Does Brukinsa (zanubrutinib) cause immunosuppression, and how should infection risk be monitored and managed?

Does Brukinsa Cause Immunosuppression?

Yes, Brukinsa (zanubrutinib) causes immunosuppression and significantly increases infection risk, requiring vigilant monitoring and prophylaxis in high-risk patients. 1

Mechanism and Extent of Immunosuppression

Brukinsa inhibits Bruton tyrosine kinase (BTK), which is critical for B-cell function and immune signaling. This mechanism inherently creates immunosuppression through:

• Direct B-cell dysfunction affecting humoral immunity 2, 3
• Impaired immune cell signaling beyond just B-cells, affecting broader immune responses 4
• Increased susceptibility to opportunistic infections including bacterial, viral, and fungal pathogens 1

The FDA label explicitly warns that "fatal and serious infections (including bacterial, viral, or fungal infections) and opportunistic infections have occurred in patients with hematological malignancies treated with BRUKINSA," with Grade 3 or higher infections occurring in 26% of patients and fatal infections in 3.2% 1.

Infection Risk Profile

Bacterial Infections

• Pneumonia is the most common serious infection, occurring in 7.9% of patients 1
• No routine antibiotic prophylaxis is recommended; instead, maintain high clinical suspicion and initiate rapid diagnostic workup 5
• Early appropriate therapy is preferred over prophylaxis 4, 5

Viral Infections

• Herpes simplex virus (HSV) and varicella zoster virus (VZV) prophylaxis should be considered only in patients with history of recurrent reactivations or additional risk factors such as concomitant high-dose steroids or rituximab 4
• Hepatitis B virus (HBV) reactivation can occur; all patients require baseline screening for HBsAg, anti-HBc, and anti-HBs 1
• COVID-19 requires special management considerations, including evaluation of drug-drug interactions with nirmatrelvir/ritonavir, which may necessitate Brukinsa dose reduction or temporary discontinuation 4

Fungal Infections

• Invasive fungal infections (IFI) occur at rates of 1.3-2.8% in BTK inhibitor-treated patients 4
• Routine mold-active antifungal prophylaxis is NOT recommended for Brukinsa monotherapy in the absence of additional risk factors 4, 5
• Consider prophylaxis only with concurrent risk factors: prior fludarabine-based therapy, alemtuzumab within 3 months, concomitant corticosteroids, or recurrent neutropenia 4
• Pneumocystis jirovecii pneumonia (PJP) prophylaxis is not routinely recommended for Brukinsa monotherapy unless additional risk factors present (prolonged high-dose corticosteroids, purine analogues) 4

Critical Monitoring Requirements

Baseline Assessment

• Complete blood count with differential 1
• Hepatitis B screening: HBsAg, anti-HBc, anti-HBs 1
• Liver function tests (transaminases and bilirubin) 1
• Assessment of infection history and risk factors 4

Ongoing Surveillance

• Monitor complete blood counts regularly during treatment, as Grade 3-4 cytopenias occur in 21% (neutropenia), 8% (thrombocytopenia), and 8% (anemia) of patients 1
• Evaluate for fever or signs of infection at every clinical encounter 1
• Screen for opportunistic infections based on clinical presentation, not routine surveillance cultures 4

Prophylaxis Algorithm

Universal Prophylaxis Required

• HBV prophylaxis with entecavir or tenofovir/tenofovir alafenamide for all HBsAg-positive patients, starting at treatment onset and continuing at least 12 months after cessation 4
• Vaccination against pneumococcus, influenza, herpes zoster, and COVID-19 preferably before starting treatment 4

Conditional Prophylaxis (Only with Additional Risk Factors)

• Anti-HSV/VZV prophylaxis: Only if history of recurrent reactivations or concurrent high-dose steroids/rituximab 4
• Anti-PJP prophylaxis: Only if concurrent prolonged high-dose corticosteroids or purine analogues 4
• Mold-active antifungal prophylaxis: Only if prior fludarabine/alemtuzumab, concurrent steroids, or recurrent neutropenia 4

Prophylaxis NOT Recommended

• Routine antibacterial prophylaxis 4, 5
• Universal anti-fungal prophylaxis in absence of risk factors 4, 5

Diagnostic Approach for Suspected Infections

First-Line Workup

• Chest CT scan (not just plain radiograph, as conventional chest X-rays show abnormalities in <2% of febrile neutropenic patients) 6
• Inflammatory markers 5
• Urinary antigens for Legionella pneumophila and Pneumococcus 5
• Two sets of blood cultures 5
• Nasopharyngeal swab for respiratory viruses including SARS-CoV-2 5
• Sputum culture if present 5
• Serum galactomannan and beta-D-glucan if aspergillosis or pneumocystosis suspected 5

Second-Line Workup (If No Etiology Identified or Lack of Response)

• Bronchoalveolar lavage with comprehensive microbiological assays 5
• Molecular analysis for atypical bacteria, CMV-DNA, and fungi 5
• BAL fluid galactomannan and fungal PCR 5
• Brain MRI and lumbar puncture if central nervous system dissemination suspected (particularly important with BTK inhibitors due to slightly increased CNS fungal infection risk) 4, 5

Critical Drug-Drug Interactions Affecting Infection Risk

• Azole antifungals (ketoconazole, posaconazole, voriconazole) significantly increase Brukinsa levels through CYP3A4 inhibition, requiring dose reduction to 80 mg once or twice daily depending on azole dose 1, 5
• Ciprofloxacin significantly increases Brukinsa plasma concentrations, requiring dose adjustments 5
• Nirmatrelvir/ritonavir (for COVID-19) causes significant increase in Brukinsa concentrations; either use alternative anti-SARS-CoV-2 therapy (remdesivir has no interactions) or discontinue/reduce Brukinsa dose until 3 days after completing nirmatrelvir/ritonavir 4

Important Clinical Pitfalls

• Do not assume Brukinsa has lower infection risk than other BTK inhibitors—while newer agents like zanubrutinib and acalabrutinib show "no clear signals of an increased infection risk" compared to ibrutinib, all BTK inhibitors cause clinically significant immunosuppression 4
• Do not provide universal prophylaxis—this approach is not supported by guidelines and may cause unnecessary drug interactions and toxicities 4
• Do not overlook HBV screening—reactivation can be fatal and is preventable with appropriate prophylaxis 1
• Do not use azole antifungals without dose adjustment—this can lead to Brukinsa toxicity 5, 1
• Do not delay diagnostic workup—early identification and treatment of infections is critical, as mortality from infections primarily occurs with delayed treatment 7

Combination Therapy Considerations

When Brukinsa is used in combination with other agents (particularly anti-CD20 antibodies like obinutuzumab or rituximab), the infection risk increases beyond monotherapy 4. In these scenarios:

• HBV prophylaxis becomes mandatory even for HBsAg-negative/HBcAb-positive patients 4
• Consider more aggressive prophylaxis strategies for opportunistic infections 4
• Monitor more frequently for cytopenias and infections 4