Intrathecal Liposomal Cytarabine Research Articles

Liposomal cytarabine in the prophylaxis and treatment of CNS lymphoma: toxicity analysis in a retrospective case series study conducted at Polish Lymphoma Research Group Centers.

Lymphomas with primary or secondary involvement of central nervous system (CNS) have poor prognosis despite specific treatment protocols which include whole brain radiotherapy and high-dose systemic and/or intrathecal chemotherapy. Toxicity of intrathecal liposomal cytarabine-based regimens collected between November 2006 and January 2012 was assessed retrospectively. Data from 120 adult lymphoma patients with, or at high risk of CNS involvement who received intrathecal liposomal cytarabine-based regimens at six Polish Lymphoma Research Group centres between November 2006 and January 2012 were assessed retrospectively. Patients were divided into three cohorts: A (high risk of CNS disease, n = 88), B (cerebrospinal fluid pleocytosis without neurological symptoms or pathological imaging findings, n = 7), and C (CNS disease/neurological involvement; n = 25). In all examined groups, toxicity of treatment was found to be acceptable (including the prophylactic setting). None of the patients in cohorts A or B who took intrathecal liposomal cytarabine 50 mg, repeated every 2–4 weeks (mean 3.8 doses) had experienced a CNS relapse at a median follow-up time of 3 years. Patients in cohort C had a 76 % overall neurological response rate (including a 40 % complete response rate) and median overall survival of 4.8 years. Regimens incorporating liposomal cytarabine seem to be safe and effective treatments for lymphomas with CNS involvement.

Updated Results Confirm Favorable Outcome of Immunocompetent Patients with Primary CNS Lymphoma Treated By C5R Protocol in Combination with Intravenous Rituximab and Intrathecal Liposomal Cytarabine: A Multicentric Prospective Phase 2 Study of the Lymphoma Study Association (LYSA)

Background: The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favorable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years. In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and intrathecal (IT) liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL in the R-C5R protocol. We previously presented the results of the primary objective of the R-C5R protocol, showing an improvement of the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT from 33% in the LNHCP93 to 66% in the R-C5R protocol. We also showed no additional severe toxicities as compare to C5R with the addition of intravenous rituximab and IT liposomal cytarabine. We present here the updated results of the 53 patients included in this multicentric prospective phase 2 study from the lymphoma study association (LYSA) with a median follow-up 28 months (range, 1.08-75.04).Methods: This prospective study was designed for 18 to 60 years old immunocompetent patients with confirmed CD20 positive diffuse large B-cell lymphoma PCNSL. Fifty-three patients included between August 2007 and September 2011 received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2 and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients and then patients were followed every 4 months during the first 2 years and then every 6 months for the next 3 years. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test.Results: The median age of the 53 PCNSL patients was 55 years (range, 36-60), 57% were male, 42% had a performance status (PS)>1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Clinical characteristics according to the MSKCC score was as follows: 16 patients (32%) ≤50 years (class 1); 23 patients (46%) >50 years and KPS≥70 (class 2); 11 patients (22%) >50 years and KPS<70 (class 3). Of the 39 available patients, 38% had 0-1, 38% had 2, 21% had 3 and 3% had 4 adverse IELSG prognostic scores, respectively. Median MMSE score assessed for 42 patients at baseline was 26 (range, 3-30). Forty-five patients (85%) completed the fourth cycles of immune-CT and three patients (5.7%) died of acute toxicity. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 28 months, 20 patients progressed or relapsed (37.7%). The 3-year progression free survival (PFS) rate of whole cohort was 58% (95%CI, 42.5% to 71%). The 3-year PFS rates were 64.2%, 63.5% and 53% for patients with MSKCC class 1, 2 and 3, respectively (P=0.53); the 3-year PFS rates were 86% and 39% for patients with 0-1 and 2-4 adverse IELSG prognostic scores, respectively (P=0.02). The 3-year PFS rates were 66% and 80% for patients who received a reduced whole brain RT with a boost and patients treated with whole brain RT (P=0.25), respectively. At relapse or progression, 18 patients received a salvage treatment that allowed five CR/CRu. Five patients received a high-dose CT with autologous stem cell transplantation at relapse. The 3-year overall survival (OS) rate for whole cohort was 67% (95%CI, 48.3% to 80.1%). The median MMSE score was 29 (range, 23-30) for the 11 patients evaluated between 18 and 24 months after the beginning of treatment.Conclusions: With the addition of intravenous rituximab and IT liposomal cytarabine, R-C5R protocol provided promising outcome results with a 3-year PFS and OS of 58% and 67%, respectively. These results compared favorably with historical controls included in the LNHCP93 who presented a 3-year PFS and OS of 44% and 58%, respectively. IELSG score remained a strong prognostic factor for the patients treated with this schedule and could be helpful to stratify consolidation treatment after response to primary immunochemotherapy in particular patients with 2-4 IELSG score. DisclosuresGhesquieres:Mundipharma: Honoraria. Off Label Use: Liposomal cytarabine formulation had demonstrated better efficacy compared to standard cytarabine for the treatment of lymphomatous meningitis and is off label use in first line therapy of primary CNS lymphoma. Morschhauser:Mundipharma: Honoraria.

Flow Cytometric Detection of Liposomes in the CSF of Patients with NHL/ALL, Treated with Intrathecal Liposomal Cytarabine: Synonymous of Toxicity?

