Clinical trial NCT00795756: Intrathecal DepoCyte and Lineage-targeted Minimal Residual Disease-oriented Therapy of Acute Lymphoblastic Leukemia
Official title: A Randomized Study on CNS Prophylaxis With Liposome-Encapsulated Cytarabine in Association With a Lineage-Targeted and MRD-Oriented Postremission Strategy in Adult ALL
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Acute Lymphoblastic Leukemia
Keywords: Adults
Central nervous system prophylaxis
Minimal residual disease
Lead sponsor: Northern Italy Leukemia Group
Sponsor class: OTHER
First posted: 2008-11-21
Enrollment: 145
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Comparative analysis of feasibility/toxicity of IT DepoCyte vs. TIT
timeFrame: weeks 5, 11, 17 and 23
Secondary outcomes:
measure: Comparative analysis of isolated and combined CNS recurrence following TIT vs DepoCyte prophylaxis
timeFrame: During study follow-up
measure: Complete remission (CR)
timeFrame: After study chemotherapy cycles 1 and 2
measure: Bone marrow MRD negativity rates
timeFrame: Four time-points at weeks 4-22
measure: Lenght of remission
timeFrame: Study follow-up
measure: Overall survival
timeFrame: Study follow-up
Other outcomes:
Locations:
city: Alessandria
country: Italy
facility: USC Ematologia, Ospedale Civile
state: (al)
city: Bergamo
country: Italy
facility: USC Ematologia, Ospedali Riuniti
state: (bg)
city: Brescia
country: Italy
facility: Divisione di 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: Ematologia e centro TMO - Ospedale Armando Businco
state: (ca)
city: Cuneo
country: Italy
facility: S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
state: (cn)
city: Cremona
country: Italy
facility: Ematologia e centro TMO, Istituti Ospedalieri
state: (cr)
city: Firenze
country: Italy
facility: Ematologia - AOU Careggi
state: (fi)
city: Milano
country: Italy
facility: Ematologia e centro TMO - IRCSS Mangiagalli Regina Elena
state: (mi)
city: Milano
country: Italy
facility: Ematologia e centro TMO, Ospedale San Raffaele
state: (mi)
city: Monza
country: Italy
facility: Ematologia e centro TMO, Ospedale San Gerardo
state: (mi)
city: Palermo
country: Italy
facility: Oncoematologia e TMO - Dipartimento Oncologico La Maddalena
state: (pa)
city: Torino
country: Italy
facility: Ematologia 2 - Ospedale San Giovanni Battista
state: (to)
city: Varese
country: Italy
facility: Medicina Interna I - Ospedale di Circolo
state: (va)
city: Noale
country: Italy
facility: Onco-Ematologia - Ospedale Civile
state: (ve)
city: Vicenza
country: Italy
facility: Ematologia - Ospedale San Bortolo
state: (vi)
Study officials:
affiliation: USC Ematologia, Ospedali Riuniti, Bergamo (Italy)
name: Renato Bassan, MD
role: STUDY_CHAIR
References:
citation: 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.