In the first half of our video interview from the 2016 European Hematology Association meeting held in Copenhagen, Denmark in June, Dr. Jeffrey Jones explains in clear, patient-friendly language how venetoclax or ABT-199 is different from the other FDA approved oral agents for use in CLL and discusses the impressive response rate of single agent venetoclax in the tough to treat to population of those who have relapsed on ibrutinib and idelalisib.
You can also read the full referenced EHA abstract here.
Please enjoy reading or viewing the video interview below.
Dr. Brian Koffman: Hi, I’m Dr. Brian Koffman. I’m a family physician and a CLL patient. I’m here at EHA, the European Hematology Association meeting in Copenhagen with my friend, Dr. Jeff Jones out of Ohio State. Dr. Jones, do you want to introduce yourself?
Dr. Jeffrey Jones: Well, you’ve heard, I’m Dr. Jeff Jones. I’m a CLL investigator at Ohio State.
BK: You’ve done a lot of very interesting trials that have been presented here, at ASCO and at ASH and here at EHA on a new drug that was just recently approved, venetoclax. Could you talk to me a little bit about your research and what you’re finding there?
JJ: Maybe we can talk a little bit, at first, about venetoclax itself
JJ: So unlike the other two orally available agents that have been approved so far, that’s ibrutinib and idelalisib, those drugs are classed as kinase inhibitors and they affect CLL cells by inhibiting proteins that are associated with growth so….kinases….kinetics….growth, so they inhibit growth.
BK: And they do that by blocking the B cell signaling
JJ: So B cell signaling
BK: and among other things
JJ: BTK and in the case of idelalisib, the PI3 kinase delta isoform. But you know, cancer cells do a couple of things. They not only grow out of control, but they also forget to die. One of the reasons they forget to die is that they overproduce a substance called BCL 2 that promotes survival of the cancer cell. That’s one of the reasons why CLL and other slow-growing lymphoid disorders that are related, diseases like follicular lymphoma and marginal zone lymphoma are somewhat resistant to curative therapy. The drug venetoclax is a very specific inhibitor of BCL 2. It appears to function primarily by restoring the death instinct for CLL cells, so they undergo programmed cell death the way that they should as abnormal cells.
BK: And that’s apoptosis
JJ: Apoptosis. Correct. It’s a very different mechanism of action distinct from the kinase inhibitors and potentially useful even among patients who are no longer responding or who have become resistant or intolerant to B cell receptor signaling antagonists. The drug, as you mentioned is now approved in the United States for patients with deletion 17P CLL relapsing after at least 1 prior therapy. It’s been commercially available now for nearly 2 months. With what most of us initially thought this was a relatively narrow initial indication, but based on the pivotal data presented at ASH by Dr. Stilgenbauer last December. In our experience, we’ve examined the drug at Ohio State, in collaboration with other investigators across the United States primarily among a very high-risk group of patients who are relapsing after previous treatment or during treatment with ibrutinib or idelalisib
As you know, and I’m sure you’ve discussed extensively with other investigators, the prognosis for those patients has been relatively poor depending upon how the patient relapses, either as Richter’s Transformation or as resistant CLL, survival after progression in those instances is often measured in months rather than years. That’s not the outcome that any of us want for the patients that we care for. In a study that we presented updated results at ASCO that will be presented here at EHA by my colleague Dr. Coutre from Stanford, we found that in patients relapsing during or after prior therapy with ibrutinib, the response rate to single agent venetoclax is about 70%, which makes it probably the single most effective therapy assessed in that context to date. With the safety profile that’s very similar to what’s been reported for the drug in other clinical settings, with the chief toxicity being neutropenia in up to about 40% of patients.
BK: That’s low neutrophil count
JJ: Low neutrophil count. In practice or clinical experience, there is a very real but small risk for something called tumor lysis syndrome. That’s where the drug, being highly effective, affects the cells, they die rapidly leading to electrolyte disturbances that, absent of careful monitoring and intervention, could have significant health consequences for cardiac and kidney function in particular.
