Dr Kittai Discusses the Impact of Complex Karyotype for Patients With CLL Treated With Ibrutinib

Adam Kittai, MD, assistant professor, The Ohio State University, discusses a study on the impact of complex karyotype in patients with CLL treated with ibrutinib.

Transcript

Hi, I'm Adam Kittai. I'm the assistant professor at the Ohio State University.

Per the International Workshop on CLL criteria, patients with CLL should undergo testing with molecular cytogenetics with FISH, conventional karyotyping, TP53 testing, and IGHV status. They should all be tested prior to treatment initiation, as they've been determined to be prognostic markers of survival. However, most of them were validated in a time when we were using mostly chemoimmunotherapy to treat our patients with CLL in the treatment-naive setting.

As there now have been multiple trials that have demonstrated superiority of our small molecule inhibitors like ibrutinib to chemotherapy, we've been using more and more ibrutinib and other small molecule inhibitors in the treatment-naive setting.

Given that this is the new standard of care, it's important to reassess previously validated prognostic markers. That way, we can get a better idea of what our patient's prognosis is when we are starting these new therapies.

One of the specific variables that has only recently been introduced into the testing for CLL is conventional karyotype analysis. Now that it's becoming more ubiquitous and feasible throughout the United States to perform this test, it's something that all of our patients should get.

Using conventional karyotype analysis, there is this status of complex karyotyping, which is defined as over 3 abnormalities in historical studies that is known as a negative prognostic marker, meaning if you have over 3 abnormalities, patients do worse. Once again, this marker was validated in patients who received chemoimmunotherapy in frontline.

There was a recent study that looked at ibrutinib compared to chemotherapy that did not find over 3 abnormalities as being prognostic of survival.

Also, there was a recent study published in Blood by Baliakas et al. that showed that increase in karyotypic complexity, defined as over 5 abnormalities, was associated with worse overall survival (OS) and worse than those who had just 3 abnormalities. Once again, this was a large study with patients mostly treated by chemoimmunotherapy.

Because of all these reasons, we wanted to reestablish and retest complex karyotype in patients treated with ibrutinib for their CLL, and specifically do it as a continuous variable.

Where, instead of making it a dichotomous one, where 3 or not 3, 5 or not 5, we were looking at for every additional abnormality that someone might have on karyotype, did they do worse? That would be a continuous variable.

Those were the studies that lent itself to our hypothesis looking at complex karyotype as a continuous variable as a prognostic score for patients with CLL treated with ibrutinib.

Our study confirmed that increasing karyotypic complexity when tested as a continuous variable with prognostic of both progression and survival for patients treated with ibrutinib for CLL. Once again, for every additional abnormality that a patient has on their karyotype, they did worse, which is a super interesting finding.

What is most interesting about this finding is when you put it in context with other negative validated markers, such as deletion 17p (del 17p) and IGHV mutational status.

We all know that patients with del 17p or NTP53 mutation in CLL fare worse than those that don't. What we found was that patients who had a del 17p was highly correlated with a high complex karyotype, so they had higher numbers of karyotypic abnormalities. The importance of del 17p was diminished as karyotypic abnormality number increased.

Ultimately, was not considered a prognostic marker when we used increasing karyotypic complexity as a continuous variable. What we can take home from this is that del 17p is probably more important when patients have a lower karyotypic complexity and not as important as the number increases.

We saw something a little bit different with IGHV-unmutated status, where interestingly, the importance of unmutated status as a negative prognostic variable increased when patients were treated after two years. I think more research needs to be done on this and looked into this over a larger cohort.

Another thing that we identified, and I believe we were the first to look at, were what I call these ultra-complex karyotypes, patients who didn't just have over 5 abnormalities but had over 10 or 15 abnormalities.

What's interesting is that these patients really did worse. Maybe it's due to genomic instability. It's hard to say, and more research needs to be done looking at these specific patients.

Also, I think that patients who have over 10 or over 15 should be treated as being very high-risk, as being a new prognostic marker for patients treated with ibrutinib for CLL.

Another thing to mention is that although our cohort was the majority with relapse/refractory (R/R), we did have a good amount of treatment-naive patients.

Using an interaction term to see if our findings were still pointed in both treatment-naive and R/R patients, we found no difference, suggesting that increasing karyotypic complexity was just as important for treatment-naive patients as it was for relapsed/refractory.

Lastly, another interesting finding that we saw was we looked at karyotypic change at progression. We looked at the karyotype at treatment start and the karyotype at progression. We found that patients who had a clonal evolution, as determined as having a new abnormality of progression, those patients all did poorly.

What makes this interesting is that as opposed to next-generation sequencing (NGS) inhibitor advanced testing, local providers not at academic centers could potentially look at conventional karyotype and be able to determine clonal evolution, knowing that if someone develops a new abnormality at progression, they are going to fare worse than if they didn't.

One of them is what I just said, where basically, non-academic physicians can order this test and be able to elucidate prognostic value from their tests. That's one for sure. The other thing to note, too, is that it helps people better counsel their patients on prognosis.

Although we didn't test this, I think this is something that we need to look into, is whether or not this finding continues to occur for patients treated with other BTK inhibitors like acalabrutinib and zanubrutinib.

If you were to put me on the spot and guess, I would guess that most likely, that is the case, because it is the same mechanism of action. Further study needs to be looked at for patients who are treated with other medications like venetoclax, which we commonly use.

Ultimately, it helps clinicians counsel their patients about their prognosis when they're being treated with these novel therapies.

One important thing to do is to validate this research in a prospective trial. That's one thing that should be done. Another thing that we should look at is look to see if this variable continues to be pertinent when we are using other therapies, as like acalabrutinib or venetoclax, like I mentioned.

The other big limitation to my study was that unfortunately, we didn't have NGS on our patients. As I mentioned before, patients who have a TP53 mutation on NGS is a known poor prognostic marker, and it is associated with del 17p, which we were able to glean from our charts. We didn't have NGS, as it's a newer test and our cohort spanned from 2010 till recent day.

Going forward, we need to look at NGS, specifically at TP53 mutations and maybe some other markers that have been showing up as being prognostically negative and seeing if they impact the increasing karyotypic complexity prognostic score.

One of the things that wasn't one of the main points of the study was we looked at the follow-up and survival for these patients. Ultimately, this was one of the largest studies with the longest follow-up looking at patients treated with ibrutinib for CLL.

We saw what we already knew was continued fantastic outcomes. We had a median follow-up of greater than 5 years, and we saw a median progression-free survival (PFS) of 70 months for all-comers. The median OS for all-comers, including R/R and treatment-naive patients, was 95.4 months.

This is remarkable numbers and fantastic for our patients. It shows how good of a medication ibrutinib is and how much of an impact it has on our patients with CLL.