Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally.
OBJECTIVE
We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment.


METHODS
Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2-3 months.


RESULTS
The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3-6 month period.


CONCLUSIONS
Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments.


METHODS
This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes.
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Anders
A
Svenningsson
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Joakim
J
Bergman
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Ann
A
Dring
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Mattias
M
Vågberg
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Richard
R
Birgander
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Thomas
T
Lindqvist
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Jonathan
J
Gilthorpe
Department of Pharmacology and Clinical Neuroscience (A.S., J.B., A.D., M.V., J.G., T.B.) and Department of Radiation Sciences (R.B., T.L.), Diagnostic Radiology, Umeå University, Sweden.
Tommy
T
Bergenheim