Safety and Efficacy of Intrathecal Liposome-Encapsulated Cytarabine for Central Nervous System (CNS) Prophylaxis in Adult Patients with Burkitt and Atypical Burkitt Lymphoma Treated with the R-CODOX-M/R-IVAC (Magrath) Regimen: Results of a Phase II Study.

Intrathecal (IT) chemotherapy is an integral component of treatment for Burkitt lymphoma (BL), together with intensive systemic chemotherapy including blood brain barrier crossing agents such as high dose cytarabine (Ara-C) and methotrexate (MTX). However, the optimal IT treatment is yet to be established. Since cytotoxic concentrations of conventional IT agents (Ara-C and MTX), are maintained in the cerebrospinal fluid (CSF) for only a few hours, repeated lumbar punctures are necessary which may turn cumbersome for patients (pts) and pose technical difficulties in some instances. The availability of a sustained-release formulation of Ara-C (liposome-encapsulated Ara-C; Depocyte®) may offer the opportunity of reducing the total number of IT administrations by maintaining/enhancing, the efficacy of CNS prophylaxis. In this regard, a single 50 mg IT injection of Depocyte is able to achieve cytoxic concentrations of free-Ara-C in the CSF for 10-14 days. We report the results of a prospective phase II study aimed at evaluating the safety/activity profile of IT Depocyte in pts with BL and atypical (a)BL.

The study was designed to assess, in untreated pts with BL and aBL, the safety and feasibility of a 50% reduction (from 8 to 4) of the number of IT injections required by substituting IT Ara-C (4 doses) and MTX (4 doses) with 4 administrations (50 mg) of IT Depocyte. IT injections were planned on days (d) 1 or 2 of each rituximab (R)-CODOX-M courses and on d 8 of each R-IVAC course. Pts with aBL received 2 additional R-CODOX courses without any further IT therapy. Primary study endpoints were safety, Depocyte-related extra-hematologic adverse events ≥G3, and CNS failure, i.e. progression/relapse at leptomeningeal and/or parenchymal sites; secondary endpoints included event- and disease-free survival (EFS, DFS).

A total of 30 HIV negative pts (15 BL and 15 aBL) were enrolled and treated with a dose-modified Magrath regimen (Lacasce, 2004). The median age of pts (M/F: 22/8) was 53 years (r, 25-78), 10 pts (33%) were considered as a low risk (LR) category by displaying ≥ 3 of the following factors: normal LDH, WHO PS 0-1, Ann Arbor stage I-II, and ≤ 1 extra nodal sites. All remaining cases (67%) were considered as high-risk (HR). At diagnosis, 3 pts (10%) had a positive CSF for lymphoma, 6 (20%) had bone marrow involvement and 12 (40%) bulky (>10 cm) disease. Each pt received a median of 4 (r, 1-6) IT injections of Depocyte at the a median day of 0.5 (r, -1 to 1) for R-CODOX-M1 (course1), 4.0 (r, -2 to 17) for R-IVAC1 (course 2), 1 (r, -1 to 1) for R-CODOX-M2 (course 3) and 6.5 (r, -3 to 14) for R-IVAC2 (course 4). On a total of 111 applications, the following IT injection-related adverse events (NCI-CTCAE v 3.0) of G1-G2 severity were recorded (pts experiencing toxicity): headache 26.6%, nausea 6.6%, vomiting 3.3%, fever 10%, lumbar pain 10%, fatigue 26.6%, somnolence 6.6% and sinus bradycardia 3.3%. A G3 headache episode, accompanied by a transient loss in visual acuity, led to refusal of further IT Depocyte by a single pt. At 51 mo.s, the EFS was 70% with a DFS of 90% at a median observation of 24 mo.s (r, 1-49). Among the 27 complete responders, no isolated leptomeningeal relapses occurred. In particular, none of the 3 responders with CSF involvement at presentation, displayed any form of CNS progression (leptomenigeal and/or parenchymal). In contrast, a parenchymal CNS involvement, with a negative CSF, was observed, at 4.0 mo.s, as a part of the systemic progression in a single pt (3.3%) with chemorefractory aBL. This pt presented with unfavorable features (hi-LDH, stage IVB, PS 2, bulky retroperitoneal adenopathy and 4 extra nodal sites including liver, pancreas, kidney and spleen) and skipped both the first IT and systemic MTX administrations.

Within the limits of a single arm study, our results show that substitution of 8 IT injections (Ara-C/MTX) with 4 IT administrations of Depocyte within the R-CODOX-M/IVAC regimen is feasible and devoid of severe and/or life-threatening/invalidating neurotoxicity. The CNS progression/recurrence rate was at least super imposable to historical results (CNS relapse rate: 6% to 11%) achieved by the Magrath regimen including double-agent IT treatment. Based on these results, it appears that Depocyte can be safely incorporated into the Magrath regimen to provide adequate single-agent CNS prophylaxis with a reduced burden of IT applications.

Off Label Use: Liposome-encapsulated Ara-C for CNS prophylaxis. Vitolo:Mundipharma: Lecture fees. Pinto:Mundipharma: Lecture fees.