Frontline Targeted Therapy for CLL

Danielle M. Brander, MD: In the past several years, we have seen an increase in the number of available therapies for patients as frontline treatment. Therefore, beyond chemotherapy there was a recent approval for the BTK [Bruton tyrosine kinase] inhibitors, originally ibrutinib, now acalabrutinib. And last year, also in the frontline setting, we saw the approval of the BCL-2 inhibitor, venetoclax. With these multiple treatment options, there’s not necessarily a head-to-head comparison of the novel agents.

However, there are important frontline randomized studies that have compared chemoimmunotherapy versus the targeted therapies in the frontline setting. Based on randomized clinical trials, data have shown superior results with a targeted agent versus chemoimmunotherapy. Therefore, for this patient I would consider using one of the targeted agents.

There are not contraindications to using ibrutinib, acalabrutinib, or venetoclax in patients in the frontline setting. They do have different mechanisms of actions and known toxicities. Therefore, there are several different comorbidities you might consider when selecting therapy for a patient in the frontline setting.

It should be noted that unlike in the past where patients with certain comorbidities, renal function, or by age were excluded from chemoimmunotherapy, all of the targeted agents have also shown success in older patients or those with comorbidities. In fact, many of the trials studied these populations specifically.

Ibrutinib is known to increase risk for atrial fibrillation. It can also increase one’s risk for bleeding. The risk for bleeding is shared among other BTK inhibitors, including acalabrutinib. Therefore, if you have a patient already on anticoagulation, other antiplatelets, or with extensive cardiac comorbidities, this is something you should discuss with the patient and, potentially, their cardiologist. They may lean you away from using agents if you have other options available.

On the other side, patients using venetoclax are at risk of tumor lysis syndrome. So if they’re at high risk due to bulky disease and they may have problems with tumor lysis due to renal function or other comorbidities, this, again, is a specific consideration that should be made when talking about these agents with patients.

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