EHA 2016
Karyotyping a CLL subset with ibrutinib susceptibility
Dr Jeffrey Jones - Ohio State University, Columbus, USA
I just came from the presentation which is an analysis of 243 patients with deletion 17p CLL who were treated in one of three ibrutinib clinical trials. Deletion 17p CLL, why would that actually matter? The presence of chromosomal deletions of the 17th chromosome or mutations of p53 that lives in that spot on chromosome 17 have been associated with distinctly poor outcomes in CLL. We often meet patients who have been told they have the ‘good’ cancer and for some patients that might actually be the case, a minority of patients may never progress to require treatment. On the other hand, patients with deletion 17p CLL, particularly if they have relapsed after prior therapy, are far more likely to die from CLL. When they’ve been treated in the past with chemotherapy or chemo-immunotherapy combinations the average survival has not been much longer than two to three years, so no better than many other kinds of common cancer. Unfortunately until very recently there weren’t many available treatments that had shown efficacy in that group of patients. That’s what really distinguished ibrutinib in its early clinical assessment was an efficiency of inducing durable remissions in patients both with and without high risk genetic features, including deletion 17p.
If you look at what the expected toxicities of ibrutinib, the response characteristics, durability of response, it distinguishes itself in all of those ways as do other novel drugs, other kinase inhibitors, drugs targeting BCL-2, smarter drugs that are more specific for the abnormal B-cell and leave less collateral damage. So, unlike chemotherapy, ibrutinib has not yet been demonstrated to promote clonal evolution to a higher risk form of CLL, it has not been as frequently associated with low blood cell counts or increased risk for infection which is a substantial problem with chemotherapy based treatments for CLL. If you look at how effective it is in the trial, the RESONATE trial, the trial that led to its formal approval both in the US and Europe, it was compared to what was then an existing standard of care for multiply relapsed CLL. That drug, ofatumumab, was known to induce an objective response in probably no more than 50% of patients with a durability of only 6-8 months. So ibrutinib, in inducing in our subset and our group of patients an objective response in 84% of patients that’s durable out to 30 months of follow-up in 55% of patients, is a dramatic advance for the majority of patients who are treated with deletion 17p CLL.
But you bring up a point about within that group of patients are there features that distinguish a subset of deletion 17p patients that are more likely to relapse. The first thing that we did is we looked at classical risk factors pretty much that are true in all lymphoid malignancies. So we looked at things like age, extent of disease, biochemical markers like beta-2 microglobulin, and what we found was that in patients who had elevated lactate dehydrogenase who had received more than one prior therapy for their CLL and had bulky lymph node disease appeared to be more likely to progress than patients without those factors. But probably the single most powerful predictor was presence of complex abnormal karyotype. This is something that our group at Ohio State has been particularly keen to promote because it appears to have independent predictive power for outcome beyond just the chromosome 17p abnormality.
Now, when you do conventional karyotype analysis in CLL it’s often unsuccessful because the cells won’t divide in culture. By stimulating them to divide you can get a higher yield of chromosomes for assessment and that’s what our group has done as standard practice. So in our 243 patients there were 60-some for whom this stimulated karyotype data was available. What we found was that in the group of patients who had complex abnormal karyotype, meaning three or greater chromosomal abnormalities, that they did worse than the group of 17p patients who didn’t have complex karyotype. So if you had deletion 17p you did worse than if you didn’t have it and then if you had complex karyotype on top then you did even worse. You were more likely to progress, you were more likely to die despite ibrutinib treatment. So this really identifies, going forward, a unique subset of CLL patients that is probably not going to achieve sustained remissions with just any single agent. So that means maybe they need closer surveillance for early signs of relapse or maybe that’s a group of patients that should be targeted for combination therapy or perhaps be sent on to more definitive consolidation therapy, things like allogeneic stem cell transplant or chimeric antigen receptor T-cell therapy which may be their first best choice in the years ahead.
When it comes to identifying that subset within a subset what kind of rates would you be looking at in terms of just the sheer patient numbers and would those be enough to develop ongoing phase II trials, so wider deployment?
Yes, it’s hard to know exactly how prevalent that finding is. Again, because many labs even in academic centres don’t routinely perform complex karyotype analysis a really reliable estimate of the percentage of patients with complex karyotype is not clear. It’s also strongly associated with extent of previous treatment with chemotherapy. Chemotherapy appears to promote clonal evolution to complex karyotype so going forward we may see even less of those patients; as patients now are treated with chemotherapy free regimens that are less prone to produce this clonal evolution the fraction of patients for whom this is even a pertinent consideration will hopefully fall. But for now when we’ve got a substantial number of chemotherapy pre-treated patients it looks like in the group with deletion 17p it could be as high as 50% but probably at least a third.
I suppose the next question would be where next with this research?
As I was just saying, we’re looking at this group of patients that despite great initial responses with single agent ibrutinib, single agent other kinase inhibitors, single agent BCL-2 inhibitor still appear likely to relapse. So for us we’re thinking about strategies to intervene early with combination therapy so maybe there’s a way of preventing disease progression by preventing resistance to any one single agent, that’s a fundamental principle of combination chemotherapy or even antimicrobial therapy for complex infections. On the other hand, it may be that we step up our surveillance. So we’re also interested in looking for molecular evidence of disease progression before we see overt clinical relapse. In many patients with CLL who are relapsing with resistant disease you can begin to see emergence of resistant sub-clones long before they overtly progress. That’s another potential place to intervene where you could, perhaps, add on another therapy at that point without stopping the one that’s controlling their disease clinically as a way of eradicating the resistant clone. Finally, I think you also select a group of patients particularly if they are young and fit, say the rare 50 year olds with high risk CLL, who should have a life expectancy ahead of him or her for another thirty years where the risk benefit balance in favour of cellular therapy increases. So thinking about total care strategies where you induce a response and then work to quickly consolidate it with a definitive therapy like transplant or CAR T therapy.
