Analyzing Clinical Outcomes in CLL Disease Progression Treated With Ibrutinib

Paul Hampel, MD, Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, evaluates outcomes of patients with CLL treated at Mayo Clinic with 2018 iwCLL disease progression on ibrutinib, aiming to establish a benchmark for evaluating available novel agents and those in development.

Transcript

My name's Paul Hampel. I am assistant professor of hematology at Mayo Clinic in Rochester, and I am here to discuss a recent study looking at outcomes beyond disease progression on ibrutinib. So ibrutinib is an inhibitor of BTK and really is one of the novel agents that led this wave, this shift from the treatment landscape from chemotherapy to novel or targeted agents. And this remains a go-to class of drugs, covalent BTK inhibitors, both in the front-line and relapsed/refractory setting for treatment of patients with CLL, or chronic lymphocytic leukemia, or SLL.

Despite the efficacy that we're so excited about with this class of drugs, the majority of patients receiving ibrutinib will ultimately discontinue that treatment most commonly due to toxicity or disease progression. Patients who stop Ibrutinib due to disease progression have worse outcomes, worse progression-free survival, worse overall survival compared to those who are discontinuing due to toxicity where an alternative covalent BTK inhibitor may still provide benefit.

However, these different discontinuation situations, patients in these various scenarios will often still be grouped together for survival analyses as ibrutinib-exposed, whether they discontinued due to toxicity or discontinued due to progression.

Another issue is that patients who were enrolled in the pivotal studies of other treatments that are available in the relapsed/refractory setting were ... the timeline of accrual was such that these patients were really minimally represented in those. So patients who had received a BTK inhibitor were not really treated in most of the studies that are leading to approval for our subsequent line therapies of these patients that are available in the clinic, at least currently. So with many promising novel therapies both in development and becoming increasingly available in the clinic, we thought it was important to better understand what the expected outcomes are for discussions in the clinic as well as evaluating future studies.

So in this study, we really focus on patients who have that true disease progression event on ibrutinib, describe what that event looks like, and look at outcomes beyond that progression event. And then specifically, what are the survival outcomes for the different next-line therapies. And so it's a retrospective cohort study. It has patients who were treated at Mayo Clinic, comprehensive cancer sites in Rochester, Minnesota; Florida; and Arizona. And the progression event was by 2018 iwCLL guidelines. The main survival outcomes that we're looking at here are of course overall survival. This is going to be analyzed as the time from date of progression on ibrutinib. So not how long your people are living with that Ibrutinib treatment, but the clock starts at the progression event; or when we're talking about subsequent treatment analyses, at the start of that subsequent therapy until death.

Treatment-free survival. This is going to be the duration from the start of treatment, that subsequent line therapy immediately after ibrutinib failure to the start of the subsequent therapy afterwards, or death. So until the next therapy beyond that. And again, this is starting. All of these are looking after the progression event on ibrutinib itself. So we had 144 patients who we identified with progression, and this includes 106 patients with progression of their CLL and 38 patients with biopsy-proven Richter transformation. The majority of the patients were treated in the relapsed/refractory setting and the median overall survival for the entire cohort from the moment of disease progression on ibrutinib was 25-and-a-half months. And as expected, this was longer for those with CLL disease progression compared to those with Richter transformation. Survival after progression was longer amongst patients who had CLL disease progression on ibrutinib in the front-line setting compared to those who had been receiving ibrutinib as a second-or-greater-line therapy in the relapsed/refractory setting.

However, amongst patients who were treated in the relapsed/refractory setting, actually survival was similar across those who had received one, two, or three-plus prior lines of therapy, which requires further validation in other studies, but appears to place some emphasis on the treatment that occurs thus beyond progression on ibrutinib. Patients, unfortunately, who experienced Richter transformation as their progression event had similarly poor outcomes regardless of whether this occurred in the setting of front-line ibrutinib use or ibrutinib being used in a relapsed/refractory setting.

Another unexpected finding was the pattern of progression. So since we were qualifying these out by iwCLL guidelines, we were able to see how did they meet those progression criteria. And what we found was actually patients who had lymphadenopathy as their pattern of progression, they had a worse overall survival and actually trend towards worse treatment-free survival as well compared to those who had lymphocytosis alone or lymphocytosis without lymphadenopathy as their progression event.

The median time from iwCLL progression to the start of next therapy was about a month-and-a-half. And when we looked at treatment outcomes with subsequent-line therapy, these findings were supportive of the standard of care in the practice currently, which is those who received a venetoclax-based treatment had amongst the best overall in treatment-free survival. The other group that did well here were those who received a CAR T-cell therapy. Of course, this was a smaller group and that would've been on trial treatment as their subsequent therapy. When looking at patients who received other approved treatments, this would be a group that includes things like chemo-immunotherapy or PI 3-kinase inhibitors, anti-CD20 monoclonal antibody therapies alone. Those patients did much worse compared to those who had received either CAR T-cell therapy or venetoclax-based treatment as their subsequent-line therapy.

Interestingly, the treatment-free survival amongst patients who continued ibrutinib with their subsequent venetoclax-based treatment was similar to those who had stopped ibrutinib. This is relevant in the discussion of how long to continue ibrutinib beyond start of subsequent therapy in the setting of wanting to avoid a disease flare that is often encountered in clinical practice. So amongst patients with Richter's transformation, there was no significant difference in their survival, overall survival, or TFS by treatment groups. I think these are important data relevant to a growing patient population who have disease progression on a BTK inhibitor. The findings support, again, the current standard of practice of venetoclax-based treatment in the clinic, but I think also really demonstrate the ongoing need for further advances and enrollment in clinical trials being key. Again, the clinical trials that we have with venetoclax-based treatment that this data kind of gives further support to, there's data from those receiving venetoclax monotherapy after ibrutinib exposure had many patients who had progressed on disease, but also many who had only been exposed. And then the venetoclax plus anti-CD20—based treatment, really the MURANO study being the large phase 3 study there, did not have a BTK previously treated population to really gain a lot of insight from.

So I think these data are important in providing some additional insight into what we're currently doing for most patients and also give some interesting pieces regarding that pattern of progression. I think these are important both when you're seeing the patient in the clinic as something to keep in mind when they require validation, but also definitely give some additional areas to evaluate at the research level from trying to better understand the varied CLL biology underpinning these findings. Thank you for your attention.