ObjectivesPatients with aggressive non-Hodgkin’s lymphoma (NHL) and acute lymphoblastic leukemia (ALL) with high risk of CNS infiltration or recurrence may receive prophylaxis or be treated with intrathecal injections (IT) of liposomal cytarabine (LC) once every 2 weeks (due to its sustained release of cytarabine).Sequential flow cytometric studies in patients with CNS involvement and treated with LC, allow to detect tumor cells as well as LC liposomes (LCL) in the CSF. The true meaning of the presence of these liposomes during the treatment with LC is still unknown.Patients and MethodsIn this study, we aimed to investigate the presence of LCL detected by Flow Cytrometry (FC) among 166 CSF samples of 69 patients treated with LC. Samples were taken before each administration of intrathecal LC and centrally processed.ResultsResults are shown in the below table. Abstract 5444. Table 1Patients with NHL/ALL, treated with Intrathecal Liposomal CytarabineNPatients69Samples166Liposomal Cytarabine Liposomes (LCL) in CSFN%Patients1319%DLBCL646%LLT215%ALL215%MCL18%MM18%CLL18%Samples2616%Males862%2616%Age66 years[33-84]LCL in CSF of patients receiving Liposomal CytarabinePROPHYLAXISNToxycityTotal nº of IT LC dosesPatients7nº of IT LC doses*3 (2-5).LCL7After 1st dose5After 2nd dose21 LLT patient: arachnoiditis, high intrathecal pressure, papillitis, without sequelae5After 3rd dose2After 5th dose1LCL in CSF of patients receiving Liposomal Cytarabine leptomeningeal disease TREATMENTNTumor: ToxycityTotal nº of IT LC dosesPatients6nº of IT LC doses*6 (4-7)LCL6After 1st dose31 DLBCL patient: Headache, dizziness and instability51 MM patient: Headache, dizziness and instability4After 3rd dose2After 5th dose11 ALL patient: Headache, dizziness and instability7* Median [range]The thirteen patients were simultaneously treated with LC and IT + IV dexamethasone. It was found no relationship between the amount of LCL and toxicity.Conclusions:Presence of LCL in CSF is detected in 15-20% of patients receiving IT LC as prophylaxis / treatment and it does not show a direct relationship with presence of toxicity.Although the true clinical significance of the presence of LCL in CSF remains unknown, their monitoring could be useful to individualize the treatment with CL IT (dose and time between doses). DisclosuresOff Label Use: Liposomal cytarabine is not approved for prophylaxys of lymphomatous meningitis..

High Doses of Antimetabolites Followed By High-Dose Sequential Chemoimmunotherapy and Autologous Stem Cell Transplant in Patients with Systemic B-Cell Lymphoma and Secondary Central Nervous System Involvement: Final Results of a Multicenter Phase II Trial

Abstract INTRODUCTION: Secondary central nervous system (CNS) dissemination is a lethal event in patients (pts) with aggressive lymphomas. A few studies focused on the treatment of this condition are available, confirming the dismal prognosis and the high rate of severe neurotoxicity in pts managed with radiotherapy-based induction. Thus, the most effective treatment for secondary CNS lymphoma remains an important, unmet clinical need. Herein, we report the final results of a multicenter phase II trial addressing a new treatment in pts with aggressive B-cell lymphoma and CNS involvement (NCT00801216). Experimental treatment is based on the encouraging experiences with high doses of antimetabolites in pts with primary CNS lymphoma (Ferreri et al. Lancet 2009), and with high-dose sequential chemotherapy combined with rituximab (R-HDS) and supported by autologous stem cell transplant (ASCT) in pts with relapsed aggressive B-cell lymphoma (Tarella et al. JCO 2008). METHODS: Selection criteria were: 1) histological diagnosis of diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma blastoid variant (MCLb) or grade-3 follicular lymphoma (FL); 2) secondary CNS involvement at diagnosis or relapse; 3) age 18-70 years; 4) ECOG PS ≤3; 5) absence of HIV infection; 6) adequate organ functions. Pts with primary CNS lymphoma (exclusive CNS disease at diagnosis) were excluded. Experimental treatment consisted of an induction phase with 2 courses of methotrexate 3.5 g/m2 d1 + cytarabine 2 g/m2 x2/d d2-3, followed by an intensification phase with R-HDS (cyclophosphamide 7 g/m2 d1; cytarabine 2 g/m2 x2/d d22-25; pts with residual extra-CNS disease received also etoposide 2 g/m2 d43) and a consolidation phase with BCNU-thiotepa conditioning + ASCT (figure). Treatment included 8 doses of rituximab and 4 of intrathecal liposomal cytarabine. The primary endpoint was 2-year PFS; the planned accrual was 38 pts. RESULTS: 39 pts were registered (age 32-70 ys, median 59; M/F ratio 1.5): 33 had DLBCL, 3 MCLb, 3 FL. CNS disease (brain 21, meninges 5, spinal cord 2, multiple 11) was detected at diagnosis in 16 pts (all with extra-CNS disease) and at relapse in 23 (8 with extra-CNS disease). The median TTP from the previous treatment line was 3 months (range 0-77 months). Thirty-four pts completed the induction phase; 73 (93%) of 78 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 77%, 63% and 5% of courses, G3-4 febrile neutropenia in 16%, CMV reactivation in 3 pts. Transient G4 transaminases increase (3% of courses) was the only G4 non-hematological toxicity. Drugs dose reduction was indicated in 3 pts. Response after induction phase was complete in 11 pts and partial in 19 (ORR= 77%; 95%CI=64-90%). Thirty pts were referred to intensification phase (figure); 58 (97%) of 60 planned courses were actually delivered; G4 neutropenia, thrombocytopenia and anemia were recorded in 67%, 60% and 7% of courses, G3-4 febrile neutropenia in 22%, G4 sepsis in 8%. CMV reactivation was diagnosed in 4 pts, pulmonary aspergillosis in 1. No cases of G4 extra-hematological toxicity were recorded. Response after intensification phase (before conditioning) was complete in 22 pts and partial in 2 (ORR= 62%; 95%CI=47-77%). ASCs were collected in 21/22 (95%) pts (median 9.5 x 106/kg; range 6-19); 20 pts underwent ASCT. Response at the end of the whole program was complete in 23 pts and partial in 1 (ORR= 62%, 95%CI= 47-77%), 1 pt had SD, 10 experienced PD (all in the CNS), and 4 died of toxicity (sepsis 2, stroke, acute tracheal obstruction). Importantly, no pt was irradiated to the brain to achieve lymphoma remission, and no evidence of neurotoxicity was recorded in pts with a survival longer than 3 years. One pt was referred to sibling-donor transplant due to sMDS, and is alive and NED at 91 months of follow-up. At a median follow-up of 42 months, 16 pts remain relapse-free, with a 2-yr PFS of 42±8%. Sixteen pts are alive, with a 2-yr OS of 42±8%; 2-yr OS of transplanted pts was 72±11%. Extra-CNS and/or meningeal disease did not affect outcome, and survival was similar in both pts treated at presentation or at relapse. CONCLUSION: This radiotherapy-free combination of high doses of antimetabolites, R-HDS and ASCT is feasible and effective in pts ≤70 ys with secondary CNS lymphoma. Toxicity is usually haematological and manageable. Survival benefit is attainable also in pts with meningeal and/or concomitant extra-CNS disease. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

