Treatment of Adult ALL With an MRD-directed Programme.

• ClinicalTrials.gov Identifier: NCT00358072
• Recruitment Status: Completed
• First Posted: July 28, 2006
• Last Update Posted: December 29, 2010
• Sponsor: Northern Italy Leukemia Group
• Collaborator: Associazione Italiana per la Ricerca sul Cancro
• Information provided by: Northern Italy Leukemia Group

Tracking Information

• First Submitted Date: July 26, 2006
• First Posted Date: July 28, 2006
• Last Update Posted Date: December 29, 2010
• Study Start Date: May 2000
• Actual Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: December 28, 2010): Disease-free survival at 5 years [ Time Frame: 5 year from date of complete remission ]
• Original Primary Outcome Measures (submitted: July 26, 2006): Disease-free survival at 5 years

Current Secondary Outcome Measures (submitted: December 28, 2010)

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

Original Secondary Outcome Measures (submitted: July 26, 2006)

• Complete remission
• Overall survival
• Cumulative incidence of relpase
• Remissional deaths
• Nonlethal toxicity

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Treatment of Adult ALL With an MRD-directed Programme.
• 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.

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.

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Lymphoblastic Leukemia

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)

Other Name: MRD-guided therapy

Study Arms

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)

Intervention: Behavioral: Postremission consolidation based on MRD status

Publications *

• 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, Romani C, Scattolin AM, Barbui T, Rambaldi A. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood. 2009 Apr 30;113(18):4153-62. doi: 10.1182/blood-2008-11-185132. Epub 2009 Jan 13.
• 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-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010 Aug 1;28(22):3644-52. doi: 10.1200/JCO.2010.28.1287. Epub 2010 Jul 6.
• Mannelli F, Gianfaldoni G, Intermesoli T, Cattaneo C, Borlenghi E, Cortelazzo S, Cavattoni I, Pogliani EM, Fumagalli M, Angelucci E, Romani C, Ciceri F, Corti C, Scattolin A, Cortelezzi A, Mattei D, Audisio E, Spinelli O, Oldani E, Bosi A, Rambaldi A, Bassan R. CD20 expression has no prognostic role in Philadelphia-negative B-precursor acute lymphoblastic leukemia: new insights from the molecular study of minimal residual disease. Haematologica. 2012 Apr;97(4):568-71. doi: 10.3324/haematol.2011.054064. Epub 2011 Nov 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 28, 2010): 280
• Original Enrollment (submitted: July 26, 2006): 250
• Actual Study Completion Date: September 2008
• Actual Primary Completion Date: December 2006 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years to 65 Years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT00358072
• Other Study ID Numbers: NILG-ALL 09/00
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Renato Bassan, MD, Ospedali Riuniti, Div. Ematologia, Bergamo, Italy
• Study Sponsor: Northern Italy Leukemia Group
• Collaborators: Associazione Italiana per la Ricerca sul Cancro

Investigators

• Principal Investigator: Bassan Renato, MD; Azienda Ospedaliera Ospedali Riuniti di Bergamo

• PRS Account: Northern Italy Leukemia Group
• Verification Date: December 2010