Intrathecal Liposomal Cytarabine Research Articles

Rituximab Plus Dose Intense Rapid-Cycling Chemotherapy with Intrathecal CNS Prophylaxis in Patients with Burkitt Lymphoma (BL) and Intermediate Unclassifiable Diffuse Large B-Cell Lymphoma/BL: Single Institution Experience

Abstract 1631Introduction. Burkitt Lymphoma (BL) and the novel category of B-cell lymphoma, unclassifiable, with features intermediate between BL and diffuse large B-cell lymphoma (intermediate DLBCL/BL) listed in the 2008 WHO classification, are mature B-cell non-Hodgkin lymphomas. They were characterized by a high degree of proliferation with an aggressive clinical course. With the introduction of dose intense, rapid-cycling chemotherapy (Magrath 1996), mainly when supplemented with Rituximab, the prognosis of BL was improved. Conversely, the issue of intermediate DLBCL/BL treatment is still a matter of debate. On this basis, we conducted a retrospective analysis to investigate the outcome of adult patients with BL and intermediate DLBCL/BL treated in a single hematological center. Methods. We retrospectively analyzed 23 adult patients divided in two groups according to histological diagnosis treated with Rituximab plus dose intense rapid-cycling chemotherapy with intrathecal CNS prophylaxis. Group 1: 18 adult BL patients, including three with a diagnosis of L3 acute lymphoblastic leukemia, treated according to CODOX-M/IVAC regimen including Cyclophosphamide, Doxorubicin, Vincristine, Methotrexate, Ifosfamide, Etoposide and high dose Cytarabine in association with Rituximab and intrathecal liposomal Cytarabine (R-CODOX-M/IVAC). Group 2: five intermediate DLBCL/BL, treated with Rituximab intensified CHOP with intrathecal Methotrexate followed by high dose Cytarabine and Mitoxantrone and high dose chemotherapy with autologous stem cell transplantation (R-HDC plus ASCT) or with R-CODOX-M/IVAC. Results. Group 1 included 18 patients with a median age of 45 years (range 29–74), stage IV in 14 cases (78%), performance status (PS) 2 in 14 (78%), LDH upper normal value in 13 (72%), bone marrow involvement in eight (44%), B symptoms in eight (44%) and liquor positivity at citoflussimetry in one (5%). Between 2006 and 2011 all 18 patients were treated according to R-CODOX-M/IVAC. Group 2 included five patients with median age of 47 years (range 32–58), stage IV in four patients (80%), PS 2 in all patients, LDH upper normal value in four (80%) bone marrow involvement in three (60%), B symptoms in three (60%) and liquor positivity at citoflussimetry in two (50%). Between 2008 and 2011 two patients were treated with R-HDC plus ASCT while the other three patients were treated with R-CODOX-M/IVAC regimen. All 18 BL patients of group 1 were evaluable for response: 15 patients were in persistent complete remission (CR) and three died of progressive disease. With a median follow-up of 70.3 months, progression free survival and overall survival were 76.5% and 80.3%, respectively. Therapy was well tolerated, with no significant acute and late treatment related toxicities and no toxic deaths. In group 2 the two patients treated with R-HDC plus ASCT died of progressive disease; of the three patients treated with R-CODOX-M/IVAC regimen, one died of early relapse disease occurred three months after achieving CR and two are still on therapy. Conclusions. Our data suggest that in BL R-CODOX-M/IVAC is a safe and highly effective therapeutic regimen providing a high rate of persistent CR. Within the limits of a small sample size, in our experience, patients with intermediate DLBCL/BL have a clinical aggressive disease with a poor prognosis regardless of the type of treatment. Additional and larger studies are warranted to clarify the behavior of this new histological entity and develop novel and efficacy therapeutic approaches. Disclosures:Vitolo:Roche Italy: Speakers Bureau; Celgene: Speakers Bureau; Jannsen-Cilag: Speakers Bureau.

Multicenter Phase I Trial of Intraventricular Immuno-Chemotherapy in Recurrent CNS Lymphoma

