Treatment of Adult ALL With an MRD-directed Programme.

Sponsor

Northern Italy Leukemia Group (Other)

Overall Status

Completed

CT.gov ID

NCT00358072

Collaborator

Associazione Italiana per la Ricerca sul Cancro (Other)

280

Enrollment

Locations

Arm

100

Duration (Months)

18.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Acute Lymphoblastic Leukemia	Behavioral: Postremission consolidation based on MRD status	Phase 2

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

280 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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.

Study Start Date :

May 1, 2000

Actual Primary Completion Date :

Dec 1, 2006

Actual Study Completion Date :

Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 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)	Behavioral: Postremission consolidation based on MRD status 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 Names: MRD-guided therapy

Arm

Intervention/Treatment

Experimental: 1

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)

Behavioral: Postremission consolidation based on MRD status

Other Names:

MRD-guided therapy

Outcome Measures

Primary Outcome Measures

Disease-free survival at 5 years [5 year from date of complete remission]

Secondary Outcome Measures

Complete remission [4 or 8 weeks from date of therapy start]
Overall survival [5 years from date of diagnosis]
Cumulative incidence of relpase [5 years from date of complete remission]
Remissional deaths [4 weeks from date of therapy start]
Nonlethal toxicity [5 years from date of therapy start]

Eligibility Criteria

Criteria

Ages Eligible for Study:

15 Years to 65 Years

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedali Riuniti di Bergamo	Bergamo	BG	Italy	24128
2	Divisione Ematologia Spedali Civili	Brescia	BS	Italy	25123
3	Divisione di Ematologia e TMO Ospedale San Maurizio	Bolzano	BZ	Italy	39100
4	U.O. Ematologia e Centro TMO Ospedale Armando Businco	Cagliari	CA	Italy	09121
5	Ematologia Azienda Ospedaliera S.Croce e Carle	Cuneo	CN	Italy	12100
6	U.S. Ematologia - Centro TMO Istituti Ospedalieri	Cremona	CR	Italy	26100
7	Ematologia AOU Careggi	Firenze	FI	Italy	50134
8	Ematologia Centro TMO Fondazione IRCSS Ospedale Maggiore	Milano	MI	Italy	20122
9	Ematologia e TMO Ospedale San Raffaele	Milano	MI	Italy	20132
10	Ematologia - TMO Ospedale San Gerardo	Monza	MI	Italy	20052
11	Oncoematologia e TMO Dipartimento Oncologico	Palermo	PA	Italy	90146
12	Ematologia 2 Ospedale San Giovanni Battista	Torino	TO	Italy	10126
13	Divisione Ematologia Ospedale Umberto I	Mestre	VE	Italy	30172
14	Oncologia ed Ematologia Oncologica Institution Regione Veneto, ULSS n.13 - Presidi Ospedalieri di Noale, Mirano, Dolo	Noale	VE	Italy	30033
15	Ematologia Ospedale San Bortolo	Vicenza	VI	Italy	36100