Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). In the OPERA trials, circulating CD19+ B-cell counts dropped to zero within 14 days of OCR infusion. Median time to repletion, defined as >79 cells/uL, was 72 weeks (range 27-175 weeks). Up to 5% of patients showed B-cell repletion during treatment. We sought to determine the frequency of patients on OCR who have significant B-cell reconstitution at the time of their next 6-month dose, and to determine if there is a correlation between early B-cell reconstitution and disease breakthrough or adverse events (AEs).

Objectives

As part of the ACAPELLA trial, a prospective study with a primary objective of assessing OCR-associated AEs in a real-world MS population, we sought to evaluate the frequency and duration of early B-cell reconstitution and its relationship to disease activity and AEs.

Methods

All subjects receiving OCR at the Elliot Lewis Center since March 2017 who consented to participate had serum immunoglobulin levels, JCV antibody titers, and lymphocyte subsets on the day of each infusion prior to receiving OCR. Subjects were followed prospectively and monitored for the occurrence of infections and other serious adverse events (SAEs).

Results

As of December 2019, 291 patients had been treated with OCR and enrolled in ACAPELLA: 181 had been treated for at least 12 months, 131 had been treated for 18 months, and 84 subjects had reached 24 months. Of the 291 subjects, 207 had CD19 values drawn at an infusion. One hundred eighteen subjects (57%) displayed ≥1 cell/uL: 81 subjects (39%) had between 1-15 cells/uL, 32 (16%) between 16-79 cells/uL, and 5 (2%) >79 cells/uL. Thirteen patients with B-cell reconstitution at 12 months had early reconstitution with future infusions. Two of the subjects with CD19 values >15 cells/uL experienced clinical or MRI relapse, compared to 8 subjects that did not have B-cell reconstitution.

Conclusions

Although many patients displayed some B-cell repopulation prior to their next dose (113 subjects), CD19 counts of >79 cells/uL were uncommon (5 subjects). Subjects with early B-cell reconstitution at one infusion were likely to continue to show early repopulation at future infusions. Thus far, we have found no significant correlation between B-cell repopulation and either disease activity or adverse events.

Background

Ocrelizumab (OCR) is a humanized anti-CD20 monoclonal antibody approved for the treatment of relapsing remitting (RRMS) and primary progressive multiple sclerosis (PPMS). Immunoglobulin levels were monitored during the phase III trials, and 1.5% of patients developed low immunoglobulin G (IgG) values after 2-3 years of OCR treatment, potentially increasing the risk of infections. The JCV antibody index used to stratify PML risk in patients treated with natalizumab was not studied and the impact of long-term B-cell suppression on JCV and IgG titers is unknown.

Objectives

As part of the ACAPELLA trial, a prospective study with a primary objective of assessing OCR-associated adverse events (AEs) in a real-world MS population, we sought to evaluate the impact of OCR treatment on immunoglobulin levels and JCV titers over time.

Methods

The study includes all subjects receiving OCR at the Elliot Lewis Center followed prospectively since March 2017. Subjects are monitored for occurrence of infections and other serious adverse events (SAEs) and have biannual assessments of serum immunoglobulin levels and JCV antibody titers.

Results

As of December 2019, 291 patients have been treated with OCR and enrolled in ACAPELLA: 181 have been treated for at least 12 months, 131 have been treated for 18 months, and 84 subjects have reached 24 months. Two hundred eighty-one of the total 291 subjects had IgG levels drawn at baseline. Twenty-seven subjects (10%) had IgG levels below the lower limit of normal (LLN) at baseline. Of the 27 patients with low IgG at baseline, 19 have received treatment for at least 12 months. Of those 19, 4 patients were seen to have a >10% drop in IgG level after 12 months. Ten patients developed at least one low IgG level after 12-24 months of treatment exposure, although many returned to normal.

Two hundred eighty-one of the 291 patients had a baseline JCV index. Ninety-three (33%) had titers <0.4, 73 (26%) between 0.4-1.5, and 115 (41% >1.5. In our two-year data, three patients had a change in JCV status from positive to negative between 12 and 24 months of treatment duration. Year three data is characterized in the poster.

Conclusions

The frequency of persistent hypogammaglobulinemia was low in this cohort of patients and thus far has not been associated with an increased risk of infection. Three patients had a change in JCV status from positive to negative, and the effect of JCV index in the remaining subjects is further characterized.

Background

Ocrelizumab (OCR) is a humanized, monoclonal antibody targeting CD20+ B cells and is approved for treatment of relapsing remitting (RRMS) and primary progressive MS (PPMS). The ACAPELLA trial is a prospective study with a primary objective of assessing OCR-associated adverse events (AEs) in a real-world MS population. ACAPELLA includes patients with preexisting conditions exempted from the phase II & III clinical trials, such as a prior history of malignancy, prior immunosuppressive treatment, and more advanced age and/or disability. Interim data analyses occur on a biannual basis and findings are reported yearly. This is the third iteration.

Objectives

We sought to determine the frequency of serious infections and malignancy in a real-world population receiving OCR with characteristics outside the inclusion parameters of the phase II and III trials.

Methods

The study includes all subjects treated with OCR at the Elliot Lewis Center since its commercial release in March 2017. Initial assessments include EDSS, brain MRI, mammograms (standard of care), collection of medical history including prior serious or recurrent infections, history of malignancy and exposure to immunosuppressive treatment, JCV index, and CD19 count.

Results

As of interim analysis in December 2019, 291 subjects were enrolled, 181 subjects had reached 12 months of treatment, 131 subjects had reached 18 months, and 84 subjects had reached 24 months. Subjects were 29% male, 71% female, with an age range of 18-73. Sixty three percent had RRMS and 37% PMS (PPMS and progressive RRMS) with an EDSS range of 0–7.5; 25% had a baseline EDSS of ≥ 6.0 with a median of 3.0.

The rate of infections for all OCR-treated patients was 43% (6% bronchitis, 2% zoster, 56% URIs, 30% UTIs, 4% HSV, and 25% other infections). Four percent of subjects had a serious infection (one that required hospitalization, was felt to be life-threatening, or resulted in death). Three percent of subjects had clinical or MRI relapses. 8% of subjects had a history of prior neoplasm (excluding basal cell carcinoma). Two malignancies have occurred during OCR treatment.

Conclusions

Thus far, the incidence of AEs is comparable to that seen in the phase III trials and in previously reported ACAPELLA data. Additional topics of interest in the ACAPELLA population include the effect of continued OCR dosing on JCV index values and immunoglobulin levels, and changes in EDSS and MRI over time.