Abstract 959 Background:We recently studied the safety and activity of intraventricular rituximab monotherapy in the treatment of recurrent intraocular and CNS non-Hodgkin lymphoma (NHL) (JCO 2007 25: 1350–1356). Rapid dissemination throughout the craniospinal axis was demonstrated and cytologic responses were detected in six out of ten patients. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. The major goals of this current trial are to perform the first study of intraventricular immuno-chemotherapy in humans and to evaluate the safety of two dose levels of intraventricular rituximab as well as its pharmacokinetics in combination with intraventricular methotrexate (MTX). Secondary goals are to obtain information regarding the efficacy of this approach in the treatment of patients with recurrent CNS lymphoma, (brain parenchyma, intraocular or the leptomeningeal compartment). Methods:Thirteen patients with recurrent/refractory CD20+ CNS NHL were treated at UCSF, Dana Farber Cancer Institute and Massachusetts General Hospital on a phase I clinical trial involving twice weekly intraventricular rituximab at 10 mg and 25 mg dose levels, administered over a planned four week schedule. Rituximab is combined with MTX (12 mg) during the second intraventricular injection each week. Patients achieving partial response or better were eligible for a second month of combination intraventricular rituximab plus MTX. Results:No serious treatment-related toxicity has been detected with intraventricular rituximab/MTX at the 10 mg and 25 mg dose levels. The most common treatment-related toxicity was paresthesias (grade 1). One patient exhibited NHL progression outside of the CNS at three weeks and thus was not evaluable for CNS response, and one patient exhibited stable disease. Complete cytologic responses were detected in ten out of thirteen patients at the one-month restaging. Parenchymal responses were detected in three out of six subjects with one partial response within the corpus callosum, and two complete regressions of lesions within temporal lobe and cerebral cortex. One patient with leptomeningeal lymphoma non-responsive to intravenous rituximab and refractory to high-dose intravenous and intrathecal methotrexate, oral temozolomide and intrathecal liposomal cytarabine, obtained a sustained complete response with the intraventricular rituximab/MTX protocol and subsequently was approved for consolidative autologous stem cell transplant. Two patients have participated in extended dosing on protocol without progression for five and eight months respectively. Thus far, there is no evidence for a relationship between FcGR3A polymorphism and therapeutic resistance in a preliminary analysis (n=8 patients). The maximum tolerated dose of intraventricular rituximab with this combination was established as 25 mg. The mean maximum intraventricular rituximab concentration after intraventricular injection of rituximab was 285 microgram/ml at the 10 mg dose level (N=3) and 882 microgram/ml at the 25 mg dose level (N=10); (p<0.038). The rate of Rituximab clearance from the intraventricular compartment at two hours post injection was 30% slower when administered in combination with methotrexate compared to intraventricular rituximab monotherapy (p <0.02). Conclusions:Intraventricular rituximab/MTX appears to be safe in recurrent CNS NHL. Twelve of thirteen patients completed at least one month of therapy, without any treatment-associated serious adverse events at any of the institutions. Intraventricular administration of methotrexate may significantly attenuate rituximab clearance from the leptomeningeal compartment. There is encouraging evidence for significant activity of intraventricular immuno-chemotherapy in the treatment of drug-resistant CNS NHL, refractory or non-responsive to intravenous rituximab. These results provide strong support for further investigation of this novel therapeutic approach. NCT00221325. Supported by Leukemia and Lymphoma Society and NIH Grant CA13908301. Disclosures:Off Label Use: We will discuss the off-label use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas. Advani:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Effectiveness of Intrathecal Liposomal Cytarabine in Treatment of Childhood Hematopoietic Malignancies – Experience of Polish Pediatric Leukemia/Lymphoma Study Group

Abstract 4240 Introduction:Liposomal Cytarabine for intrathecal administration is characterized by prolonged activity and better penetration to central nervous system (CNS). This makes it promising medicine for treating children with hematopoietic malignancies relapsing in CNS or refractory CNS disease. The purpose of the Study:The study aimed at retrospective evaluation of the effectiveness of liposomal Cytarabine (Depocyte®) administrated intrathecally as a part of the treatment of hematopoietic malignancies in Polish children. Patients and methods:The study group consisted of 23 patients, 11 boys and 12 girls, treated in the centers of Polish Pediatric Leukemia/Lymphoma Study Group, including 18 patients with acute lymphoblastic leukemia (ALL), 3 patients with acute myeloid leukemia (AML) and two children with high grade Non-Hodgkin's Lymphomas (NHL). The median age of the children was 10.8 years (range: 1.3 to 18 years). Liposomal cytarabine treatment was administered on compassionate basis to 20 children with relapsed acute leukemia / NHL, a single child with secondary leukemia, one patient with severe neurotoxicity after intrathecal Methotrexate during front-line treatment and in one child with large granulocytic sarcoma, penetrating into CNS. Thirteen patients received liposomal cytarabine dosage of 50 mg, while the remaining 10 children were exposed to the doses of 25–35 mg, all in association with prophylactic dexamethasone administration. The number of liposomal Cytarabine injections ranged from 1 to 11, mean 5 doses per patient. Results:The clearance of CNS disease was achieved in 15 of 23 patients (65%). Eight children were alive during the follow-up procedure, including 3 patients in complete remission after treatment completion. Grade IV neurotoxicity was observed in five children, which might be also partly related to CNS malignancy. Another side effects occurred in 4 patients, including headache, vertigo, paresthesias and seizures. Conclusion:Liposomal cytarabine administered intrathecally is effective treatment for CNS disease in children with relapsed acute leukemia/NHL with acceptable toxicity profile. Disclosures:No relevant conflicts of interest to declare.

What Is Your Guess? Which Count Is Correct?

