Role of Chemoimmunotherapy in the Era of Rapid Development of CLL Treatment Strategies and Emergence of New Drugs

The Golden Era of CLL Treatment

In recent years, there has been tremendous progress in the clinical practice of chronic lymphocytic leukemia (CLL), leading to what can truly be called the “golden era of CLL treatment”. Numerous new drugs have been recently approved, including small-molecule inhibitors. This has resulted in longer and more stable disease control, especially when used in second and subsequent lines of treatment following the failure of previous modalities.

Key Points from the Discussion

The expert discussion at the 2019 National Comprehensive Cancer Network (NCCN) Congress aimed to address current questions in this context. Here is a brief summary of some of the discussed points:

• Currently, there are two approaches available for treatment other than chemoimmunotherapy. Bruton’s tyrosine kinase (BTK) inhibitors have allowed for prolonged disease control. The second strategy involves achieving deep remission using selective Bcl-2 inhibitors. According to experts, these small-molecule inhibitors may represent a more advantageous option compared to genotoxic chemotherapy. It is also crucial to emphasize that a thorough cytogenetic analysis should be conducted prior to treatment, considering the deletion of the region in chromosome 17 (17p13−) encoding p53 (TP53) and IGHV mutations.
• Phase III studies RESONATE-2, iLLUMINATE, Alliance, and ECOG E1912 have confirmed the efficacy of ibrutinib as a first-line treatment for patients with CLL. A positive effect leading to prolonged progression-free survival (PFS) with ibrutinib has been demonstrated compared to chemoimmunotherapy. The CLL14 study also showed positive results with the administration of venetoclax and obinutuzumab compared to control treatment. While ibrutinib administration is long-term, the CLL14 study indicated that even time-limited administration of venetoclax (12 cycles) achieved comparable results (2-year PFS of 80–90%).
• The debate also noted that chemotherapy represents a genotoxic approach, which may increase the risk of long-term complications. Some regimens carry a 3–5% risk of developing myelodysplastic syndrome.
• It is important to note that there remains a number of patients for whom PFS does not improve with the new drugs, making chemoimmunotherapy still very important for them. This largely includes patients with IGHV mutations. For them, therapy with fludarabine, cyclophosphamide, and rituximab may represent a potentially curative approach.

Conclusion

The discussion among experts at NCCN 2019 suggests that it is still too early to definitively formulate recommendations for the widespread use of new drugs in first-line therapy. It also holds true that after the failure of standard treatment, it can always be adjusted based on disease progression. Clinical practice experience indicates that the effect of new drugs can be expected once chemotherapy fails. Thus, while the complete abandonment of chemoimmunotherapy may not be justified yet, further developments in treatment strategies can be anticipated soon as experience grows.

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Source: Brown J. R., Wierda W. G. Evolving strategies in first-line chronic lymphocytic leukemia: Is there a role for chemoimmunotherapy? J Natl Compr Canc Netw 2019; 17 (11.5): 1408–1410, doi: 10.6004/jnccn.2019.5026.