Treatment Updates in Chronic Lymphocytic Leukemia - Episode 2

Other Prognostic Factors in Chronic Lymphocytic Leukemia


William Wierda, MD, PhD: There are other prognostic factors that we’ve done a lot of work with that are important. They’re important in terms of selecting treatment, and others are less important than they used to be. Mutation status, the immunoglobulin heavy chain variable gene mutation status, is an important prognostic factor, particularly for patients who are younger and fit for whom we’re thinking about chemoimmunotherapy. Those patients who have a mutated V gene do much better with FCR. In fact, we may be curing some of those patients with FCR chemoimmunotherapy. If they have a mutated V gene and they can tolerate FCR and they don’t have a 17p deletion, those patients should be considered for FCR. Patients who have an unmutated V gene tend to have a shorter progression-free survival with chemoimmunotherapy, where we’re talking about giving them treatment and a treatment-free interval.

If we’re talking about small molecule inhibitor therapy like ibrutinib or idelalisib or venetoclax—so BTK inhibitor—treated patients, PI3-kinase inhibitor–treated patients, or BCL2 small molecule–treated patients—the patients who have a mutated V gene do as well as patients who have an unmutated V gene, or vice versa. Patients who have an unmutated V gene do as well as with those with a mutated V gene. If we’re talking about the small molecule inhibitors, mutational status of the V gene is perhaps not as significant a factor as it is for patients who are getting chemoimmunotherapy. That may change because right now with the base chemoimmunotherapy treatment, we give a defined treatment period and an observation period, and the disease usually will come back.

For the small molecule inhibitors, such as ibrutinib monotherapy or venetoclax monotherapy, for that matter, patients go on treatment and they stay on treatment. I think it’s because they stay on treatment that you don’t see a big difference between the unmutated and the mutated cases in terms of progression-free survival. But I think it may emerge as an important feature if we’re talking about giving patients small molecule inhibitor therapy that gets them in a good deep remission and then stopping treatment and monitoring them for relapse. It may be in that setting where patients who have an unmutated V gene have the disease start growing quicker and their progression-free survival may be shorter off of treatment.

Regarding the other features—for example, 11q deletion or loss of the ATM gene—those patients do very well with alkylator agent—based chemoimmunotherapy. They also do very well with BTK inhibitor–based treatment. There are more recent data that have shown the progression-free survival was actually a little bit better for patients who have an 11q deletion on ibrutinib than patients who don’t have an 11q and or a 17p deletion.

Deletion 11q used to be a higher-risk feature, but in the era of small molecule inhibitors, not so much. We pay less attention to the deletion 11q group than we used to. Trisomy 12 is neither favorable nor unfavorable, and 13q deletion is also neither favorable nor unfavorable in the era of small molecule inhibitors. Those are the main prognostic factors. There are others, but they’re not as clinically useful. ZAP70, for example, is not really clinically useful these days. We don’t use it to direct treatment or to monitor prior to starting treatment. We’ve had insistent findings in our data in terms of how useful CD38 is, and that changes, too. In any particular patient, you’ll see at times they will be negative or positive. So, it’s not as useful a marker.

Mutational status is very important. It tells us the intrinsic characteristics of the disease for a particular patient. We divide patients into those who have a mutated immunoglobulin heavy chain variable gene and an unmutated variable gene. The determination between those 2 requires sequencing of the immunoglobulin gene. All of the leukemia cells have the same variable gene in them. You sequence the gene, and you compare it to the germline sequence. If there’s more than 2% deviation from germline, those cases are considered mutated. If there’s less than 2% deviation from germline, those are considered unmutated cases.

The disease characteristics correlate with which category patients belong to: mutated versus unmutated. The mutated cases tend to be more indolent. They grow slower; they respond very well to treatment, particularly chemoimmunotherapy; and they have longer remission duration and longer overall survival. The biology is a little bit different for the mutated cases than it is for unmutated cases. The unmutated cases are more proliferative. They tend to have a shorter doubling time, they tend to progress and need treatment sooner, and they tend to have a shorter remission duration. But the determination of whether or not patients are mutated requires sequencing of the variable gene and comparison of that sequence to the germline.

There is one exception, and that is patients who have a 3-21 gene. It belongs to the subfamily or the family of 3-21. Those patients have a higher-risk disease, so they fall into the category of unmutated whether or not they’re mutated. If they have mutations in the 3-21 variable gene, they still behave like an unmutated case despite the fact that they’re mutated.

There are markers that associate or correlate with mutational status. As I mentioned, ZAP70 is a marker. Patients who are ZAP70 positive tend to be unmutated, and patients who are ZAP70 negative tend to have a mutated V gene. CD38 also has been reported, but it’s less highly correlated in our experience because patients can change their expression levels of CD38 and cross between positive and negative over time.

Transcript Edited for Clarity