DR WILLIAMS: It is a very exciting area right now, and I think a lot of us are thinking hard about how to incorporate these regimens into not only the treatment of relapsed patients, but maybe bring in toward the front line. So it’s going to be a very dynamic area over the next few years.
But simply put, B-cell receptor pathway signaling through the IGM surface molecule is constitutively activated in many, if not the vast majority, of B-cell malignancies, and there’s a whole cascade of molecules, many of them tyrosine kinases, including SYK and BTK and PI3 kinase and then down into the mTOR molecules and NF-kappa-B. So, there’s a whole proximal and distal segment of that cascade with many targetable molecules within the string.
So a number of molecules have been looked at. Jonathan reported a SYK inhibitor at ASH several years ago. Of course the BTK inhibitors, ibrutinib, and you heard about ABL, idelalisib, which targets PI3 kinase delta, which is the isoform most commonly expressed in the B-cell malignancies. And there are other now multiple isoform inhibitors of PI3 kinase.
But taken together, each of these molecules seems to have not only impressive but fairly dramatic activity in relapsed and refractory disease as a single agent. Most of them are oral, and they seem to overcome patients who are refractory to other traditional therapies and to overcome, as in this case, people with adverse subtypes, such as the 17P-deleted CLL. So, by themselves, they’ve got a lot of activity. Complete remissions with them are relatively unusual, but responses are often impressively quick.
DR LOVE: Chris, can you talk a little bit about what’s been seen in terms of tolerability?
DR FLOWERS: The toxicity varies a fair amount across the agents. But in general, the cytopenias are somewhat less than what you would see with chemotherapy-based approaches for the same types of patients, although cytopenias, particularly neutropenia, is still a toxicity associated with these agents. Diarrhea has been a toxicity associated with these agents, broadly, although it differs a little bit across different trials and across the agents.
DR LOVE: I guess one thing, Andy, that we have seen, at least with idelalisib, I think there is hepatic toxicity. Correct?
DR EVENS: There is. It’s more transaminases that are seen, but some of them are Grade 3/Grade 4, which is many times elevated — over 5 to 20 times elevation. Thankfully, though, those have been mostly self-limited and with usually stopping the drug and possibly a dose reduction they seem to recover those counts. But it has been one to — transaminitis, that needs to be followed.
DR LOVE: Julie?
DR VOSE: I think based upon all this new information and the new drugs that have excellent activity but pretty minimal toxicity, I think we’re probably going to be seeing a nonchemotherapy approach in CLL up front very soon, especially in the older patient. I think that’s a very appealing type of a treatment to do. But even in the younger patients, depending on what the studies show, so I think the field of CLL is going to greatly be modified in the next few years.
DR LOVE: Any guesses about whether that’s going to be with R or not?
DR VOSE: I think it probably will be with R to start with and potentially look for some synergy. So yes, I do.
DR LOVE: Jon, what about this syndrome where you see elevated white counts shortly after starting treatment?
DR FRIEDBERG: That seems to be a class effect. The SYK inhibitors, the BTK inhibitors, the PI3 kinase inhibitors — and, if you look carefully enough, the mTOR inhibitors — all really demonstrate the phenomenon, where in the setting of often rapid shrinkage of bulky lymphadenopathy, the white count goes up. And some of these patients develop profound lymphocytosis.
I think it’s appreciated that this does not represent disease progression. In fact, CLL experts have identified a new response category of PR with lymphocytosis to demonstrate that when these agents are used, it may take months for this lymphocytosis to resolve. And I think it’s felt to be due to selective microenvironment effects. Some people call it a mobilization phenomenon. It does appear that CLL cells in lymph nodes are more sensitive to B-cell receptor blockade than in other compartments. And for many patients, it’s the bulky lymphadenopathy that is contributing to morbidity at the end of this disease and, therefore, I think that’s a reason why patients feel so much better so quickly on these agents, even though it can take time for the white count to normalize.
The CR rates are relatively low and, in fact, the observation has been made that if the drug is stopped — there were a few patients where surgery was needed or some other reason why the drug was stopped — in some of those patients the disease can come back very quickly. So I don’t think these drugs are curing these patients. I think they’re clearly managing these patients.
And the only other thing to emphasize is I don’t think we can say enough about how exciting it is that these drugs are active in the subsets of CLL where normally our chemotherapies don’t work. And, for example, with ibrutinib, paradoxically, it’s the unmutated CLL that has the fastest and most complete responses. That’s traditionally been felt to be the refractory form of CLL, but it speaks to the fact that some of our highest-risk CLL subsets seem to rely disproportionately on B-cell receptor signaling as a survival mechanism.