Mitigating alemtuzumab-associated autoimmunity in MS

Abstract

ObjectiveTo determine whether the punctuated administration of low-dose rituximab, temporally linked to B-cell hyperrepopulation (defined when the return of CD19+ B cells approximates 40%–50% of baseline levels as measured before alemtuzumab treatment inception), can mitigate alemtuzumab-associated secondary autoimmunity.MethodsIn this hypothesis-driven pilot study, 10 patients received low-dose rituximab (50–150 mg/m2), a chimeric anti-CD20 monoclonal antibody, after either their first or second cycles of alemtuzumab. These patients were then routinely assessed for the development of autoimmune disorders and safety signals related to the use of dual monoclonal antibody therapy.ResultsFive patients received at least 1 IV infusion of low-dose rituximab, following alemtuzumab therapy, with a mean follow-up of 41 months. None of the 5 patients developed secondary autoimmune disorders. An additional 5 patients with follow-up over less than 24 months received at least 1 infusion of low-dose rituximab treatment following alemtuzumab treatment. No secondary autoimmune diseases were observed.ConclusionsAn anti-CD20 “whack-a-mole” B-cell depletion strategy may serve to mitigate alemtuzumab-associated secondary autoimmunity in MS by reducing the imbalance in B- and T-cell regulatory networks during immune reconstitution. We believe that these observations warrant further investigation.Classification of evidenceThis study provides Class IV evidence that for people with MS, low-dose rituximab following alemtuzumab treatment decreases the risk of alemtuzumab-associated secondary autoimmune diseases.

Treating MS after surviving PML: Discrete strategies for rescue, remission, and recovery patient 2

“…We believe that the timely identification of PML, followed by prompt intervention with PLEX and employment with one of the AIDS-PML corticosteroid IRIS-dampening regimens in those undergoing highly active antiretroviral therapy 13 were paramount to mitigating both our patient's morbidity and mortality. Furthermore, alemtuzumab therapy in conjunction with our “Whack-A-Mole” B-cell depletion strategy 14 was used for purposes of promoting a durable remission and potentially to obviate the development of alemtuzumab-associated secondary autoimmunity.…”

“…After cellular depletion, bone marrow mobilization of B lymphocytes in large numbers occurs producing a discordant B cell hyper-repopulation (generally within 3–6 months) with T cells approximating baseline levels at 12–24 months. This period of B cell hyper-repopulation includes the presence of CD20 + T cells—exhibiting a proinflammatory phenotype, which has been hypothesized to promote B cell antigen presentation in the absence of T cell help—a time where B cells cannot differentiate between self and non–self-epitopes; and which may be mechanistically germane to the high incidence of secondary autoimmunity associated with alemtuzumab DMT in MS. 14 …”

“…Furthermore, she was treated with the “Whack-A-Mole” B cell depletion regimen with 100 mg of rituximab when her CD19 + cells approximated 40%–50% of baseline levels. 14 …”

“…After cellular depletion, bone marrow mobilization of B lymphocytes in large numbers occurs producing a discordant B cell hyper-repopulation (generally within 3-6 months) with T cells approximating baseline levels at 12-24 months. This period of B cell hyper-repopulation includes the presence of CD20 + T cells-exhibiting a proinflammatory phenotype, which has been hypothesized to promote B cell antigen presentation in the absence of T cell help-a time where B cells cannot differentiate between self and non-self- epitopes; and which may be mechanistically germane to the high incidence of secondary autoimmunity associated with alemtuzumab DMT in MS. 14 A recently published report theorized that a "Whack-A-Mole" B cell depletion strategy involving the punctuated administration of 100 mg of rituximab, temporally synchronized with the return of B lymphocytes, may be capable of mitigating secondary autoimmunity associated with alemtuzumab DMT for MS by abolishing the discordant and precocious B cell hyper-repopulation while also deleting CD20 + T cells.…”

N2 year in review

“…Independent of alemtuzumab treatment, the corresponding primary (idiopathic) humoral autoimmune conditions are sometimes treated with anti-CD20 B-cell depletion. Meltzer et al 55 therefore hypothesized that scheduled anti-CD20 B-cell depletion could mitigate against the risk for alemtuzumab-induced secondary autoimmunity. In a 10-patient pilot study, they administered low-dose (50–100 mg/m 2 ) RTX after the first or second cycle of alemtuzumab.…”