Clinical outcomes of patients with multiple sclerosis treated with ocrelizumab in a US community MS center: an observational study

Study design

This was a prospective cohort study that used data collected from patients who participated in the POR. Patients were provided information about voluntary participation in the POR after their physicians prescribed ocrelizumab in accordance with the FDA approved label for the treatment of MS. Upon obtaining patient consent, demographic, clinical, MRI, medication history and laboratory data were collected through chart review by an experienced RN data abstractor at the time each patient started ocrelizumab and at each subsequent ocrelizumab 600 mg treatment course.

Setting and participants

This ongoing registry enrolls patients at an outpatient MS centre located in Portland, Oregon, which consists of 5 clinicians and a team of clinical and research support staff treating over 2500 patients with MS. The Providence MS Center is part of a non-profit health system, providing care to an ethnically and socioeconomically diverse patient population throughout Oregon and Southwest Washington State.

Patients, aged 18 years and older, irrespective of sex, diagnosed with RMS, secondary progressive MS (SPMS) and PPMS, prescribed ocrelizumab between 28 March 2017 and 29 February 2020, and signed a research authorisation form to participate in the POR, were included in this study. There were no excluding criteria except for patients who did not sign the authorisation form, and they were not enrolled in the registry. Patients could withdraw their authorisation to participate in the registry at any time, but the data collected up to the time of withdrawal has remained in the database.

Demographic data collected include age, sex, race and ethnicity, date of symptom onset, date of diagnosis, history of heart disease, history of cancer, and MS pattern. Baseline data collected included the three most recently previously prescribed disease-modifying treatments (DMTs), relapses in the 24 months prior to starting ocrelizumab, MRI results prior to start of ocrelizumab, and Expanded Disability Status Scale (EDSS). Data collected after starting ocrelizumab included routine lab studies, AEs, hospitalisations, reason for discontinuation, relapses, MRI and EDSS.

Each chart review included all office visit notes, emergency room visits and hospital records. If a patient had healthcare encounters outside of the Providence Health System, those notes were made available for review either directly from the outside facility where care was provided or through the EPIC electronic medical record (EMR) Care Everywhere function, which, with patient consent, allows sharing of information in the EMR across clinics and hospitals. The occurrence of AEs of interest, including infections, hospitalizations and cancer, were collected at each clinic visit. Ocrelizumab (600 mg) was administered intravenously every 6 months in a hospital or clinic infusion centre under supervision of medically qualified personnel. The first course included two infusions of ocrelizumab 300 mg given 14 days apart.

Clinical relapses, EDSS, laboratory assessment, and MRI results

Each clinical relapse was verified at an in-person office visit by one of the treating neurologists of the Providence MS Center, each an expert in the diagnosis and treatment of MS. Clinical relapse was defined as new or worsening neurological symptoms, which persisted for more than 24 hours, in patients who had been clinically stable for 30 or more days before the event and was not attributable to other factors such as fever or infection. Although EDSS was not calculated at relapse assessment visits, each relapse required objective evidence of a change on neurological examination and/or MRI. The annualised relapse rate (ARR) was calculated by dividing the number of relapses by the number of years on medication for each patient.

Baseline EDSS scores were obtained, by the treating physician, prior to the first course of ocrelizumab, and at yearly clinic visits. EDSS was not calculated for other clinic visits. All the examiners were level C Neurostatus-certified Kappos 2009 revision EDSS raters.

Laboratory testing, including hepatic panel, complete cell count and immunoglobulin levels, was performed prior to starting ocrelizumab and within a month prior to each subsequent infusion.

The MRIs were performed prior to initiating ocrelizumab, 6 months after starting ocrelizumab and yearly thereafter. Imaging was performed on a 1.5 or 3.0 T MRI scanner, using a standardised MS protocol, with 5 mm contiguous gap-free slices of the brain. Neuroradiologists with extensive experience in diagnostic imaging for MS interpreted the scans. Brain MRI sequences included T1-weighted and T2-weighted axial, fluid-attenuated inversion recovery axial and sagittal, diffusion-weighted axial and gadolinium-enhanced T1-axial views and axial diffusion weighted images. MRI changes were defined as new or enlarging T2 lesions and/or presence of gadolinium-enhancing (Gd+) T1 lesions. For spinal MRIs, sagittal T2 imaging was performed with a 3 mm slice thickness and a 4 mm gap, and axial T2 imaging consisted of volumetric acquisition, reconstructed at 1 mm interval with 0.5 mg gap.