A 77-year-old woman with Burkitt leukemia and lymphomatous meningitis was started on the PETHEMA (Programa para el Estudio de la Terapeutica en Hemopatia Maligna) protocol of chemotherapy. After the first chemotherapy cycle, the patient's leukocyte count in the cerebrospinal fluid (CSF) was 0. On cycle 2, the patient received intrathecal liposomal cytarabine (Depocyte®). Two weeks later, there was …

Fulminant chemical ventriculomeningitis following intrathecal liposomal cytarabine administration

Intrathecal liposomal cytarabine (ITLC) has shown prolonged time to neurological deterioration in some patients with leptomeningeal spread of breast cancer. We describe a patient with fulminant chemical ventriculomeningitis leading to cerebral edema and death following ITLC administration. A 56-year-old Caucasian female developed progressive headache, depressed level of consciousness and adventitious movements immediately following ITLC. Neurological examination was normal prior to injection. This progressed to loss of all brainstem function and a head CT scan demonstrated diffuse cerebral edema. Due to the absence of neurological function on examination, the family opted to withdraw care. To our knowledge we report the first patient with fulminant chemical ventriculomeningitis leading to cerebral edema and death following ITLC administration. Adjunctive glucocorticoids are recommended. Treatment options are limited and complicated by the liposomal formulation of intrathecal cytarabine.

Paroxysmal non-kinesigenic dyskinesia due to spinal cord infiltration of low-grade B cell non-Hodgkin's lymphoma

Dear Editor, A 65-year-old female patient was referred to our clinic due to singultus, nausea and vomiting. Splenomegaly without lymphadenopathy was found. The remaining clinical examination and an MRI scan of the brain were normal. Bone marrow examination was morphologically unremarkable, but the light-chain scattergram in flow cytometry showed a significant B cell population which was double negative although a clear light-chain restriction indicating a clonal population was not present. We therefore planned a splenectomy for further diagnosis. However, the patient developed rapidly progressing symmetrical tetraparesis. A spinal MRI scan revealed an extensive intramedullary area of intense contrast enhancement on T1-weighted images, comprising the spinal cord from C1 downwards (Fig. 1a). A biopsy was not possible without a significant potential risk for irreversible neural damage. The cerebrospinal fluid (CSF) contained CD20positive lymphocytes of lymphoplasmocytoid aspect compatible with non-Hodgkin's lymphoma. We began a treatment with high-dose steroids and intrathecal liposomal cytarabine and performed a splenectomy to classify the suspected B cell lymphoma. The spleen showed an infiltration of the red pulp with neoplastic CD5-negative B lymphocytes with some lymphoplasmocytoid differentiation. However, due to the artefacts caused by the preceding treatment with high-dose glucocorticosteroids, a further subclassification of the lymphoma was not possible. Two weeks after the initial lumbar punction, no lymphoma cells could be detected in the CSF. The patient received a treatment with rituximab (375 mg/m) on day 1 followed by methotrexate (3,500 mg/m) on day 2 (3 cycles every 14 days). The MRI of the neuroaxis normalised completely (Fig. 1b). Unfortunately, 3 weeks after the onset of the initial symptoms, the patient started to have episodes of involuntary hand movements. During these episodes, she noted forceful adduction and flexion in the metacarpo-phalangeal joints of both thumbs, as well as flexion in the metacarpo-phalangeal joints of the fingers. Either hand alone or both hands simultaneously could be affected (video Segment 1). The individual episodes lasted 30 to 40 s and occurred every 60 s to 30 min, both during wakefulness and sleep. They started and ceased spontaneously. In particular, they could not be triggered by active hand or finger movements or by sensory stimuli applied to the arms or the neck (video Segment 2). We diagnosed symptomatic short-lasting paroxysmal non-kinesigenic dyskinesia (PNKD). While carbamazepine had only a minor and short-lived effect, benzodiazepines, pregabalin, levetiracetam and morphine had none. The missing response to pharmaceutical treatment was reminiscent of idiopathic PNKD. During rehabilitation, both the tetraparesis and dyskinesia gradually resolved, and 4 months Electronic supplementary material The online version of this article (doi:10.1007/s00277-011-1258-4) contains supplementary material, which is available to authorized users.

Prospective follow-up of 96 patients with breast cancer with leptomeningeal metastasis recruited from 2007 to 2010.