P08.19 * PRIMARY INTRATHECAL MELANOMA ARISING FROM MENINGEAL MELANOCYTOSIS: A CASE REPORT

INTRODUCTION: Primary melanocytic tumours of the leptomeninges are rare diseases. The WHO classification of 2007 described four entities: diffuse melanocytosis, melanocytoma, malignant melanoma and meningeal melanomatosis. Meningeal melanocytosis is a benign proliferation of melanocytes with a risk of malignant transformation and is often associated with neurocutaneos melanosis. CASE REPORT: A 65-year-old male patient presented with low back pain and disturbed micturition. Neurological examination revealed left sided S1- sensory radiculopathy. His medical history was unremarkable. MRI of the lumbar spine showed a contrast-enhancing intrathecal tumour of the conus medullaris and MRI of the brain was suspicious of neoplastic meningitis. Spinal surgery exhibited a brown tumour mass with diffuse spreading of pigmented lesions along the arachnoidea. Histological, immunohistochemical, and molecular analyses showed an intrathecal melanoma with a wild-type BRAF genotype. Dermatological examination was unremarkable. Lumbar stereotactic radiotherapy was applied. Subsequently, 3 cycles of temozolomide (150mg/m2 on 5 days out of 28) and bi-weekly intrathecal liposomal cytarabine were administered. Despite the poor prognosis of neoplastic meningitis in melanoma, the patient survived without clinical for more than one year. 15 months after the initial diagnosis spinal MRI showed a local relapse and a second surgery was performed. This time molecular analysis of the tumor revealed the presence of the BRAF V600E mutation. Due to the initially slow tumor progression treatment with B-Raf inhibitors was withheld and immunotherapy with the anti-CTLA-4 antibody ipilimumab was initiated together with stereotactic radiotherapy of the conus medullaris. Three months later, the patient complained about diplopia and dizziness. Neurological examination revealed oculomotor nerve palsy. MRI of the brain showed a meningeal contrast-enhancement in the brainstem area. The B-Raf inhibitor vemurafenib was initiated in combination with intrathecally administered liposomal cytarabine and whole brain radiotherapy. Despite this the patient's condition deteriorated and he died two weeks later. Considering the long progression-free interval and the diffuse intrathecal melanocytic spread, the initial diagnosis of neoplastic meningitis was re-evaluated. Differential diagnoses include neoplastic meningitis from an unknown primary melanoma and malignant transformation of leptomeningeal melanocytosis. Retrospectively, we speculate that the patient had a leptomeningeal melanocytosis and consecutive malignant transformation. Treatment options are palliative and include intrathecal and systemic chemotherapy, radiotherapy, immunotherapy, as well as kinase inhibitors. Since evidence based guidelines are lacking therapy has to be selected on an individual basis.

Breast Cancer Leptomeningeal Metastasis: The Results of Combined Treatment and the Comparison of Methotrexate and Liposomal Cytarabine As Intra–Cerebrospinal Fluid Chemotherapy

BackgroundThis was a prospective observational study to assess the results of the treatment of patients with breast cancer leptomeningeal metastasis (LM) and to compare the efficacy of methotrexate and liposomal cytarabine in patients treated intrathecally by lumbar puncture. Patients and MethodsIn this prospective observational study, 149 consecutive patients with breast cancer and LM treated between the years 1999 and 2011 were assessed. Multimodality treatment methods were used: systemic therapy in 77 patients, radiotherapy in 92 patients, intrathecal methotrexate in 81 patients, and intrathecal liposomal cytarabine in 15 patients. ResultsThe median survival of all patients was 4.2 months. The median survival of patients in whom systemic intravenous/oral treatment was used was 6 months, in those who did not have systemic treatment, the median survival was 2 months (P < .001). The median survival of patients treated with intrathecal methotrexate was 4.2 months; in patients treated with intrathecal liposomal cytarabine, the median survival was 4.6 months, and in patients who did not receive intrathecal treatment, the median survival was 3.7 months (P = .717). Median survival after whole-brain radiotherapy was 4.6 months and with no radiotherapy, it was 3.2 months (P = .028). Multivariate analysis revealed a Karnofsky performance status (KPS) of > 70. Systemic intravenous/oral treatment and bone as a site of metastasis were factors prolonging survival from LM. ConclusionAmong treatment methods, only systemic therapy prolonged survival in patients with LM. Neither radiotherapy nor lumbar intrathecal therapy influenced survival in those patients; however, both methods alleviated signs and symptoms of LM. No difference in survival was observed in patients treated intrathecally with methotrexate and those treated with liposomal cytarabine. Treatment with both drugs was comparable.

