Considerations in choosing a targeted therapy
| . | Favors . | Relative contraindications . | Drug interactions . |
|---|---|---|---|
| Ibrutinib | Longest follow-up of PFS to date | High bleeding risk including lack of data with platelets <30 × 109/L | Anticoagulants (avoid if possible, especially warfarin; if necessary, use NOACs) |
| Nodal predominant disease has rapid response; cytopenias can be slower to resolve | Cardiac disease | Avoid dual antiplatelet therapy | |
| Active infection, especially fungal | Strong CYP3A inhibitors: generally avoid, but can use higher-dose posaconazole if ibrutinib dose is reduced to 70 mg daily | ||
| Difficult to control hypertension or atrial fibrillation | Moderate CYP3A inhibitors or voriconazole: reduce ibrutinib dose to 140 mg daily | ||
| Active autoimmunity can show early flare before achieving longer-term control | |||
| Not studied in patients with comorbidities; recent study suggests worse outcomes58 | |||
| Hepatic disease* | |||
| Venetoclax (± rituximab) | Extremely effective in bone marrow clearance, with potential to achieve MRD negativity rarely seen with kinase inhibitors; allows more easily for fixed-duration therapy | Renal failure | Strong CYP3A inhibitors: avoid during escalation, later 75% dose reduction |
| Spontaneous tumor lysis | |||
| Possibly safer than kinase inhibitors with active infection (eg, fungal) | Cytopenias, particularly neutropenia, resulting from hypocellular bone marrow or myeloid disorder | Moderate CYP3A inhibitor or P-gp inhibitors: avoid during escalation; later, 50% dose reduction | |
| Possibly safer in setting of active autoimmunity | No contraindication to anticoagulation in general, but will increase serum warfarin concentration | ||
| Difficulty tolerating a fluid load for dose escalation | |||
| Idelalisib + rituximab | Nodal predominant disease has rapid response; cytopenias can be slower to resolve | Adverse effect profile can be more challenging but is likely better in older patients with multiple prior therapies (particularly CIT) | Strong inhibitor of CYP3A4 itself; avoid combining with CYP3A4 substrates (including venetoclax) |
| Not contraindicated in cardiac or renal disease | Hepatic disease* | ||
| Registration trial enrolled patients with high level of medical comorbidities17 | Inflammatory bowel disease | ||
| RT less commonly reported at relapse than with ibrutinib or venetoclax | Active autoimmunity | ||
| Active infection† |
| . | Favors . | Relative contraindications . | Drug interactions . |
|---|---|---|---|
| Ibrutinib | Longest follow-up of PFS to date | High bleeding risk including lack of data with platelets <30 × 109/L | Anticoagulants (avoid if possible, especially warfarin; if necessary, use NOACs) |
| Nodal predominant disease has rapid response; cytopenias can be slower to resolve | Cardiac disease | Avoid dual antiplatelet therapy | |
| Active infection, especially fungal | Strong CYP3A inhibitors: generally avoid, but can use higher-dose posaconazole if ibrutinib dose is reduced to 70 mg daily | ||
| Difficult to control hypertension or atrial fibrillation | Moderate CYP3A inhibitors or voriconazole: reduce ibrutinib dose to 140 mg daily | ||
| Active autoimmunity can show early flare before achieving longer-term control | |||
| Not studied in patients with comorbidities; recent study suggests worse outcomes58 | |||
| Hepatic disease* | |||
| Venetoclax (± rituximab) | Extremely effective in bone marrow clearance, with potential to achieve MRD negativity rarely seen with kinase inhibitors; allows more easily for fixed-duration therapy | Renal failure | Strong CYP3A inhibitors: avoid during escalation, later 75% dose reduction |
| Spontaneous tumor lysis | |||
| Possibly safer than kinase inhibitors with active infection (eg, fungal) | Cytopenias, particularly neutropenia, resulting from hypocellular bone marrow or myeloid disorder | Moderate CYP3A inhibitor or P-gp inhibitors: avoid during escalation; later, 50% dose reduction | |
| Possibly safer in setting of active autoimmunity | No contraindication to anticoagulation in general, but will increase serum warfarin concentration | ||
| Difficulty tolerating a fluid load for dose escalation | |||
| Idelalisib + rituximab | Nodal predominant disease has rapid response; cytopenias can be slower to resolve | Adverse effect profile can be more challenging but is likely better in older patients with multiple prior therapies (particularly CIT) | Strong inhibitor of CYP3A4 itself; avoid combining with CYP3A4 substrates (including venetoclax) |
| Not contraindicated in cardiac or renal disease | Hepatic disease* | ||
| Registration trial enrolled patients with high level of medical comorbidities17 | Inflammatory bowel disease | ||
| RT less commonly reported at relapse than with ibrutinib or venetoclax | Active autoimmunity | ||
| Active infection† |
NOAC, non–vitamin K oral anticoagulants.
Screen all patients on any of these drugs for hepatitis B and C, and treat if found.
In the relapsed setting, my practice is to recommend prophylaxis against Pneumocystis jirovecii pneumonia and against varicella zoster virus for all patients with CLL. This recommendation is stronger with idelalisib plus rituximab.