On the last day of ASH (American Society of Hematology) annual meeting in Atlanta in December, 2017, I sat down with my personal doctor at Ohio State, Dr. John Byrd to review what we had learned and not learned at the most important meeting in blood cancer research.
In our rambling overview of the CLL research presented at ASH, we get Dr. Byrd’s view of some of the themes that emerged.
- There are many very active combinations therapies in chronic lymphocytic leukemia but we don’t know:
- What are the best combinations?
- What is the proper sequencing of drugs?
- Is there a role for chemo-immunotherapy in these combinations?
- How do we measure success of our CLL treatments?
- Is MRD (minimal residual disease) negativity as robust a surrogate marker for a durable remission with novel therapies as it has proven to be in old school chemo-immunotherapy?
- Little was presented on CAR T treatments for chronic lymphocytic leukemia. The first results in CLL had been disappointing, but with the addition of ibrutinib to “modulate” the immune response and perhaps improve the activity of the genetically engineered T cells, responses rates are much better and remissions can be very durable.
- CAR NK (natural killer) cell therapy is a few years behind CAR T in development, but may offer advantages as the NK cells are short lived. They do their work and then disappear. They also don’t need to me made to order as to CAR T cells.
There has never been a time with more rapid research that is significantly improving lives for those of us with CLL, but there is much yet to do in terms of what combinations of drugs to use, in what order and for how long; how we track the disease in the novel drug era, and the emerging role of cellular therapy. Clinical trials will tell us what is best.
On personal note, my interview with Dr. Byrd occurred before I had decided on CAR T therapy for my own CLL. I concur with his view that it is not for the faint of heart, but it sure can knock back the cancer.
You can watch my interview with Dr. Byrd below or read our interview here:
Dr. Brian Koffman – Hi. Dr. Brian Koffman. I’m a family doctor and a CLL patient here at the last day of ASH 2017, as the medical director of the CLL Society, and I’m here with my personal physician, who’s been taking care of me for the last six years in a clinical trial at Ohio State.
Dr. John Byrd – Hi. Yeah. Thanks, Brian for inviting me. John Byrd, I’m a professor at the Ohio State University and I am actively involved in drug development in CLL and other blood cancers. Thanks for having me today.
BK – So, ASH is coming to an end and I think we heard the last late-breaking abstracts earlier this morning. Is there any takeaway message(s) that you think we should be sharing with the patients, in terms of what you learned from ASH 2017, and kind of the state-of-the-art in CLL these days?
JB – I think maybe the more appropriate question is “what we don’t know”.
BK – Okay. That’s even a better question.
JB – Because there’s so much here. When you have great therapies, and we’re blessed to have multiple great therapies, and so the questions that I see emerging from this meeting are the role of combinations verses monotherapy. And we just saw lots and lots of active combinations with ibrutinib/venetoclax, venetoclax/obinutuzumab… sequential use of chemotherapy with obinutuzumab and ibrutinib or with venetoclax. And so, everybody is sort of trying to figure out what’s the right combination to give to try to get deeper remissions. And so that’s going to unfold over the next several years, I believe.
The second thing is ‘how do we measure the success, because we’re blessed as well that pretty much everybody, whether you give one drug or three drugs, responds’. And probably, right now, the only surrogate… and a surrogate marker sort of is something that we can look at early in a clinical trial that predicts for how people are going to do later. And a surrogate marker for survival in CLL…how long patients will live with therapy… that’s often used is minimal residual disease absence. And that’s just not being able to detect CLL by CAT scan, by flow cytometry, by sequencing, in the lymph nodes, blood, and bone marrow. So, the field is really struggling with that because some of our best therapies that were presented at this meeting haven’t really been adequately tested to see how this impacts. Is it going to be the same as chemotherapy that we used before? And so that’s going to be an emerging question.
We’re lucky, compared to our colleagues with AML for instance, where they don’t even know how to measure the minimal residual disease. We have good assays, but it’s just going to be answering how this is important. I was a little sad that there were not as many presentations about CAR-T cells in CLL. It seems like the phenomenal success in pediatric ALL and young adult ALL and lymphoma sort of has overshadowed a role for these. And what’s exciting, and again, this is not in the abstracts as much, but it’s the meetings around where, you know, because people come together to plan things and it’s obvious that all of the pharmaceutical companies, big companies that are developing CAR-T cells now see these… because initially they didn’t work well. But what’s been shown, and we’ve been part of this with Carl June, of showing that when you change the microenvironment of CLL… and with ibrutinib, that you make the CAR-T cells work better. And so, the companies, all the big companies, Juno, Kite and others, are coming forward, I believe, hopefully, with plans to do studies of CAR-T cells in CLL. And, say some of the preliminary results, not necessarily presented here but presented at ASCO for instance, show that by the group at Penn, published earlier by David Maloney, that these CAR-T cells are inducing durable remissions in CLL patients. That’s exciting because that sort of gives us an avenue to get away from… potentially get away from… transplant, or at least as an alternative to transplant.