Safety and tolerability of intrathecal liposomal cytarabine as central nervous system prophylaxis in patients with acute lymphoblastic leukemia

Central nervous system recurrence in acute lymphoblastic leukemia (ALL) occurs in up to 15% of patients and is frequently associated with poor outcome. The purpose of our study was to evaluate the efficacy and safety of a slow-release liposomal formulation of cytarabine for intrathecal (IT) meningeal prophylaxis in patients suffering from ALL. Forty patients aged 20–77 years (median 36) were preventively treated with a total of 96 (range 1–6) single doses containing 50 mg of liposomal cytarabine on a compassionate use basis. After a median observation period of 23 months (range 2–118) only two patients experienced a combined medullary–leptomeningeal disease recurrence after primary diagnosis. Except for headache grade 2 in two patients, no specific toxicity attributable to IT liposomal cytarabine application was noted. Long-term neurological side effects were not observed. IT liposomal cytarabine therapy with concomitant dexamethasone appears to be feasible and well tolerated.

Clinical Characteristics and Treatment Outcome Of CNS Involvement (Bing-Neel Syndrome) In Waldenstrom's Macroglobulinemia

BackgroundWaldenstrom's Macroglobulinaemia (WM) is an IgM secreting lymphoplasmocytic lymphoma characterized by involvement mainly in the bone marrow, and occasionally in the lymph nodes and spleen. Central nervous system involvement of WM, known as Bing-Neel syndrome (BNS), is very uncommon and as such the clinical characteristics and treatment outcomes remain to be clarified. MethodsWe evaluated the incidence, clinical characteristics, and treatment outcome of BNS among patients with WM who were diagnosed at our Institution. ResultsWe identified 13 patients with BNS from our database of 1,523 patients diagnosed with WM from 1999 -2013. The median age at diagnosis of BNS was 60 (range 51-75 years). The median time to development of BNS after WM diagnosis was 6.3 (range 0.3-11.9 years). Patients presented with a variety of neurological signs and symptoms including seizures, hearing loss, cognitive impairment, gait instability and lower extremity weakness. The diagnosis of BNS was confirmed by MRI in 11, and by examination of the CSF in 12 patients. CSF cytopathologic analysis demonstrated definitive evidence of malignant lymphoplasmacytic cells in 6 patients, and was suspicious for malignant cells in 2 patients. CSF flow cytometry was positive in 8, and a clonal immunoglobulin heavy chain gene rearrangement was identified in 6 patients. MYD88 L265P was identified in CSF sample of two patients in whom this examination was undertaken, and who demonstrated malignant disease by flow cytometry and cytological examination. Seven patients were treated with high-dose methotrexate (HD-MTX), 2 with intrathecal liposomal cytarabine, 1 with rituximab and intrathecal methotrexate, and 1 with rituximab and bendamustine. One patient was recommended treatment with HD-MTX and was lost to follow-up, 1 has been initiated on HD-MTX. Of 11 patients, 5 had a response in CSF and/or MRI, 4 had stable disease and 1 progressed following therapy. Of the responders, 2 patients had received HD-MTX, 2 intrathecal liposomal cytarabine and 1 rituximab-bendamustine. Four patients with stable disease had received HD-MTX. One patient who received intrathecal MTX developed treatment related “chemical meningitis”, and was subsequently treated with HD-MTX to which she had a CSF response. The median overall survival was not reached. Eleven patients are alive, 1 died and 1 was lost to follow-up. ConclusionsBNS is an uncommon late complication of WM. MYD88 L265P may help in the diagnosis of BNS, and may represent a novel approach for targeted therapy of WM. HD-MTX is active in the treatment of BNS, though prospective studies are required to standardize treatment and improve outcomes. Disclosures:No relevant conflicts of interest to declare.

Risk-Tailored CNS Prophylaxis In 194 Patients With Diffuse Large B-CELL Lymphoma (DLBCL) Treated In The Rituximab ERA: Risk Definition By Clinical Variables and Ontogenic Stratification

