Treatment Research Landscape in Chronic Lymphocytic Leukemia
John Allan, MD, provides insights on novel agents and treatment strategies currently being studied in chronic lymphocytic leukemia.
Case: A 72-Year-Old Woman with Newly Diagnosed Chronic Lymphocytic Leukemia (CLL)
- Patient KM is a 72 y/o woman.
- PMH: Hypertension (well controlled on medication)
- SMH: Does not smoke; drinks occasional glass of wine in social setting; Walks with friends 2-3 times weekly.
Clinical Presentation:
- In October 2022, KM visited her PCP for her annual checkup. She reported having persistent fatigue and recent occurrences of night sweats.
Clinical Workup and Diagnosis:
- WBC: 186,000; 80% lymphocytes
- Hgb, 9.4 g/dL
- Platelets, 85 x 109/L
- ECOG PS 0
- Elevated serum beta-2-microglobulin
- Flow cytometry, CD5+, CD20+, CD23+
- TP53 mutation status – unmutated; IGHV mutation status – unmutated
- Bone marrow biopsy confirms diagnosis of chronic lymphocytic leukemia (CLL)
Current Treatment:
- After discussions with her family and clinical team, KM was initiated on fixed duration of venetoclax + obinutuzumab.
- KM was started on obinutuzumab at 100 mg IV Day 1, followed by 900 mg IV on Day 2, then 1000 mg IV on Days 8 and 15 of Cycle 1; Currently infused with 1000 mg IV on Day 1 of remaining cycles.
- She was initiated on a ramp-up dosing schedule of venetoclax starting on C1D22 and currently taking the recommended dose of 400 mg PO daily.
Transcript:
John Allan, MD: At ASH [American Society of Hematology Annual Meeting] 2022 and in January 2023, we got good news around novel agents that are up and coming in the CLL [chronic lymphocytic leukemia] space, and they’ll likely trickle into other disease states in lymphoma as well. The first that made the biggest splash was pirtobrutinib. Pirtobrutinib is a reversible BTK [Bruton tyrosine kinase] inhibitor that has been proven, preclinically and now clinically, to overcome BTK cysteine 481–resistant mutations. It’s done through this reversible nature. It doesn’t need to bind the cysteine 481 residue within the kinase pocket. It irreversibly inhibits the protein via other interactions within that kinase pocket. It has a very long half-life and is very safe. It now has FDA approval in mantle cell lymphoma. Studies are being done in CLL as well.
If anything, there are more data in CLL than in any other disease histology. With over 300 patients treated in the phase 1 expansion study with pirtobrutinib, the data are really encouraging. Response rates are pushed up to 80%. These patients are refractory or double refractory to BTK inhibitors plus venetoclax. The response rates are very high. Close to 80% of patients are responding. It deepens over time. The median PFS [progression-free survival] for all comers is 15 to 16 months, and these are the highest-risk patients we have. For patients with BTK mutations, the median PFS is a little over a year. But it’s an agent that’s going to be very relevant in the CLL space. It’s FDA approved in mantle cell lymphoma. Continue to look for that drug’s development.
The other agents highlighted at ASH would were BCL2 inhibitors, like lisaftoclax. Beijing [China] has a molecule, a BCL2 inhibitor, which may differentiate this class of drugs in ramp-up safety and tolerability, ease of use, and potential effectiveness. Those drugs are very early in development, but that’s something to keep an eye out for. There are other drugs to overcome BTK resistance, most notably BTK degraders. There are several in clinical development. At ASH we saw 1 from Nurix Therapeutics, which has the lead in terms of clinical development, though many others are right behind it. We’re going to see more data develop over the next year or so in congresses. These BTK degraders are going to be important. They’re showing some efficacy. We need to understand the toxicities of these agents a little better and see if these drugs can differentiate themselves based on toxicity and efficacy. Several companies have agents within that class, and that development is proceeding rapidly.
The last compound that we saw was a PKCβ inhibitor. This drug can inhibit PKCβ, which is downstream of the B-cell receptor of BTK. In BTK-resistant patients, sometimes the B-cell receptor pathway turns back on, even in the absence of BTK mutations. This drug may be able to overcome that. It’s very early, but there are encouraging, promising data. We’re also seeing bispecific antibodies. Epcoritamab has taken the lead in the CLL space with a CD20/CD3 subcutaneous bispecific antibody, showing encouraging responses in heavily pretreated patients. We’re seeing some responses with epcoritamab, which is a bispecific antibody. Other drugs are developing in this space as well. [It’s a] very interesting and exciting time to be treating patients with CLL and following these data. But there are a lot of interesting drugs coming [that are designed] to overcome resistance and new combinations coming together. We’ll see how best we can put these drugs together and optimize our outcomes.
With that, I’d like to thank everybody for joining us. That concludes our case in Peer Perspectives. I appreciate the time to be with you.
Transcript edited for clarity.
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