2089 Background: Around 5% of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). Incidence of LM may increase. The aim of this study was to report the outcome of patients diagnosed with BC LM. Methods: 96 consecutive female BC patients diagnosed with LM were prospectively followed up in our institution from 2007 to 2010. Characteristics and outcomes of patients were reported. Correlations between characteristics and overall survival (OS) were analyzed using usual statistical methods (Kaplan Meier, Log-rank, Cox). Results: Median time between BC and LM was 42,5 months. BC were invasive ductal carcinoma in 72%. Estrogen and progesterone receptors were detected in respectively 61,5 and 43% of the tumors. HER2 expression was observed in 26,5%. 24% were triple negative. At LM diagnosis, median age was 52 and median Performance Status (PS) was 2. CSF cytology and cerebrospinal MRI were positive in respectively 72% and 87%. Median time between LM diagnosis and 1st intrathecal (IT) was 3 days. 80 LM patients received IT liposomal cytarabine (ventricular device in 55%) associated with systemic treatment in 52 cases and whole brain radiotherapy in 12 cases. Clinical stabilization or improvement was observed in 46%, CSF response in 37%, MRI stabilization or improvement in 67,5%. 12 patients were staying alive. Median OS of the whole cohort and the 80 treated patients were respectively 2,8 and 3,5 months. Initial PS was the mainly variable correlated with OS (p<0,0001). Median OS of the whole cohort was 5 months in 0-2 PS patients (n=56), 24 days in 3-4 PS patients (n=40). Median OS of the treated patients was 5,6 months in 0-2 PS patients (n=50), 31 days in 3-4 PS patients (n=30). Other significant predictors of survival were: RP and triple negative status RP (p=0,01/p=0,004), time between LM diagnosis and 1st IT injection (p), systemic and IT treatment (p<0,0001/p=0,0002), radiotherapy (p=0,0076), clinical, cytological and MRI responses (p<0,0001/p=0,0366/p=0,0343). Conclusions: Our results confirm the importance of an early diagnosis and the interest of the association of IT and systemic treatment in treating BC LM.

Carcinomatous meningitis related to patients with breast cancer patients: A new approach of an individual treatment regimen with liposomal cytarabine.

e11532 Background: Carcinomatous meningitis occurs in 5 % of patients with breast cancer. The median survival amounts from 4 to 6 months and only 15% of patients survive more than 1 year. The best result of carcinomatous meningitis treatment is achieved by the use of the combined systemic and intrathecal chemotherapy accompanied by the spinal and whole brain radiotherapy. The patients with carcinomatous meningitis are treated with intrathecal methotrexate as the initial therapy. However the results of methotrexate treatment are not satisfactory. It seems that liposomal cytarabine treatment might be promising for the patients with carcinomatous meningitis. Therefore this therapy was investigated. Methods: In year 2010, 8 patients of Breast Cancer Department in Cancer Center in Warsaw with carcinomatous meningitis received the intrathecal chemotherapy with liposomal cytarabine. The diagnosis was based on the presence of cancer cells in cerebro-spinal fluid and/or cerebrospinal MRI. Liposomal cytarabine was administered in the intrathecal injection of 50 mg, every 2 weeks for 5 cycles followed by 5 cycles of 50 mg every 4 weeks. Results: Generally the liposomal cytarabine therapy was well tolerated. No serious adverse events were observed. The regimen of the treatment was more convenient than weekly administering of methothrexate. Intrathecal liposomal cytarabine treatment results in the rapid cancer cells count decrease in cerebrospinal fluid. It does not seem to correspond with clinical benefits. The progression of the disease was observed in each case after two weeks after drug administration Conclusions: The results suggest that liposomal cytarabine intrathecal chemotherapy is well tolerated. The clarification of cerebrospinal fluid from cancer cells can not to be the factor of the termination of the liposomal cytarabine intrathecal treatment. It seems that the better results could be achieved by the change of the used regimen of treatment, as the every 4 weeks treatment is not efficacious and the progression of disease occurrs after two weeks. The individual timetable of the treatment scheme should be considered in every case according to the clinical status.

Intrathecal liposomal cytarabine (lipoCIT) administration in patients with leukemic or lymphomatous meningitis

There is limited information regarding the efficacy and long term safety of intrathecal injection of liposomal cytarabine in leukemic or lymphomatous meningitis. We studied 20 consecutive HIV-negative patients with leukemic or lymphomatous meningitis who were treated with intrathecal liposomal cytarabine between 2004 and 2007. We focused on efficacy and on any late effects of the drug. Twenty patients who received intrathecal liposomal cytarabine injection as part of their treatment; of these, 9 were alive and in complete remission at the end of the study. Median survival from the time of the first injection was 22.7 months (range, 0.5 to 64 months). Short-term toxicity related to intrathecal of liposomal cytarabine was observed in 2 cases; headache in 1 case and regressive facial palsy and diplopy in 1 case. Long-term toxicity was seen in 2 cases; clinical symptoms were urinary and fecal dysfunction with confusion in 1 case, and urinary dysfunction in 1 case. Both patients had been heavily pre-treated with neurotoxic drugs and neuraxis irradiation. In our experience, intrathecal liposomal cytarabine injections were convenient in the management of leukemic and lymphomatous meningitis, and can lead to long-term survival. Although neurotoxicity was rare, clinicians should exercise caution when retreatment is required in relapsing patients.

