Intrathecal DepoCyte and Lineage-targeted Minimal Residual Disease-oriented Therapy of Acute Lymphoblastic Leukemia

NCT ID: NCT00795756

Last Updated: 2014-10-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 145 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-01-31
• Study Completion Date: 2013-10-31

Brief Summary

The aim of this clinical study in adult ALL is to compare by risk category (1) the feasibility of two different CNS prophylaxis regimens and (2) the overall disease-free survival in relation to the achievement of an early MRD negative status and following consolidation with lineage-targeted methotrexate infusions and other disease-specific therapeutic elements, with or without the application of allogeneic or autologous SCT depending on risk class and MRD study results.

In this multicentric prospective pilot randomized phase II trial on CNS prophylaxis, all patients receive induction/consolidation therapy incorporating lineage-targeted high-dose methotrexate plus other drugs (with additional imatinib in Ph/BCR-ABL+ ALL), for the achievement of an early negative MRD status. The MRD study supports a risk/MRD-oriented final consolidation phase.

Detailed Description

A) Risk Classification

Newly diagnosed patients are hierarchically clustered into very high, high and standard risk cases (VHR, HR, SR) using international risk criteria modified according to NILG:

A1) VHR (any criterium): B-precursor: WBC count >100x109/L; adverse cytogenetics/molecular biology such as t(9;22)/BCR-ABL, t(4;11)/MLL rearrangement at 11q23, +8, -7, del6q, t(8;14), low hypodiploidy with 30-39 chromosomes, near triploidy with 60-78 chromosomes, complex with >5 unrelated anomalies. T-precursor: WBC count >100x109/L; early/late non-cortical immunophenotype (CD1a-); adverse cytogenetics/molecular biology (as above).

A2) HR (any criterium, VHR excluded): B-precursor: WBC count >30x109/L; pro-B immunophenotype; complete remission after cycle 2. T-precursor: complete remission after cycle 2.

A3) SR (all criteria, VHR/HR excluded): B-precursor: WBC count <30x109/L; T-precursor: WBC count <100x109/L; cortical immunophenotype (CD1a+).

B) CNS Prophylaxis Stratification before randomisation

1. by immunophenotype, i.e. B-precursor vs. T-precursor

2. by risk class, i.e. SR vs. non-SR (using only known factors) Randomisation: intrathecal (IT) CNS prophylaxis with standard triple therapy (TIT, 12 total injections) vs. DepoCyte (6-8 total injections by disease subset). Cranial irradiation is omitted in both arms, and all patients receive the same chemotherapy program including CNS-crossing agents.

C)Induction/Early Consolidation and MRD Study

Randomised patients receive homogeneous induction/early consolidation chemotherapy, including subset-specific elements for B-precursor ALL (3x targeted-infusion methotrexate 2.5 g/m2), T-precursor ALL (3x targeted-infusion methotrexate 5 g/m2), age >55 years (methotrexate reduced to 1.5 g/m2), Ph/BCR-ABL+ ALL (imatinib, reduced-intensity chemotherapy), radiation therapy (LL). Patients not in CR after cycles 1-2 are off study. For CR evaluation bone marrow is checked on days 28 and/or 56. Consolidation cycles are administered at 21-28 day intervals Concurrent MRD analysis is performed at four timepoints (weeks 4, 10, 16 and 22 of induction/consolidation), to optimize risk classification and support risk/MRD-oriented therapy:

C1) MRD negative (M-NEG): negative MRD study (<10-4 at timepoints #2 and #3, and negative at timepoint #4) C2) MRD positive (M-POS): positive MRD study (>10-4 at timepoints #2 or #3, or positive at timepoint #4)

D)MRD/Risk-Oriented Final Therapy D1) VHR patients are candidate to an early allogeneic SCT (related/unrelated donor/cord blood; ablative/non-ablative conditioning according to current protocols/guidelines) after CR, regardless MRD study results.

D2) M-POS as well as HR patients with unknown MRD are allocated to allogeneic SCT after MRD timepoint 2 (M-POS >10-4) or MRD timepoint 4 (others). When an allogeneic SCT is not possible, patients complete consolidation and receive autologous-type SCT followed by maintenance.

D3) M-NEG as well as SR patients with unknown MRD are allocated to maintenance therapy.

Age-limited therapeutic procedures: Patients aged >55 years are treated with age-adapted therapy, and when indicated will be included in SCT programs whenever possible and according to performance status and comorbidity.

