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How has the era of personalized medicine changed the way you think about treatment for patients with chronic lymphocytic leukemia (CLL)?
Personalized medicine is a complex topic because it generally refers to the notion that you might find some feature or marker that’s unique to a patient and then select therapy on the basis of that marker. In the case of CLL, the disease is divided primarily into 2 groups of patients: those who have what’s called a mutated B-cell receptor and those who have an unmutated B-cell receptor.
In this case, mutation is good. It means you tend to have a slower-growing disease, fewer high-risk genetic markers for chemotherapy resistance, and so forth. So, [if we look] at the IGHV mutation or the B-cell receptor mutation status, those patients who have mutated disease are generally [the] patients who are going to benefit from a chemoimmunotherapy approach, whereas the patients who are unmutated are going to clearly benefit more from the novel targeted agent approach.
I think that there is debate—frank debate—within the field, even among those who know the disease best, as to whether or not those patients with the mutated disease should get ibrutinib or chemoimmunotherapy, and I think that in a lot of cases, that would be subject to patient preference.How would you like to see chimeric antigen receptor (CAR) T-cell therapy and other innovative but expensive therapies reimbursed?
At the Community Oncology Conference, the keynote speaker, Dr Scott Gottlieb, the FDA commissioner, voiced concern about how these new technologies— specifically, CAR [chimeric antigen receptor] T- cell therapy—will be reimbursed and expressed great concern about that. And we share that concern. This is not your normal drug; this is more of an overall therapy, and I think that we have to look at different, new ways of reimbursing it.
I think we also have to look at the cost of these therapies, which I know is why Dr Gottlieb is looking at speeding up the approvals of not only generics and biosimilars but [also] new brands, so you introduce competition into the market. When you have competition, you will bring down prices. That will, in part, handle some of the reimbursement problem, but I think we really have to look at a different approach to reimbursement of these very expensive therapies.What has been the progress in treatments for chronic lymphocytic leukemia (CLL)?
What I say to patients is: “There’s never a good time to have a CLL diagnosis, but there’s never been a better time.” And the best treatments today will be upstaged by better treatments tomorrow.
So, right now we’re looking at a significant percentage of CLL patients who—we’ve always had this group, but we’ve better defined them now— will never need treatment and will have the same life expectancy of an age-matched cohort. We’re also looking at data for some of the patients who get ibrutinib, a [Bruton tyrosine kinase] inhibitor front line, who have the same life expectancy, again, as a matched cohort. So, these aren’t cures, but they’re incredible responses.
There’s still tremendous unmet need for CLL patients, though. Some patients can’t tolerate the treatments. Some patients progress on the treatments, and our follow-up therapies aren’t necessarily as good. Also, patients develop complications of the treatments or of the disease itself. All CLL patients are immunocompromised, so they have a higher risk of infections, which is often a fatal event, and they often succumb to secondary malignancies—50% of CLL patients get some sort of secondary malignancy. So, we need to be looking at therapies for that group, and that’s where therapies like CAR [chimeric antigen receptor] T-cell therapy and some of the combinations of novel therapies or combinations of novel therapies with chemoimmunotherapies are coming into play.
Since chimeric antigen receptor (CAR) T-cell therapy is a new treatment, do you think patient-reported outcomes should be considered in coverage decisions for the therapy?
I run a patient support and advocacy organization, so I’m very big on patient-reported outcomes, and I think that has to be part of any decision. I don’t think it’s the whole story, and I think when people look at the CAR T evidence—like in my case, you’ve got to look at what did the bone marrow show, what did the blood show—but I think it’s very important to understand the patient’s perspective, the patient’s outcome.
And for a lot of these patients, CAR T therapy is really their last and best option. It’s not a frontline therapy, so people are often getting this when they’ve run out of other options. And when you see someone who really didn’t have much chance at being around 6 months to a year from now, years out, that certainly gives you pause, and I think that’s a data point that needs to be considered when that patient talks about what their lifestyle has been like.
I had CAR T 6 months ago, and since then, I’ve been to the European Hematology Association meeting, I’ve been to the European Research Initiative on CLL—both of those in Europe—and I’ve traveled around the country talking about CAR-T therapy. So, I think that’s a data point that “Look, somebody can get this and in the next 6 months be traveling all around, working as a family doctor, working in a not-for-profit.” I think those are important points that people have to understand.
As someone treated with CAR-T cells, what do you do regarding follow-up? What is your physician keeping an eye out for?
Since CAR T is a new therapy and the first genetic therapy that’s been approved in the United States by the FDA, I’m being followed for 15 years—which I’m very happy about, because if [I’ve been] followed for 15 years, that will mean I’m 82 years old, so it means I’ve lived 15 years with this.