BackgroundCNS dissemination is an uncommon but lethal event in non-Hodgkin lymphomas. Early detection of CNS disease and a timely and effective CNS prophylaxis are the main strategies to reduce related mortality. However, both the criteria for recognition of lymphoma patients (pts) with increased risk of CNS involvement and the most effective prophylaxis modality remain important, unmet clinical needs. Some international guidelines recommend intrathecal chemotherapy by lumbar injection as exclusive prophylaxis; however, this strategy results in erratic, short-lived drug bioavailability and does not prevent brain parenchymal relapses. Herein, we report a retrospective analysis of the value of clinical variables and immunohistochemical ontogenic stratification in predicting CNS dissemination and of risk-tailored CNS prophylaxis in a mono-institutional series of 194 pts with DLBCL treated in the rituximab era. MethodsConsecutive HIV- adults with DLBCL without CNS involvement at diagnosis treated with first-line rituximab-CHOP or similar ± radiotherapy were considered. Primary CNS, mediastinal and cutaneous leg-type lymphomas were excluded. ‘High risk' of CNS relapse was defined by the involvement of the testis, spine, skull, orbit, nasopharynx, kidney, and/or breast or by IPI ≥2 (including two among extranodal sites ≥2, advanced stage and high serum LDH). DLBCLs were ontogenically subclassified in ‘germinal-centre B-cell-like' (GCB) and ‘non-germinal-centre B-cell-like' (non-GC) by immunohistochemistry following the Hans algorithm. Results194 patients were analyzed (median age 65, range 18-89; M:F ratio 1.1). Risk of CNS relapse was low in 90 pts and high in 104. Low-risk pt did not receive CNS prophylaxis, while 40/104 (38%) high-risk pts received 3-4 courses of methotrexate 3 g/m2 ± intrathecal (IT) liposomal cytarabine (n=30), cytarabine 16 g/m2 in 4 days (n=2) or IT chemotherapy (n=8). In the high-risk group, IPI ≥2 was more common among pts who did not receive prophylaxis (89% vs. 68%; p=0.006), while “high-risk” extranodal lymphomas were more common among pts who did (88% vs. 33%; p= 0.0001). One hundred and forty-one cases were assessable for Hans algorithm: 74 (52%) were GCB and 67 (48%) were non-GCB DLBCL. GCB DLBCLs were significantly associated with low CNS risk (55% vs. 31%; p= 0.004), and normal LDH levels (57% vs. 36%; p= 0.02); ontogenic stratification was not associated with high-risk extranodal sites, IPI ≥2, bone marrow infiltration, stage and systemic symptoms.After first-line treatment, 160 pts achieved a CR (82%; 95%CI= 77-87%), 34 pts had PD. At a median follow-up of 60 months (13-156), a single low-risk pt and 9 high-risk pts (1% vs. 9%; p= 0.016) experienced CNS relapse (exclusive site in all cases; brain in 5 pts, meninges in 5), with a median TTP of 12 months (7-55). CNS relapses occurred in 3 pts with IPI ≥2, in 1 pt with extranodal disease (testis) and in 5 pts with both features (kidney 3; testis, orbit). Ontogenic stratification was not associated with CNS recurrence, which was 5% for GCB and 6% for non-GCB; these figures were confirmed when analysis was limited to high-risk pts managed without prophylaxis.In the high-risk group, CNS relapses occurred in 7/64 (11%) pts who did not receive prophylaxis, in 2/8 (25%) pts who received only IT chemotherapy, whereas no CNS relapses were detected in the 32 pts treated with intravenous (IV) prophylaxis. CNS relapse rate was 13% for pts treated with “inadequate” prophylaxis (none or IT only) and 0% (p= 0.03) for pts managed with IV prophylaxis.Eight pts with CNS relapses died of lymphoma after 7-37 months (median 12), which represented 28% of all lymphoma-related deaths (n=29) in the high-risk group. Pts treated with IV prophylaxis had a significantly better OS than the other high-risk pts (5-yr: 94 ± 7% vs. 49 ± 6%; p= 0.001). ConclusionsStratification by specific extranodal sites and IPI is superior to ontogenic stratification to recognize CNS risk groups in DLBCL. However, the low sensitivity of predictive clinical variables suggests that molecular studies focused on the predictive and pathogenic role of molecules involved in CNS tropism will contribute to a more accurate definition of lymphoma candidates for CNS-directed strategies. In this context, IV high-dose methotrexate-based prophylaxis may significantly reduce CNS failures in high-risk pts. Disclosures:No relevant conflicts of interest to declare.

Pharmacokinetics and Toxicity of Intrathecal Liposomal Cytarabine in Children and Adolescents Following Age-Adapted Dosing

Assessment of the optimal drug dose for intrathecal therapy in children is challenging because of the non-linear increase in cerebrospinal fluid (CSF) volume throughout childhood and potential differences in the elimination rate in children versus adults. The present study was designed to prospectively collect pharmacokinetic and safety data on age-adapted intrathecal liposomal cytarabine in children aged >3years. Sixteen patients with malignant brain tumours were included in the study. Children aged 3-10years received liposomal cytarabine 35mg with concomitant dexamethasone, and those aged >10years received 50mg. Serial CSF and plasma samples were collected before administration and 1h, 12h, 24h, 1week and 2weeks post-dosing. CSF was analysed for free and encapsulated cytarabine, and plasma was analysed for free cytarabine. The average elimination half-life values in children aged 3-10years and in those aged >10years, treated with liposomal cytarabine 35mg and 50mg, respectively, were 40.9 and 43.7h for free cytarabine and 31.5 and 36.4h for encapsulated cytarabine in CSF. Although these values were lower than those previously reported, cytarabine concentrations exceeded the cytotoxic threshold of 0.1mg/L in all patients until 1week post-intraventricular administration. Cytarabine concentrations in plasma were negligible. In general, liposomal cytarabine was well tolerated, with relevant but manageable toxicities. Liposomal cytarabine in doses of 35mg for children aged 3-10years and 50mg for older patients shows sufficient drug exposure for at least 1week and appears to be well tolerated.