Methotrexate and Temozolomide Plus Intrathecal Liposomal Cytarabine for Primary or Secondary Central Nervous System Lymphoma

AbstractAbstract 4899Treatment of central nervous system (CNS) lymphoma remains challenging, and balance between therapeutic effectiveness and toxicity is difficult to find. The addition of systemic chemotherapy to whole brain radiotherapy has significantly improved the outcome of these patients. However, this combined strategy is burdened with possible acute and/or delayed severe neurotoxicity, particularly in elderly patients. Chemotherapy-only approaches, with or without concomitant intrathecal (IT) therapy, for CNS lymphoma have been explored. Moreover, deferring radiotherapy to the time of first or subsequent relapse may reduce the risk of severe neurotoxicity, without altering outcome. Recently, high-dose methotrexate and temozolomide (HD-MTX-TMZ) without IT CNS prophylaxis have been studied in PCNSL elderly patients. This regimen appears effective, while substantially decreasing acute and/or delayed neurotoxicity. Conflicting data exist regarding the safety of combining IT liposomal cytarabine (LC) and systemic CNS-penetrating therapy. We report our preliminary experience with HD-MTX-TMZ plus IT LC used upfront or as salvage in 4 primary or secondary CNS lymphoma patients, only one of which under the age of 60 (56). Treatment consisted of induction: MTX 3g/ms d 1, 10, 20, TMZ 100 mg/ms d 1–5; and maintenance for ≥SD patients, and for up to 5 additional cycles: MTX 3g/ms d 1, TMZ 100 mg/ms d 1–5, every month. Fifty mg IT LC were given concomitantly for up to 6 doses planned. LC doses were separated by at least 14 days from one another and at least 7 days from HD-MTX. Pt n. 1 (56 year-old male) had a history of testicular diffuse large B cell lymphoma (DLBCL), stage IVA. He received chemo-radiotherapy with 4 concomitant IT LC injections as CNS prophylaxis. Complete response (CR) was achieved. Two months later, he presented with headache and dizziness. MRI and PET revealed metabolically active righ cerebellar lesion. Karnofsky performance status (KPS) was 50%. Rituximab plus TMZ and IT MTX were initiated but soon discontinued due to a G4 CMV-related pneumonia. After complete recovery, HD-MTX-TMZ was started with concomitant 4 IT LC injections, and precautionary stem cell harvest. No significant G3-4 toxicities were observed during treatment. At 9 months of follow-up post-treatment, the lesion is stable with no contrast enhancement at MRI and PET is negative, suggesting a CRu. Pt 2 (76 year-old male) was referred in May 2009 with a diagnosis of CNS peripheral T-cell lymphoma not otherwise specified with MRI- and PET-documented multiple brain localizations (i.e. hypophyseal infundibulum, cavernous sinus, cerebellum). KPS was 60%. He was treated with systemic steroids and TMZ 150 mg/ms d 1–5/28. In August 2009 disease progressed after two cycles, and HD-MTX-TMZ was started. IT LC was added as CNS prophylaxis with 4 drug injections. Toxicity consisted of G2 renal insufficiency and G3 steroid-induced diabetes mellitus, both resolved. Treatment resulted in marked shrinkage of all lesions, with no contrast enhancement and PET is negative, indicating CRu, which is stable at 5 months of follow-up. Pt 3 (68 year-old female) was diagnosed with PCNSL, DLBCL, with left cerebellar localization. KPS was 50%. HD-MTX-TMZ and concomitant IT LC injections were initiated as first-line therapy. Four maintenance cycles and 5 IT LC injections have been performed so far. Toxicities included G3 atrial fibrillation. Interim MRIs documented very good partial remission of the disease. Pt 4 (71 year-old female) was diagnosed with DLBCL stage IIIE (i.e. subcutaneous facial localization) in July 2009, and treated with R-COMP (liposomal doxorubicine in lieu of the free formulation) for 8 cycles. She obtained CR, but in July 2010 presented with aphasia and facial hemiparesis. Brain MRI showed multiple subcortical lesions in both hemispheres, biopsy-confirmed to be lymphoma. The first IT LC injection and HD-MTX dose were given without significant toxicity. All patients completed induction and 5 maintenance cycles. HD-MTX-TMZ and concomitant IT LC therapy appeared feasible and overall well tolerated. No acute neurologic complications were observed. Follow-up is too short to make comments on delayed neurotoxicity. Increasing the number of LC injections might be reasonable and at least 7 days should be interposed between systemic and IT therapy. HD-MTX-TMZ plus IT LC deserves further evaluation in a larger prospective setting. Disclosures:No relevant conflicts of interest to declare.

Phase II Study of Intrathecal Long Acting Liposomal Cytarabine (Depocyte®) In the Prophylaxis of Lymphomatous Meningitis In HIV-Related Non-Hodgkin's Lymphoma

