Treating CLL With Bruton's Tyrosine Kinase Inhibitors

Part 1: Frontline Treatment Options for CLL by Risk

During a live virtual event, Sameer A. Parikh, MBBS, discussed with participating physicians the treatment options for patients with chronic lymphocytic leukemia in the front-line setting by risk assessment.

CASE

  • A 71-year-old woman reported symptoms of weight loss and increasing fatigue.
  • Medical history: hypertension, medically controlled
  • Physical examination: axillary lymphadenopathy, spleen palpable about 4 cm below costal margin; appears ill, does only limited daily activity
  • Laboratory results:
    • White blood cell count: 47,000/mm3; 76% lymphocytes
    • Hemoglobin: 8.7 g/dL
  • Platelet count: 115,000/mm3
  • Absolute neutrophil count: 3600/mm3
  • Lactate dehydrogenase: 250 U/L
  • β2-Microglobulin: 4.3 μg/L
  • Flow cytometry: CD5+, CD20+, CD23+
  • Fluorescence in situ hybridization (FISH): deletion 11q (del[11q])
  • Molecular analysis: IGHV unmutated
  • Bone marrow biopsy: diffuse infiltration by chronic lymphocytic leukemia (CLL), 90%-95%

Editor’s Note: This article is based on an earlier event. As such, more recent updates to the chronic lymphocytic leukemia landscape may not be reflected.

Targeted OncologyTM: How do you assess risk for a patient with newly diagnosed CLL?

PARIKH: The mutation status of the IGHV gene is an important marker to analyze because an unmutated-IGHV status is associated with a shorter time to first therapy and an inferior response to chemoimmunotherapy. That’s something that we, at my institution, try to obtain on all patients.

The other thing to remember is that the IGHV mutation status generally does not change over time. You just need to get it once during the course of the patient’s disease process and then that doesn’t change, [which is] unlike FISH status that can change over time. For a CLL FISH panel, the most problematic [finding] is del(17p), which this patient did not have. This patient had del(11q).

How you would approach the treatment of this patient, and what are some of the treatment options?

The NCCN [National Comprehensive Cancer Network] guidelines for the management of patients with CLL [are categorized in] respect to prognostic information.1 TP53 mutation testing is an important parameter that I will routinely get for all patients prior to starting therapy. Mutated TP53 is associated with an unfavorable prognosis. Flow cytometry–based markers—CD38, ZAP70, and CD49d—have not been that helpful except for perhaps CD49d. In multivariate analyses where there were many markers used, the relative importance of CD38 and ZAP70 has fallen out of favor. But I think with TP53, IGHV mutational status, and perhaps CD49d, we’re able to give all the prognostic information to a patient.

We all know about the importance of the CLL FISH panel with del(11q) and del(17p) being associated with unfavorable risk. Increasingly now, the complex karyotype is becoming an important parameter to check, and this can be done from the peripheral blood. This, ideally, should be done from a bone marrow biopsy. If you have more than 3 unrelated chromosomal abnormalities, then that’s called a complex karyotype.

What would you offer this patient at this point?

There weren’t any chemoimmunotherapy takers, which is surprising, but I suspect that is probably reflective of how our practices have evolved. The vast majority of the votes are for ibrutinib [Imbruvica] plus or minus anti-CD20. This is why we always refer to the NCCN guidelines, and it’s incredible that these keep changing 3 or 4 times a year.1 It’s always hard to keep up.

[Patients are split up by 2 categories of] frail patients with significant comorbidities—all patients who are older, or patients who are younger and have significant comorbidities—or patients who are less than 65 years of age. Regardless of what kind of patient you treat, it’s incredible now that for first-line therapy, the treatment options are essentially the same. You either have ibrutinib, acalabrutinib [Calquence] plus or minus obinutuzumab [Gazyva], or venetoclax [Venclexta] and obinutuzumab.

[Treatment selection] has to be taken into context after discussions with patients, but I think this is just completely different from how we had approached treatment options [in the past]. There are other options available for frail patients with comorbidities, such as chlorambucil-based therapies or bendamustine/rituximab [Rituxan; BR], but these treatment options have fallen out of favor. In the young patients, you could consider FCR [fludarabine, cyclophosphamide, and rituximab], but that is only for patients who have mutated IGHV genes with low-risk features. I don’t think a lot of people are doing this treatment regimen anymore.

Reference:

1. NCCN. Clinical Practice Guidelines in Oncology. Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2021. Accessed October 2, 2020. https://bit.ly/3nb3O1g