Hello. In this session we're going to discuss the various aspects of leukemia, and we're very please to have, today, Doctor David Porter, professor in medicine. So, good morning. Thank you for coming. >> Good morning. >> Could you please tell us a little bit who you are in the school and where you work. >> Well, I'm David Porter. I'm the director of the Blood and Marrow Transplant Program here at the University of Pennsylvania, and I'm a professor of medicine. I have a chair at the Jodie Fischer Horowitz share in leukemia care excellence here at University of Pennsylvania. I have a clinical practice and I do a lot of clinical research and work with a lot of scientists collaborators to try and develop new therapies for patients undergoing blood and marrow transplantation and for patients with various types of blood cancers, hematologic malignancies including leukemia. I have been doing this for a little over 25 years now, I've been here at Penn for a little over 20 years. And, Have been very excited about some of the new advances and some of the work we've been doing trying to develop these newer therapies. >> So getting to thing in a while, but first of all could you please tell us a little bit about some of the more common cancers of the blood? >> [COUGH] Sure. There are a number of different cancers of the blood called hematologic malignancies, or blood cancers, the most common being leukemia. When we talk about leukemia, we generally divide it into acute leukemias and chronic leukemias. Those leukemias are then generally divided into myeloid leukemias or lymphoid leukemias. Acute leukemias tend to be, just as it says, acute. They are very aggressive and fast growing. They are imminently life threatening if they are not diagnosed quickly and treated quickly. The treatments generally for acute leukemias are very intensive. They tend to be very risky. They are aggressive. They often involve very intensive types of chemotherapy and even things like bone marrow or blood, stem cell transplants. Chronic leukemias on the other hand tend to be slower growing. They are more indolent in most cases. They often take a longer time to develop and as the term implies they are chronic. They are often long-lived diseases. Patients can often live with chronic leukemia with no symptoms or very few symptoms. Eventually, over time, even chronic leukemias can progress, and become very dangerous and life-threatening and so the term shouldn't imply that they are benign. But they generally have a very different prognosis in implication. Treatments tend to be milder. We often think of chronic leukemias as incurable but very treatable and in fact, many people with chronic leukemias don't need treatment, at least for a long period of time. Acute leukemias, we typically divide into myeloid leukemias, like acute myelogenous, or acute myeloid leukemia versus ALL, or acute lymphoblastic leukemia. ALL tends to be more of a disease in children, it's the most common type of leukemia in kids. AML is the more common type of leukemia in adults. We approach them with a similar philosophy, with very aggressive intensive chemotherapy, but, that are similar, though they are different diseases. Likewise, we can divide chronic leukemias into chronic myelogenous leukemias, myeloid leukemias, CML and related diseases verses lymphoid leukemias, the most common being CLL, chronic lymphocytic leukemia. In that category are some of the lymphomas we consider blood cancers, though they tend not to circulate in the blood, things like Non-Hodgkin's lymphoma which can be very aggressive or like the acute leukemias. >> How frequent are those diseases in different populations? >> They vary according to the disease. I think one really important point here is that all of these leukemias really are different diseases. One can't just say, blood cancer and one can't just say leukemia. But when we talk about acute leukemias, AML or ALL, in adults certainly they occur somewhere between 3 to 5 for every 100,000 people. So the incidence is really rather low. But when they happen it can be quite devastating. Some of the chronic leukemias, when you think about something that we treat very often, CLL, Chronic Lymphocytic Leukemia, there are about 16,000 new cases a year in the United States. So it's certainly not rare. All of these leukemias particularly for the adults increase in age and the instance is much higher once patients get over 60, 65 years old. And people over 65 the instance of acute leukemia for instance may be is high as ten or 12 per 100,000 people. So it really does increase with age similarly the Chronic leukemias go up in age. >> Have the leukemias been associated with certain risk factors, such as risk factors such as environmental, viral, genetic? >> Some are, and some aren't. The genetic association is fascinating. The first identification of a genetic abnormality in cancer was actually identified in leukemia. It was identified in Chronic Myelogenous Leukemia, in fact, right here at the University of Pennsylvania across campus by a just wonderful physician, pathologist and scientist Peter Nowell, who in fact just passed away in the last month. It was Dr. Nowell's lab that first looked at the chromosomes in cells of patients who had CML and found a recurrent genetic abnormality translocation between two chromosomes, chromosome 9 and 22 and that later got termed the Philadelphia Chromosome. It was the first representation of a consistent reproducible genetic abnormality, and this was in 1960 when very little was known about genetics and chromosomes and it was really the identification that