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BCL-2i AE Management

CE / CME

Expert Management of Treatment-Related Adverse Events From BCL-2 Inhibitors

Nurses: 1.00 Nursing contact hour

Pharmacists: 1.00 contact hour (0.1 CEUs)

Physicians: maximum of 1.00 AMA PRA Category 1 Credit™

Released: October 01, 2024

Expiration: March 31, 2025

Courtney DiNardo
Courtney DiNardo, MD, MSCE
Caitlin R. Rausch
Caitlin R. Rausch, PharmD, BCOP
CME/CE Information

Activity

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Introduction

In this activity, Courtney DiNardo, MD, MSCE, and Caitlin Rausch, PharmD, BCOP discuss currently approved indications for B-cell lymphoma 2 (BCL-2) inhibitor therapy in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and acute myeloid leukemia (AML) with a focus on key considerations for managing patients experiencing adverse events (AEs) secondary to BCL-2 inhibitor therapy. This activity is part of a larger program that also includes an interactive decision support tool for the management of AEs associated with BCL-2 inhibitor treatment in patients with hematologic malignancies. To use the tool, patient characteristics including the specific malignancy, the type and grade of AE, and the intended management approach are entered by the user. Then, the tool provides management recommendations based on NCCN guideline recommendations, prescribing information for venetoclax, and expert guidance from Farrukh Awan, MD, MS, MBA; Courtney DiNardo, MD, MSCE; Daniel A. Pollyea, MD, MS; and Caitlin R. Rausch, PharmD, BCOP.

The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset, which can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.  

Clinical Care Options plans to measure the educational impact of this activity. Some questions will be asked twice: once at the beginning of the activity and then once again after the discussion that informs the best choice. Your response will be aggregated for analysis, and your specific response will not be shared.

How many people receiving BCL-2 inhibitor therapy do you provide care for in a typical month?

Major Mechanisms of Action of Current CLL Therapies

Caitlin Rausch, PharmD, BCOP:
The current treatment landscape for CLL/SLL mostly includes targeted agents for both frontline therapy and relapsed disease. An example of these targeted agents is the BTK inhibitors—ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib. As a frontline option, acalabrutinib and zanubrutinib are typically preferred over ibrutinib due to a more favorable toxicity profile, while pirtobrutinib is approved after 2 or more previous lines of therapy including a BTK inhibitor and a BCL-2 inhibitor. Another option for patients with CLL is the BCL-2–targeted therapy venetoclax, paired with a CD20-targeted monoclonal antibody (mAb), either rituximab or obinutuzumab. Treatment with traditional chemotherapy is an option for only a subset of patients with CLL due to better efficacy and tolerability with the oral targeted agents.1 

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Treatment Algorithm for Newly Diagnosed CLL

Caitlin Rausch, PharmD, BCOP:
When determining the initial treatment for patients with CLL, as well as for patients receiving later lines of treatment, we consider whether they have high-risk characteristics such as del(17p) or TP53 mutation using FISH and next-generation sequencing (NGS). If a patient has IGHV-mutated disease and is young and fit, you may consider using chemotherapy, but that has fallen out of favor with the introduction of venetoclax-based therapy and BTK inhibitors. When determining whether to initiate therapy with venetoclax plus a CD20 mAb vs BTK inhibitor–based therapy, considerations primarily include patient preference, the toxicity profile of these agents, and the logistics for each therapy.

The combination of venetoclax and obinutuzumab is fixed-duration therapy, while BTK inhibitor therapy with or without a CD20 mAb is continuous treatment until disease progression. BTK inhibitors are often not preferred in patients with a history of cardiac arrythmia, on therapeutic anticoagulation, or with difficult-to-control hypertension. On the other hand, venetoclax is less preferred in patients with a high tumor burden or reduced creatinine clearance (CrCl).2

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Frontline Venetoclax + Obinutuzumab vs Chlorambucil + Obinutuzumab (CLL14): PFS

Caitlin Rausch, PharmD, BCOP:
The rationale for frontline use of venetoclax and obinutuzumab in CLL is based on the phase III CLL14 trial, where venetoclax and obinutuzumab resulted a significant improvement in progression-free survival (PFS) compared with chlorambucil and obinutuzumab (median PFS: 76.2 vs 36.4 months, respectively; HR: 0.40; 95% CI: 0.31-0.52; P <.0001).

Of importance, these results were observed after a fixed duration of 12 months of therapy, which included 12 months of venetoclax and 6 months of obinutuzumab.3

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Potential Treatment Algorithm for Relapsed/Refractory CLL

Caitlin Rausch, PharmD, BCOP:
When determining treatment for patients with relapsed or refractory (R/R) disease, we typically consider their initial treatment—whether it was BTK inhibitor–based therapy, the combination of venetoclax and a CD20 antibody, or chemotherapy—and response to that treatment.

In patients who were previously treated with venetoclax plus obinutuzumab, understanding their tolerance of the regimen and how long after completing therapy they experienced disease progression will help decide whether to change to a different class of therapy or try another round of venetoclax. Because venetoclax plus obinutuzumab is a time‑limited therapy, patients may be considered for retreatment with this regimen if they had a durable response to therapy. The definition of a durable response varies, but most would consider retreatment after a time of at least 12 months off therapy. For patients who did not tolerate venetoclax-based treatment well or progressed while still receiving or soon after ending treatment, switching to BTK inhibitor‑based therapy is recommended. 

For patients who were receiving a BTK inhibitor and experienced disease progression, switching to venetoclax‑based therapy is recommended. For patients who are intolerant of their current BTK inhibitor, switching to a different BTK inhibitor may help alleviate AEs, particularly if switching from ibrutinib to one of the second-generation BTK inhibitors—acalabrutinib or zanubrutinib.

For patients who have received chemotherapy as first-line therapy, switching to one of the available targeted treatment options would be preferred.4

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MURANO: Venetoclax + Rituximab vs BR in Previously Treated CLL/SLL

Caitlin Rausch, PharmD, BCOP:
The phase III MURANO trial compared venetoclax plus rituximab to bendamustine plus rituximab in patients with R/R CLL after 1-3 previous lines of therapy. Similar to the frontline setting, venetoclax plus rituximab is given as a fixed-duration therapy. 

In this setting, venetoclax is given for up to 2 years, with rituximab completed after the initial 6 months. This is longer than when administered in the frontline setting, as in the CLL14 trial.5,6

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MURANO: Venetoclax + Rituximab Induces Long Remission Durations

Caitlin Rausch, PharmD, BCOP:
The MURANO trial showed that fixed-duration therapy with venetoclax plus rituximab resulted in a prolonged PFS compared with bendamustine plus rituximab (median PFS: 53.6 vs 17.0 months, respectively; HR: 0.19; 95% CI: 0.15-0.26; P <.0001) even in patients with previously treated CLL.6 

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