AbstractAbstract 1750 Background:Around 5% of patients with aggressive non-Hodgkin's lymphoma (NHL) develop central nervous system (CNS) progression or relapse during the course of their disease. Patients with human immunodeficiency (HIV)-related NHL often develop CNS progression despite the use of adequate prophylaxis. Liposomal cytarabine has show a significant activity in lymphomatous meningitis but there are limited data in the prophylactic setting. Methods:Since May 2006, we are running a prospective phase II study of intrathecal liposomal cytarabine (Depocyte®) at the dose of 50 mg in 40 patients with HIV-NHL with the aim to evaluate the feasibility and activity of this drug in the prevention of lymphomatous meningitis. Results:Thirty-five patients were males and the median age was 44 years (range 18–69 yrs). As far as the histological subtype of NHL, 47% of patients had a diffuse large B-cell (DLBC) NHL and 40% Burkitt NHL. Stage III-IV was diagnosed in 80% of patients and 68% of DLBC were age-adjusted IPI 2 or more. An extranodal involvement was diagnosed in 70% of patients (gastrointestinal 30%, bone 27%, spleen 10%, liver 22%, bone marrow 17%). Liposomal cytarabine was well tolerated with headache grade I to III being the most frequent side effect in only 37% of patients. Less common toxicity (all grade I) included cortical changes (5%), fever (3%), vomiting (3%), hypertension (3%), chills (3%). With a median follow up of 12.4 months only one patient (3%) with Burkitt lymphoma developed a combined systemic and meningeal relapse. Moreover, in our experience previously the present study, we used methotrexate as practical use in 426 HIV-NHL with a meningeal progression or relapse of 14% (p=0.09). The use of a liposomal formulation allowed to significantly reduce the number of lumbar injections in comparison to the standard schedules (approximately of 50%) with an improvement of quality of life of patients and with a reduction of professional exposure risk for health care staff. Discussion:In this first prospective study on prophylaxis of lymphomatous meningitis in HIV-NHL reported in the literature, liposomal cytarabine seems safe and active and it reduces of approximately 50% the number of lumbar punctures and exposure risk for health staff as well. Disclosures:No relevant conflicts of interest to declare.

Intrathecal Liposomal Cytarabine in Relapsed or Refractory Infant and Pediatric Leukemias: The Children's Hospital of Philadelphia Experience and Review of the Literature

Intrathecal chemotherapy is integral to curing childhood leukemia; however, bioavailability is limited by the blood-brain barrier. Recently FDA-approved, intrathecal liposomal cytarabine (ITlipAC) increases drug concentration over time with fewer invasive procedures. We present a series of 4 children, including 2 infants, with relapsed central nervous system leukemia who went into remission using ITlipAC, with a review of the literature reporting ITlipAC use in children with relapsed leukemia. Drug-attributable side effects were observed more frequently in children with preexisting neurologic conditions and with adult dosing. Combined with other pediatric reports, our experience supports the efficacy of ITlipAC in pediatric and infant leukemic meningitis.

Neurologic complications of intrathecal liposomal cytarabine administered prophylactically to patients with non-Hodgkin lymphoma

Central nervous system (CNS) prophylaxis is required during initial treatment of non-Hodgkin lymphoma (NHL) subtypes that carry a high risk of CNS involvement. Intrathecal (IT) liposomal cytarabine, a formulation with prolonged half-life, has been shown to be safe and effective in the treatment of meningeal disease in patients with high-grade lymphoma. We retrospectively reviewed all adult patients with high-grade NHL that received prophylactic therapy with IT liposomal cytarabine and developed neurologic complications in our institution between April 2007 and May 2009. We recorded information on hospital admission, chemotherapy regimens, clinical features, neuroimaging, cerebrospinal fluid, neurophysiology data, and outcome. Neurotoxicity was graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC). Four of fourteen patients (28%) developed moderate or severe neurotoxicity (grades 2 and 3 of the NCI-CTC), manifested as conus medullaris/cauda equine syndrome or pseudotumour cerebri-like syndrome, after a median of 3.5 IT courses of liposomal cytarabine. All patients had received corticosteroids to prevent arachnoiditis. Liposomal cytarabine given via the IT route, even with concomitant corticosteroid administration, can result in significant neurotoxicity in some patients. We discuss the potential pathogenesis of these effects and suggest hypothetical therapeutic measures to prevent these complications. Specialists should be aware of these possible complications when administering prophylactic IT liposomal cytarabine in high-grade NHL patients, and additional prospective studies should be conducted to more clearly delineate the frequency and characteristics of these complications.

Neurologic complications after intrathecal liposomal cytarabine in combination with systemic polychemotherapy in primary CNS lymphoma

Intrathecal application of liposomal cytarabine (Ara-C) (DepoCyte(®)) has been associated with neurotoxicity when applied as part of a polychemotherapy regimen. Patients with primary central nervous system lymphoma treated with high-dose systemic methotrexate (MTX)- and Ara-C-based polychemotherapy including six cycles of liposomal Ara-C (50 mg intrathecally every 3 weeks) were prospectively monitored for neurotoxic side-effects. Between November 2005 and February 2009, 149 intrathecal applications of liposomal cytarabine (DepoCyte(®)) were carried out in 33 patients, 7 (21%) of whom developed an incomplete conus medullaris/cauda equina syndrome with incontinence for bladder (6) and bowel function (3) or lumbosacral polyradicular paresis (1), resolving only incompletely over a follow-up period of 9-30 months. In six of these seven patients, lumbosacral magnetic resonance imaging (MRI) was negative for leptomeningeal infiltration or arachnoiditis. Cerebrospinal fluid (CSF) analysis performed in six of these seven patients showed normal cell count in all and increased total protein in four of them. One patient among these seven suffered a seizure without other identifiable causes. Conus/cauda syndrome has to be considered as a serious potential neurotoxic side-effect in patients receiving liposomal Ara-C as part of a multimodal regimen including high-dose systemic MTX and Ara-C.