BK: Now my understanding is that, with the new ramp up, this has changed after a couple of tragedies where people didn’t realize how potent a drug this was. The tumor lysis syndrome risk has been mostly mitigated and most of what you’re seeing are more electrolyte disturbances, but you’re not seeing where patients are clinically getting into trouble because you’re staying ahead of it.
JJ: Yes, so with very careful intrapatient ramp up from a starting dose of 20 mg daily to 400 mg daily over the course of 5 weeks, with careful laboratory monitoring at each dose escalation, the risk for tumor lysis syndrome has largely been eliminated, but that is again with very careful monitoring and close attention to the electrolyte disturbances that you described. The abnormalities of potassium, calcium, phosphorus, uric acid – all breakdown products of dying CLL cells – that can be addressed with medical interventions and prevent overt tumor lysis syndrome.
BK: Once you get to the maintenance dose, it seems like the tumor lysis syndrome risk is almost negligible.
JJ: That is a problem solely during the initial exposure phase. As the disease is meeting venetoclax for the first time and, in most cases, is responding within the first month of therapy. In the pivotal trial that Dr. Stilgenbauer presented, the median time to response or the time at which 50% of patients had responded was less one month. It was 0.8 months
JJ: So in the order of three and a half weeks. During that period, of the initial ramp-up, is when this risk is pertinent. In patients who are on mature therapy, there really is no risk of tumor lysis. Then it’s all of the usual risks of exposure to cancer medicines. In this case, the most significant one is an ongoing risk for neutropenia, low white blood cell counts, that can be managed, in some cases with either dose adjustments or more typically, an occasional injection of white blood cell growth factor, so Neupogen or drugs like it.
BK: GI side effects which are so common with cancer drugs. Have you seen those?
JJ: There’s a reported rate of diarrhea in about 20% of patients. It’s in most cases mild, self-limited, and manageable with routine interventions, over-the-counter medications like loperamide – Imodium.
BK: So it sounds like once you get through the ramp-up period, it’s a very well-tolerated drug for the most part for most people.
JJ: Right. That seems to be the case. It’s part of the reason why there’s great interest, both its unique mechanism of action, unique from the kinase inhibitors, as well as its favorable toxicity profile (after the initial ramp-up)…makes it kind of an ideal candidate for thinking about combination therapy. That’s where people are headed next. We’ve gotten to the point where many of us think we’ve well characterized the response dynamics and toxicity of the single agents. Now people are thinking creatively about how you might exploit them in combination.
BK: I’m going to follow-up on that in a minute from now, but I did mean to ask a question about the neutropenia, which is sometimes associated with very serious infections. Are you seeing this febrile neutropenia, the fevers where people get quite septic, and end up in the ICU.
JJ: So like any trial of patients with relapsed CLL, many of those patients have had extensive pretreatment and are very mature in their CLL disease course. As a consequence, they come into a trial, no matter the drug, with a substantial amount of immune compromise, increasing their risk for infection. Neutropenia related to any drug can certainly magnify this risk. In the case of venetoclax, the rates of infection that have been reported seem similar to rates reported in other studies of patients with relapsed refractory CLL. The neutropenia in this case, unlike chemotherapy where there appears to be direct suppressive effects on the bone marrow from the drug, doesn’t seem to follow that course in venetoclax treatments. For instance, we’ve had patients who develop severe neutropenia, say an absolute neutrophil count (ANC) of 500-600, and with a single dose of Neupogen can see their neutrophil count recover to 2,000. So a very different dynamic than we usually experience with other drugs causing neutropenia, most particularly chemotherapy where the bone marrow itself is stunted and requires a significant amount of time, often measured in weeks, to recover, even with growth factor support.
BK: Thanks so much for explaining what you’re doing and even more for doing what you’re doing in terms of looking at this important issue. Thanks very much, Dr. Jones.
JJ: Thank you.
Dr. Jeffrey Jones is Associate Professor of Clinical Internal Medicine in the Division of Hematology, Department of Internal Medicine at The Ohio State University and Disease Specific Research Group Leader for CLL/HSL, at the Ohio State University Comprehensive Cancer Center in, Columbus, OH.
Dr. Brian Koffman, a well-known doctor, educator and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the unpaid medical director of the CLL Society Inc.
Originally published in The CLL Tribune Q2 2016.