Conditions

Acute Lymphoblastic Leukemia

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intrathecal DepoCyte

I.t. DepoCyte 50 mg admninistered x6-8 (depending on immunophenotypic disease subset) during induction/consolidation/eraly maintenance phases

Group Type: EXPERIMENTAL

liposome-encapsulated cytarabine (DepoCyte)

Intervention Type: DRUG

DepoCyte 50 mg injected intrathecally x6-8 (6: B-lineage, 8: T-lineage) during induction/consolidation phases

Triple intrathecal therapy (TIT)

Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg injected intrathecally x12 during indiction/consolidation phases

Group Type: ACTIVE_COMPARATOR

Triple intrathecal therapy (TIT)

Intervention Type: DRUG

Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg. injected intrathecally x12 during induction/consolidation therapy

Interventions

liposome-encapsulated cytarabine (DepoCyte)

DepoCyte 50 mg injected intrathecally x6-8 (6: B-lineage, 8: T-lineage) during induction/consolidation phases

Intervention Type: DRUG

Triple intrathecal therapy (TIT)

Methotrexate 12,5 mg + Cytarabine 50 mg + Prednisolone 40 mg. injected intrathecally x12 during induction/consolidation therapy

Intervention Type: DRUG

Other Intervention Names

DepoCyte; DepoCyt; Methotrexate; Cytosine arabinoside; Cytosar

Eligibility Criteria

Inclusion Criteria

• Age 18-65 years.
• Diagnosis of untreated ALL with B-/T-precursor phenotype or B-cell lymphoblastic lymphoma (B-LL), either de novo or secondary to chemo-radiotherapy for other cancer.
• Full cytological, cytochemical, cytogenetic and immunobiological disease characterization by revised FAB, EGIL and WHO criteria.
• Bone marrow and peripheral blood sampling (ALL) or biopsy specimen (LL) for MRD study.
• ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of complications.
• Signed informed consent.

Exclusion Criteria

• Diagnosis of B-ALL (FAB L3 ALL/Burkitt's leukemia or lymphoma) and T-LL (T-cell lymphoblastic lymphoma).
• Down's syndrome.
• Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrythmias, NYHA classes III and IV), severe liver disease with serum bilirubin >3 mg/dL and/or ALT >3 x upper normal limit (unless attributable to ALL/LL), kidney function impairment with serum creatinine >2 mg/dL (unless attributable to ALL/LL), and severe neurological or psychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan.
• Known HIV positive serology.
• Other active hematological or non-hematological cancer with life expectancy <1 year.
• Pregnancy (fertile women will be advised not to become pregnant while on treatment; and male patients to adopt contraceptive methods), unless therapeutic aborption/early discharge is carried out.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northern Italy Leukemia Group

OTHER

Sponsor Role: lead

Responsible Party

DR RENATO BASSAN

Medical Doctor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Renato Bassan, MD

Role: STUDY_CHAIR

USC Ematologia, Ospedali Riuniti, Bergamo (Italy)

Locations

USC Ematologia, Ospedale Civile

Alessandria, (al), Italy

USC Ematologia, Ospedali Riuniti

Bergamo, (bg), Italy

Divisione di Ematologia - Spedali Civili

Brescia, (bs), Italy

Divisione di Ematologia e TMO, Ospedale San Maurizio

Bolzano, (bz), Italy

Ematologia e centro TMO - Ospedale Armando Businco

Cagliari, (ca), Italy

S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle

Cuneo, (cn), Italy

Ematologia e centro TMO, Istituti Ospedalieri

Cremona, (cr), Italy

Ematologia - AOU Careggi

Florence, (fi), Italy

Ematologia e centro TMO - IRCSS Mangiagalli Regina Elena

Milan, (mi), Italy

Ematologia e centro TMO, Ospedale San Raffaele

Milan, (mi), Italy

Ematologia e centro TMO, Ospedale San Gerardo

Monza, (mi), Italy

Oncoematologia e TMO - Dipartimento Oncologico La Maddalena

Palermo, (pa), Italy

Ematologia 2 - Ospedale San Giovanni Battista

Torino, (to), Italy

Medicina Interna I - Ospedale di Circolo

Varese, (va), Italy

Onco-Ematologia - Ospedale Civile

Noale, (ve), Italy

Ematologia - Ospedale San Bortolo

Vicenza, (vi), Italy

Countries

Italy

References

Bassan R, Masciulli A, Intermesoli T, Audisio E, Rossi G, Pogliani EM, Cassibba V, Mattei D, Romani C, Cortelezzi A, Corti C, Scattolin AM, Spinelli O, Tosi M, Parolini M, Marmont F, Borlenghi E, Fumagalli M, Cortelazzo S, Gallamini A, Marfisi RM, Oldani E, Rambaldi A. Randomized trial of radiation-free central nervous system prophylaxis comparing intrathecal triple therapy with liposomal cytarabine in acute lymphoblastic leukemia. Haematologica. 2015 Jun;100(6):786-93. doi: 10.3324/haematol.2014.123273. Epub 2015 Mar 6.

Reference Type: DERIVED

PMID: 25749825 (View on PubMed)

Related Links

https://heart.negrisud.it/ALL/login.php?pleaselogin

Web site of NILG-ALL 10/07 protocol. Accessible to study participants only.

Other Identifiers

NILG-ALL 10/07

Identifier Type: -

Identifier Source: org_study_id