Statistical analysis

Demographics, prior DMT use, ARR for 24 months prior to starting ocrelizumab, number of ocrelizumab courses received, EDSS, AEs, hospitalisations, time on ocrelizumab, serum IgM/IgG levels and ocrelizumab discontinuations were summarised as percentages, means (SD) or medians (IQR = (Q1, Q3)) as appropriate. Bivariate analyses were performed using chi-square and t-test to determine if there were any differences between patients who relapsed and those who did not, as well as for those who did and did not have infections. Paired t-test were used to determine if there were improvements over time in Modified Fatigue Impact Scale (MFIS) and the Beck Depression Inventory-II (BDI-II) comparing baseline and 12 months. SPSS V.26 (IBM Corp.) was used for analysis.

To examine the effect of serum immunoglobulin (Ig) levels on the risk of infection, analyses were conducted separately for OCR courses starting at 6, 12 and 18 months. For each course, the Ig levels collected immediately before OCR treatment were included in logistic regression analyses as potential predictors for the risk of infection developed during the 6-month course following OCR treatment. Low IgG levels were defined as IgG ≤680 mg/dL and low IgM levels as IgM ≤45 mg/dL. A total of six univariate and multivariable logistic regression analyses were conducted: one per course for both IgG and IgM as the predictors of interest. Proportions of subjects who developed infections as well as unadjusted and adjusted ORs with 95% CIs and associated p values are presented. Multivariable logistic regression analyses included age (≤55 vs >55), sex, previous DMT (treatment naïve vs at least one DMT), disease duration, and MS pattern (PMS vs not PMS) as the covariates. For each analysis, only subjects with complete outcome and covariate data were included.

Patients missing lab values, EDSS, imaging, MFIS or BDI-II scores were excluded from those analyses.

Demographics

Of 355 patients enrolled, 71.9% were female, 90.5% were white, 78.3% had RMS, 13.2% had SPMS, and 8.5% had PPMS. The mean (SD) age was 51.8 (12.5) years (table 1). The median duration of disease was 12 years (IQR: 6.5–18.4) for RMS, 18.7 years (IQR: 12.1–23.7) for SPMS, and 12.7 years (IQR: 7.7–17.2) for PPMS (table 2).

Almost 50% of patients switched from natalizumab (NTZ) (18.9%), dimethyl fumarate (15.1%) or fingolimod (15.1%), and 27.4% were treatment naïve. Median time on ocrelizumab (IQR) was 23.6 (19.0–29.7) months. Approximately 59% of patients had been on ocrelizumab for 2 years or more. Of 332 patients who had two or more 600 mg courses of ocrelizumab, more than 85% have had at least four chart reviews since their first infusion.

Safety

Infusion reactions were more prevalent in patients receiving the initial course of ocrelizumab and became less frequent with each subsequent infusion (figure 1). Other common AEs were respiratory infections, occurring in 40.1%, and urinary tract infections (UTI) in 33.1% of patients (table 3). There was no difference in the percentage of infections among patients under the age of 55 (68.5%, n=122), and those 55 or older (67.5%, n=104) (p=0.94). Sixty-three hospitalisations occurred in 37 patients; 24 of the hospitalizations resulted from infection, the majority being UTIs (63%) and five of these patients developed urosepsis. Sixty-nine percent of hospitalised patients were 55 years or older (mean age 58.2±12.5). The mean EDSS of those who were hospitalised was 5.7 (±1.86). Thirty-two patients (9%) had a history of cancer, and eight patients were newly diagnosed with cancer after starting ocrelizumab (basal cell (4), breast cancer (2), each diagnosed at 7 and 23 months after starting ocrelizumab), recurrent thyroid cancer (1), and melanoma (1)). Forty-three (12%) patients discontinued ocrelizumab after a median duration (IQR) of 10.8 (6.1–18.9) months, 24 due to side effects, 15 due to a relapse or clinical progression, and 4 due to death (table 4).

