Ocrelizumab and Its Use in Pediatrics

Introduction

Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20-expressing B cells. It has emerged as an important treatment option for multiple sclerosis (MS) in adults. While its use in pediatric populations is still evolving, there is growing interest in its potential applications for children and adolescents with MS and other autoimmune disorders. This clinical note aims to provide pediatricians with a comprehensive overview of ocrelizumab, its mechanism of action, current approved indications, emerging pediatric applications, dosing considerations, safety profile, and important clinical pearls for its use in younger patients.

Mechanism of Action

Ocrelizumab targets CD20, a cell surface antigen expressed on pre-B cells, mature B cells, and memory B cells. Upon binding to CD20, ocrelizumab triggers B cell depletion through several mechanisms:

Antibody-dependent cellular cytotoxicity (ADCC)
Complement-dependent cytotoxicity (CDC)
Apoptosis induction

The depletion of B cells is thought to modulate the immune response in MS and other autoimmune conditions by:

Reducing antigen presentation to T cells
Decreasing production of pro-inflammatory cytokines
Limiting formation of ectopic lymphoid follicles in the central nervous system
Potentially depleting pathogenic memory B cells

Importantly, ocrelizumab does not deplete plasma cells or pro-B cells, allowing for maintenance of humoral immunity and B cell reconstitution over time.

Current Approved Indications

As of 2024, ocrelizumab is FDA-approved for use in adults with:

Relapsing forms of multiple sclerosis (RMS), including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS
Primary progressive multiple sclerosis (PPMS)

It is important to note that ocrelizumab is not currently FDA-approved for use in pediatric patients. However, off-label use in pediatric MS is increasing, particularly in cases refractory to other disease-modifying therapies.

Emerging Pediatric Applications

Pediatric Multiple Sclerosis

While pediatric MS is relatively rare, accounting for approximately 3-5% of all MS cases, it can have a significant impact on a child's development, education, and long-term quality of life. The rationale for using ocrelizumab in pediatric MS includes:

High efficacy demonstrated in adult RMS populations
Potential to prevent early axonal damage and cognitive impairment
Convenient dosing schedule (every 6 months after initial doses)
Growing safety data in adult populations

Several case series and retrospective studies have reported on the use of ocrelizumab in pediatric MS patients, generally showing good efficacy and tolerability. However, larger prospective studies are needed to establish its long-term safety and efficacy in this population.

Neuromyelitis Optica Spectrum Disorders (NMOSD)

While not as extensively studied as in MS, there is emerging interest in the use of ocrelizumab for pediatric NMOSD. The rationale includes:

The critical role of B cells in NMOSD pathogenesis
Success of other B cell-depleting therapies (e.g., rituximab) in NMOSD
Potential for improved tolerability compared to long-term steroid use

Case reports have described successful use of ocrelizumab in pediatric NMOSD patients, but larger studies are needed to establish its role in this condition.

Other Potential Pediatric Applications

Research is ongoing to explore the potential of ocrelizumab in other pediatric autoimmune conditions where B cells play a significant role, including:

Autoimmune encephalitis
Systemic lupus erythematosus (SLE)
Refractory myasthenia gravis
Certain subtypes of juvenile idiopathic arthritis

These applications are still in early stages of investigation and should be considered experimental at this time.

Dosing Considerations in Pediatrics

In the absence of established pediatric dosing guidelines, most clinicians extrapolate from adult dosing regimens with adjustments based on body weight. A typical approach includes:

Induction Phase:

Initial dose: 300 mg IV infusion
Second dose: 300 mg IV infusion 2 weeks later

Maintenance Phase:

600 mg IV infusion every 6 months

For smaller children or adolescents, some clinicians use weight-based dosing, typically 300 mg/m² (maximum 300 mg) for each of the first two doses, followed by 600 mg/m² (maximum 600 mg) every 6 months.

It is crucial to note that these dosing regimens are based on clinical experience and extrapolation from adult data. Ongoing pediatric trials will help establish more definitive dosing guidelines for different age groups and indications.