Central nervous system prophylaxis with intrathecal liposomal cytarabine in diffuse large B‑cell lymphomas

Central nervous system (CNS) involvement is a serious and potentially fatal complication in patients with lymphoma because it is associated with a particularly poor prognosis (median progression‑free survival [PFS] of 4-6 months). Although CNS prophylaxis is considered necessary, there are no clear guidelines on identifying high‑risk patients or selecting treatment regimen. The aim of the study was to assess the safety and efficacy of CNS prophylaxis with intrathecal liposomal cytarabine. We analyzed the data of 79 patients (46 men and 33 women; median age, 48.5 years [20-79]) with diffuse large B‑cell lymphoma (83.5% of the patients) and primary mediastinal large B‑cell lymphoma (16.5%). Patients were treated in the departments of hematology in Kraków and Wrocław, Poland, between the years 2009-2012. They were considered to be at a high risk of developing CNS involvement associated with a lymphoma. Adverse reactions after intrathecal liposomal cytarabine were reported in 59 patients (74.7%); in 7 cases, the reactions were severe. The most common side effect was headache (67.1%). During antilymphoma therapy and prophylaxis, the functional status assessed by the Karnofsky score improved in 56 patients (70.9%) and remained unchanged in the remaining cases. A median follow‑up time did not exceed 28 months (range, 1.4-52.1); during follow‑up, neither median overall survival (OS) nor PFS were reached (projected OS and PFS at 48 months are 86.1% and 90.1%, respectively). Our results encourage the use of intrathecal liposomal cytarabine in CNS prophylaxis in patients with lymphoma.

Skuteczność liposomalnej cytarabiny w leczeniu pierwotnego i wtórnego zajęcia ośrodkowego układu nerwowego w przebiegu chłoniaków nieziarniczych – ocena retrospektywna pacjentów leczonych w Klinice Hematologii UJ CM

Intrathecally-administered liposomal cytarabine (DepoCyte – slow release formula) is an efficient way of treatment in primary and secondary central nervous system (CNS) involvement in patients with non-Hodgkin lymphoma. Thirty-six patients with CNS lymphoma were analyzed. Median age was 48 years (18–73). There were 18 males and 18 females.In patients with lymphoma infiltrations circumscribed to cerebro-spinal fluid, intrathecal liposomal cytarabine alone allowed for 100% responses, with concomitant improvement of performance status (as assessed by Karnofsky score). None of the patients relapsed in CNS within an average observation time of 28 months.Intrathecal liposomal cytarabine combined with whole brain radiotherapy or/and CNS-penetrating chemotherapy allowed to obtain 85.7% cytological responses (90.9% in patients with primary CNS lymphoma): 50% CR and 28.6% PR. Patient's general status improved in 50% of patients.The treatment was well tolerated. Most of the associated adverse events (AE) were mild and moderate (grade 1–2 according to CTCAE); only 5.6% of AE were considered as severe. Headache was the most common complication; whereas cauda equina syndrome was considered as potentially the most dangerous condition. Transient cauda equina syndrome was observed in 1 patient (2.8% of all AEs).

Neurological and cytological response as potential early predictors of time-to-progression and overall survival in patients with leptomeningeal carcinomatosis treated with intrathecal liposomal cytarabine: a retrospective cohort study

Interesting neurological and cytological response rates after intrathecal (i.t) liposomal cytarabine have been observed in patients with leptomeningeal carcinomatosis (LMC) from solid tumors. However, the potential use of those responses as early predictors of time-to-progression (TTP) and overall survival (OS) is unexplored. 27 consecutive patients with LMC treated with 50 mg i.t liposomal cytarabine under compassionate drug use were retrospectively studied. All patients received i.t treatment every 2 weeks during induction and every 4 weeks during maintenance periods. Neurological and cytological responses were assessed before every liposomal cytarabine cycle. Most of the patients were female (17/27) diagnosed with breast cancer (15/27). A complete neurological response was seen among 11 % of the patients; partial response in 22 % of the patients; stable disease in 30 % of the patients and progressive disease in 37 % of them. Cytological assessment was available in 11/27 patients showing a 26 % complete response rate. The median time to neurological and cytological response was 15 days and 14 days, respectively. Patients showing a combined neurological and cytological response showed a significantly longer median TTP (122 vs. 3 days; p = 0.001) and OS (141 vs. 3 days; p = 0.002) compared to those showing both neurological and cytological progression. No grade 4 toxicities were recorded. According to these preliminary results, early neurological and cytological responses may be further studied as early predictors of TTP and OS in patients receiving i.t liposomal cytarabine for LMC.

A Multicentric Prospective Phase 2 Study of Intravenous Rituximab and Intrathecal Liposomal Cytarabine in Combination with C5R Protocol Followed by Brain Radiotherapy for Immunocompetent Patients with Primary CNS Lymphoma: A Lymphoma Study Association (LYSA) Trial

