Addressing Treatment Challenges in CLL

Danielle M. Brander, MD: I’d like to note that in this discussion we’ve been weaving a lot of the conversation around some of the toxicities to look for when treating patients with a novel agent. Some of these are agent-specific. Others, like risk for infection, are really shared among all treatments. Therefore, learning about these toxicities and how to manage them is really important and can be found across several guidelines.

I also want to point out that in this case the patient had disease progression, or resistance to ibrutinib. However, as we’re learning across several retrospective studies and clinical trials, resistance to ibrutinib, especially in the frontline setting, is relatively uncommon. Rather, the more common reason for patients to discontinue ibrutinib, including in 2 large randomized frontline studies, was intolerance. In other words, development of toxicities where the patient could no longer continue on the therapy.

Managing patients who develop intolerance or an adverse effect to therapy that can no longer be managed safely for the patient to continue on that treatment is still an important area of unmet need for patients with CLL [chronic lymphocytic leukemia]. It is very important that we follow the clinical trials that specifically look for agents, for therapies, for these patients who develop intolerance. It also is a good reminder that more treatment options for patients, including both next-generation inhibitors for certain targets as well as different targets entirely, or clinical trials that combine with a fixed-duration drug, remain important for our patients.

Other unmet needs that deserve attention in clinical trials are especially important for patients, such as this one in our case, who develop resistance to ibrutinib. We know other targeted therapies can achieve response in these settings, but often these responses, especially if patients don’t achieve a complete response or have MRD [minimal residual disease] negativity, may not be long-lived and they progress to their next line of therapy.

Other options such as cellular therapy, CAR T-cell treatments, and, as I mentioned, combination therapies will remain important to try to address these challenges and allow patients with CLL to achieve the best response with the best quality of life for as long as possible.

And this, I think, remains and will continue to be what drives us all to continue clinical trials and consider clinical trials for all patients with relapsed or refractory CLL.

Transcript edited for clarity.

Case: A 73-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

Initial Presentation

• A 73-year-old man presented to his PCP for an annual checkup; he complained of mild intermittent fatigue and occasional night sweats
• PMH: hypertension, medically controlled
• PE: palpable axillary and right-sided cervical lymphadenopathy
  
  

Clinical Work-up

• Labs: WBC 48,000, lymphocyte 72%, ANC 3700/mm3, Hb 9.4 g/dL, plt 100 x 109/L, LDH 240 U/L, Beta-2-microglobulin 4.1 mg/L
• FC CD 5+, CD23+, CD20+ monoclonal B-cell population
• FISH: normal for all CLL probe set tested, no evidence t11;14
• IGHV mutational status: unmutated
• Rai stage IV; Binet stage B
• ECOG PS 0

Treatment and Follow-up

• He was started on ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease resolution of lymphadenopathy
• After about 3 years he complained of increasing fatigue and decreased appetite, on PE return of palpable lymphadenopathy spleen was palpable ~4 cm below costal margin; creatinine clearance 56 mL/min