Liposomal Cytarabine for Central Nervous System (CNS) Relapse in Acute Promyelocytic Leukemia (APL).
Authors: Castagnola Carlo , Lunghi M. , Calatroni S. , Lazzarino M. 
Published: October 2019

Abstract
CNS relapse occurs in ~5% of cases of APL. Conventional treatment includes intrathecal (IT) chemotherapy with methotrexate (MTX) and/or cytarabine, systemic salvage chemotherapy, and sometimes cranial irradiation: survival is poor, ranging from weeks to a few months. Liposomal cytarabine (DepoCyte®) is a novel sustained-release formulation with a terminal half-life ~40 × longer than free cytarabine (Bleyer et al. Clin Cancer Res 99;5:3349) and is approved for the treatment of adults with lymphomatous meningitis (LM): liposomal cytarabinbe has been shown to be more effective than free cytarabine in patients with LM (Glantz et al. JCO1999;17:3110). Intrathecal (IT) injections of this agent are given once every 2 weeks during treatment, as opposed to 2–3 × per week for free cytarabine or MTX, and an Ommaya reservoir is not required. In this report we present the case of a patient with CNS relapse of APL, refractory to conventional treatment including chemotherapy with high-dose (HD) cytarabine plus idarubicin, IT MTX, and cranial irradiation, who has been treated successfully with liposomal cytarabine.In July 2003, a 33-year-old woman was admitted with low-risk APL (hypergranular leukemic promyelocytes). Blood counts showed: Hb 5.3 g/dL, leukocytes 9.3 ×109/L, platelets 53 ×109/L. Cytogenetics showed t(15;17) and RT-PCR was positive for PML/RARα (bcr1 isoform). The patient achieved a hematological remission after induction and a molecular remission after consolidation using the AIDA protocol (Mandelli et al. Blood1997;90:1014). Molecular relapse during maintenance was treated with idarubicin plus ATRA resulting in a second molecular remission. In June 05, autologous peripheral blood stem cell transplant (PML/RARα-negative) was performed during molecular remission. Following a third molecular relapse in September 2005, with headache, APL cells and PML/RARα transcript were identified in the cerebrospinal fluid (CSF). Prolonged cytopenia characterized by fever and possible fungal pneumonia followed IT MTX, HD cytarabine plus idarubicin and cranial radiation, which induced a bone marrow molecular remission, but CSF showed persistence of APL cells, confirmed by PML/RARα. In November, the patient was treated with IT liposomal cytarabine 50 mg every 2 weeks with concomitant dexamethasone. CSF was obtained before each IT treatment: 14 days after the first treatment, no APL cells or PML/RARα transcript were found in CSF. Unfortunately, despite the use of dexamethasone, after the third IT injection, arachnoiditis developed, with headache, pain, confusion, somnolence and agitation. Arachnoiditis can be caused by meningeal infiltration by tumor cells, cranial irradiation and IT administration of drugs: it is difficult to distinguish between these causes. HD steroid was started, and the patient recovered after a few days. The patient remains in CNS remission, but suffered a bone marrow relapse in May 2006, which was treated with chemotherapy. In this patient, IT liposomal cytarabine resulted in a prolonged remission of CNS disease. Unfortunately, treatment of her systemic disease proved less successful.