No Early Effect of Intrathecal Rituximab in Progressive Multiple Sclerosis (EFFRITE Clinical Trial).

BACKGROUND: The progressive phase of multiple sclerosis (MS) is characterized by an intrathecal (IT) compartmentalization of inflammation, involving B-cells within meningeal follicles, and resisting all the available immunosuppressive treatments. A new therapeutic paradigm may be to target this inflammation by injecting immunosuppressive drugs inside the central nervous system compartment. METHODS: We designed a single-center, open-label, randomized, controlled, phase II study designed to evaluate the safety and efficacy of IT rituximab in progressive MS (EFFRITE trial; ClinicalTrial Registration NCT02545959). Patients were randomized into three arms (1 : 1 : 1): control group, IT rituximab (20 mg, IT) group, and intravenous+IT (IV+IT) group. The main outcome was a change in levels of CSF biomarkers of inflammation (osteopontin). Secondary outcomes were changes in levels of CSF biomarkers of axonal loss (neurofilament light chain) and clinical and MRI changes. RESULTS: Ten patients were included (2 : 4 : 4). No adverse event occurred. OPN level remained stable in CSF at each time point, whereas NFL had slightly decreased (-8.7%) at day 21 (p = 0.02). Clinical parameters remained stable and leptomeningeal enhancements remained unchanged. CONCLUSION: Clinical outcome and biomarkers of inflammation were not dramatically modified after IT injection of rituximab, probably due to its limited efficiency in CSF. Drug issues for future studies are discussed.

Intrathecal rituximab therapy in multiple sclerosis: review of evidence supporting the need for future trials.

Rituximab has demonstrated a major effect in B-cell lymphoma and in a wide range of autoimmune disorders. Unfortunately, the blood-brain-barrier excludes the disorders restricted to the central nervous system (CNS) from the action of rituximab. The progressive phase of multiple sclerosis (MS) is a prototypical CNS autoimmune disorder characterized by an intrathecal compartmentalization of inflammation resisting all the available immunosuppressive treatments. As a consequence, intrathecal therapeutics are promising new approach in progressive MS. We first review data gathered from animal models and human off-label intrathecal rituximab use in CNS lymphomas, then summarize the recent evidence supporting the need for trials based on the intrathecal use of rituximab in multiple sclerosis. The experience obtained in these settings offers valuable preliminary data for future studies in CNS autoimmunity.

Environmental and biological monitoring of platinum-containing drugs in two hospital pharmacies using positive air pressure isolators.

Environmental and biological monitoring of platinum containing drugs was implemented in two French hospital pharmacies using positive air pressure isolators and having similar working procedures when preparing antineoplastic drugs. Wipe sampling of surfaces, gloves, and vials was performed in the preparation room and in storage areas. All employees involved in the preparation of antineoplastic drugs were tested for urinary platinum on Monday before work and Friday after shift. Only traces of platinum were detected on surfaces in the preparation room outside the isolators (less than 1.61 pg cm(-2)). However, in one center, significant contamination was found in the storage area of the drug vials, which can most likely be linked to the rupture of a platinum vial and due to inefficient cleaning procedures. Surfaces inside the isolators were found to be contaminated (maximum: 198.4 pg cm(-2)). A higher level of contamination was detected in one pharmacy and could be explained by the lack of overgloving with regular changes during the preparation process. Nitrile gloves used during drug handling outside the isolator showed the highest platinum concentration (maximum: 5.86 ng per pair). With regards to platinum urine concentration, no significant difference was found between exposed and unexposed pharmacy personnel. Isolator technology combined with individual protective measures seems to be efficient to protect workers from occupational exposure to antineoplastic drugs, whereas specific individual protective procedures implemented were focussing on the risk of handling vials outside the isolator (e.g. high frequency of glove changing). Moreover, overgloving inside the isolator would contribute to substantially decrease inner surface contamination and should be recommended in order to limit the transfer of chemical contamination to the end products.

Severe sinusoidal lesions: a serious and overlooked complication of oxaliplatin-containing chemotherapy?

The main toxicity of Oxaliplatin, a major drug in the treatment of metastatic colorectal carcinoma, is neurologic. Severe sinusoidal lesions of the liver have been recently described in patients receiving pre-operative (neoadjuvant) oxaliplatin-containing chemotherapy, but their clinical relevance is unknown. Four patients with metastatic colon cancer receiving oxaliplatin, 5 fluorouracil and elvorin, developped a progressive increase in gammaglutamyl transpeptidase and alkaline phosphatase, contrasting with tumour regression established by CT-scan and decrease in serum carcinoembryonic antigen concentrations. Histological examination of liver biopsies showed sinusoidal dilatation in all cases, with perisinusoidal fibrosis and centrilobular vein lesions in 3, peliosis in 1 (in a patient receiving oxaliplatine by intraarterial hepatic route), and nodular regenerative hyperplasia in 1. The patient with peliosis developped ascites, and died from hepatic failure, despite withdrawal of the drug. The patient with nodular regenerative hyperplasia developped jaundice, ascites and severe infection following a right hepatectomy. In the three surviving patients, liver function tests improved after the withdrawal of oxaliplatin, and, in one, deteriorated again after reintroduction of the drug. The prevalence of liver sinusoid lesions induced by oxaliplatin-containing chemotherapeutic regimens is probably underestimated. Careful monitoring of gamma-glutamyl transpeptidase and alkaline phosphatase is mandatory in treated patients, especially in those receiving adjuvant therapy, in whom significant sequelae could occur despite initially asymptomatic lesions.

Imatinib mesylate-induced acute hepatitis in a patient treated for gastrointestinal stromal tumour.

We report the first case of hepatocellular injury occurring in a patient treated for metastatic gastrointestinal stromal tumour (GIST) with imatinib mesylate, with two positive rechallenges including one with 2.5% of the current therapeutic dosage. The patient could be treated later with sunitinib without liver toxicity. Grade 3-4 liver toxicity could occur in one out of 40 treated patients with imatinib for GIST, and fatalities have been reported. Regular monitoring of liver function tests is essential in patients treated with imatinib.