Administration and Monitoring

Pre-medication:

To reduce the risk of infusion-related reactions, the following pre-medications are typically administered 30-60 minutes before each ocrelizumab infusion:

Methylprednisolone 100 mg IV (or equivalent)
Antihistamine (e.g., diphenhydramine 50 mg PO/IV)
Antipyretic (e.g., acetaminophen 650 mg PO)

Infusion Protocol:

Ocrelizumab is administered as an IV infusion under close supervision. The infusion rate is typically started slow and gradually increased if well-tolerated:

Initial 30 minutes: 30 mL/hour
Next 30 minutes: 60 mL/hour
Every 30 minutes thereafter: increase by 30 mL/hour up to a maximum of 180 mL/hour

Monitoring:

During and after the infusion, patients should be closely monitored for:

Vital signs (every 15-30 minutes during infusion, then hourly for at least 1 hour post-infusion)
Signs and symptoms of infusion-related reactions
Neurological status

Safety Considerations in Pediatrics

While the safety profile of ocrelizumab in pediatric populations is still being established, clinicians should be aware of the following potential concerns based on adult data and limited pediatric experience:

Infusion-Related Reactions:

These are the most common adverse events associated with ocrelizumab. They typically occur during or within 24 hours of infusion and may include:

Pruritus
Rash
Throat irritation
Flushing
Fever
Fatigue
Headache
Dizziness
Nausea
Tachycardia

Most reactions are mild to moderate and can be managed by slowing or temporarily stopping the infusion. Severe reactions are rare but may require discontinuation of treatment.

Infections:

B cell depletion can increase the risk of certain infections. Particular attention should be paid to:

Upper respiratory tract infections
Herpes virus reactivation
Opportunistic infections (e.g., Progressive Multifocal Leukoencephalopathy, although no cases have been reported with ocrelizumab to date)

Pediatric patients should be up-to-date on vaccinations before starting ocrelizumab, and live or live-attenuated vaccines should be avoided during treatment and for at least 6 months after the last dose.

Malignancy:

While no clear association has been established, there is a theoretical risk of malignancy with long-term B cell depletion. This risk may be of particular concern in pediatric patients with a longer potential exposure time. Ongoing surveillance is crucial.

Reproductive Considerations:

For adolescent females of childbearing potential, it's important to discuss:

Potential risks to the fetus if exposed to ocrelizumab during pregnancy
Need for effective contraception during treatment and for 6 months after the last dose
Potential impact on future fertility (current data suggest no significant impact, but long-term studies are lacking)

Immunoglobulin Levels:

Long-term B cell depletion can lead to decreased immunoglobulin levels, particularly IgM. Regular monitoring of immunoglobulin levels is recommended, with consideration of immunoglobulin replacement if levels become significantly low and the patient experiences recurrent infections.

Laboratory Monitoring

Regular laboratory monitoring is crucial for pediatric patients receiving ocrelizumab. A suggested monitoring schedule includes:

Baseline (before treatment initiation):

Complete blood count (CBC) with differential
Liver function tests
Renal function tests
Quantitative immunoglobulins (IgG, IgA, IgM)
Hepatitis B serology (surface antigen, core antibody)
Tuberculosis screening
Varicella zoster virus (VZV) serology if vaccination history unknown

During Treatment:

CBC with differential: Every 3-6 months
Liver and renal function: Every 6-12 months
Quantitative immunoglobulins: Every 6 months

As Needed:

JC virus antibody testing (if PML is suspected)
CD19+ B cell counts (to assess B cell reconstitution if considering treatment discontinuation)

