Phase II Randomized Trial Of Radiation-Free Central Nervous System (CNS) Prophylaxis Comparing Intrathecal Triple Therapy With Liposomal Cytarabine (DepoCyte^®) In Adult Acute Lymphoblastic Leukemia (ALL)

Since the landmark study of Omura et al. (Blood 1980;55:199), validating cranial irradiation as an adjunct to intrathecal (IT) methotrexate, no other randomized trial of CNS prophylaxis was performed in adult ALL. Although the risk of CNS relapse is now only 1-4%, irradiation contributes to cumulative CNS toxicity together with high-dose methotrexate/cytarabine (HD-M/A), or is logistically difficult, so that developing an effective radiation-free CNS prophylaxis remains an important clinical task. IT DepoCyte^® (ITD) might be advantageous, the slow release of liposome-associated cytarabine allowing therapeutic concentrations in the cerebrospinal fluid for 14+ days. An open trial reported prohibitive CNS toxicity from ITD in 6/31 patients (Jabbour et al. Blood 2007;109:3214), but ITD to ITD and HD-M/A to ITD intervals were short (14 and 10 days, respectively) and no patient suffered from CNS relapse.

In a phase II randomized trial (ClinicalTrials.gov NCT-00795756) we evaluated toxicity and feasibility (as primary study endpoint) of ITD 50 mg in comparison with IT triple therapy (ITT: methotrexate 12,5 mg, cytarabine 50 mg, prednisone 40 mg). Stratification was by cell lineage and risk class. ITT was given on d1 of courses 1,2,4,6,8; d15 of courses 1,2,8; and d1 of maintenance cycles 2-5 (12x). ITD was given on d1 of courses 1,2,4,6,8; d15 of courses 1,8 (T-ALL only); and d1 of maintenance cycle 2 (6-8x). The shortest ITD to ITD interval was 14 days in T-ALL (courses 1-2 [3x] and 8 [2x]), otherwise it was 21 days between ITD and any prior/subsequent ITD and HD course. ALL therapy consisted of eight induction-consolidation courses followed by risk/minimal residual disease-oriented maintenance or stem cell transplantation (SCT). In HD courses 3,7 (M/A) and 5 (M/Asparaginase) M dosage was 2.5 g/m² (Ph- B-ALL) and 5 g/m² (T-ALL) up to 55 years, and A 2 g/m². Imatinib was used with de-intensified chemotherapy in Ph+ ALL; selected high-risk subsets received early SCT.

Between 2007-12 201 total patients were enrolled and 141 randomized to ITT (n=73) or ITD (n=68). Median age was 42 years (range 18-68) and risk subsets (ITT/ITD) were SR-B 27.4%/29.4%; HR-B Ph- 26%/25%, Ph+ 23.3%/22.1%, SR-T 5.5%/5.9%, HR-T 17.8%/17.7%. Complete remission was 89% (n=65)/89.7% (n=61). Rates of actual v planned IT injections during induction-consolidation cycles 1-8, after removal of study losses (resistance, early death, SCT, toxicity and relapse), were ITT 374/415 (90.1%) v ITD 219/245 (89.3%) (P=0.76). Although toxicity/medical reasons caused 5 ITD patients to discontinue permanently the study v none in ITT arm (P=0.02), toxicity-driven omissions of IT therapy were marginally increased in ITD arm (29/415 [6.9%] v 24/245 [9.8%]; P=0.20). Neurologic toxicity occurred in 20 (27.4%) ITT v 36 (53%) ITD patients, respectively (P=0.002). According to NCI CTC grading (G), neurotoxicity episodes were GI 7 v 10 (P=0.36), GII 13 v 32 (P=0.003), GIII 4 v 12 (P=0.04), GIV 1 v 5 (P=0.12). GIII-IV neurotoxicity developed in 5/73 (6.8%) ITT patients v 10/52 (19.2%) and 5/16 (31.2%) B- and T-ALL ITD patients, respectively (P= 0.01), correlating in T-ALL with the second/third q14d ITD at courses 1,2,8 (4/5 patients, 5/6 episodes). Apart from reversible headache/radicular pain, the most serious toxicity occurred in 3 (4.1%) ITT patients (seizures 1; leukoencephalopathy 1; loss of consciousness 1) v 5 (7.3%) ITD patients (loss of consciousness 4, 1 with seizures; cerebral oedema/pseudotumor cerebri 1) (P=0.48). Four-year overall and disease-free survival were 54% and 52.2% v 58.9% and 47.7% in ITT and ITD arms, respectively, and relapse rate was 32.3% v 24.6% (all P=NS). In ITT arm there were 2 (3%) CNS and 2 (3%) combined CNS/marrow relapses. In ITD arm only one poorly compliant subject not given any HD course had an isolated CNS relapse (1.6%); no other patient had a CNS recurrence.

A radiation-free CNS prophylaxis with six spaced ITD in conjunction with HD-M/A may be feasible and at least as effective as other regimens. Excluding reversible headache/radiculitis, serious CNS toxicity was not significantly increased compared with ITT regimen, although some patients were forced to discontinue IT prophylaxis. The occasionally severe CNS toxicity prompts the investigation of a lower ITD dosage (25 mg), also to limit GI-II side effects, and the tighter schedule used in T-ALL should be abandoned because too toxic.

Bassan:Mundipharma Oncology; Sigma-Tau; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: Liposome-encapsulated cytarabine (DepoCyte®) used in a prospective phase II randomized trial of CNS prophylaxis in ALL. Masciulli:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo Osseo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Gallamini:Millenium: Consultancy. Marfisi:Novartis: Research Funding; Ospedali Riuniti di Bergamo: Research Funding; AIFA (Italian Regulatory Agency: Research Funding; AMGEN S.p.A.: Research Funding; Genzyme Olanda: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Università Cattolica del Sacro Cuore-Roma: Research Funding; Università degli Studi di Firenze: Research Funding; Sigma-Tau: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Celgene: Research Funding; Associazione Italiana Linfomi (AIL): Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding. Marchioli:Associazione Italiana Linfomi (AIL): Research Funding; Celgene: Research Funding; Myeloproliferative disorder Research Consortium: Research Funding; Sigma-Tau: Research Funding; Università Cattolica del Sacro Cuore, Roma: Research Funding; Pierre Fabre Italia S.p.A.: Research Funding; Gruppo Italiano Trapianti di Midollo (GITMO): Research Funding; Genzyme Olanda: Research Funding; AMGEN S.p.A.: Research Funding; AIFA (Italian Regulatory Agency): Research Funding; Ospedali Riuniti di Bergamo: Research Funding; Novartis: Research Funding; Fondazione Italiana Linfomi (FIL): Research Funding; LaRoche: Research Funding; Università degli Studi di Firenze: Research Funding. Rambaldi:Italfarmaco: Honoraria; Sanofi: Honoraria; Novartis: Honoraria.