AbstractAbstract ▪796▪This icon denotes a clinically relevant abstract Background:The LNHCP93 trial is an intensive high-dose methotrexate and cytarabine containing chemotherapy (CT) derived from CT regimens used for Burkitt lymphomas (C5R protocol) followed by brain radiotherapy (RT) showing favourable long-term survival in Primary CNS Lymphoma (PCNSL) patients younger than 60 years: the complete response (CR) rate was 33%, the 5-year progression-free survival (PFS) and overall survival (OS) rates were 31% and 42%, respectively with however 9% of toxic death. Rituximab improves outcome of systemic Diffuse Large B-Cell Lymphoma (DLBCL) but it is unclear if its addition is useful in PCNSL with DLBCL histology. Intrathecal (IT) liposomal cytarabine (Depocyt) which shows a long-CSF half-life and better efficacy compared to IT methotrexate and free cytarabine in lymphomatous meningitis is also an attractive treatment for PCNSL. Methods:In order to improve antitumor activity of C5R protocol, we prospectively evaluated the addition of intravenous rituximab and IT liposomal cytarabine to CT before RT for 18 to 60 years old immunocompetent patients with PCNSL. The primary objective of this study is the complete and unconfirmed complete response rate (CR/CRu) after immuno-CT, according to International Primary CNS Lymphoma Collaborative Group response criteria. The number of patients was calculated in order to improve the 30% CR/CRu rate of LNHCP93 study up to 50%. The secondary objectives were side effect profile including acute and late neurological toxicities, PFS and OS. Patients received two courses of methotrexate, cyclophosphamide, doxorubicin, vincristine, prednisone (COPADEM) followed by two courses of methotrexate, cytarabine (CYM) administred at 21-day intervals from day 1 to day 21. At each day 1, intravenous rituximab 375mg/m2and at each day 3 IT liposomal cytarabine 50mg were infused. After immuno-CT, a brain RT was planned for all patients. A new response assessment was performed after RT. Patients were followed every 4 months for the first two years and then every 6 months. Neurotoxicity was evaluated by a Mini-Mental State Examination (MMSE) test. Results:Fifty-three PCNSL patients with a confirmed diagnosis of CD20 positive DLBCL were included between August 2007 and September 2011: median age was 55 years (range, 36–60), 57% were male, 42% had a performance status >1, 55% had an involvement of deep structures of brain, 45% a high CSF protein level and 36% a high LDH level. Median MMSE score assessed for 42 patients at baseline was 26 (range 3–30). After immuno-CT, 22 patients achieved a CR and 13 a CRu (CR + CRu, 66%), 7 a partial response (13%), 6 had a stable or progressive disease (11%) and 5 (10%) were not evaluated due to early death (n=2) or toxicities (n=3). For 45 patients who completed the fourth cycles, CR/CRu rate was 75.6%. Thirty-one patients (58%) presented at least one serious adverse event, mainly infections (25 patients, 47%). At least one red blood cell and platelet transfusions were given in 94% and 68% of patients, respectively and 57% of patients experienced a febrile neutropenia. Forty-two patients (79%) underwent RT, 23 of them with a reduced whole brain RT (median 26 Gy) and a boost to the tumor bed. With a median follow-up of 22 months, 15 patients progressed or relapsed (28.3%) and 13 patients died (24.5%), 3 (5.7%) of them from acute toxicity. The 2-year PFS and OS rates are 67% (95%CI, 50.0% to 79.4%) and 82% (95%CI, 67.0% to 90.7%), respectively. Median MMSE score was 27 (range, 26–30) for the 7 patients evaluated between 12 and 18 months after the beginning of treatment. Conclusions:With the addition of intravenous rituximab and intrathecal liposomal cytarabine, C5R protocol provided higher CR/CRu rate and promising outcome results with a 2-year PFS of 67% as compared to historical controls. No additional severe toxicities were observed compared to C5R protocol and with short follow-up no neurocognitive decline was observed. Disclosures:Off Label Use: Depocyt (intrathecal liposomal cytarabine) is off-label used in first line therapy of Primary CNS Lymphoma but approval for treatment of lymphomatous meningitis. Morschhauser:Roche: Honoraria. Blay:Roche: Honoraria, Research Funding.

429P - Neurological (NEU) and Cytological (CYT) Response (R) As Early Predictors of Time-To-Progression (TTP) and Overall Survival (OS) in Patients (PTS) with Leptomeningeal Carcinomatosis (LMC) Treated with Intrathecal (I.T) Liposomal Cytarabine (LYC)

ABSTRACT Background The palliative treatment of LMC involves i.t chemotherapy or supportive care. Lcy is a slow-releasing cytarabine formulation approved for leptomeningeal involvement of hematological malignancies. In pts with LMC from solid tumors interesting Neu and Cyt R rates after i.t Lcy have been observed. However, the potential use of those responses as early predictors of TTP and OS has never been explored. Here we show how both Neu and Cyt R can precociously predict a longer TTP and OS. Patients and methods: Twenty-seven pts with LMC consecutively treated at our institution with i.t Lcy under compassionate use (17/27 female), were studied. All pts received i.t Lcy (50 mg) every 2 weeks (w) during induction and every 4 w during maintenance. Neu and Cyt responses were assessed before every Lcy cycle. Results The predominant primary tumor origin was breast (15/27), followed by gastrointestinal (3), lung (3), brain (2), and 4 other organs. A complete Neu R (resolution of all Neu symptoms) was seen in 3/27 pts; partial R (improvement of >50% of Neu symptoms for >2 w) in 6/27 pts; stable disease (no change in Neu symptoms) in 8/27 pts and progressive disease (progression or appearance of new Neu symptoms) in 10/27 pts. The Cyt assessment was available in 9/27 pts with a Cyt complete R confirmed in 7/9 pts. The median time to Neu and Cyt R was 15 days (d) and 14 d, respectively. The overall median TTP was 22 d and the median OS was 41 d. In a subgroup analysis regarding the type of R achieved with the treatment, the median TTP and OS for pts showing a combined Neu and Cyt R were significantly longer compared to those in pts showing both, Neu and Cyt progression as shown in table 1. The most frequently reported adverse event was grade 2 headache with no grade 4 toxicities. Conclusions For the first time, Neu and Cyt R are shown to be early predictors of TTP and OS in pts receiving i.t Lcy for LMC. This result could help to early select patients most likely to benefit from i.t Lcy and to consider discontinuation when very poor prognosis is estimated. Neu R Cyt R TTP (d) OS (d) p Yes Yes 122 141 0.001 Yes No 14 32 0.001 No Yes 42 72 0.001 No No 3 3 0.001 Disclosure All authors have declared no conflicts of interest.