Clinical Pearls for Pediatric Use

Patient Selection: Carefully consider the benefit-risk profile for each pediatric patient. Ocrelizumab may be most appropriate for those with highly active disease or who have failed other therapies.
Informed Consent: Thoroughly discuss the off-label nature of ocrelizumab use in pediatrics with patients and caregivers, including potential risks and the limited long-term safety data in this population.
Vaccination: Complete all required vaccinations at least 6 weeks before initiating ocrelizumab. This is particularly important for pediatric patients who may not have completed their standard vaccination schedule.
Infection Precautions: Educate patients and caregivers about the increased risk of infections and the importance of prompt reporting of any signs or symptoms of infection.
School Considerations: Discuss potential impact on school attendance due to infusion schedules and the need for increased vigilance regarding infections in the school setting.
Growth and Development: Regularly assess growth, pubertal development, and cognitive function in pediatric patients receiving long-term ocrelizumab therapy.
Transition Planning: For adolescents approaching adulthood, develop a plan for transition to adult care providers familiar with ocrelizumab management.
Psychological Support: Consider the psychological impact of chronic illness and long-term immunosuppressive therapy on pediatric patients. Provide access to mental health resources as needed.
Family Education: Involve the entire family in education about ocrelizumab, its administration, potential side effects, and necessary precautions to ensure a supportive home environment for the patient.
Multidisciplinary Approach: Collaborate with other specialists (e.g., neurologists, rheumatologists, immunologists) to provide comprehensive care and monitor for potential multi-system effects of B cell depletion.

Ongoing Research and Future Directions

Several clinical trials are currently underway to better understand the efficacy, safety, and optimal use of ocrelizumab in pediatric populations:

A phase 3, randomized, double-blind, double-dummy study comparing ocrelizumab to interferon β-1a in pediatric MS (ages 10-17)
An open-label extension study evaluating long-term safety and efficacy of ocrelizumab in pediatric MS patients
A phase 2 study of ocrelizumab in pediatric NMOSD
Investigator-initiated studies exploring ocrelizumab in other pediatric autoimmune conditions

Future research directions may include:

Optimizing dosing regimens for different pediatric age groups and indications
Investigating biomarkers to predict response and guide treatment decisions
Assessing the long-term impact of B cell depletion on immune system development in children
Exploring combination therapies to enhance efficacy or mitigate potential long-term risks
Evaluating the effects of ocrelizumab on neurodevelopment and cognitive outcomes in pediatric patients
Investigating the potential role of ocrelizumab in preventing or delaying the onset of MS in high-risk pediatric populations

Pharmacokinetics and Pharmacodynamics in Pediatric Populations

Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ocrelizumab in pediatric populations is crucial for optimizing its use. While data specific to children are limited, extrapolations from adult studies and emerging pediatric data provide some insights:

Pharmacokinetics:

Distribution: Ocrelizumab has an estimated central volume of distribution of 2.78 L. It is primarily distributed within the vascular space, with limited penetration into the central nervous system.
Metabolism and Elimination: As a monoclonal antibody, ocrelizumab is expected to be degraded into small peptides and amino acids through catabolism. It is not metabolized by cytochrome P450 enzymes or other hepatic enzymes.
Half-life: The elimination half-life is approximately 26 days. However, the pharmacodynamic effect (B cell depletion) lasts significantly longer than the pharmacokinetic half-life.
Clearance: The constant clearance of ocrelizumab is estimated at 0.17 L/day, with time-dependent clearance decreasing with subsequent doses, likely due to B cell depletion.

Preliminary data suggest that the pharmacokinetics in adolescents (12-17 years) are similar to those in adults when adjusted for body weight. However, more research is needed to fully characterize PK parameters in younger children and infants.

Pharmacodynamics:

B cell Depletion: Ocrelizumab rapidly depletes CD19+ B cells in peripheral blood, with levels typically falling to near-zero within 2 weeks of infusion.
Duration of Effect: B cell depletion is sustained with repeated dosing every 6 months. Upon discontinuation, B cell recovery typically begins within 6-9 months, with median time to return to baseline/lower limit of normal ranging from 72 to 104 weeks.
Immunoglobulin Levels: Long-term treatment may lead to a gradual decrease in immunoglobulin levels, particularly IgM. The clinical significance of this decrease in pediatric populations is not yet fully understood.

It's important to note that the pharmacodynamic effects of ocrelizumab may differ in children compared to adults due to the developing immune system. Ongoing studies are investigating whether children experience faster B cell reconstitution or have different patterns of immunoglobulin level changes compared to adults.

