Benefits of Time-Limited CLL Therapy
The advent of new targeted molecules has significantly influenced the possibilities of therapy for chronic lymphocytic leukemia (CLL) and are now an integral part of treatment regimens, including the 1st line. Individual therapeutic approaches and strategies based on them have their advantages and disadvantages as well as their target patient group, but the concept of time-limited treatment is increasingly gaining ground. Therapy today is significantly individualized, and its optimal choice is based on the assessment of various circumstances on the patient’s part and their disease.
Introduction
Bruton's tyrosine kinase inhibitors (BTKi) and inhibitors of the anti-apoptotic protein bcl-2 (BCL2i) were initially used in monotherapy, but several combination regimens emerged over time. We can choose from continuous monotherapy with BTKi, administered until disease progression or unacceptable toxicity, and time-limited therapy for 1–2 years, where BCL2i is given in combination with another drug.
Continuous monotherapy with BTKi (ibrutinib, acalabrutinib, zanubrutinib) is recommended and covered in the 1st line for patients with TP53 mutation or del17p, according to the latest recommendations of the Czech Hematology Society ČLS JEP. In cases of relapsing or refractory diseases (R/R), especially in the presence of unfavorable genetic changes such as del17p and/or TP53 mutation, continuous BTKi therapy is commonly encountered in practice. Time-limited treatment is used in previously untreated patients with CLL but also significantly benefits relapsing or refractory patients.
Options for Combination Treatment Regimens
BCL2i venetoclax is currently most commonly combined with an anti-CD20 antibody (rituximab, obinutuzumab) or BTKi.
The V+O regimen (venetoclax + obinutuzumab) is currently the primary funded regimen in the 1st line for patients with significant comorbidities. It was examined in the CLL14 study, where authors compared the V+O regimen with chlorambucil + obinutuzumab in previously untreated patients with comorbidities, with V+O treatment lasting 12 months. The venetoclax regimen showed more overall and complete remissions, and long-term analysis confirmed longer progression-free survival (PFS).
The V+R regimen (venetoclax + rituximab) is a standard treatment for patients with relapsing or refractory disease. This regimen offers several benefits for 2nd line treatment in patients with relapse/refractoriness to chemoimmunotherapy. It has high efficacy in terms of frequently achieving undetectable minimal residual disease (uMRD). Additionally, venetoclax treatment is limited to 2 years compared to BTKi, where long-term continuous treatment until progression (or unacceptable toxicity) is necessary, increasing the risk of accumulating adverse effects, decline in drug compliance, and selection of resistant clones. The V+R regimen can also be used in cases of 17p deletion and/or TP53 mutation.
An exploitable regimen for 1st line CLL patients is the combination of BTKi and BCL2i – venetoclax + ibrutinib, which is fully oral and thus not associated with the need for infusion application as in the case of obinutuzumab. Noteworthy is the CAPTIVATE study, where this regimen led to complete remission in 55% of patients, with a total of 77% achieving uMRD in peripheral blood. However, this is not yet a funded therapy modality.
The combination of venetoclax + acalabrutinib is also being tested in clinical evaluations, such as in the MAJIC and CLL16 studies, but we are still awaiting their results and longer-term follow-ups.
Similarly, regimens that utilize all three drug groups (BTKi, BCL2i, anti-CD20) are still experimental treatments awaiting evaluation.
Advantages of Time-Limited Therapy
From the patient's perspective, time-limited therapy offers the potential for better compliance due to the shorter treatment duration and reduced risk of adverse effects or drug interactions. Shorter exposure to therapeutic molecules could also mean a lower probability of developing resistance to treatment. Available studies also suggest that time-limited therapy has the potential to achieve better therapeutic responses, often at the level of undetectable minimal residual disease, which translates to longer intervals of progression-free survival and time to the next therapy. Last but not least, there is the possibility of retreating with the same regimen upon disease progression.
Data on direct comparisons of continuous and fixed-therapy venetoclax regimens are not yet available.
Conclusion and Discussion
BTKi and BCL2i have brought several changes to CLL therapy. These are highly effective drugs with a good safety profile, suitable for both previously untreated and relapsing or refractory patients, including those with high-risk CLL. A variety of treatment regimens can be chosen from, with options for both continuous and time-limited therapy. However, deciding between these therapeutic modalities is currently done within the context of the overall approach (disease and patient characteristics, assessment of pros and cons), as direct comparative studies are still lacking.
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Source: Lysák D. Time-Limited Therapy in Patients with Chronic Lymphocytic Leukemia. Oncology 2023; 17 (5): 323-328.
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