An update on the efficacy of Venetoclax for chronic lymphocytic leukemia.

INTRODUCTION: The BCL2 inhibitor venetoclax has dramatically changed the treatment of chronic lymphocytic leukemia (CLL) and has introduced the concept of time-limited therapy with targeted agents. AREAS COVERED: This review discusses the mechanism of action of venetoclax, adverse effects, and the clinical data with this agent as identified by a selective search of clinical trials in the PubMed database. Venetoclax is FDA-approved with anti-CD20 monoclonal antibodies; however, research is ongoing evaluating its efficacy when given in combination with other agents, such as the Bruton's Tyrosine Kinase (BTK) inhibitors. EXPERT OPINION: Venetoclax-based therapy is an excellent treatment option for patients interested in time-limited therapy and can be offered in both the front-line and relapsed/refractory settings. Tumor lysis syndrome (TLS) risk evaluation, preventative measures, and strict monitoring should be conducted, while these patients ramp up to target dose. Venetoclax-based therapies produce deep and durable responses with patients often achieving undetectable measurable residual disease (uMRD). This has led to a discussion of MRD-driven, finite-duration treatment approaches, although longer term data is still needed. While many patients eventually lose uMRD status, re-treatment with venetoclax remains an area of interest with promising results. Mechanisms of resistance to venetoclax are being elucidated, and research is ongoing.

Treatment de-escalation in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia: the emerging role of chemotherapy-free regimens.

The management of Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL) has witnessed major progress over the past two decades. Initially, the incorporation of the first-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) imatinib into intensive chemotherapy regimens improved outcomes compared with chemotherapy alone. The combinations of chemotherapy with second- or third-generation TKIs further improved outcomes, with higher rates of complete molecular remission (CMR) and superior survival. The combination of ponatinib plus chemotherapy resulted in durable remissions and prolonged long-term survival, even in patients who did not receive allogeneic stem cell transplantation (SCT). The promising results seen with later-generation TKIs have caused many to re-evaluate the role of allogeneic SCT for patients who achieve CMR with potent TKI regimens. Recently, the chemotherapy-free combinations of blinatumomab plus TKIs were shown to be safe and effective in newly diagnosed Ph-positive ALL, sparing patients the toxicities associated with intensive chemotherapy. In particular, encouraging early results have been seen with the combination of blinatumomab plus ponatinib, suggesting that this regimen may represent a chemotherapy-free and SCT-sparing strategy for patients with Ph-positive ALL. Herein, we discuss the current evidence for frontline therapies of Ph-positive ALL, the treatment de-escalation strategies over time, and the role of allogeneic SCT in view of the emergence of newer chemotherapy-free regimens using potent TKIs.