Abstract

Background: CNS involvement in acute lymphoblastic leukemia/AUL is a well-recognized event and CNS prophylaxis is considered mandatory. In NHL, meningeal relapse occurs more rarely, ranging from 4–14% depending on histology, anatomical location and biological parameters. Flow cytometric analysis of cerebrospinal fluid (CSF), however, detected occult lymphomatous meningitis in 22% of NHL cases at risk at diagnosis (

Hegde et al.
Blood
2005
;
105
:
496
). CNS prophylaxis is currently recommended only in high-risk disease (stage IV/high IPI score) and in patients with extranodal NHL. Sustained-release liposomal cytarabine (DepoCyte®), which is licensed for meningeal relapse in NHL, has proved effective in treating lymphomatous and leukemic meningitis (
Glantz et al.
J Clin Oncol
1999
;
17
:
3110
;
Sancho et al.
Haematologica
2006
;
91
:
ECR02
). Intrathecal (IT) liposomal cytarabine is distributed throughout the CSF and has an extended half-life, allowing administration once every 2–4 weeks (
Chamberlain et al.
Arch Neurol
1995
;
52
:
912
). We therefore tested the efficacy of liposomal cytarabine in CNS prophylaxis for elderly patients with aggressive NHL or AUL, with the aim of testing the safety of IT treatment in elderly patients and the efficacy of liposomal cytarabine in preventing lymphoma/leukemia CNS relapse.

Methods: From June to November 2005, 4 patients > 70 years of age entered the study. Diagnoses were: 2 stage IV, IPI 3, diffuse large B-cell lymphoma (DLBCL); 1 mantle cell lymphoma (MCL), and 1 AUL; 2 patients had extranodal bulky disease (1 psoas muscle, 1 retro-orbital plus paranasal sinus involvement). As first-line treatment, the 3 NHL cases were given R-CHOP every 21 days for 6 cycles. The patient with AUL received conventional 3-drug induction (vincristine/idarubicine/prednisone) every week for 3 weeks, followed by 3 courses of L-VAMP (vincristine/cytarabine/intermediate-dose methotrexate/leucovorin rescue) and then conventional maintenance (6-mercaptopurine/methotrexate and monthly re-induction with vincristine/prednisone). All patients received CNS prophylaxis with IT liposomal cytarabine 50 mg followed by systemic steroid injection. In NHL cases, IT therapy was given the day before systemic chemotherapy for a total of 4 administrations; in AUL, prophylaxis was given every 4 weeks during induction and maintenance for a total of 6 doses.

Results: Three (2 NHL and 1 AUL) patients achieved a complete response (CR) and 1 (NHL) achieved a partial response, with response durations of 4, 5, 6+ and 8+ months, respectively. As of July 2006, after a median follow-up of 10 months (range 9–12), all patients were alive; 2 (1 DLBCL, 1 AUL) were in continuous CR, and 2 (1 DLBCL, 1 MCL) had progressive disease and were receiving second-line treatment. Isolated relapse of leukemia/lymphoma in the CNS was not seen. Liposomal cytarabine was well tolerated; no drug-related side effects or hematological toxicities were recorded.

Conclusions: As occult CNS involvement has been shown to occur in >20% of newly diagnosed patients with high-risk NHL, flow cytometry and cytospin analysis of CSF at diagnosis should be implemented in order to adequately target CNS prophylaxis. Liposomal cytarabine should be the drug of choice for CNS prophylaxis, particularly in elderly patients.

Disclosure: No relevant conflicts of interest to declare.

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