Intrathecal liposomal cytarabine for treatment of leptomeningeal involvement in transformed (Richter’s syndrome) and non-transformed B-cell chronic lymphocytic leukaemia in Spain: a report of seven cases

Intrathecal liposomal cytarabine for treatment of leptomeningeal involvement in transformed (Richter’s syndrome) and non-transformed B-cell chronic lymphocytic leukaemia in Spain: a report of seven cases

Phase 2 study of intrathecal, long‐acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus‐related non‐Hodgkin lymphoma

Patients with aggressive non-Hodgkin lymphoma (NHL) develop central nervous system (CNS) progression or recurrence during the course of their disease. Patients with human immunodeficiency virus (HIV)-NHL often develop CNS progression despite the use of prophylaxis. Liposomal cytarabine (DepoCyte) has shown activity in lymphomatous meningitis, but there are limited data for prophylaxis. Between May 2006 and December 2008, a phase 2 study of intrathecal liposomal cytarabine was performed at the dose of 50 mg in 30 patients with HIV-NHL, with the aim of evaluating feasibility and activity for prophylaxis. Liposomal cytarabine was well tolerated, with headache grade I to III being the most frequent side effect in 40% of patients. With a median follow-up of 10.5 months, only 1 (3%) patient developed a combined systemic and meningeal recurrence. The use of liposomal cytarabine allowed significant reduction of the number of lumbar injections in comparison to the standard schedules (around 50%), improving the quality of life of patients and reducing the professional exposure risk. In this first study on prophylaxis of lymphomatous meningitis in HIV-NHL, liposomal cytarabine seems safe and active; it reduces by approximately 50% the number of lumbar punctures, and exposure risk for health staff as well.

Intrathecal Liposomal Cytarabine (DepoCyte®) for Treatment of Leptomeningeal Involvement From Transformed (Richter's syndrome) and Non-Transformed B-Cell Chronic Lymphocytic Leukemia (B-CLL) in Spain: Report of 8 Cases.

Abstract 4411 BackgroundLeptomeningeal disease (LD) is an uncommon and severe complication in the course of B-CLL and may occur particularly in the course of transformation into an aggressive lymphoma, so-called Richter's syndrome. Commonly, repeated administrations of intrathecal (IT) chemotherapy with either methotrexate or cytarabine is the mainstay treatment in these B-CLL patients (pts). IT chemotherapy with standard agents is limited by the need for multiple injections via lumbar puncture or an Ommaya reservoir. A depot formulation of liposomal cytarabine (DepoCyte®) has already demonstrated to be well tolerated and effective in the treatment of lymphomatous meningitis. However, there are no studies that have analyzed the efficacy of liposomal cytarabine in the treatment of leptomeningeal involvement from B-CLL and/or Richter′s syndrome. AimA multicenter and retrospective study was performed in pts with meningeal involvement from transformed (Richter's syndrome) and non-transformed B-CLL in which IT depot liposomal cytarabine was employed as compassionate therapy. All the cases were evaluated for cytological negativization of the cerebro-spinal fluid (CSF) from neoplastic cells and improvement of neurological symptoms. Patients and MethodsFrom October 2005 to February 2009, eight patients (median age 66 years; range 44–81; 3 females) treated with liposomal cytarabine at the standard dose of 50 mg every 15 days, for a total of 39 doses (median cycles/pt: 5; range 1–9) were recorded. Six patients had a diagnosis of Richter′s syndrome from B-CLL [ (diffuse large B-cell lymphoma (DLBCL; n = 5); or secondary involvement of Central Nervous System (CNS) from acute myeloid leukaemia (AML) (n = 1)] and the remainder (n = 2) were diagnosed of non-transformed B-CLL. At time of meningeal involvement, the eight patients were also in hematological relapse. The patients had been previously treated by cytotoxic chemotherapy according to the current protocols; intrathecal prophylaxis had not been administered previously. In all patients neurological symptoms were present; lymphomatous cells were identified in the CSF of 7 patients (median, 296/μL; range, 3–1440/μL) and CNS localizations were detected by CT scan and/or MR imaging in 2 patients. The treatment with liposomal cytarabine (50 mg IT every 15 days) was associated with systemic chemotherapy in 7 patients [ R-CHOP (n = 1), CHOP (n = 1), R-FC (n = 1), high or intermediate methotrexate-based regimens in combination with cytarabine and vincristine (n = 3) or only chlorambucil in 1 elderly pt]. The patient with AML meningeal involvement was treated only with DepoCyte®. Six patients received concurrent dexamethasone therapy as prophylaxis for chemical arachnoiditis; oral dexamethasone (4 mg bid for 5 days per cycle) (n = 1), IV dexamethasone at varying dosages (n = 2) or IT dexamethasone (4 mg) (n = 3). ResultsThe patient with AML meningeal relapse was not evaluable for response because he received only 1 administration of liposomal cytarabine before dying for disease progression. In seven evaluable cases, overall neurological and cytological responses were obtained in five cases with Richter′s syndrome (71.4%; 3 complete responses, 2 partial responses) whereas 2 complete responses (100%) was observed in B-CLL pts. Median time from treatment to cytological response was 15 days, (range, 2 - 60). Neurological progression was not subsequently reported in any patients (median follow-up 5 months; range 1 – 12). Two patients were still alive and in CR at the time of reporting, including 1 of 7 patients with Richter's syndrome, whereas the remaining six died from systemic relapse (5) or infection (1), without evidence of neurological progression at hematological disease progression. No adverse effects due to the IT administration of liposomal cytarabine were reported. No dose reduction was required for toxicity. ConclusionsThese preliminary data indicate that IT liposomal cytarabine is effective in clearance of tumoral cells from CSF in transformed and non-transformed B-CLL patients. The association with systemic chemotherapy has been demonstrated to be suitable and well tolerated. Studies with higher number of patients and longer-term follow-up will be warranted to evaluate the efficacy and safety of IT depot liposomal cytarabine in meningeal involvement from B-CLL and Richter′s syndrome. Disclosures:No relevant conflicts of interest to declare.

