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Assessing <i>IgHV</i> Mutations in CLL
Should You Use IgHV Mutation Status to Select Optimal Choice of Therapy for Your Patients With CLL?

Released: November 16, 2016

Expiration: November 15, 2017

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In normal B cells, antigen stimulation is mediated through the B-cell receptor, which comprises different combinations of variable V, D, and J segments for the Ig heavy chain of the receptor and variable V and J gene segments for the light chain of the B-cell receptor. In CLL, IgHV mutation analysis (referring to the V region of the B-cell receptor Ig heavy chain) has emerged as a critically important marker for optimal disease management. In the past, ZAP-70 served as an approximation of the IgHV mutation status, but it is a more challenging test to perform and does not correlate adequately with the B-cell receptor mutation status. Furthermore, IgHV mutation testing was previously difficult to obtain but is now more readily available. As such, routine clinical testing of this marker should be implemented for patients with CLL and are now included as part of the treatment recommendations in the NCCN guidelines.

Unfortunately, the marker itself is poorly understood by many practitioners, and data from registry studies show that it is only tested in approximately 6% of patients with the disease.

Several new data sets highlight the central importance of this marker as it pertains to potential treatment selection and prognosis, as discussed below.

Current Clinical Data
Long-term follow-up from the M. D. Anderson Cancer Center clinical trial of FCR chemotherapy in 300 patients with CLL shows that those patients with IgHV mutated CLL experience the greatest benefit of intensive chemoimmunotherapy, with the possibility of a cure in a significant fraction of patients. Although this patient group was not representative in terms of age and comorbidities (median age of trial participants was 57 years of age vs 71 years of age at initiation of first-line therapy in routine practice), the study demonstrates the remarkable efficacy of intensive chemoimmunotherapy in appropriately selected patients.

In the multicenter German CLL 8 study comparing FC with FCR (with a median patient age of 61 years), similar impressive outcomes for those patients with IgHV mutated CLL were demonstrated with substantially less favorable outcome for those patients with IgHV unmutated B-cell receptor. Detailed molecular analysis from this study shows that those patients with IgHV unmutated receptor have higher frequency of adverse FISH results and resistance mutations including TP53, SF3B1, and NOTCH1. Furthermore, those patients with IgHV unmutated receptor typically have disease that is more rapidly proliferative. Consequently, it is simultaneously faster growing and more resistant to chemoimmunotherapy.

In the era of novel targeted agents, selecting a chemoimmunotherapy regimen vs a BTK inhibitor in the frontline setting is a choice between brief therapy with the hopes of long-term benefit vs continuous therapy with less severe but more chronic adverse events, respectively. Those patients with IgHV mutated CLL who do not have adverse FISH findings are the most likely to experience sustained disease control with chemoimmunotherapy, such that the balance of risks and benefits might lead toward selecting a chemoimmunotherapy approach suitable to the patient performance status rather than a targeted agent.

Although this represents judgment extrapolated from several different studies, the question will be directly addressed when the results from pivotal studies are released in which ibrutinib is directly compared with bendamustine and rituximab or FCR. These studies have fully enrolled and results should be available in 2018.

Current Recommendations
To help you address the challenges associated with treatment decisions for your patients with CLL, my colleagues (Farrukh Awan, MD, MS; Steven E. Coutre, MD; Jeffrey A. Jones, MD, MPH; and Andrew D. Zelenetz, MD, PhD) and I have updated an online treatment decision aid for patients with CLL. Using this tool, you can enter your specific patient’s disease characteristics and overall fitness to see recommendations from each of the experienced faculty listed above specifically for the case you enter into the tool.

When entering a patient’s information into our online treatment decision tool, all of the experts thought it was important to include a question on IgHV mutation status for patients who have non-del(17p) CLL and are considering first-line therapy. For some experts, including myself, the presence of mutated IgHV can help determine the best course of therapy for specific patients. Click here to go to the treatment decision aid and see how IgHV status would affect each expert’s treatment recommendations.


Please share your questions or thoughts on your current management approaches for patients with CLL in the comment box below.
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In your current clinical practice, do you test for IgHV mutation status in newly diagnosed patients with CLL?
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