BTK Monotherapy as Frontline Treatment of CLL

Danielle M. Brander, MD: In this case, the patient was started on ibrutinib monotherapy and had an excellent response, as measured by the symptoms he had prior to starting treatment—the fatigue as well as the lymphadenopathy. Patients started on ibrutinib can often see rapid reduction in their bulky disease, both the lymphadenopathy or splenomegaly. Most patients will have a rise in their lymphocyte counts when they first start treatment. This does not represent disease progression but instead movement of the atypical CLL [chronic lymphocytic leukemia] lymphocytes from the lymph nodes to the blood. But, as in this case, that improves over time, and then you often will see improvements in the blood counts.

So patients can have rapid improvement. Most patients started on ibrutinib or other BTK [Bruton tyrosine kinase] inhibitors as monotherapy will not achieve what is called a complete response [CR], mostly because they have residual CLL in the bone marrow, if the bone marrow were to be tested.

However, in the case of ibrutinib and other BTK inhibitors, achievement of CR initially, even in a lower percentage of patients, does not necessarily translate to the fact that the patient could not have long progression-free survival on the drug. It would not be standard in clinical practice, for example, to have to perform serial bone marrow to look for complete response, but the data that we derive from clinical trials can help us determine what to expect for these patients.

In this case, the patient was found to have mild symptoms and started on therapy fairly quickly after the time of diagnosis. However, even with all of these novel agents, by iwCLL [International Workshop on Chronic Lymphocytic Leukemia] criteria, patients start treatment only if they meet indications for therapy. These indications are mainly based on disease-related symptoms that cannot be managed and affect quality of life significantly, big or bulky lymphadenopathy or splenomegaly that is symptomatic to the patient or is causing organ dysfunction, or disease that is impacting their other blood counts due to marrow involvement. In this case, after work-up the patient had both anemia and borderline thrombocytopenia that would have met indications for treatment. But again, regardless of the novel agents, regardless of patient risk factors, even patients with highest-risk disease do not start treatment upon diagnosis unless they meet indications for therapy.

In this case, the patient was started on ibrutinib in the frontline setting as a result of randomized clinical trials. The standard of care for treatment with ibrutinib, acalabrutinib, or certain other targeted therapies is that they are continued daily until the patient shows evidence of clinical progression or is not tolerating the drug. There are other targeted agents, like venetoclax, that have been studied in a time-limited course in the frontline setting, including venetoclax for a total of 12 months.

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