Predicting Disease Progression in CLL Patients on Ibrutinib

Inhye E. Ahn, MD

As part of our coverage of the American Society of Hematology (ASH) Annual Meeting, held December 3–6 in San Diego, California, we are speaking with Inhye E. Ahn, MD, of the National Cancer Institute, National Institutes of Health (NIH), in Bethesda, Maryland, who treats patients with hematological malignancies and conducts clinical trials. At the ASH meeting, Dr. Ahn gave a talk on developing prognostic models that may be able to predict disease progression in patients with chronic lymphocytic leukemia (CLL), treated with the targeted agent ibrutinib.

- Interviewed by Anna Azvolinsky 

Cancer Network: Can you briefly talk about how ibrutinib fits into the treatment paradigm in CLL?

Dr. Ahn: The treatment of CLL used to be centered on chemo-immunotherapy, which combines two or three agents including a monoclonal antibody targeting CD20. Such chemo-immunotherapy regiments include FCR (fludarabine, cyclophosphamide, and rituximab) and BR (bendamustine and rituximab). The limits of chemotherapy, however, were that they were intensive treatments often associated with serious side effects and are not very effective once patients develop relapsed, refractory disease or if they have an aggressive type of CLL, specifically those with a deletion of 17p. So ibrutinib is a small molecule that inhibits B-cell receptor signaling. By turning this signaling off, which is critical to the survival of CLL cells, we can treat CLL patients in a targeted manner.

In patients, ibrutinib improved the survival of both CLL patients who had relapsed, refractory disease, and previously untreated patients, and it’s also important to note that ibrutinib was highly effective in patients with high-risk disease, specifically deletion 17p. So this led to the approval of ibrutinib by the US Food and Drug Administration for the treatment of CLL patients regardless of prior treatment and cytogenetic status. So at our clinic, ibrutinib is our first recommendation for those who have relapsed, refractory disease and those with deletion 17p outside of clinical trials. Patients without these two factors, we basically individualize treatment options.

So, for example, in a medically fit young CLL patient without any adverse cytogenetics assayed by fluorescence in situ hybridization (FISH) who is looking for a first therapy, I would lay out all options, including chemo-immunotherapy and ibrutinib, and then go over side effects, effectiveness of each therapy, duration of their treatment, and listen to what the patient prefers. Oftentimes people voice their preferences on one option or the other: some people may be totally fine with taking ibrutinib daily for a long time, some people may prefer chemotherapy because it is a time-limited therapy approach that has been tested long-term. There is a phase III trial comparing FCR with ibrutinib plus rituximab in previously untreated patients. So this trial will, in the future, help answer some of these questions that we have in selecting regimens for CLL.

Cancer Network: You and your colleagues recently performed a study to identify factors that could be used to predict disease progression in patients to be treated with ibrutinib. What was previously known about what may affect disease progression on this drug, and what data did you use in your analysis?

Dr. Ahn: So there are two questions. As you know, disease progression during treatment with ibrutinib is an important area of research. The key mechanism of ibrutinib resistance is related to mutations of Bruton tyrosine kinase (BTK), the drug binding site, and the PLCG2 gene, which is downstream of BTK. The mutation of these two genes rewires the B-cell receptor survival signals in CLL cells and makes them survive. So several studies have shown that patients who develop resistance to and progress on ibrutinib undergo a relatively aggressive clinical course, and their survival is shorter than those who stop ibrutinib due to reasons other than progression. In summary, progression is the most important cause of death in CLL patients on ibrutinib.

So the questions is how to identify patients that are at a higher risk of progression, and CLL has many prognostic tools. Some examples are Rai stage, FISH cytogenetics, cell-surface markers such as CD38 and CD49d,  immunoglobulin mutation status, and other genetic mutations such as TP53. However, most of these established prognostic tools were developed in previously untreated patients or in the context of chemo-immunotherapy.

So there is a paucity of data right now whether these tools can also be used in patients on ibrutinib or whether we need to develop another prognostic system. What is known and published regarding prognostic factors relevant to ibrutinib is the genetic changes. Patients with deletion 17p appear to have a shorter progression-free survival in long-term follow-up data reported by Dr. Byrd. Complex karyotype was shown to predict inferior outcome on ibrutinib based on the MD Anderson data. Other than these, we really don’t have much about prognostic factors.

So in order to identify a simple yet comprehensive prognostic tool relevant to risk stratification in ibrutinib treated patients, we turn to our patients treated with ibrutinib at the NIH. Dr. Wiestner and Dr. Farooqui implemented and ran a phase II trial using single agent ibrutinib in 84 patients. This study opened in 2010 and is currently ongoing for follow-up, and we reached a median follow-up of 3 years at the time of the data analysis for the abstract.

Cancer Network: Could you discuss what the study found?

Dr. Ahn: We applied the clinical and molecular characteristics for univariate analysis, and then selected the factors associated with inferior outcomes, progression, or death for multivariate analysis. The factors that turned out to be significantly associated with inferior outcomes on ibrutinib were TP53 aberrations, advanced Rai stage, high β2-microglobulin, and previously treated disease. Advance Rai stage also had a trend toward inferior outcome.

Surprisingly we could not see a progression-free survival difference in patients with older age or nonmutated immunoglobulin heavy chain gene, which were the traditional poor prognostic factors in CLL. These patients appeared to be doing very well and no longer appeared to be high-risk while being treated with ibrutinib.

Using the factors associated with inferior progression-free survival based on the multivariate analysis, we developed two model systems. The reason we developed two models was that there was a correlation between β2-microglobulin and prior treatment status, so we have to separate them.

In model 1 we had three factors: TP53 aberration, advanced Rai stage, and β2-microglobulin. In model 2, we also had three factors: TP53 aberration, advanced Rai stage, and relapsed refectory disease. By using each factor as a score of 1, we stratified patients into three groups:

• low risk for those who scored 0 or 1,
• intermediate risk for those who score 2,
• and high risk for those who score 3.

By using these three risk-group systems, both models showed significant difference in progression-free and overall survival. The 4-year progression-free survival in the high-risk group was 45% by model 1 and 16% by model 2, and these were in contrast with the low-risk group, whose 4-year progression-free survival was up to 100% and 92%, so a wide separation.

Cancer Network: As far as this risk-score, what is next as far as implementing this in the clinic? Are there more studies that are needed?

Dr. Ahn: Absolutely, our next steps in research are to validate these models before fully implementing them in a clinical setting. Once validated, I believe our model is a simple and easily applicable system, which will be a very useful tool to risk-stratify CLL patients being treated with ibrutinib. Potentially, the low-risk patients based on our model have an excellent outcome with single-agent ibrutinib, whereas those with higher risk had a higher likelihood of progression or death, and these patients may be an ideal target population for clinical trials testing new drugs or a combination approach, so our models could help identify trial candidates.

Another strength of our model system is that this can be applied to previously untreated CLL patients. More and more patients are getting ibrutinib as their first-line CLL treatment and thus identifying high-risk patients among these patients may be important. Conversely, our model also highlights prior treatment status as an important risk factor and integrates biological correlates such as TP53 aberration on top of treatment status, and this helps narrow down the high-risk population within the large patient population of CLL.

Cancer Network: Thank you so much for joining us today, Dr. Ahn.

Dr. Ahn: Happy to be here.