Chronic Lymphocytic Leukemia Moon Shot CLL update

MD Anderson Cancer Center
Date: August 7, 2014

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Dr. Michael Fish: Welcome to Cancer Newsline, a podcast series from the University of Texas MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family's cancer risk. I'm your host, Dr. Michael Fish with the Department of General Oncology at MD Anderson Cancer Center. And today, we're talking with Dr. Michael Keating. Dr. Keating is a professor in the Department of Leukemia and an expert in chronic lymphocytic leukemia, often abbreviated, CLL. He is a truly beloved faculty here, not only with his patients but with faculty throughout the institution and also with physicians from various specialties in Texas and throughout the world. Dr. Keating, thanks for being here today.

Dr. Michael Keating:  It's a pleasure. I'm not sure that I agree with the introduction, being beloved but I'll take it anyway.

Dr. Michael Fish: How wonderful. Well, I'll tell you, when I think about chronic lymphocytic leukemia, I've always thought about this as a classic slow-growing but relentlessly reoccurring kind of tumor, one of those diseases that's often described as treatable but not curable. Yet, you don't seem to settle for that depiction and I notice that CLL is one of the diseases in the scope of the MD Anderson Moon shot Program with the goal to increase the cure rate. So, my first question is how has the approach to CLL evolved in the course of your career?

Dr. Michael Keating: The early part of my career at MD Anderson was working in acute leukemia and I switched track at one point and that's not important as to why that happened. But, in acute leukemia, if you didn't get rid of the last leukemic cell, it relentlessly came back and killed the patient. So, that the goal was always to eradicate the disease and that increased your comfort level and we were the first to report a series of 20 patients with acute leukemia in 1978 that had been cured, and the rest of the world that only reported 16 cases at that time. So, this was the first time that adult AML was considered curable. And, I was working on a drug but--fludarabine which was being looked at in acute leukemia but there were these dramatic responses in low-grade lymphoma and CLL. And, this led to the concept for the first time, a very significant number of patients getting through complete remissions. And, I've just been following up on those patients that got started in 1983. And, a few of those patients is still alive and free of their disease, so that even with a single drug, a few patients were actually doing pretty well. But, I worked in conjunction with Dr. Bill Plunkett who taught this at--how to combine two different drugs. And also, Susan O'Brien that did some of the pioneering work on rituximab have in CLL, we came up with this drug combination called FCR or over in Europe, they call it RFC just because it's Europe and so that we are then able to get about 72 percent of the patients' in complete remission. And, we now have a third of these patients that haven't had recurrence of their disease at 10 to 15 years. So, it's gone from being a very slow-moving, slow-reacting by physicians to the disease and to a situation where we have to figure out how we can double that cure fraction in the next few years.

Dr. Michael Fish: That is just remarkable. You know, sometimes, people facing CLL ultimately die of the effects of the disease but not directly due to tumor growth, but rather from infections or transformations to a different kind of blood cancer or even from another kind of solid tumor of cancer. So, why does this happen so much with CLL patients?

Dr. Michael Keating: I think the problem that we have is we don't really know what causes CLL to occur in the first place. There are some clues and that there's an ethnicity that, you know, it hardly ever occurs over in Asia. It occurs in the US and Europe with roughly a growth frequency. But, it's very common in Ashkenazi Jews and it's also--there are some familial clustering so that there's a strong sense that there is a genetic component to the disease. And, one of the features is that when Dr. Carlo Croce first developed an animal model and he and Dr. Gribben were looking at the immune system in the animal model. Before, you could identify the leukemia occurring, the immune system was dramatically dysfunctional. So, one of the thoughts about the unusual infections that you have in cancer generally and lymphoid cancers in particular is that you need an intact immune system to prevent that from happening. There's also the sense that as people get older, those that are the--without an intact immune system are much more likely to get other cancers. And, so that, at the present time, we probably have about 40 percent of the patient to die of CLL, die with an active second cancer. And, we have to figure out whether it's predominantly due to the disease process and the immune weakness or whether the chemotherapy part of the treatment has contributed to it by worsening the immune parameters, and also, damaging the DNA of other tissues. So, the big push that we have at the present time is to see if we can start off the majority of patients with non-chemotherapy programs, so that we've gone over the last, probably five to six years from about 90 percent of patients starting off with a chemotherapy regimen to probably five to ten percent of patients starting off of that at the present time.