Potential Impact on Childhood Vaccinations

The use of ocrelizumab in pediatric populations raises important considerations regarding childhood vaccinations:

Pre-treatment Vaccinations: Ideally, patients should complete all age-appropriate vaccinations at least 6 weeks before initiating ocrelizumab. This includes routine childhood vaccines as well as any additional vaccines recommended for high-risk individuals.
Live and Live-attenuated Vaccines: These are contraindicated during ocrelizumab treatment and for at least 6 months after the last dose due to the potential risk of vaccine-associated infections in B cell-depleted individuals. This affects several important childhood vaccines, including:
- Measles, Mumps, and Rubella (MMR)
- Varicella
- Rotavirus
- Intranasal influenza vaccine
Inactivated Vaccines: While these can be administered during ocrelizumab treatment, the immune response may be attenuated. Consider:
- Administering inactivated vaccines at least 4 weeks before the next ocrelizumab dose when possible
- Checking post-vaccination titers to ensure adequate protection
- Potential need for booster doses once B cell counts recover
HPV Vaccination: For adolescents, timing of human papillomavirus (HPV) vaccination should be carefully considered in relation to ocrelizumab treatment.
Travel Vaccines: Families should consult with healthcare providers well in advance of any international travel to discuss vaccination needs and potential risks.

Healthcare providers should work closely with patients and families to develop individualized vaccination plans that balance the need for disease prevention with the constraints imposed by ocrelizumab treatment.

Quality of Life Considerations

When considering ocrelizumab treatment for pediatric patients, it's crucial to assess the potential impact on quality of life:

Treatment Burden: While the every-6-month dosing schedule of ocrelizumab may be less burdensome than more frequent treatments, the infusion process still requires significant time commitment and may disrupt school and family routines.
Social and Emotional Impact: Chronic B cell depletion and the need for regular hospital visits may affect a child's social interactions and emotional well-being. Provide access to support groups and mental health resources.
Educational Considerations: Work with schools to ensure accommodations for infusion days and potential absences due to infections. Cognitive monitoring may be necessary to identify and address any treatment-related effects on learning.
Physical Activity: While ocrelizumab doesn't directly limit physical activity, the increased infection risk may impact participation in certain sports or activities. Provide guidance on balancing physical health benefits with infection precautions.
Long-term Planning: Discuss how long-term treatment might affect future plans, including higher education, career choices, and family planning.
Financial Impact: Consider the long-term financial implications of treatment, including insurance coverage and potential out-of-pocket costs for families.

Regular assessment of quality of life metrics should be incorporated into the care plan for pediatric patients receiving ocrelizumab to ensure that the treatment benefits outweigh any negative impacts on daily living and long-term goals.

Ethical Considerations in Pediatric Use

The use of ocrelizumab in pediatric populations raises several ethical considerations that healthcare providers must carefully navigate:

Off-label Use: As ocrelizumab is not yet FDA-approved for pediatric use, prescribers must carefully weigh the potential benefits against the risks of off-label use and ensure thorough informed consent processes.
Long-term Unknowns: The long-term effects of B cell depletion on the developing immune system are not fully understood. Clinicians must grapple with the ethical implications of potentially altering immune development to treat current disease manifestations.
Autonomy and Assent: While parents/guardians provide legal consent, it's important to involve pediatric patients in decision-making to the extent appropriate for their age and maturity. This includes discussing the treatment, its potential effects, and respecting the child's assent or dissent.
Equity and Access: Consider how socioeconomic factors may influence access to ocrelizumab treatment and work to ensure equitable access to this potentially beneficial therapy.
Research Ethics: As more pediatric clinical trials are conducted, ensure that they adhere to the highest ethical standards for research involving children, including appropriate risk-benefit ratios and robust safety monitoring.

Ongoing ethical discussions and guidance from institutional ethics committees can help navigate these complex issues as the use of ocrelizumab in pediatric populations evolves.