How should IgG levels be monitored and managed in patients with a history of infections or increased risk of infections while on Calquence (Acalabrutinib) therapy?

IgG Monitoring and Management in Calquence (Acalabrutinib) Patients with Infection Risk

Patients on Calquence with recurrent infections and IgG <400 mg/dL should receive monthly IVIG replacement therapy, with a target trough level of 500-800 mg/dL, while continuing Calquence therapy. 1, 2

Baseline Assessment Before Starting Calquence

• Measure baseline IgG levels in all patients prior to initiating Calquence, as BTK inhibitors can cause or worsen hypogammaglobulinemia 2, 3
• Document infection history including frequency, severity, and types of infections (particularly respiratory tract infections and opportunistic infections) 2
• Screen for hepatitis B surface antigen and core antibodies before starting therapy, as reactivation can occur 2
• Consider baseline pneumococcal vaccine response testing if IgG levels are borderline (400-500 mg/dL) to assess functional antibody production 1

Monitoring Schedule During Calquence Therapy

• Check IgG trough levels every 3 months during the first year of Calquence therapy, then every 6 months if stable 4, 1
• Monitor complete blood counts monthly to detect cytopenias that increase infection risk 2
• Assess infection frequency and severity at each visit, documenting culture-proven bacterial infections, hospitalizations for infections, or antibiotic failures 1
• If patient develops recurrent infections, increase IgG monitoring to monthly until stable on replacement therapy 4

Indications for IVIG Replacement Therapy

Initiate IVIG if any of the following criteria are met:

• IgG levels <400 mg/dL regardless of infection history 4, 1
• ≥2 severe recurrent infections by encapsulated bacteria per year (pneumonia, sepsis, meningitis, osteomyelitis) regardless of IgG level 4, 1
• Life-threatening infection with documented hypogammaglobulinemia 4
• Documented bacterial infection with insufficient response to antibiotic therapy 4
• IgG levels 400-500 mg/dL with ≥3 infections per year requiring medical intervention 1

IVIG Dosing Protocol

• Initial dose: 0.4 g/kg body weight every 3-4 weeks (typically 400-600 mg/kg monthly) 4, 1
• Target trough IgG level: 500-800 mg/dL (some experts recommend 600-800 mg/dL for patients on B-cell depleting therapies) 1
• Check trough IgG level immediately before the next scheduled IVIG dose after 2-3 months of therapy 4, 1
• If recurrent infections persist despite IVIG, increase dose by 0.1-0.2 g/kg increments or shorten interval to every 3 weeks 1
• Alternative: Subcutaneous immunoglobulin (SCIG) weekly may provide more stable levels and fewer systemic reactions 1

Management of Infections While on Calquence

Prophylactic antimicrobials should be considered for:

• Pneumocystis jirovecii pneumonia (PCP) prophylaxis with trimethoprim-sulfamethoxazole in patients with Grade 3/4 lymphopenia or history of opportunistic infections 2
• Herpes virus prophylaxis with acyclovir or valacyclovir for all patients, as Calquence increases risk of viral reactivation 4, 2
• Consider bacterial prophylaxis (amoxicillin 500-1000 mg daily or twice daily) in patients with recurrent sinopulmonary infections despite IVIG 4

For active infections:

• Continue Calquence during IVIG treatment unless severe neutropenia (ANC <0.5 × 10⁹/L) or life-threatening infection develops 4, 2
• Withhold Calquence temporarily for Grade 3/4 infections until clinical resolution 2
• Use aggressive and prolonged antimicrobial therapy (longer courses than standard) given immunocompromised state 4
• During active infection, check IgG trough every 2 weeks as infection accelerates IgG catabolism, potentially requiring higher or more frequent IVIG dosing 1

Duration of IVIG Therapy

• Continue monthly IVIG for the duration of Calquence therapy if IgG remains <400 mg/dL or recurrent infections persist 4
• Do not attempt to discontinue IVIG while patient remains on Calquence, as BTK inhibition causes sustained B-cell dysfunction 1, 3
• Monitor for recovery of endogenous IgG production by keeping IVIG dose constant and watching for rising trough levels over time 1

Common Pitfalls to Avoid

• Do not delay IVIG waiting for multiple infections to occur if IgG is <400 mg/dL—this threshold alone warrants replacement 1
• Do not measure IgG subclasses routinely—total IgG trough level is more clinically relevant for monitoring adequacy of replacement 1
• Do not discontinue Calquence solely due to hypogammaglobulinemia—IVIG allows continuation of effective CLL therapy 4, 2
• Do not use fixed IVIG dosing without monitoring trough levels—individualize based on IgG measurements and clinical response 4, 1
• Do not assume all respiratory infections are bacterial—maintain high suspicion for opportunistic infections (fungal pneumonia, PCP, CMV, EBV reactivation) and obtain appropriate diagnostic testing 2

Special Considerations for Calquence

The FDA label specifically warns that "fatal and serious infections, including opportunistic infections, have occurred" with Calquence, with serious infections occurring in 19% of patients (respiratory tract infections in 11%, pneumonia in 6%) 2. Importantly, these infections "predominantly occurred in the absence of Grade 3 or 4 neutropenia," indicating that hypogammaglobulinemia rather than neutropenia is the primary driver of infection risk 2. Research demonstrates that BTK inhibitors like acalabrutinib can lead to partial reconstitution of humoral immunity over time, but patients remain immunocompromised and require ongoing monitoring 3.