Request permission

The first death occurred in a 58-year-old patient with RMS and a baseline EDSS of 6.0 4 months after the second course of ocrelizumab at 6 months. The patient reported increased shortness of breath, declined to be seen at the emergency department, and was found dead at home the following day. The second death was a 56-year-old with SPMS and a baseline EDSS of 7.5. The patient died just prior to receiving the scheduled 12-month infusion of ocrelizumab due to urosepsis. The patient had multiple hospitalisations for treatment of infections during the 2 months prior to their death. The third death was a 45-year-old patient with RMS and a history of severe depression, who committed suicide 3 months after their 2 baseline 300 mg ocrelizumab infusions. The fourth death was a 61-year-old patient with RMS who died of pneumonia and septic shock 2 months after receiving the 2 baseline 300 mg ocrelizumab infusions.

Grade III lymphopenia occurred in three patients with a mean age (SD) of 67.2 (0.459) years compared with 52.6 (12.4) in patients without grade III lymphopenia. Seventy-seven patients (27.0%) had at least one absolute lymphocyte count of 0.50 to 0.99 that indicated grade I or II lymphopenia while on ocrelizumab.

Three hundred and thirty-seven patients (88.7%), who had at least one IgM/IgG value measured and received at least two courses of ocrelizumab, were included in the immunoglobulin analyses. Serum IgG/IgM levels were obtained within a month before each ocrelizumab infusion. The median time on ocrelizumab (IQR) was 26 months (21–29.8). Infections were seen in 226 of the 337 patients (67.1%). The median age (IQR) for those who had an infection was 53.5 (42.5–62.7) and was 53.0 (42.2–60.2) for those who did not.

Logistic regression analyses showed no evidence of a higher risk of infection for subjects with low IgG or IgM levels. After adjusting for covariates, the likelihood of infection during the 6-month course following OCR treatment was not significantly different for subjects with high vs low IgG levels at course 2 (adjusted odds ratio (AOR)=1.41 (95% CI 0.64–3.23); p=0.399), course 3 (AOR=0.53 (95% CI 0.24, 1.15); p=0.110), and course 4 (AOR=0.62 (95% CI 0.26, 1.51); p=0.295) (table 5). It was also not significantly different for subjects with high vs low IgM levels at course 2 (AOR=0.84 (95% CI 0.39, 1.81); p=0.644), course 3 (AOR=0.61 (95% CI 0.28, 1.29); p=0.201), and course 4 (AOR=1.51 (95% CI 0.65–3.60); p=0.341) (table 6).

Efficacy

On-ocrelizumab ARR was 0.09 as compared with 0.34 over the 24 months prior to starting ocrelizumab for the RMS cohort. Thirty-three of the 332 patients who had at least two courses of ocrelizumab relapsed. Almost 28% of the relapses occurred in patients transitioning from NTZ; however, the rate of relapse was not significantly higher than that of the other DMT groups. The patients who transitioned from NTZ had a mean (SD) washout period of 4.4 (±1.4) weeks and a median time (IQR) to first relapse of 8.7 (3.3–13.9) months. Bivariate tests for age, disease duration, sex, pre-drug ARR, number of previous DMTs used and prior DMT used demonstrated no significant differences between those who did or did not relapse (data not shown).

Brain MRIs prior to ocrelizumab initiation were obtained in 347 of 355 patients, with median time of 3.0 months (IQR: 1.2–5.9) between the last preocrelizumab MRI and first ocrelizumab dose. First follow-up MRIs were obtained in 291 (81.9%) patients 5.6 (4.4–7.7) months after the first ocrelizumab course, 76% solely brain MRI, 19% brain plus spinal cord, and 5% spinal cord only. Of the 291 patients with post-ocrelizumab scans, 262 (90.0%) had stable MRI results. Enhancing lesions were seen in 4 (1.4%) patients. Insurer refusal was primarily responsible for those patients who did not obtain MRI scans within the first year after starting ocrelizumab.

Baseline median EDSS (IQR) for RMS, SPMS and PPMS subgroups was 3.0 (2.0–4.0), 6.5 (6–7.5), and 6.5 (6.0–7.0), respectively, and remained unchanged at 12 months (table 2). In addition to the favourable ARR and MRI outcomes, treatment efficacy was also evidenced by the absence of disability progression as measured by EDSS.

There were no significant differences in BDI from baseline to 12 months (n=88, mean difference −0.61 (±7.6), p=0.4), but MFIS score improved at 12 months (n=87), with a mean difference of −3.7 (±14.1) (p=0.02).