First-Line Treatment in Chronic Lymphocytic Leukemia

Jeff Sharman, MD: I think all patients who are going to be treated with CLL, it’s imperative for us to know their mutation status, their IgHV mutation status, as well as their FISH upfront. In this particular case, it may be that it was done, and we don’t have records. Or, possibly, it wasn’t done. We know that there is an inadequate degree of testing with FISH for patients with CLL who need therapy, so it depends on whether or not that was done.

I do think that ibrutinib is an appropriate first-line treatment option for patients with CLL. This has been a field that has been changing very quickly, and we’re seeing a number of new treatment options in this setting, including acalabrutinib, with or without obinutuzumab. Also, obinutuzumab-venetoclax can be utilized in the front-line setting. I certainly would not fault ibrutinib monotherapy, particularly since this likely predated the approval of acalabrutinib- or venetoclax-based therapies.

When you’re thinking about comorbidities that determine upfront treatment, there are several that are important; more and more, it used to be that treatment was decided based upon IgHV status, FISH status, and patient fitness. More and more, we can say that all these novel agents are particularly effective in the front-line setting, so it becomes more about the patient’s unique features. So, patients with cardiac risk factors, hypertension, maybe a history of atrial fibrillation who has left atrial enlargement on EKG, these are patients for whom ibrutinib, over the long-term, may exacerbate those symptoms. We don’t have head-to-head data, but at least it appears from preliminary data that acalabrutinib may not have those same toxicities in the front-line setting. Although, again, head-to-head studies are pending on this.

In a patient with cardiac risk factors, I may choose obinutuzumab-venetoclax. However, as this case importantly highlights, this patient had some significant chronic kidney disease, and that certainly exacerbates the risk of tumor lysis syndrome with venetoclax. In fact, a glomerular filtration rate of less than 80 increases the risk of tumor lysis syndrome when patients are treated with venetoclax.

For a patient with a very significant renal insufficiency, such as this patient with a GFR of just 30, that’s an important consideration. I’ll think about the medications that they’re on. Patients who are on proton pump inhibitors, that’s going to reduce their absorption of acalabrutinib but not impact the absorption of ibrutinib.

Conversely, if patients are on medications with CYP3A4 interactions, that may influence their exposure to BTK, or increase their exposure to venetoclax, you have to be very careful about drug interactions. Those are some of the things I think about when addressing a patient’s fitness or comorbidities when picking a therapy.

In terms of triggers to initiate therapy, those haven’t changed. Just because a patient has a 17p does not influence when we choose to pursue therapy. In fact, I’ve had many patients in my own practice who can have 17p and maintain asymptomatic disease for a length of time. Indications for therapy remain, like a rapid rise in the white blood cell count. By rapid, we generally mean lymphocyte doubling in less than 6 months. Symptomatic bulky lymphadenopathy can be an indication for therapy, as is an emergence of bone marrow dysfunction, such as anemia or thrombocytopenia. These are the reasons to initiate therapy, and it is inaccurate to begin therapy just because the patient has a diagnosis or a high-risk marker.

With the BTK agents, we do continue that until disease progression, and at this point, there’s no science that would support treatment discontinuation. However, for patients started on obinutuzumab venetoclax, that is an approach that is fixed duration with 6 months of obinutuzumab and 12 months of venetoclax.

Transcript edited for clarity.

Case: A 79-Year-Old Man With Relapsed Chronic Lymphocytic Leukemia

Initial presentation

• A 79-year-old man presented to a new medical oncologist for the first time complaining of vague intermitted abdominal pain, and progressive fatigue
• PMH:
  • Hypertension, medically controlled
  • MI, 8 years ago, on 81 mg aspirin
  • CLL, diagnosed 7 years ago
  • After a period of watchful waiting he began treatment with ibrutinib 420 mg PO qDay; symptoms improved and achieved stable disease, resolution of lymphadenopathy
  • After 5 years of disease control on ibrutinib he complained of increasing fatigue and decreased appetite, on physical exam there was return of palpable lymphadenopathy; spleen was palpable ~4 cm below costal margin
  • He was started on rituximab
  • Currently after 6 months on rituximab monotherapy he presents to the clinic
• PE: palpable bilateral cervical and right-sided inguinal lymphadenopathy
  
  

Clinical workup

• Labs: WBC 55,000, lymphocyte 82%, ANC 3100/mm3, Hb 9.4 g/dL, plt 90 x 109/L, LDH 220 U/L, Beta-2-microglobulin 3.9 mg/L; creatinine clearance 31 mL/min
• FC CD 5+, CD19+, CD20+ monoclonal B-cell population
• FISH: CLL probe set tested, deletion 17p
• IgHV mutational status: unmutated
• Rai stage IV; ECOG PS 1
• Treatment of idelalisib 150 mg PO BID was added to rituximab