Considerations for the Selection of Therapy

Despite many therapeutic options, asymptomatic or minimally affected patients with CLL are often offered observation outside the context of a clinical trial. Therapy often begins when patients develop profound cytopenias, or when symptoms, such as enlarging bulky lymphadenopathy or debilitating symptoms, substantially impact their quality of life.

Because nontransplant curative therapy has not been found, the initial goal of therapy is to maximize efficacy (with improvement of overall survival), while introducing the least overall short- and long-term toxicity.

The U.S. Food and Drug Administration approved the biological agents ibrutinib, acalabrutinib, and venetoclax for first-line use in newly diagnosed patients with CLL who require therapy.[16] In patients with poor prognostic factors (especially those with del(17p) or TP53 pathogenic variants), ibrutinib, acalabrutinib, or venetoclax should be considered.[17]

Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce DNA damage that can manifest as more aggressive and refractory phenotypes upon relapse and can induce secondary malignancies. Yet, prolonged DFS (over 10 years) can be seen with the use of the FCR regimen in younger patients (<60 years) with IGH hypermutation.[12-14]

Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce DNA damage that can manifest as more aggressive and refractory phenotypes upon relapse and can induce secondary malignancies. Yet, prolonged DFS (over 10 years) can be seen with the use of the FCR regimen in younger patients (<60 years) with IGH hypermutation.[12-14]

Avoiding alkylating agents and purine analogues also prevents prolonged cytopenias and the recurrent, long-lasting, and sometimes fatal infections seen after therapy with these agents.

Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce DNA damage that can manifest as more aggressive and refractory phenotypes upon relapse and can induce secondary malignancies. Yet, prolonged DFS (over 10 years) can be seen with the use of the FCR regimen in younger patients (<60 years) with IGH hypermutation.[12-14]

Avoiding chemotherapeutic agents up-front, when possible, is a new paradigm of sequencing therapy for CLL.

Older patients with comorbidities may better tolerate the newer biological agents (such as ibrutinib or venetoclax), monoclonal antibody therapy alone (such as high-dose rituximab), or dose modification of standard chemotherapeutic agents combined with rituximab. For older patients (>65 years), the combination of rituximab plus bendamustine (BR regimen) resulted in fewer adverse events and better outcomes than the FCR regimen.[18]