Therapeutic Management of CLL - Episode 3
Thomas J. Kipps, MD, PhD: What are the considerations for using a drug such as ibrutinib? Ibrutinib has been approved for the treatment of patients with CLL, because it has very good activity—excellent activity. It blocks some important signaling that the B cell, the leukemia cell, requires in order to survive or grow, as well as to migrate to the lymph nodes. And when you block these signaling pathways, it confuses the leukemia cells and it takes away the sustenance that keeps the leukemia cell alive. Over time, you find the leukemic cell dying. It’s not a very quick, accelerated death, but it’s something that takes place over months, if not longer.
The advantage, though, of this therapy is that it seems to be one that’s mild, going into it. You can actually get started on ibrutinib therapy—it’s orally active and doesn’t require infusions, antibodies or other drugs. And it’s something that we’ve gained a lot of experience with over the last few years in how to manage potential toxicities. In terms of deciding who would be best suited for ibrutinib, this is something that should be considered perhaps in patients who are unable to tolerate regimens of chemoimmunotherapy—certainly FCR, which is difficult for patients over age 65 or if they have medical comorbidities. Or, our patients who potentially have indications that they may have a shorter duration of successful remission after chemotherapy: namely, those patients who have, for example, leukemic cells that express unmutated antibody genes.
Certainly, I think we should consider it for patients with leukemic cells that have deletions in chromosome 17. I would recommend that we don’t consider chemotherapy for such patients because, in my opinion, it can actually make the disease worse off than it was before treatment. So, patients who have deletions in chromosome 17 should be considered for treatment with ibrutinib, because it’s been shown that patients with these types of genetic changes actually respond very favorably and have a longer survival after therapy than patients treated with chemotherapy.
The indications for transplant have become fewer and fewer. Now we have the advent of these new targeted therapies. We now have newer monoclonal antibodies. As I mentioned, obinutuzumab is very active against this disease and, therefore, makes patients have better outcomes after treatment. We’ve got newer targeted therapies, some of which are orally active. I mentioned ibrutinib. Also, there’s this new drug venetoclax, which targets a protein called BCL-2. And so, more and more patients can respond and achieve a great response, even if they have failed to respond to chemoimmunotherapy. I have many patients who are alive today in clinic who would not be alive just a few years ago. That’s a testament to the activity of these newer drugs.
So now, we are faced with an issue: Who would you recommend for transplantation? It’s a difficult decision. Certainly, with transplantation, there is a chance for achieving a home run. You can actually go through transplantation, allogenic transplant, and there’s a fraction of patients who might have complete eradication of the leukemia. We may say that those patients are cured of their leukemia, and that’s quite exciting.
However, getting to that cure is not so easy. In the process, we could have patients succumb to what’s called a graft-versus-host disease, where the grafted cells actually reject the patient’s own body. Or, we can have the chance of infection, because of the need for immune suppression to prevent the patient from rejecting the graft. And so, we have a certain transplant-related mortality that has to be factored in the equation. Are we willing to go for a home run and, in the process, risk giving up the ball game? That is what we are doing when we look at transplantation.
The indications for transplant are, I would say, that patients may have exhausted some of the newer treatment regimens for sure. Also, patients who are younger and fitter who can better tolerate the rigors of transplantation. Plus, it has been shown it’s very important that, before going for a transplant, we have some measure of control of the disease. It’s been shown that if you have a patient who has florid disease relapse, with very large lymph nodes and what have you, and who is wanting to go through transplant, the outcome generally is not very good. So, this is a trick here, because you have to find the right patient who is young and fit, who has certainly failed existing options to the point where you’re sure that going on any further would not keep the patient alive. But you have to time it such that you still have some response to treatment to allow you to have a better shot at achieving a favorable outcome transplant. It’s like hitting the sweet spot—not an easy call, and one that should be not taken lightly.
Transcript Edited for Clarity