Overview of Treatment
Chronic lymphocytic leukemia is the most common adult leukemia, characterized by accumulation of mature-appearing B lymphocytes. Treatment has transformed from chemotherapy-based regimens to highly effective targeted therapies. BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) and BCL-2 inhibitor venetoclax have revolutionized outcomes with superior efficacy and tolerability compared to chemoimmunotherapy.
Treatment Approach
- First-line: BTK inhibitor (acalabrutinib, zanubrutinib preferred) OR venetoclax + obinutuzumab for fit patients
- Relapsed/Refractory: Alternative BTK inhibitor, venetoclax combinations, or PI3K inhibitor
- High-risk (del17p/TP53): BTK inhibitor or venetoclax-based preferred
Epidemiology & Impact
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, with approximately 20,700 new cases expected in the United States in 2025. The disease predominantly affects older adults, with a median age at diagnosis of 70 years, and occurs approximately twice as often in men as in women. CLL shows notable geographic variation, being common in Europe and North America but rare in East Asia, suggesting both genetic susceptibility and environmental factors. Approximately 25% of patients are diagnosed incidentally through routine blood work and may never require treatment, as early-stage CLL can remain indolent for years or even decades. However, the disease is heterogeneous, with some patients experiencing rapid progression requiring immediate therapy. First-degree relatives of CLL patients have a 6-9 fold increased risk, making it the most heritable common cancer. Five-year survival has improved substantially to approximately 88%, reflecting the dramatic impact of novel targeted therapies.
Molecular Biology & Biomarkers
CLL is molecularly stratified by immunoglobulin heavy chain variable region (IGHV) mutation status, which divides patients into two fundamentally different prognostic groups. IGHV-unmutated CLL arises from pre-germinal center B cells, has a more aggressive course, and is enriched for high-risk genomic features. IGHV-mutated CLL originates from post-germinal center B cells and has a more indolent course. Key cytogenetic abnormalities include del(13q) (favorable, ~55% of cases), trisomy 12 (intermediate, ~15%), del(11q) (unfavorable, ~18%), and del(17p)/TP53 mutation (very unfavorable, ~5-10%). TP53 disruption predicts resistance to chemoimmunotherapy but not to BTK inhibitors or venetoclax, fundamentally altering treatment selection. BTK mutations (C481S and others) and BCL2 mutations can emerge under therapeutic pressure with ibrutinib and venetoclax respectively, driving acquired resistance. The tumor microenvironment, including T-cell exhaustion and nurse-like cell support, plays a critical role in CLL biology and represents an area of active therapeutic investigation.
Evolving Treatment Landscape
CLL treatment has been transformed from chemoimmunotherapy to targeted therapy-based approaches. BTK inhibitors — ibrutinib (first-generation), acalabrutinib and zanubrutinib (second-generation with improved selectivity) — have become backbone therapies for both frontline and relapsed CLL. The ELEVATE-TN and ALPINE trials established acalabrutinib and zanubrutinib as preferred options with fewer cardiac and bleeding side effects than ibrutinib. Venetoclax, a BCL-2 inhibitor, offers time-limited combination therapy (typically 12 months with obinutuzumab) that achieves deep remissions including undetectable MRD in a majority of patients. The CLL14 trial demonstrated durable responses with fixed-duration venetoclax-obinutuzumab. Ongoing research focuses on combination strategies (BTK inhibitor + venetoclax), novel non-covalent BTK inhibitors (pirtobrutinib for BTK-inhibitor resistant disease), and bispecific antibodies. The current treatment paradigm has made chemoimmunotherapy largely obsolete in CLL, with targeted agents achieving superior outcomes and better tolerability.