At the ASH (American Society of Hematology) Annual Meeting and Exposition 2017, we heard not only about new trials, but also learned from retrospective research that looked at how drugs are actually being used in the real world, away from trials and away from top research centers, to treat chronic lymphocytic leukemia (CLL).
Dr. John Pagel of Swedish Medical Group discusses the real-world experience of 204 CLL patients being treated in the community with venetoclax.
Venetoclax is another game changing drug in CLL that is taken orally and can produce very deep remission including complete response that are MRD- (no CLL cells found in 1 out of 10,000 cells).
The principal investigator for the trial was Dr. Anthony Mato whom we also interviewed at ASH 2017 about some of his other research and who is the lead CLL doctor helping us with our CLL Society patient survey.
Take Away Points:
- 98% of the patients were relapsed/refractory and the average age was 67.
- This was a tough group of patients:
- 44% had del17p, 28% del11q, 41% TP53 mutation, and 33% had complex karyotype (≥ 3 abnormalities).
- 27% were NOTCH1 mutated (n=73 tested), 27% BTK mutated (n=51), 10% PLCγ2mutated (n=49), and 81% were unmutated IGHV (n=102)
- As might be expected, most patients (64%) had received a prior KI (kinase inhibitor, such as ibrutinib), while 15% had had 2 or more KIs and 5.4% had previous cellular therapy (CAR-T or transplantation)
- ORR (overall response rate) was 77%, with 28% achieving a complete response.
- Venetoclax was most commonly stopped due to CLL progression (47%), Richter’s transformation (21%), and venetoclax toxicity (11%), usually low blood counts.
- The incidence of TLS or tumor lysis syndrome, a serious complication of venetoclax therapy where the cancer cells are killed too quickly and can damage the kidney and even lead to death, was relatively rare and similar to the incidence in clinical trials.
The trial abstract with all the data can be read here.
I find this encouraging. Venetoclax is a very potent CLL drug that if not used correctly can kill the patient. This study shows that the community doctors were doing a good job of managing venetoclax and getting responses similar to those seen on clinical trials.
While we encourage all patients to seek an expert opinion in treating their chronic lymphocytic leukemia, this study suggests it is quite appropriate to have a community hematologist manage your venetoclax treatment, especially if you are a low-risk patient.
You can view or read my interview with Dr. Pagel discussing the trial below.
Dr. Brian Koffman – Hi. Dr. Brian Koffman. I’m the founder and medical director of the CLL Society, here on day two of ASH 2017.
Dr. John Pagel – Hello. I’m John Pagel. I’m an oncologist. I do CLL research and treat patients in the clinic, and I’m at Swedish Cancer Institute in Seattle, Washington.
BK – So, Dr. Pagel, there’s a growing body of experience using venetoclax, which has been a breakthrough drug in CLL. And you’ve been involved in some of the research, in terms of what’s happening. How does it work? What are its toxicities? What’s the pattern of use? Can you give us some reflection on some of the research that you’re involved in that’s being presented here at ASH?
JP – You bet, Brian. I think venetoclax is continuing to show that it’s a very important drug for patients who have CLL; not everyone, of course. There are many patients who will not get venetoclax. But one of the most important factors that we haven’t really understood is how to use this drug in the community, as opposed to major academic research centers, such as the ones that many of us are familiar with, or perhaps I might be located at. And the question really is, how are our patients doing in the community? How is the drug delivered there? And is it safely administered? And we all know that venetoclax’s primary toxicity is that it can cause tumor lysis syndrome. So, we really wanted to ask some questions about how community oncologists are working with venetoclax in the real world. So, we did that. We looked at over 200 patients. The study was primarily led by Anthony Mato, who’s at the University of Pennsylvania. And what we really wanted to look at was patterns of toxicity, as well as outcomes for patients getting venetoclax outside of, again, academic centers. And what we largely learned is that the profile is pretty much exactly what we would expect. People will be able to escalate on a ramp-up, as you’re supposed to do, and tolerate the drug, and that people will have a very low risk of having tumor lysis, but it’s something that we need to pay attention to. And that is something that’s critically important, and we’re pleased to see that the community understands that, as well.
BK – So, there hasn’t been a higher risk of tumor lysis syndrome, which can be a life-threatening complication of venetoclax, because it’s so potent, that we haven’t seen that in the community, versus the academic settings?
JP – Yeah. And I think the only spot where we have a hint that that could slightly be true are in what we call high-risk patients. So those are patients with bulky adenopathy or lymph nodes, or patients with a very high white count. So those are the patients that have a little higher incidence, perhaps, in the community. However, it’s still within what we think is safe and appropriate. And as long as we’re doing this with the ramp-up schedule, paying very close attention to laboratory parameters, most patients are going to do extremely well with this drug.
BK – And anything else you learned from this trial, or this investigation I should say, yeah?
JP – Yeah. And I think the important thing, again, is that this is what’s happening in the real world. And what we’ve learned is that the sequencing of using venetoclax, in particular, after a prior kinase inhibitor… mostly that’s ibrutinib…
BK – So, a kinase inhibitor would be ibrutinib, idelalisib, or in a clinical trial… something.
JP – Exactly. Or even newer drugs, such as acalabrutinib… use of venetoclax after one of those agents can be very efficacious, and is probably the right sequencing that we should be doing outside of a clinical trial right now, and in fact, that’s what’s being done in the community quite effectively.
BK – So, this is all very encouraging for a patient who may not have access to a Dr. Pagel or a CLL expert, that their CLL is… at least the management of what can be a complicated drug to use, and a very potent drug to use, is being used done appropriately, in the right timing, in the right setting, being managed appropriately in the community?
JP – Yeah. And I want to point out, of course, this is a small subset, snapshot of what happens, of course, across the country. We’re encouraged by it. It was a multicenter analysis across the country. However, each patient who is getting ready to start venetoclax should always have a very in-depth conversation with the doctor about how the toxicities, and in particular, assessment for tumor lysis, is going to actually happen.
BK – Any final thoughts on this investigation that you’re involved in for patients, that they might benefit from?
JP – I think the important thing that we have to say is that we still need to make sure that we’re evolving our research and doing the best, understanding the best way to use these drugs. Right now, with venetoclax, we’re continuing in the community to administer this drug daily, indefinitely. We’re very encouraged by the results, not just with venetoclax alone, but in combinations, and what we need to find out as we move forward is, “How do we stop the drug, and be able to restart it, if and when the patient were to relapse?” And that’s the data and the research that is starting to emerge right now.
BK – And yeah, going for a durable response, but a finite time of therapy is certainly one of the Holy Grails of CLL.
JP – Absolutely. No question.
BK – Dr. Pagel, thanks so much.
JP – Great. Thank you.
Dr. John Pagel is Chief of the hematologic malignancy program at the Swedish Cancer Institute in Seattle, WA.
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 medical director of the CLL Society Inc.
Originally published in The CLL Tribune Q4 2017.