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

Treatment of Chronic Lymphocytic Leukemia (CLL)

Initial Management: Watch and Wait for Early Disease

For asymptomatic patients with early-stage CLL (Binet A/B or Rai 0-II without active disease), the standard approach is observation with monitoring every 3-12 months, as early treatment does not improve survival. 1

• Blood counts and clinical examinations should be performed every 3-12 months after the first year (when 3-monthly intervals are recommended for all patients) 1
• No routine imaging is recommended during the watch-and-wait period unless clinical symptoms develop 1

When to Start Treatment: Active Disease Criteria

Treatment should only be initiated when patients meet criteria for "active disease," which includes 1:

• Significant B-symptoms (fever, night sweats, weight loss) 1
• Cytopenias not caused by autoimmune phenomena 1
• Massive or progressive lymphadenopathy (≥10 cm in longest diameter) or splenomegaly (≥6 cm below left costal margin) 1
• Progressive lymphocytosis with lymphocyte doubling time <6 months (in patients with >30,000 lymphocytes/µL) 1
• Autoimmune anemia or thrombocytopenia poorly responsive to corticosteroids 1

Essential Testing Before Treatment

Before initiating any therapy, the following must be assessed 1, 2:

• FISH for del(17p) and TP53 mutation testing - this is mandatory as it fundamentally changes treatment selection 1, 2
• IGHV mutational status - determines whether time-limited or continuous therapy is preferred 1, 2
• Patient fitness assessment including comorbidities, renal function, and performance status 1

First-Line Treatment Algorithm

For Patients WITH del(17p) or TP53 Mutation (5-10% of patients)

Second-generation covalent BTK inhibitors (acalabrutinib or zanubrutinib) administered continuously until progression are the preferred first-line options, as these patients do not respond adequately to chemoimmunotherapy or venetoclax-based regimens. 1

• Acalabrutinib has shown 88% survival at 4 years 3
• Zanubrutinib has shown 94% survival at 2 years 3
• Ibrutinib (first-generation BTKi) is an alternative with 78% survival at 7 years, but has more cardiovascular toxicity 3

For Patients WITHOUT del(17p)/TP53 Mutation: Treatment Based on IGHV Status

Mutated IGHV Status (Better Prognosis)

Time-limited therapy with venetoclax plus obinutuzumab for 12 months is the preferred first-line option, as it provides excellent outcomes with a defined treatment duration. 1

• This combination showed 88% PFS at 24 months and 82% overall survival at 5 years 1, 3
• Treatment is completed after 12 cycles, avoiding indefinite therapy 1

Unmutated IGHV Status (Poorer Prognosis)

Both continuous BTK inhibitor therapy and time-limited venetoclax plus obinutuzumab are valid first-line options; BTK inhibitors may be preferred given the higher-risk biology. 1

• BTK inhibitors (acalabrutinib, zanubrutinib, or ibrutinib) are given continuously 1
• Venetoclax plus obinutuzumab for 12 months is an alternative 1

For Elderly/Unfit Patients Without High-Risk Features

Chlorambucil plus obinutuzumab is the standard for patients with significant comorbidities who cannot tolerate more intensive regimens. 1

• Bendamustine-based regimens are alternatives 1
• Dose-reduced purine analog therapies (FC, PCR) can be considered 1

Chemoimmunotherapy: Now Reserved for Specific Situations

FCR (fludarabine, cyclophosphamide, rituximab) is no longer first-line except when targeted agents are unavailable, as it has been superseded by better-tolerated targeted therapies. 1

• FCR was previously standard for physically fit patients and showed improved survival 1
• It remains an option only when BTK inhibitors and venetoclax are not accessible 1
• Bendamustine plus rituximab (BR) is an alternative chemoimmunotherapy regimen 1

Treatment of Relapsed/Refractory Disease

First Relapse After Time-Limited Therapy

If relapse occurs ≥24-36 months after chemoimmunotherapy or ≥12 months after venetoclax-based therapy, the first-line regimen may be repeated. 1

If relapse occurs earlier, switch to an alternative drug class: 1

• If prior chemoimmunotherapy → BTK inhibitor or venetoclax-based regimen 1
• If prior venetoclax → BTK inhibitor 1
• If prior first-generation BTKi → second-generation BTKi or venetoclax 1

After BTK Inhibitor Failure

Pirtobrutinib (non-covalent BTKi) has shown >70% overall response rate after failure of covalent BTK inhibitors and venetoclax, making it the preferred next option. 3

• Venetoclax-based therapy is an alternative if not previously used 1
• PI3K inhibitors (idelalisib, duvelisib) can be used but require close monitoring for severe infections, diarrhea/colitis, and autoimmune complications 4, 3

Multiply Relapsed Disease

For patients who have failed both BTK inhibitors and venetoclax, CAR-T cell therapy with lisocabtagene maraleucel achieved 45% complete response rates and should be considered. 3

• Allogeneic stem cell transplantation remains the only potentially curative option and should be considered in young, fit patients with multiply relapsed disease 1, 3
• High-dose ofatumumab or rituximab with high-dose steroids can be attempted 1

Special Considerations for High-Risk Patients

For young, physically fit patients with del(17p)/TP53 mutation who progress on BTK inhibitors, alemtuzumab followed by allogeneic stem cell transplantation should be considered within clinical trials. 1

• Del(17p) or TP53 mutation confers the poorest prognosis with median overall survival of 2-3 years with conventional therapy 1
• These patients require the most aggressive available therapy followed by consideration of transplant 1

Supportive Care and Prophylaxis

When using targeted agents, specific prophylaxis is required 4:

• PJP prophylaxis during all CLL treatment, continued until CD4+ count >200 cells/µL 4
• CMV monitoring at least monthly during therapy, with consideration of prophylactic antivirals 4
• Close monitoring for infections given the immunocompromised state inherent to CLL 3

Common Pitfalls to Avoid

• Do not treat asymptomatic early-stage patients - this does not improve survival and exposes patients to unnecessary toxicity 1
• Do not use chemoimmunotherapy in del(17p)/TP53 mutated patients - they have very short progression-free survival even with FCR 1
• Do not forget to retest for TP53 abnormalities before each line of therapy - clonal evolution can occur 1
• Do not use PI3K inhibitors without close monitoring - they carry significant risks of fatal infections, colitis, and pneumonitis 4