Flow cytometric detection of liposomal cytarabine in cerebrospinal fluid of patients treated with intrathecal chemotherapy

We report the unusual flow cytometric detection of liposomes in the cerebrospinal fluid of patients with aggressive non-Hodgkin's lymphoma and acute myeloid leukemia, treated with intrathecal liposomal cytarabine.

High-dose methotrexate and temozolomide associated with intrathecal liposomal cytarabine for the treatment of primary or secondary central nervous system lymphoma: A preliminary experience

Treatment of central nervous system (CNS) lymphoma remains challenge for clinicians. Historically, whole-brain radiotherapy WBRT) has been the cornerstone of treatment for brain lymhomas. However, after initial response, virtually all patients elapsed within short periods of time. The addition of systemic ytotoxic chemotherapy has significantly improved the outcome of NS lymphoma patients, but is often burdened with severe acute nd/or delayed neurotoxicity. Particularly in the over-60 populaion. Moreover, deferring radiotherapy to the time of relapse may educe or postpone the risk of severe neurotoxicity, without apparnt detrimental effect on overall survival (OS). Finally, a recent andomized trial suggested that there may not be an OS benefit rom the addition of radiation to systemic cytotoxic therapy [1]. Chemotherapy-only approaches, have therefore been explored. ecently, high-dose methotrexate and temozolomide (HD-MTXMZ), without IT therapy or consolidating radiotherapy have een tested in previously untreated PCNSL patients older than 60 ears. This regimen showed considerable activity, while apparently ecreasing neurotoxicity [2]. Liposomal cytarabine (LC) is a sustained-release intrathecal IT) preparation approved for the treatment of lymphomatous

Treatment for recurrent medulloblastoma with intrathecal liposomal cytarabine and systemic metronomic combination therapy

The prognosis of recurrent medulloblastoma is dismal, with a median survival of less than 1 year. Our patient was initially diagnosed with high-risk medulloblastoma when he was 14 years old. He had a recurrence 18 months after the end of therapy. Recurrence treatment consisted of 13 intrathecal applications of liposomal cytarabine over an 18-month period, and oral metronomic antiangiogenic therapy with thalidomide, celecoxib, and etoposide. Side effects from the intrathecal treatment were most likely related to arachnoiditis despite prolonged prophylaxis with steroids. He also developed partial hearing loss. Neutropenia was the main side effect of the metronomic therapy. He remains alive, with a good quality of life and without evidence of disease 34 months from the start of recurrence therapy. This combination of local antineoplastic and systemic antiangiogenic therapy seems to be promising for recurrent medulloblastoma. However, more patients and standardized protocols are needed to verify the benefit of this combination therapy and to define the correct duration of treatment.

Hearing Loss due to Infiltration of the Tympanic Membrane by Chronic Lymphocytic Leukemia.

Central nervous system (CNS) involvement by chronic lymphocytic leukemia (CLL) can present with dramatic neurologic findings or can be quite subtle, discovered only at the time of autopsy. We describe a case of CLL in a patient who presented initially with hearing loss and was ultimately found to have involvement of the tympanic membrane. She noted improvement of her hearing after induction therapy but was not aware at the time of the involvement of her CNS with CLL. Upon worsening of hearing at the time of relapse, she was evaluated by imaging and CSF analysis as well as biopsy of the tympanic membrane, and involvement of the CNS was confirmed. She has received CNS-directed therapy with intrathecal liposomal cytarabine and intravenous CNS-directed therapy and has noted improved hearing and resolution of her imaging and CSF findings. This is the first reported case of tympanic membrane involvement with CLL and describes potentially effective methods for managing this challenging complication.

RD‐CODOX‐M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and ‘unclassifiable’ highly aggressive B‐cell lymphoma

Specific trials on adult Burkitt lymphoma (BL) and 'unclassifiable' lymphomas with features intermediate between BL and diffuse large B-cell lymphoma (BL/DLBCL) are advocated which include substantial numbers of older patients, to improve treatment feasibility, while countering risks of systemic and central nervous system (CNS) recurrences. We prospectively evaluated a modified CODOX-M/IVAC (CODOX-M: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate; IVAC: ifosfamide, etoposide and high-dose cytarabine) regimen by the addition of rituximab (R) and liposome-encapsulated cytarabine (D) to increase antitumour activity and halve the number of intrathecal treatments. Thirty adults (40% >60years) with BL (n=15) and BL/DLBCL (n=15) were accrued. Primary endpoints were progression-free survival (PFS), CNS recurrence, and liposomal cytarabine-associated toxicity. Eighty percent of patients received the whole treatment programme, the remaining cases received at least three full courses. Application of the RD-CODOX-M/IVAC regimen resulted in remarkable 4-year PFS (78%) and complete remission (CR) rates (93%). However, PFS was significantly lower in patients older than 60years as compared to younger ones (49%vs 93%, P=0·03; median, 36months), despite high actual dose-intensity, CR rate and tolerability. Reduced-intensity intratechal prophylaxis through liposomal cytarabine was effective because the CNS failure rate was low (3·4%) and without severe neurological toxicities. The RD-CODOX-M/IVAC strategy is feasible and highly effective, but improving outcomes in elderly patients remains a priority.