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

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)

For example, beta-2 microglobulin is a very strong factor that correlates with outcomes in all three of those parameters. Presence of 17p deletion also is highly correlated with outcome, although the frequency of that in the front-line setting is relatively low; in front-line trials, probably 8% of the patients have a 17p deletion.

There were other parameters that were correlated with various endpoints, whether they were response, progression-free survival, or overall survival. We’ll be using those parameters to identify high-risk patients and, in terms of developing new therapies for them, adding agents to FCR to try to improve response rate for maintenance strategies. There haven’t been any strategies that have been shown to be effective in terms of maintaining remission or consolidating patients.

You mentioned lenalidomide with the addition of a CD20 monoclonal antibody as a potentially promising treatment. What is known about that combination so far, and why do you find it exciting?

There were about 500 patients in a study that we’re in the process of analyzing. Several prognostic factors did correlate with outcomes—the presence of 17p deletion was a high-risk feature, patients with an unmutated V-gene were higher risk, and patients with an 11q deletion were higher risk, although not for shorter survival but for shorter remission duration.

We know treatment makes a difference in terms of the front-line patient population. It also makes a difference in terms of the relapsed patient population. In the 500 patients we analyzed, there were a number of different treatments that the patients received. One of the treatments was outstanding in terms of its ability to have a prolonged remission duration, or a prolonged time to treatment failure, as well as an improvement in overall survival when we compare it with the others and in our historic comparisons, and that was lenalidomide plus rituximab.

That data were somewhat striking because we hadn’t seen improvement in overall survival for a particular treatment regimen until these analyses. I’m excited about that combination. We are just now in the process of submitting the manuscript for publication for lenalidomide plus rituximab.

We also have an ongoing trial with lenalidomide plus nofetumomab in the salvage setting. I’m hopeful that that regimen will be further investigated in a randomized trial in previously treated patients. That needs to be confirmed, but it potentially represents an advance for patients with chronic lymphocytic leukemia.

In summary, where do we stand with CLL research?

This field is continuously evolving. We’re getting new data. As follow-up on our trials continues, we get more and more information about endpoints like overall survival. Because this is a chronic disease, patients live a long time, and it takes a lot of followup before we can appreciate the true weight and significance of the various prognostic factors.

Hopefully, we will see in the future that the utility of these factors will be in identifying high-risk patient populations and developing treatments for those high-risk groups based on chromosome abnormalities or mutation analyses, etc. So it’ll be a more personalized strategy to therapy for patients with CLL.

Reference

1. Wierda WG, O’Brien S, Wang X, et al. Multivariable model for time to first treatment in patients with chronic lymphocytic leukemia [published online ahead of print October 3, 2011. J Clin Oncol. 2011; 29(31):4088-95.