BK – Yeah. I agree with you. I think that things that I’m seeing exciting are these novel combinations, how to put them together. It’s no longer theoretical. These trials are actually happening now and we’re getting some astonishing results early… but some astonishing results …and we’re learning what combos work and what combos don’t work. We’re looking the role of MRD negativity… how important that is with the novel agents. It’s clearly important with the old-school agents, the chemo-immunotherapies… how important it is… It’s looking to me like it’s going be important and that’s, I think, what the early evidence suggests. I think those are the big things. And I do agree with you, there wasn’t very much on CAR-T. I don’t think there was an oral presentation on CAR-T in the CLL space at all. But we know that the research is ongoing. We know that new trials are going to be rolling out and we know that CAR-T is part of the future in CLL.
JB – We’re, in some ways, probably next year at this meeting, there’ll be presentations, and look, CAR-T cells are not going to be appropriate for every CLL patient. There are going to be trials that are emerging and, particularly for patients, where one or more of the targeted therapies haven’t worked, and that’s going to be something appropriate. And for the patients that are out there listening, that are considering those trials, thank you for considering that because we have one. CAR-Ts are approved for lymphoma and ALL, and it’s going to take a formal study and approval to make these available outside of a clinical trial because they’re very expensive and very laborious to do.
BK – Let me ask you one follow-up question on that. CAR NKs. I know that these are just being developed. I think there’s a trial actually in CLL now at MD Anderson with Doctor Wierda. Do you have sense, a read, or any advice you give to patients on what to watch for there?
JB – I think that NK cells are very good at killing tumor cells.
BK – Natural killer cells.
JB – Natural killer cells, NK cells, are very good at killing tumor cells. They don’t expand like T-cells but they’re like T-cells in that they can kill a lot of cells… per CAR NK. So there still needs to be sort of a proof of principle that this is going to really, really, really work and I think CAR-, you know NK cells, are probably a couple of years behind. It’s something that I’m excited about because, you know… the fact… if they have an effect, and they don’t rapidly expand like T cells, they may end up being better tolerated and–
BK – Safer with this cytokine release syndrome and neurotoxicities.
JB – Right. And particularly for other diseases, where… maybe not CLL, but for… because CLL… there’s a good target… CD19. But for other diseases, where there’s not a target that’s that different from the normal bone marrow… so like an AML. These cells go away with time. Whereas CAR-T cells, unless they have a suicide gene, don’t go away… so they can do their work and go away. They die. Whereas, with the CAR-T cells, they stay around for a long time. It’s a very early area. It’s a fun area too, as an immune pharmacologist to sort of bring the drug expertise that I have and work with very smart people that are working in this area. And I think for the patients, the patients that have gone on these studies at this point, have been very brave, because as you pointed out, this is not a walk in the park, easy therapy. But those early patients have paved the way to (hopefully) this really being tested in a rigorous way and to advance another therapy forward for CLL.
BK – Dr. Byrd, thanks so much for all you’re doing.
JB – Thank you.
To learn more about one of the powerful combinations that Dr. Byrd references, please read this about the MURANO trial that combined venetoclax and rituximab presented at ASH 2017.
For more on the astonishing complete remission rate seen with another combination, namely combining the gold standard chemo-immunotherapy, FCR, with the game changing novel oral therapy, ibrutinib, here is a link to my interview with the lead investigator, Dr. Matt Davids of Dana Farber done at the same ASH meeting.
Here’s a link to an interview on CAR T therapy by Dr. David Maloney of the Fred Hutch who was in charge of my trial in Seattle. Dr. Maloney discusses why ibrutinib improves CAR T therapy on CLL.
For more on CAR-NK cellular therapy, here’s some background.
Dr. Byrd is the D Warren Brown Chair of Leukemia Research and Director, Division of Hematology at The Ohio State Comprehensive Cancer Center in Columbus, OH. He is a member of the Medical Advisory Board for the CLL Society.
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 Q2 2018.