Written informed consent

Exclusion criteria

• Any co-morbidity precluding the administration of intensive chemotherapy for adult ALL

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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280 participants in 1 patient group

1

Experimental group

Description:

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)

Treatment:

Behavioral: Postremission consolidation based on MRD status