CLL Specialists' Strategies for Side Effect Management and Third-Line Treatments

In a PeerView educational session at the 2024 American Society of Hematology (ASH) conference, CLL specialists discussed common questions and controversies clinicians have about treating chronic lymphocytic leukemia (CLL). 

In this article, we’ll discuss portions of the session, including side-effects management strategies for CLL therapies and treatment options for patients who have stopped responding to treatment or who experienced a relapse after receiving two different therapies. 

To read other segments from this session which cover considerations for your first CLL treatment and insights on combining BTK and BCL-2 inhibitors, click here.

Managing the Side Effects of BTK and BCL-2 Inhibitors 

Most people with CLL/SLL do well with targeted therapies like BTK inhibitors, venetoclax, and obinutuzumab. However, these treatments can cause side effects. 

To learn about how to manage the side effects caused by CLL treatments, click the button below to explore an educational guide for people with CLL/SLL and their care partners. 

Managing CLL Treatment Side Effects Guide

Dr. Farrukh T. Awan from UT Southwestern shared additional insights about strategies to manage side effects associated with CLL therapies. Read them below. 

Reducing the Risk of Bleeding from BTK Inhibitors

BTK inhibitors can increase the risk of bleeding and bruising. To minimize this risk, it is advised to stop anti-platelet and anticoagulant (blood thinners) medications, such as warfarin or apixaban, before starting BTK inhibitor treatment. 

You will be closely monitored for signs of bleeding, particularly during the early stages of treatment. If you are scheduled for minor or major surgery, your doctor will likely advise pausing the BTK inhibitor three to seven days beforehand to further reduce bleeding risks.

Managing Heart-Related Effects from BTK Inhibitors

BTK inhibitors may increase patients' risks of developing heart conditions. To learn about the relationship between heart side effects and BTK inhibitors, click here. 

Dr. Awan advised oncologists to work closely with a heart doctor (cardiologist) while patients are taking a BTK inhibitor, actively monitor blood pressure, and watch for signs and symptoms of heart arrhythmias. 

Reducing the Risk of Side Effects from Venetoclax and Obinutuzumab

Dr. Awan stated that the risk of patients experiencing a rare side effect called tumor lysis syndrome (TLS) from venetoclax can be reduced if you receive the obinutuzumab infusions beforehand. Obinutuzumab may also cause TLS; however, if patients are pretreated with a BTK inhibitor, the risk can be reduced even further. 

Infusion reactions can occur with obinutuzumab. Taking a BTK inhibitor before the obinutuzumab infusion can reduce the risk of experiencing a reaction. 

Third-Line Treatment Options for Relapsed/Refractory CLL 

If you have taken BTK inhibitors and BCL-2 inhibitors in the past and these therapies have stopped working, other treatment options available are listed below.  

Pirtobrutinib

Dr. Bita Fakhri from Stanford University School of Medicine discussed that doctors may consider the non-covalent BTK inhibitor pirtobrutinib (Jaypirca, by Eli Lilly) for people with relapsed/refractory CLL/SLL. 

Pirtobrutinib is FDA-approved for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK and BCL-2 inhibitor. 

To learn about how pirtobrutinib works, its effectiveness, and its side effects, click here. 

CAR T-cell Therapy Liso-cel

The CAR T-cell therapy liso-cel (Breyanzi by BMS) is FDA-approved for CLL/SLL patients who have received previous treatment with a BTK and BCL-2 inhibitor. 

To learn about how liso-cel works, its effectiveness, and its side effects, click here. 

Additional insights about liso-cel were presented by Dr. William G. Wierda from U.T. M.D. Anderson Cancer Center. These included: 

• While most side effects of liso-cel were manageable, patients with high inflammation markers, poor kidney health, or a high tumor burden before treatment faced a greater risk of worse brain-related side effects.
• Liso-cel appears to work the same regardless of high-risk CLL/SLL type, such as unmutated IGHV, del(17p)/TP53 mutation, and complex karyotype.
• The fewer prior treatments a patient has had, the better liso-cel seems to work.
• Early but promising data shows that combining liso-cel with other CLL therapies, such as ibrutinib, might be safe and improve results.

BTK Degraders

BTK degraders are another treatment option in clinical trials for people with relapsed/refractory CLL/SLL. Click here to learn about how they work. 

The BTK degraders being investigated in trials include NX-5948 (by Nurix Therapeutics), ABBV-101 (by AbbVie), and BGB-16673 (by BeiGene). Dr. Wierda presented early findings about BGB-16673 from the CaDAnCe-101 study. 

• Out of the 43 CLL/SLL patients who received BGB-16673 at a dose of 200 mg, 88% of patients experienced either a partial or complete reduction of cancer signs/symptoms (overall response).
• For the most part, the side effects from BGB-16673 were manageable. However, low blood counts and infections were a risk. To learn how side effects from BTK degraders are managed, please speak with your CLL specialist. 

Bispecific Antibodies

Bispecific antibodies are a treatment option available for people with relapsed/refractory CLL/SLL in clinical trials. The types of bispecific antibodies being investigated for CLL/SLL include epcoritamab (Epkinly, by Genmab and AbbVie), mosunetuzumab (Lunsumio by Genentech), and glofitamab (Columvi by Genentech). 

Dr. Wierda shared that after people with CLL/SLL were treated with epcoritamab, 63% of them experienced a full or partial reduction in cancer signs/symptoms (overall response). This included high-risk CLL patients. 

Another promising finding was that most patients who achieved a response also achieved MRD negativity, a highly sensitive test that finds little to no cancer cells in a sample. 

For side effects from epcoritamab, cytokine release syndrome (CRS) was predictable, happening after the first full dose. Another notable finding was that any side effects patients did experience resolved. 

Click here to learn about how bispecific antibodies work and how to receive them in clinical trials. 

Additional New CLL Treatments in Clinical Trials 

Various other treatments are being investigated for CLL/SLL. These therapies are in the early stages of testing. We’ll write additional content on these treatments below as more data comes to light about their effectiveness in treating CLL/SLL. 

Therapies in the early stages of clinical trials for CLL:

• Non-covalent BTK inhibitors: Nemtabrutinib, TT-01488, LP-168, AS-1763
• Second-generation BCL-2 inhibitors: lisaftoclax, sonrotoclax, ABBV-453
• BCLxL/BCL-2 inhibitor: LP-118
• MALT1 inhibitor: ABBV-525
• CDK9/MCL-1 inhibitors 

Stay tuned to read more news about active research in chronic lymphocytic leukemia by clicking the button below. 

Continue Reading CLL News

Summary 

In conclusion, the PeerView educational session offered valuable insights on managing CLL treatment side effects and exploring third-line options such as pirtobrutinib, liso-cel, BTK degraders, and bispecific antibodies. 

These discussions provide helpful information for people with CLL and their care partners to navigate the complex treatment landscape. It can be challenging to keep up with the advancements of so many new treatments, but it's inspiring to witness the exploration of numerous innovative therapies for people with chronic lymphocytic leukemia. 

Sources: 

• Addressing Current Questions and Controversies in the Management of Chronic Lymphocytic Leukemia
• What Clinicians Want to Know: Addressing Current Questions and Controversies in the Management of Chronic Lymphocytic Leukemia - A CME Friday Satellite Symposium and Webcast Preceding the 66th ASH Annual Meeting