Treatment of Adult ALL With an MRD-directed Programme.

Acute Lymphoblastic Leukemia Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00358072
• Other study ID #: NILG-ALL 09/00
• Status: Completed
• Phase: Phase 2
• First received: July 26, 2006
• Last updated: December 28, 2010
• Start date: May 2000
• Est. completion date: September 2008

Study information

• Verified date: December 2010
• Source: Northern Italy Leukemia Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: Ministry of Health
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 280
• Est. completion date: September 2008
• Est. primary completion date: December 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years to 65 Years

Eligibility

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

Study Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia, Lymphoid
• Neoplasm, Residual
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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)

Locations

Country	Name	City	State
Italy	Ospedali Riuniti di Bergamo	Bergamo	BG
Italy	Divisione di Ematologia e TMO Ospedale San Maurizio	Bolzano	BZ
Italy	Divisione Ematologia Spedali Civili	Brescia	BS
Italy	U.O. Ematologia e Centro TMO Ospedale Armando Businco	Cagliari	CA
Italy	U.S. Ematologia - Centro TMO Istituti Ospedalieri	Cremona	CR
Italy	Ematologia Azienda Ospedaliera S.Croce e Carle	Cuneo	CN
Italy	Ematologia AOU Careggi	Firenze	FI
Italy	Divisione Ematologia Ospedale Umberto I	Mestre	VE
Italy	Ematologia Centro TMO Fondazione IRCSS Ospedale Maggiore	Milano	MI
Italy	Ematologia e TMO Ospedale San Raffaele	Milano	MI
Italy	Ematologia - TMO Ospedale San Gerardo	Monza	MI
Italy	Oncologia ed Ematologia Oncologica Institution Regione Veneto, ULSS n.13 - Presidi Ospedalieri di Noale, Mirano, Dolo	Noale	VE
Italy	Oncoematologia e TMO Dipartimento Oncologico	Palermo	PA
Italy	Ematologia 2 Ospedale San Giovanni Battista	Torino	TO
Italy	Ematologia Ospedale San Bortolo	Vicenza	VI

Sponsors (2)

Lead Sponsor	Collaborator
Northern Italy Leukemia Group	Associazione Italiana per la Ricerca sul Cancro

Country where clinical trial is conducted

Italy, 

References & Publications (3)

Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, Lambertenghi-Deliliers G, Mannelli F, Levis A, Ciceri F, Mattei D, Borlenghi E, Terruzzi E, Borghero C, Romani C, Spinelli O, Tosi M, Oldani E, Intermesoli T, Rambaldi A. Chemotherapy-ph — View Citation

Bassan R, Spinelli O, Oldani e et al. Minimal residual disease (MRD) and risk-oriented therapy in adult acute lymhoblastic leukemia (ALL). Blood (ASH Annual Meeting Abstract) 106: abstract 1836, 2005.

Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B, Rossi G, Borlenghi E, Pogliani EM, Terruzzi E, Fabris P, Cassibba V, Lambertenghi-Deliliers G, Cortelezzi A, Bosi A, Gianfaldoni G, Ciceri F, Bernardi M, Gallamini A, Mattei D, Di Bona E, Ro — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease-free survival at 5 years		5 year from date of complete remission	No
Secondary	Complete remission		4 or 8 weeks from date of therapy start	No
Secondary	Overall survival		5 years from date of diagnosis	No
Secondary	Cumulative incidence of relpase		5 years from date of complete remission	No
Secondary	Remissional deaths		4 weeks from date of therapy start	Yes
Secondary	Nonlethal toxicity		5 years from date of therapy start	Yes