Emerging Markers Point to Future Strategies in CLL: An Interview With William G. Wierda, MD, PhD

Ben Leach
Published: Friday, Apr 27, 2012
Dr. William G. Wierda

William G. Wierda, MD, PhD

During the conference, William G. Wierda, MD, PhD, associate professor of Medicine and an internist in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, discussed the management of chronic lymphocytic leukemia (CLL), a slowly progressing form of the disease that tends to affect older adults. CLL accounts for approximately onethird of all leukemias, and the average age of diagnosis is about 72, according to the American Cancer Society.

In this interview, Wierda explains current and emerging strategies to manage the disease.

OncologyLive: What tests are essential to establish a diagnosis of CLL?

Wierda:
The patient should receive the standard diagnostic workup, which includes flow cytometry of the blood to characterize the lymphocyte population. Typically, the way patients present to their referring physician is that they will have their blood count checked and their white count will be elevated, and there will be an abnormally high number of lymphocytes. The standard practice or approach would be to send a blood sample for flow cytometry and confirm that the diagnosis is CLL. The typical markers on the surface of the cells are demonstrated through flow cytometry. They should be monoclonal by light-chain restriction, and should express CD5, CD19, and CD23.

Fluorescence in situ hybridization (FISH), mutation status, and prognostic factor tests are not required at the time of diagnosis to make the diagnosis or confirm the diagnosis of CLL. They are, I think, helpful in terms of counseling patients and determining the frequency of their follow-up. In the watch-and-wait phase, the prognostic factors are additional information that isn’t really used to manage the patient, other than determining what the frequency of their visits should be in the first year or two after their diagnosis. When patients need treatment, one of the prognostic factors that is very important to test is the FISH, because that allows us to identify chromosome abnormalities, and we can make modifications in how we manage patients based on the results of that test.

How do you determine the time to first treatment in patients with CLL?

For CLL, there haven’t been any trials that have shown that early treatment improves outcome. We wait to treat them until they develop an indication for treatment—the indications being bone marrow failure reflected by low hemoglobin or low platelet count, or if patients develop disease-related symptoms that can be improved with treatment. We watch and wait for patients who don’t have one of the formal indications to start therapy.

Some of the prognostic factors that have been reported and are being evaluated are independently associated with a shorter time to first treatment. Factors that correlated with a shorter time to first therapy include the presence of a 17p deletion, an unmutated immunoglobulin heavy-chain variable (IGHV) gene, extensive lymphadenopathy (more than one involved nodal area), the size of the cervical lymph nodes, and lactate dehydrogenase (LDH), as well as beta-2 microglobulin.

The treatment should be initiated based on the formal criteria for treatment. But the prognostic factors are informative in terms of identifying high-risk patients. We have several ongoing clinical trials at MD Anderson looking at patients with high-risk features and whether or not we can delay, for example, time to treatment by giving them monoclonal antibody therapy.

Please discuss your research into fludarabine, cyclophosphamide, and rituximab (FCR)-based treatment for CLL.1

Assume you have a patient who has developed an indication for treatment. If they have anemia, thrombocytopenia, or fatigue that needs to be treated, then we will initiate therapy. We’ve done a lot of work with FCR, which is our standard front-line therapy for patients who can tolerate it.

You can generally categorize patients who are getting front-line therapy into two categories: those who can tolerate a chemoimmunotherapy such as FCR, and those who cannot and need some other, less toxic treatment. For patients who could tolerate the FCR regimen, we reported in historic comparison improved survival for patients in the front-line setting. German researchers have confirmed that in a randomized trial.

Table. Prognostic Factors
in First-Line FCR-Based Treatment

17p deletion
High-risk: lower response rate, shorter TTF & OS
Consider stem cell transplant in first remission
β-2 Microglobulin ( ≥4 mg/L)
High-risk: lower response rate, shorter TTF & OS
11q deletion & IGHV unmutated
High response rate with FCR, but shorter TTF
Consider maintenance strategies
Advanced age is high-risk feature

FCR indicates fludarabine / cyclophosphamide / rituximab; IGHV, immunoglobulin heavy-chain variable; OS, overall survival; TTF, time to treatment failure.

There are a number of prognostic factors that correlate with the outcomes: response to treatment, time to treatment failure, and overall survival for patients who were treated with front-line therapy. (Table)


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