Dr. Wierda: There are a number of traditional prognostic factors like age, clinical stage, lymphocyte doubling time, and bone marrow pattern of involvement. We still assess those, and it is useful information. We've tended to focus more recently on the newer prognostic factors: Immunoglobulin heavy-chain variable gene sequence analysis, or mutation status is one of those; ZAP70 [Zeta-chain-associated protein kinase 70] expression in the leukemia cells is another; cytogenetics by either karyotype or by FISH is [yet] another.1-11 And then we've also had data published more recently about response assessment and minimal-residual disease evaluation at the end of treatment.12-13
I think most importantly for the practicing clinician is to think about these prognostic factors in terms of how they may be used to manage their patients. Immunoglobulin heavy-chain mutation status, ZAP70—they can help us to anticipate how frequently we need to see patients; however, they're not really used at this point in terms of making management decisions.
Narrator: Dr. Wierda notes that some of the factors, including immunoglobulin heavy-chain variable gene sequence and mutational status, don’t change throughout the course of the disease, but many of them do.
Dr. Wierda: So, if you have a patient who's newly diagnosed and you evaluate chromosome abnormalities by FISH, for example, the results that you see may be different for that same patient after the patient's been treated with their initial therapy and has developed relapsed disease. So for the factors that can change—particularly FISH and cytogenetic abnormalities—the important time to evaluate that factor would be whenever you're considering either starting treatment or changing treatment for a patient.
FISH is really the prognostic factor that's most useful in evaluating and managing patients' treatment decisions, and treatment changes are made based on FISH and identification of the high-risk features. The first one is 17p deletion. When that abnormality is identified, that particular group of patients is typically refractory to alkylating-agent–based therapy and purine-analog–based therapy. They have very poor outcomes when they start to need treatment and have active disease.7,14-15
There is a subgroup of those patients who don't need treatment. It's a small portion of them, 20[%] to 30%,16 so you shouldn't act on the presence of 17p because you may be doing the patient a disservice by initiating therapy if they don't need therapy.
However, if you have a patient who has developed indications for treatment—they have active disease, symptomatic [disease], or have developed anemia or thrombocytopenia—and they have a 17p deletion, we really don't have any standard treatments for those patients. So that's a particular group that we've been focusing on for developing and identifying novel agents that can be used to treat them and to improve their outcomes—both progression-free and overall survival.
The other cytogenetic abnormality that we identify with FISH that can potentially impact on how patients are managed is the presence of an 11q deletion.7,17-20 We have found in randomized trials that those patients are sensitive particularly to alkylating agent/purine analog combinations, or alkylating-agent–based therapies, particularly the FCR [fludarabine/cyclophosphamide/rituximab] regimen. And they are also responsive to bendamustine/rituximab. So if you have a patient who needs either front-line therapy or salvage therapy, and they have an 11q deletion, then you should be considering a chemoimmunotherapy-based regimen that has an alkylating agent in it.
You can typically get them into a remission, but the problem is their consistently relapsing disease—even though they are sensitive to chemotherapy—and for that reason, this patient population with 11q deletion remains in what I could consider a higher-risk category.
The other feature that's a prognostic factor is refractory disease—and particularly purine-analog refractoriness. If a patient becomes purine-analog–refractory, then management clearly will need to change for that patient. Those are patients for whom we try to get to a stem cell transplant. It's not necessarily a factor that can be measured, but more of a clinical feature.
The biggest area in terms of new prognostic factors is gene sequencing analysis and identifying genes that are mutated in patients with CLL. There are data out there with regard to p53 and identifying patients who have mutations in p53 as a high-risk group.21-23 So if it's possible to do gene sequencing, I would recommend doing sequencing for TP53. And we would put that type of patient with TP53 mutations into the high-risk category, such as those with a 17p deletion.
Other genes that have been reported in the literature that aren't routinely sequenced but that we're generating data for and trying to identify what are the important prognostic ones are SF3B1. NOTCH1 is another one [that], when mutated, can put patients in a high-risk group.23-25 BIRC3 is another, again, [that] when mutated, would put patients into a high-risk category.23 We've made efforts to include and are generating and collecting data with regard to ATM mutations, and how that's prognostic and how that might also impact on patient management issues.
Again, this is all research-based, so most of these tests and sequencing analyses are not readily available to the practicing clinician. It's a complicated field. Again, most of the prognostic factors that we evaluate can change in an individual patient over time. And most likely a lot of the treatments that we use may drive or alter those changes. So, clearly, we need to have a concerted effort to first collect information on the prognostic factors for patients and also to have serial sampling for patients and to be able to connect that information with the patient's clinical course, particularly what treatments they've received, and when and how they develop refractory disease.