I’m being followed to see are there any undiscovered adverse events that we don’t know about. It is gene therapy; I have foreign genes in my body, that’s why it’s a chimera—a mix of 2 different creatures in me. So, I have foreign protein in me. Is this going to cause a problem? Other gene therapies have been disastrous in the past. So far with CAR T, things have gone well. But is there something that’s going to pop up 5 years from now, 10 years from now? We really don’t know the answer to that, so that’s one thing that I’m being looked at for.
The other thing is, how persistent are the CAR T cells themselves? There’s not clarity on how important that is in terms of the duration of the response. So, some people lose their CAR Ts and they still have very durable responses, and other people have persistent CAR Ts, but the cancer comes back.
And that leads to the other big question: Do I remain in a complete response, or is the cancer creeping back again? That’s the main thing that they want [to know]. So, in CLL, the responses have tended to be quite durable for most patients. But in other blood cancers, sometimes people get a deep response—MRD [minimal residual disease] undetectable—but the disease can be back again in 6 months. So, I think that those are the things that they’re looking for, plus the usual kind of things: Am I getting more infections, am I getting anemic, am I getting problems with my platelets? Things like that. The follow-up isn’t too onerous. I essentially get a physical exam and blood work once a year.What concerns you as medical innovations continue to advance treatment?
CAR [chimeric antigen receptor] T is unbelievable. I don’t know what [percentage] of people are cured. My guess is it doesn’t cure nearly as many people as they say it cures, because that’s always what happens in oncology. But let’s go back a half step. The ascension of I-O [immuno-oncology] into the front line of therapy, now the potential for combined I-O to increase efficacy, is amazing, and yet our ability to understand how to pay for those really expensive therapies has not kept up with the science. In fact, the science has outstripped the ability to help patients. And, unfortunately, as a consequence, patients are not getting access to those therapies.
I mean, it is well known—well known—that CAR T for Medicare patients is largely a no-go if you’re a Medicare fee-for-service patient. Why? Because the compensation is inadequate. And every patient that’s treated in an academic medical center—or a CAR-T center; many of them are academic—winds up costing that institution, on average, between $150,000 and $200,000. They lose that much money on every single patient. What kind of business can you run if you’re losing that much money on very patient? Which means we’re denying Medicare patients access to that potentially lifesaving therapy, which...well, I’m an oncologist. I’m very unhappy with that. That’s just not right.
Now we’re going to have gene therapy—holy moly. We had an announcement from Novartis that it’s going to be $3 million for the gene therapy for spinal muscular atrophy—which is a horrible disease; it’s not very common—$3 million a patient...$3 million a patient. So, we better start thinking about what we need to do to allow our patients to have access to this therapy that could basically turn a disease that is both fatal and horrible on the way to fatal into something that is cured.
That’s the thing that I think is the most interesting subject. And we better come up with some ideas, because the [International Pricing Index] is not going to fix that problem. It’s not even going to come close to fixing it. And I know that the European countries, the health technology assessment organizations at [the National Institute for Health and Care Excellence in the United Kingdom], for example—they are really concerned that they don’t have the tool to decide how to accommodate this for their population.What barriers still remain in knowing how and when to test for genetic mutations and deciding which treatment is best for a patient?
I think the biggest barrier right now is a financial one. Many insurance companies still deny approval for molecular profiles. While they will approve specific mutational events, they won’t approve the profile. I think that’s shortsighted. I think that as these profiles become less expensive, and as we learn about the importance of mutational events over and above the initial 6 or 10 mutational events that are now recognized, we’re going to earn more about acute myeloid leukemia, and we’re going to learn more about how to effectively treat these patients.
Mutational events can help to delineate minimal residual disease, as well. So, if you have a mutational profile at the time of diagnosis, you can use those identified molecular events at the time of remission to determine the depth of that remission. And you can make deci- sions, potentially, although not yet proven, you can at some point in the future, you might be able to make decisions about what therapy to give next, especially with respect to allogeneic transplant or intensification of therapy or capitalizing on some of these targeted therapeutics to drive deeper remissions and thereby get better long-term outcomes for patients.
I think these molecular profiles help us to think about patients. I think if you have a patient with 6 or 9 mutational events, that patient is overall less likely to do well than a patient who has less events. And Elli Papaemmanuil [assistant attending computational oncologist, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center] has shown that in her original paper in 2016 published in the New England Journal of Medicine.
I think that approach with casting a broader net and capturing the mutational events that characterize leukemia is likely to help us in the long-term manage patients more effectively.