What are alternative treatment options for Chronic Lymphocytic Leukemia (CLL)?

Alternative Treatment Options for Chronic Lymphocytic Leukemia (CLL)

For relapsed/refractory CLL, the two primary alternative treatment options are venetoclax plus rituximab for 24 months or continuous BTK inhibitor therapy (ibrutinib or acalabrutinib), with the choice depending on prior therapy, genetic risk factors, and patient-specific comorbidities. 1

When Alternative Treatment is Needed

Treatment should be changed when symptomatic relapse occurs within 3 years after fixed-duration therapy or when there is non-response to initial therapy, regardless of whether first-line treatment was chemoimmunotherapy or novel targeted agents. 1

• Asymptomatic relapsed CLL can be observed without immediate alternative therapy for extended periods 1
• Even after stopping continuous BCR inhibitors or venetoclax due to side effects, immediate alternative treatment is not required if CLL remains in remission 1
• Rapid progression on targeted agents mandates immediate therapy change 1

Primary Alternative Treatment Options for Relapsed/Refractory Disease

First-Tier Alternatives (Level I, A Evidence)

Venetoclax plus rituximab for 24 months 1

• Preferred after prior BTK inhibitor therapy 1
• Fixed-duration regimen with defined endpoint 1
• Requires dose ramp-up with weekly monitoring for 5 weeks to prevent tumor lysis syndrome 1
• Higher risk in patients with impaired renal function and neutropenia 1

BTK inhibitors as continuous therapy (ibrutinib or acalabrutinib) 1

• Preferred if venetoclax was used first-line 1
• Oral administration with 2-4 week monitoring intervals 1
• Acalabrutinib may have lower arrhythmia incidence compared to ibrutinib 1
• Contraindications include concurrent arrhythmias, significant cardiovascular disease, anticoagulation therapy, or strong CYP3A4 inhibitor use 1

Second-Tier Alternative Options

PI3K inhibitor idelalisib plus rituximab (Level II, B Evidence) 1

• Reserved for patients ineligible for venetoclax or BTK inhibitors 1
• Used when other targeted therapies are not feasible 1

Chemoimmunotherapy (CIT) 1

• Only if TP53 mutation or del(17p) is absent 1
• Bendamustine-rituximab (BR) can be re-administered if prior response lasted at least 3 years 1
• FCR should NOT be repeated due to increased toxicity and secondary myeloid neoplasm risk 1

Special Populations Requiring Specific Alternatives

Patients with TP53 Mutation or del(17p)

BTK inhibitors (ibrutinib or acalabrutinib) are the preferred alternative (Level I, A Evidence) 1

• Chemoimmunotherapy is contraindicated regardless of IGHV status 1
• If BTK inhibitors are contraindicated, venetoclax-based therapy is the alternative 1
• Venetoclax plus obinutuzumab shows reduced efficacy in this population but remains superior to CIT 1
• Consider allogeneic stem cell transplantation in fit patients refractory to both BTK inhibitors and venetoclax 1, 2

Patients with Cardiovascular Comorbidities

Venetoclax-based regimens are preferred over ibrutinib 1

• Ibrutinib carries risks of atrial fibrillation, ventricular arrhythmias, and bleeding complications 1
• Acalabrutinib may be considered as it has a different cardiac side-effect profile 1

Patients Progressing on BCR Inhibitors

Venetoclax-based therapy is the preferred alternative 1

• More evidence exists for ibrutinib first-line followed by venetoclax second-line than the reverse sequence 1

Critical Decision Factors for Choosing Between Alternatives

Treatment duration considerations: 1

• Venetoclax plus rituximab: fixed 24-month duration
• BTK inhibitors: continuous until progression or intolerance

Administration route and compliance: 1

• Venetoclax: oral with intensive initial monitoring
• BTK inhibitors: oral with less frequent monitoring
• Rituximab: intravenous infusions

Comorbidity-specific risks: 1

• Bleeding/cardiac issues favor venetoclax over BTK inhibitors
• Renal dysfunction and neutropenia favor BTK inhibitors over venetoclax

Prior therapy response: 1

• Switch drug class if relapse occurs <36 months after initial therapy
• May repeat same class if remission lasted >36 months

Common Pitfalls to Avoid

Do not repeat FCR in the relapsed setting due to excessive toxicity and secondary malignancy risk 1

Do not use chemoimmunotherapy in patients with TP53 mutation or del(17p) regardless of other favorable prognostic factors 1

Do not initiate treatment immediately upon stopping targeted therapy unless rapid progression occurs; many patients can be observed 1

Do not overlook drug interactions with BTK inhibitors, particularly CYP3A4 inhibitors including common antiarrhythmics and antihypertensives 1

Do not skip tumor lysis syndrome prophylaxis when initiating venetoclax, especially in patients with high tumor burden 1