CLL Treatment: Managing Adverse Events With Venetoclax and Obinutuzumab
John Allan, MD, an expert on chronic lymphocytic leukemia, details adverse events seen with venetoclax and obinutuzumab.
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: The venetoclax-obinutuzumab approach is a very safe and well-tolerated agent. In fact, venetoclax compared with BTK [Bruton tyrosine kinase] inhibitors may be the best-tolerated drug we have. With venetoclax, we see issues with tumor lysis syndrome [TLS] and how we mitigate that. Outside that issue, it’s a very well-tolerated drug. With venetoclax, we see some cytopenia issues, such as neutropenia and thrombocytopenia. They may be more often and more severe than with BTK inhibitors. We also see some GI [gastrointestinal] adverse effects, such as diarrhea, which is very low grade and very manageable; most patients don’t have issues with diarrhea. Outside those major toxicities—TLS, cytopenias, and GI issues—we don’t see a lot of other toxicities. We get away from bleeding, cardiac toxicities, atrial fibrillation, arthralgias, and rash. Some of these things that we see with BTK inhibitors, we don’t commonly see with venetoclax.
This regimen does require obinutuzumab to have the best outcome. Obinutuzumab clearly is adding something to the venetoclax regimen in terms of getting to MRD [minimal residual disease]–negative states and allowing for tumor debulking. I’m absolutely convinced that’s part of why we see such great long-term outcomes in patients who are able to stop treatment. When you add in that obinutuzumab, you add in the effects of infection risk. Infection risk increases from B-cell depletion in anti-CD20. Obviously, when you combine venetoclax and obinutuzumab, particularly in patients with a lot of disease, we sometimes see cytopenias exacerbated. You see a lot of grade 3 and 4 neutropenia. Upward of 53% of patients have grade 3/4 neutropenia. We do see some tumor lysis with just the obinutuzumab. During this tumor debulking, we need to worry about that.
When you initiate the treatment—we initiate obinutuzumab first for the first 3 weeks—it wipes out this peripheral blood lymphocytosis very quickly. Obinutuzumab is a great agent. Many times with just a 100-mg dose, you start to see dramatic shifts in the lymphocytosis by that day 2 dose. By day 8, they have a 198,000 white blood cell count. This is either normal or it’s already knocked down to under 20,000. It’s really been mitigated. I can’t remember the last patient I put all the way through day 15 who still had an elevated white blood cell count after the obinutuzumab lead-in. It’s very effective. It debulks the patients. In the first 2 weeks, you have to watch for TLS, particularly in patients with white blood cell counts this elevated or bulky disease.
We don’t have this patient’s true tumor lysis risk because we don’t have imaging on her and how bulky she might be. Let’s say she’s a moderate risk by the lymphocyte count. Ultimately, once she gets debulked, when you get into the venetoclax, it’s cycle 1 on day 22. That’s going to make her tumor lysis escalation much easier. In her case, she had a very uneventful escalation to 400 mg. By cycle 3 day 1, she was fully escalated to 400 mg and had no issues. It’s a great regimen and well tolerated. It can be choppy in the first 2 weeks with obinutuzumab. As you see some lysis, you can see some LFT [liver function test] bumps, infections, and cytopenias. But if you can push through that and clear out these bone marrows, the counts will start to improve. G-CSF [granulocyte colony-stimulating factor] is our friend when using this regimen, and we can keep patients maximized and get them to full doses by using growth factor and allopurinol and monitoring the labs according to the prescriber insert.
Transcript edited for clarity.
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