Intrathecal liposomal cytarabine in combination with temozolomide in low-grade oligoastrocytoma with leptomeningeal dissemination

Leptomeningeal dissemination of low-grade gliomas is an uncommon event. A 43-year old male presented with dizziness, gait ataxia, and diplopia. A nonenhancing lesion in the right cerebellar peduncle was identified, subtotally resected, and diagnosed as a grade II astrocytoma. After one year a nodular spread in the brain and leptomeninges was diagnosed, so the patient started chemotherapy with temozolomide and liposomal cytarabine. Complete remission was achieved after 12 months of treatment and the patient is still free from the disease after a follow-up of 24 months. We suggest that this combination may be a valuable treatment option.

Safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with recurrent or refractory brain tumors: a multi-institutional retrospective study

This retrospective study aimed to evaluate the safety and toxicity of intrathecal liposomal cytarabine (Depocyte) in children and adolescents with refractory or recurrent brain tumors. Nineteen heavily pretreated patients (males, n = 14; females, n = 5; median age at diagnosis 8.5 years; range, 1.4-22 years) were given intrathecal liposomal cytarabine on a compassionate use basis for recurrent refractory medulloblastoma (n = 12), mixed germ cell tumor (n = 2), central nervous system primitive neuroectodermal tumors of the pons (n = 1), anaplastic ependymoma (n = 1), anaplastic oligodendroglioma (n = 1), atypical teratoid rhabdoid tumor (n = 1), or rhabdoid papillary meningioma (n = 1). Eighteen patients received concomitant systemic radiochemotherapy. A total of 88 intrathecal injections of liposomal cytarabine (dose range, 20-50 mg) were administered with concomitant dexamethasone prophylaxis. The median number of doses per patient was four (range, 1-10). Duration of treatment ranged from (1/2) to 10 months. Eleven patients (57.9%) did not show any side effects, whereas eight patients (42.1%) developed side effects related to either chemical arachnoiditis (n = 4) or neurological progression (n = 2). Less typical treatment-related symptoms (e.g. lethargy, ataxia, and slurred speech) were observed in two patients. Treatment with intrathecal liposomal cytarabine was discontinued twice because of side effects. In conclusion, although intrathecal liposomal cytarabine was generally well tolerated, it should be used cautiously and only with dexamethasone prophylaxis in extensively pretreated patients with recurrent brain tumors. Proof of efficacy requires a prospective single-agent phase II study.

Intrathecal liposomal cytarabine in children under 4 years with malignant brain tumors

Infants and very young children with malignant brain tumors usually have unfavourable locations and are not candidates for craniospinal irradiation. New therapeutic approaches must be attempted to improve poor survival rates. The primary goal of the present study was to report on the safety profile and toxicity of intrathecal administration of liposomal cytarabine in children <4 years with malignant brain tumors. This is the first study including this group of patients receiving intrathecal liposomal cytarabine. Nine patients with a median age of 26 months were eligible for the study. The diagnoses were ependymoma (3), peripheral neuroectodermic tumor (PNET) (2), meduloblastoma, atypical teratoid rhabdoid tumor (ATRT), cerebral lymphoma, and rhabdomyosarcoma with CNS invasion. Liposomal cytarabine at doses between 20 and 35 mg were administered by lumbar puncture. Dexamethasone was given for arachnoiditis prophylaxis. A total of 44 doses (median = 6) of liposomal cytarabine were administered. Neurological side effects possibly related to liposomal cytarabine were observed in five patients (55.6%). This incidence was higher than previously reported in children older than 3 years. Eight of the patients (89%) experienced an initial improvement of clinical symptoms after initiation treatment, confirmed by MRI. This study demonstrates the feasibility of using intrathecal liposomal cytarabine in children under 4 years of age with malignant brain tumors.