Clinical trial NCT00358072: 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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Keywords: Acute lymphoblastic leukemia
Adult patients
Minimal residual disease
Risk-oriented therapy
Lead sponsor: Northern Italy Leukemia Group
Sponsor class: OTHER
Collaborators: name: Associazione Italiana per la Ricerca sul Cancro
First posted: 2006-07-28
Enrollment: 280
Sex: ALL
Minimum age (years): 15
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Disease-free survival at 5 years
timeFrame: 5 year from date of complete remission
Secondary outcomes:
measure: Complete remission
timeFrame: 4 or 8 weeks from date of therapy start
measure: Overall survival
timeFrame: 5 years from date of diagnosis
measure: Cumulative incidence of relpase
timeFrame: 5 years from date of complete remission
measure: Remissional deaths
timeFrame: 4 weeks from date of therapy start
measure: Nonlethal toxicity
timeFrame: 5 years from date of therapy start
Other outcomes:
Locations:
city: Bergamo
country: Italy
facility: Ospedali Riuniti di Bergamo
state: BG
city: Brescia
country: Italy
facility: Divisione Ematologia Spedali Civili
state: BS
city: Bolzano
country: Italy
facility: Divisione di Ematologia e TMO Ospedale San Maurizio
state: BZ
city: Cagliari
country: Italy
facility: U.O. Ematologia e Centro TMO Ospedale Armando Businco
state: CA
city: Cuneo
country: Italy
facility: Ematologia Azienda Ospedaliera S.Croce e Carle
state: CN
city: Cremona
country: Italy
facility: U.S. Ematologia - Centro TMO Istituti Ospedalieri
state: CR
city: Firenze
country: Italy
facility: Ematologia AOU Careggi
state: FI
city: Milano
country: Italy
facility: Ematologia Centro TMO Fondazione IRCSS Ospedale Maggiore
state: MI
city: Milano
country: Italy
facility: Ematologia e TMO Ospedale San Raffaele
state: MI
city: Monza
country: Italy
facility: Ematologia - TMO Ospedale San Gerardo
state: MI
city: Palermo
country: Italy
facility: Oncoematologia e TMO Dipartimento Oncologico
state: PA
city: Torino
country: Italy
facility: Ematologia 2 Ospedale San Giovanni Battista
state: TO
city: Mestre
country: Italy
facility: Divisione Ematologia Ospedale Umberto I
state: VE
city: Noale
country: Italy
facility: Oncologia ed Ematologia Oncologica Institution Regione Veneto, ULSS n.13 - Presidi Ospedalieri di Noale, Mirano, Dolo
state: VE
city: Vicenza
country: Italy
facility: Ematologia Ospedale San Bortolo
state: VI
Study officials:
affiliation: Azienda Ospedaliera Ospedali Riuniti di Bergamo
name: Bassan Renato, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
citation: 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.
citation: 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.