CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

BACKGROUND: CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown. METHODS: Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal. RESULTS: Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab. CONCLUSIONS. Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

Case Report: Improvement Following Immunotherapy in an Individual With Seronegative Down Syndrome Disintegrative Disorder

Down syndrome disintegrative disorder (DSDD) is a condition of unknown etiology characterized by acute cognitive decline, catatonia, insomnia, and autistic features in individuals with Down syndrome. A prior report of four patients with DSDD suggested a potential autoimmune etiology based on the presence of autoantibodies and on successful treatment with immunotherapy that included intravenous immunoglobulin (IVIG). Herein, we present the case of an 8-year old girl who developed acute cognitive decline to a dementia-like state, insomnia, catatonia, and autistic features. In contrast to the four patients with DSDD above, she had no evidence of autoimmunity and presented at a younger age. Given the gravity of her acute deterioration and the exclusion of other etiologies, she was treated with immunotherapy presumptively. She responded with near complete resolution of symptoms, but demonstrated a pattern of mild decline as she approached each monthly dosing of IVIG and steroids, reversed by treatment. Mycophenolate mofetil (MMF) was therefore added, with stability throughout the month and the ability to taper off IVIG. After stopping IVIG, she had a mild recurrence of symptoms that again resolved with repeat IVIG followed by tapering off. Outcome was assessed at 2.5 years after presentation, at which time she was back to her premorbid condition, except for persistent tics off immunotherapy. This case supports the contention that patients with a rapid onset of severe symptoms consistent with DSDD, who have a thorough evaluation with the exclusion of other etiologies, may warrant a trial of immunotherapy with steroids, IVIG and/or other agents like MMF even in the absence of evidence of autoimmunity on standard evaluation.

Dosing interval adjustment of denosumab for the treatment of giant cell tumor of the sphenoid bone: A case report

Background: In the treatment of giant cell tumor of bone (GCTB), the efficacy and safety of denosumab, a receptor activator nuclear factor κ-B ligand inhibitor, has previously been demonstrated, especially for unresectable tumors. One of the current issues in denosumab treatment for unresectable GCTB is whether it can be discontinued, or whether the dosage or the dosing interval can safely be adjusted, if discontinuation is not possible, to avoid the occurrence of side effects. Case Description: A 15-year-old boy with diplopia was referred to our hospital after a space-occupying lesion in the sphenoid bone was found on head CT. Partial removal of the tumor was performed through an endoscopic endonasal approach, and pathological diagnosis was confirmed as GCTB. Thereafter, the patient received 120 mg subcutaneous injections of denosumab every 28 days for the first 2 years. Since bone formation was induced and sustained along with tumor reduction, the dosing interval was gradually extended, with 4 monthly dosing for the next 1 year, followed by 6 monthly dosing for the succeeding 2 years. With the extension of the dosing interval, the ossified tumor has regrown slightly, but within an acceptable range. Conclusion: Discontinuation of denosumab treatment for unresectable GCTB was not thought to be possible for the current case due to the nature of the drug, as reported in the literature. Extending the dosing interval up to 6 monthly, as could be done safely in the current case, can be considered a useful and appropriate measure.

Model Based Approach to Evaluate Isatuximab Monthly Dosing Regimen in Relapsed/Refractory Multiple Myeloma Patients

Background: Isatuximab (Isa) is a CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement (Moreno, Clin Cancer Res, 2019). The addition of Isa to pomalidomide (P) and dexamethasone (d) was associated with a significant and clinically meaningful benefit in progression-free survival (PFS) in heavily pre-treated patients with relapsed/refractory multiple myeloma (RRMM) (ICARIA-MM, NCT02514668) (Attal, Lancet, 2019). Isa, in combination with Pd, is approved in the United States, the European Union, Canada, Australia, Switzerland, and Japan for the treatment of adult patients with RRMM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. Aim: The objectives were to characterize the relationship between serum M-protein kinetics and PFS in RRMM using data from the Phase 3 ICARIA-MM study and to simulate expected longitudinal serum M-protein and PFS when switching to a hypothetical monthly dosing regimen after 6 months. Methods: A joint model of serum M-protein dynamics and PFS was developed using data from 256 evaluable ICARIA-MM patients. Patients received Isa intravenously at 10 mg/kg once weekly (QW) for 4 weeks, then every other week (Q2W) for 28-day cycles in combination with standard Pd (Isa-Pd) or Pd alone in the control arm. A tumor growth inhibition model was used to describe the serum M-protein kinetics under treatment effects of Isa-Pd or Pd alone, in which Isa exposure was predicted using individual PK parameters obtained from the population PK analysis (Fau, Population Approach Group in Europe, 2019) and Pd exposure was predicted from K-PD model using dosing history. Trial simulations were then performed using individual PK/PD parameters of ICARIA-MM patients to evaluate whether efficacy is maintained after switching to a monthly dosing regimen. Results: The joint model identified the instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and also identified baseline patient characteristics impacting serum M-protein kinetics (serum albumin and serum β2 microglobulin on the baseline serum M-protein levels and the non-IgG type on the serum M-protein growth rate, the serum M-protein slope), and PFS (presence of plasmacytomas). Non-IgG MM patients have similar behavior on serum M-protein kinetics for the first 60 weeks even with higher exposure and similar progression free survival compared to IgG MM patients supporting the non-dose adjustment based on IgG status. Clinical trial simulation of the ICARIA-MM Isa-Pd regimen demonstrated that switching all patients on treatment at 6 months to a monthly Isa regimen would shorten the median time to progression (TTP) (i.e. increase in serum M-protein greater than 25% and an absolute increase greater than 5 g/L compared to nadir) by 4.1 weeks and would shorten median PFS by 2.3 weeks (from 14.03 to 13.45 months). Based on TTP criteria, patients with no risk of earlier progression (57.7%) due to 6 months switch tend to have lower baseline tumor burden (lower serum M-protein and lower percent of bone marrow plasma cell) and better prognostic factors (higher glomerular filtration rate, higher albumin, lower β2 microglobulin). At 6 months, 85% of these patients had predicted stable "at least" VGPR status. Conclusions: Trial simulations supported the choice of the approved isatuximab 10 mg/kg QW/Q2W regimen and showed that switching to a monthly Isa regimen after 6 months may reduce clinical benefit in overall population. However, a subpopulation of patients with good prognosis and obtaining stable at least VGPR status by 6 months may switch to a monthly regimen after 6 months without compromising disease progression risk; this hypothesis will be tested in a prospective clinical trial. Model-based drug development has been successfully applied to support treatment decisions in RRMM patients. Disclosures Thai: Sanofi: Current Employment. Gaudel-Dedieu:Sanofi: Current Employment. Cerou:Sanofi: Current Employment. Sebastien:Sanofi: Current Employment. van de Velde:Sanofi: Current Employment, Current equity holder in publicly-traded company. Semiond:Sanofi: Current Employment. Veyrat-Follet:Sanofi: Current Employment.