Review Outlines Management of Patients Receiving Venetoclax for CLL

Venetoclax (Venclexta; Abbvie/Genentech) is a highly effective treatment for chronic lymphocytic leukemia (CLL), but it also requires careful patient management to avoid serious complications such as tumor lysis syndrome (TLS).

In a new review in the journal Cancers, study authors explain the current research on how best to treat patients using venetoclax and discus how they would handle hypothetical scenarios based on their collective experience.

Venetoclax cancer drug molecule-BCL-2 inhibitor | Image Credit: molekuul.be - stock.adobe.com

Venetoclax is a highly selective B-cell lymphoma 2 inhibitor, the authors said, that has been shown in clinical trials to be effective in the relapsed/refractory (R/R) and first-line settings.

“Treatment of CLL cells with venetoclax induces the rapid onset of apoptosis in vitro and in vivo via a TP53-independent mechanism, providing the rationale for evaluating use of venetoclax as targeted therapy in CLL,” they wrote.

However, that strong pro-apoptotic capability also creates a risk of TLS. The investigators said it is important to assess TLS risk before initiating venetoclax, and to ramp up dosage and use appropriate debulking, prophylaxis, and monitoring to reduce the risk of TLS. However, they added, implementing these precautions in a real-world setting can be challenging. To address those challenges, the authors highlighted potential scenarios and how they would approach them.

For instance, they laid out a scenario in which a 70-year-old man with a history of heart disease, chronic kidney disease, and type 2 diabetes was being treated for CLL.

“A current molecular and cytogenetic workup revealed an unmutated IGHV (immunoglobulin heavy variable region) gene status, the presence of a TP53 mutation, and a complex karyotype,” they wrote.

In the scenario, the patient had already been treated with fludarabine and cyclophosphamide plus rituximab (Rituxan; Genentech/Biogen), followed by continuous ibrutinib (Imbruvica; Pharmacyclics/Janssen). Both regimens led to temporary progression-free survival (PFS), but the patient’s cancer was slowly progressing.

“At this point, the patient had R/R CLL with a high tumor burden due to a retroperitoneal conglomerate lymph node mass of 12 cm, a splenomegaly of 15 cm, and an absolute lymphocyte count of 80 × 109/L; noncontrast radiographic evaluation was used due to the patient’s increased risk of renal damage,” they wrote.

Per guidelines, the patient should be kept on ibrutinib while ramping up venetoclax before being transitioned to venetoclax monotherapy.

“Because this hypothetical patient is at high risk of TLS, a more intensive intervention and specialized attention is required with close monitoring of renal function, serial tumor burden, and splenomegaly reduction,” they wrote.

The patient would require appropriate prophylaxis with adequate hydration, they continued, and antihyperuricemic therapy at the physician’s discretion, along with careful monitoring of any emergent biochemical abnormalities.

“If available, the utilization of a nurse specialist is essential for continued patient education, the promotion of the patient’s adherence to the dosing schedule, the monitoring of blood chemistries, hydration, and supportive medications,” they wrote.

At the other end of the risk spectrum, the authors posited a low-risk case in which a 55-year-old man with no major comorbidities who is working full time was seeing CLL progression after 8 years with a partial response to acalabrutinib (Calquence; AstraZeneca). In this case acalabrutinib was stopped a day before venetoclax initiation, although the authors said in some cases patients should continue to receive acalabrutinib during venetoclax ramp-up, such as when the patient has aggressive disease progression. After ramp-up, this hypothetical patient was set to receive venetoclax plus rituximab.

In this case, the major challenge to the patient was the fact that he had a busy schedule, including family commitments.

“To navigate these challenges, the clinician will need to be aware of and understand the necessity of on-label initiation and identify red flags regarding patient stress that pose potential risks to optimal treatment and drug adherence,” the authors said.

They added that electronic tools to track dosing, tests, and appointments, can be beneficial, and that careful scheduling of dosing, bloodwork, and other tests can help accommodate the patient’s busy schedule.

Overall, they concluded that venetoclax administration poses challenges for physicians, but they said those challenges can be managed with careful risk stratification, planning, and monitoring.

“Alongside proper education, optimal patient-based treatment strategies can be achieved with a multidisciplinary care team and shared decision-making to navigate potential challenges in this continually evolving treatment landscape,” they concluded.

Reference

Anderson MA, Walewska R, Hackett F, et al. Venetoclax initiation in chronic lymphocytic leukemia: international insights and innovative approaches for optimal patient care. Cancers (Basel). 2024;16(5):980. doi:10.3390/cancers16050980