Cases in CLL: Frontline Therapy Selection and Clinical Trial Considerations for a Patient With Multiple Comorbidities

In this case is a 68-year-old man who has a history of posttraumatic stress disorder, mood disorder, and steroid psychosis, as well as diabetes requiring insulin control. He was diagnosed with CLL in 2018, when he presented to his primary care physician after a period of not having routine labs. His white blood cell count was 101 x 10⁹/L with a hemoglobin level of 7.3 g/dL and platelet count of 75 x 10⁹/L. Flow cytometry with peripheral blood demonstrated CLL with a CD5/CD23-positive monoclonal B-cell population, and CT imaging showed diffuse adenopathy up to 5 cm above and below the diaphragm. Because of his anemia and thrombocytopenia, CLL-directed therapy was indicated.

Frontline Therapy
We had a long discussion with the patient about frontline options, including BTK and BCL-2 inhibitors. Venetoclax plus obinutuzumab is currently approved for treating patients with CLL and has been studied as a time-limited therapy per the CLL14 regimen. The approved BTK inhibitors ibrutinib and acalabrutinib have been studied as continuous therapy. The specific adverse event (AE) profile is different with these agents. With this patient, the idea of treatment with an anti-CD20 antibody was concerning, given both his history of steroid-induced psychosis and his history of diabetes with sensitive glucose control. As such, we wanted to avoid the potential need for steroids and thought that continuous therapy with a BTK inhibitor might be a better fit. In terms of potential AEs with these agents, we discussed that there is a possibility of musculoskeletal toxicities and rash with ibrutinib. We also discussed that headache that can occur with initial acalabrutinib treatment. The patient has a history of severe migraines and wanted to avoid the possibility of a headache; he also has a history of gastroesophageal reflux disease and required daily proton pump inhibitors, which can have an interaction with the current formulation of acalabrutinib. So, with shared decision-making and based on comorbidities, we decided to proceed with ibrutinib.

While receiving ibrutinib, the patient had stable disease but experienced persistent anemia to the point that he was requiring frequent transfusions. Because of a lack of response, we repeated a bone marrow biopsy, which showed 90% involvement by CLL. He also was experiencing other constitutional symptoms, including night sweats and fatigue. Because of these factors, we decided to reevaluate his treatment choices.

Subsequent Investigational Therapy
Given the patient’s nonresponse to ibrutinib (which is rare), we discussed the potential of  venetoclax as monotherapy; however, a clinical trial also was an option for this patient. In this case, we opted to enter a trial of pirtobrutinib (a novel BTK inhibitor that has shown efficacy in cases of intolerance or resistance to earlier-generation BTK inhibitors) in combination with venetoclax. This was an interesting and appealing option, as this trial was designed for time-limited therapy, and the patient liked that idea. When deciding on treatment, we discussed the AE profile of pirtobrutinib, which has shown favorable safety and tolerability. 

The patient enrolled on the trial and tolerated treatment very well with minimal AEs. By cycle 12, he demonstrated evidence of a complete response by laboratory and physical examination, and this was confirmed with a bone marrow biopsy. At the time of this writing, he has continued his therapy and continues to have a complete response, with a plan for time-limited therapy; he will continue for 24 cycles and then discontinue therapy.

Your Thoughts?
What are key factors that you consider when selecting frontline and subsequent therapy for patients with CLL? What investigational CLL treatment strategies are you most excited about? Answer the polling question and join the conversation by posting a comment in the discussion section below.