Dr. Michael Fish: Well, what a change that is. I see there is an explosion of new therapies and unique approaches to a variety of tumors and other blood cancers, drugs like ibrutinib and new immunotherapy drugs have been approved and are being used in other diseases. Are these drugs promising in CLL also?

Dr. Michael Keating: I think that ibrutinib is probably leading the revolution because it's an oral medication. By and large, it's very, very well-tolerated. So, very few people have to come off because of, you know, the usual side effects that occur with chemotherapy programs. There are couple of somewhat unusual manifestations and number of them getting a irregular heartbeat or AFib in about 5 percent then many of them had AFib beforehand. But, it's a new thing. And, there's a weakness in platelet function which is again not usually very impressive but often irritating. So, that we can set these patients off and there are couple of dramatic things that happen within one to two weeks, all of their enlarged lymph glands basically gone. And, then the patient comes in and has--there are evaluation, they say, "Doc, this is magic." And then, they look at their blood count and their blood count has gone up dramatically. And, it's because the drug makes the CLL cells leave the comfort of the nodes and the comfort of the marrow and the spleen and get into the bloodstream where they're no longer supported by nutrients, et cetera. And, they just gradually die off. So, that what we found is that even with patient with far advanced disease, about 70 percent of them will get a very good remission. And, we're identifying the ones that may begin to come back and usually, the patients that have a characteristic abnormality with loss of part of chromosome 17 with the so-called wicked p53 gene being incriminated. So, that we have now got to the point where we've very dramatically improved not only the progression free survival, that is the disease not coming back, but also the overall survival compared to what we did in the past and the quality of life of these patients is dramatically different. So, that at the present time, we can online prescribe that in patients that had treatment before but clinical trials are being put in place so that we can establish that it's a very, very effective treatment for our frontline patients as well. There's another drug that's somewhat similar called idelalisib and it used to be called CAL-101 and GS-1101. So, the alphabet soup is alive and well. And, I think that that will be the next one that will be approved and there are few more complications with that. But again, it's very effective. You mentioned the immune system. Up until recently, they only thought that stem cell transplant was the only modality that would cure the patients. And, we found out that it was not that we had to give very strong doses of therapy to eradicate the disease, but we put in a new immune system that would recognize the leukemic cells and kill those off. So now, there's a lot of interest in enhancing the patient's own immune system and this is a tremendously fertile area research right now.

Dr. Michael Fish: It's amazing how much oncologist and practice like me are having to recalibrate and rethink all of the things that we've learned and the reflexes that we have for thinking about these diseases. But, it's certainly very exciting to see how tolerable these therapies are, and as you said, how people's quality of life has improved so dramatically. Now, the famous Moon Shot Program is something I mentioned earlier and I wonder if your patients ask you about the Moon Shot Program and how you explain that to them.

Dr. Michael Keating: Our patients address the Moon Shot when there was a lot of early publicity. There is less publicity now and I think people are now saying, "Well, what's happening?" So, that the informed people that have heard of it initially still following up on that. But, every patient we see with CLL, we introduce the Moon Shot concept. We have people who come over and explain why we want to collect some of their blood cells or their marrow cells and what the benefit is from their point of view. So, one of the things that is happening now is that we can now sequence all of the genes that make a protein in patients with cancer. So, that if there's a mutation in one of these proteins, it may lead to the disease activation and making it progressed. But, the good side of it is that we can identify drugs which will specifically neutralize those abnormal mutations and an example of this is that there is a gene BRAF which has been found to be abnormal in a number of situations and incredibly in melanoma. But, there is a very rare type of leukemia, hairy cell leukemia, and a friend of mine in Italy discovered that the BRAF mutation occurred in one of his patients. And then, he looked at all of those patients with hairy cell leukemia and almost all of them have this mutation. So, that a melanoma drug is now a leukemia drug. So, that not only are we trying to specifically look at, you know, does this drug work in leukemia blindly, but we have directed therapy now. We can identify the patient population that we should explore which makes the whole clinical trial methodology much more efficient.

Dr. Michael Fish: That's amazing. Now, there's great interest also in the link between inflammation and cancer. And, I know that there are drugs called JAK2 inhibitors that have worked for other blood cancers and at ASCO, the national meeting is coming up, there's even studies looking at JAK2 inhibitors and solid tumors. Is this something promising in CLL also?

Dr. Michael Keating: You know, the--one of the dirty secrets about CLL is that the most common symptom is fatigue. And, even if you are--have relatively little CLL, fatigue can often be quality of life limiting that people have to resign their positions or cut back to part-time, et cetera and they don't go out with their families often, et cetera, because they're just too tired to do it. And, the--when JAK2 inhibitors were first used in myeloproliferative neoplasm like myelofibrosis, et cetera, the most dramatic thing was how the symptoms improved and that it was noted that it dropped down these inflammatory chemicals called cytokines and we're very interested now and have a protocol that's about to be activated looking at the JAK2 inhibitor in the patients that don't need treatment for their leukemia so much. But, they need their fatigue treated. And, we've also found that there are funky things that happened, you know, some of the agents that are used in attention deficit disorder, like Ridalin and Adderall, et cetera, are very impressive in a number of patients, particularly women. And, that it's a very strong sex related response and that leads to why is that, et cetera. But, I think in all of the cancers, the inflammatory response is really important. Dr. Estrov here has found that there is a constitutive that is everyone has over expression of a STAT3. And, instead of having a tyrosine STAT3, it's a serine STAT3 and it regulates a whole bunch of things inside the leukemic cells. So, that it's nice at the present time, working on a place like Anderson where every aspect of cancer is being looked at. And, you can beg, borrow, or steal ideas and apply them to your patient population and just make everything work better.

Dr. Michael Fish:  Well, it's clear that the focus is really on the patient and everything that can be understood that can improve the patient's quality of life and function, and it almost sounds like these JAK2 inhibitors are like symptom drugs more than disease-focused drugs.

Dr. Michael Keating: I think that that's true but, and I think that there are increasing number of abnormalities. There's a very rare type of leukemia called T-cell prolymphocytic leukemia and they're now finding that they're on mutations in a number of other JAKs--kinases and also I think STAT5 and that's an imprint which is present on the majority of significant number of these patients with this rare disease. And, there are also some receptors for other inflammatory agents such as IL-2 receptor. And, as we find out more of this, we can then begin to figure out if you neutralize this, what happens. And, the problem is that many of the new agents that we have very, very expensive and I think that this is at important for a reality check in the United States is, you know, we just can't be developing drugs that no one can afford to have.

Dr. Michael Fish:  Sure. What about old fashion anti-inflammatories like aspirin or statins?

Dr. Michael Keating: We have a paper that we presented at the ASH meeting last year. And, we took patients that had a relapse of their leukemia or were being put on a salvage program. That's a terrible word, OK, a rescue program or rejuvenation program. So, we looked at all the patient that got a standard treatment and separated them into patients that were having aspirin alone, statin alone, the combination, and those that didn't have either. And, the ones with the combination had a significantly improved survival over those that did not. So, it brings everything back. The inflammatory cytokines, et cetera, are quite possibly very important in the second cancers that occur, because a lot of the anti-inflammatories I used for cancer prevention. So, one of the witnesses of the aspirin or causes that weakened platelet function which is pretty important in blood cancers. But, we can get around that. Yeah, we can get around anything. It's just a matter of time.

Dr. Michael Fish:  Well, and it is just remarkable that robust number of new leads and the sort of head spinning excitement that is brewing in the treatment of CLL.

Dr. Michael Keating: Yeah.

Dr. Michael Fish:  Thank you so much for being with us today. And, if people have any questions about anything you've heard today on Cancer Newsline, please contact to askMDAnderson at 1-877-MDA-6789 or online at www.mdanderson.orgsask. Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.

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