genetics play a major part in cancer biology and certainly leukemia biology. There has been a great deal learned over the years. Different leukemias have different risk factors. There is no doubt that certain chemical exposures, for instance, predispose patients to myeloid leukemias, things like acute leukemia or a related disease called myeloid dysplasia. Some other chemical exposures may be associated with other types of leukemia. There's some suggestion for instance that people who were exposed to Agent Orange in Vietnam have a higher risk of CLL. Radiation has been known to at least predispose people to leukemia. All of these may be from causing recurring genetic abnormalities that then lead to abnormal growth of cells and leukemia, so there are a number of associations. I think one of the biggest advances probably over the last five years has been identification of many different recurrent genetic abnormalities that you find in leukaemia cells. >> What about some medications that they currently use to the heavy fact on the leukemia development? >> Yeah, as a risk factor there are. It's particularly important from certain types of chemotherapy drugs. Drugs that may be used to treat other cancers, there's a class of chemotherapy called alkylating agents that directly affects DNA. And it is known that these drugs can cause mutations that can then predispose to developing leukemia. That's relevent for instance, for people who get chemotherapy for various kinds of cancers like breast cancer for instance. Who 10 years later, may have an increased risk of myeloid cancers. There are other drugs that we use as chemotherapy for different cancers that predispose patients to ALL. The risk is relatively low, but in fact it's significant enough. That one takes us very, very seriously and has to taken into account when your developing chemotherapy programs for patients with other diseases. >> So what are the first signs and symptoms of a patient who is developing blood malignancy? >> The signs and symptoms are really quite variable, some of it depends on what type of blood cancer a patient may have. I will say these days it's very common to make a diagnosis of a blood cancer just incidentally. Somebody goes in for their yearly physical exam, they have blood work and it's abnormal, leading to an evaluation. When signs and symptoms develop, they are often a function of one of the blood cell abnormalities. In general, when patients develop leukemia or extensive leukemia anyhow, they may have anemia. The red cells may be low, they may have neutropenia with a low normal white blood cell count, low neutrophil count and a low platelet count. And the signs or symptoms we see are generally related to one of those abnormalities. Fatigue is very common when patients are anemic. Patients will come and say, I've just haven't been feeling right, I'm tired, I'm fatigued. They may develope trouble breathing, particularly with activity when they are anemic and their red cells are too low. Another common presenting symptom particularly for people with acute leukemia who present neutropenic, with low neutrophil counts or some sign of infection. Having fever's a very common presenting symptoms, having infections, one of the very common sites of infection. In fact, may be the oral cavity, one of the things we're talking about today. Patient's may present with recurrent mouth sores or ulcers or sore throats or pneumonia and other types of infection. And I think that the third presenting sign or symptom may be abnormal bleeding or bruising. When the platelets are too low, it predisposes the bleeding and easy bruisability. And so sometimes people will present saying, boy, just all of the sudden I find that I bruise very easily. There are other presenting signs and symptoms depending on the type of leukemia. So some of the lymphoid leukemias like CLL or lymphomas may present with adenopathy, swollen lymph nodes. And the first sign may just be they notice swollen lymph nodes in various places. In acute leukemia, there are some unique manifestations of different types of leukemia. There are certain types of AML, acute myeloid leukemia for instance that are very prone to infiltrating various organs. One type that is very prone to infiltrating the mucosa in the mouth. In fact, it's a common diagnosis that a dentist may make. Somebody goes in, they have gum swelling or gum bleeding and sores. And that is how a diagnosis of AML can be made in some cases. So the manifestations really are quite variable depending on the type of leukemia how long somebody's had it, and when it's diagnosed. >> So what I would like to discuss perhaps is the treatment of leukemia. Both the traditional one, and then perhaps you can tell us how your research involves something that's completely new. >> The treatments of leukemia again vary depending on the type of leukemia. And I think it's more straight forward to divide it into treatment of acute leukemia versus treatments of chronic leukemias. Treatments of acute leukemias generally involve today very intensive, aggressive types of chemotherapy. Again, this can divided into treatment of AML versus the treatment of ALL. I would say when we talked about ALL and various treatments. This is one of the best success stories in all of medicine in the last 40, 50 years. ALL used to be a death sentence. In the 1960s, kids diagnosed with ALL, almost all died. With the development of very aggressive chemotherapy regimens, it is one of the most curable types of cancer at least in kids today. But treatment is intensive and risky, treatments are similar in AML. The cure rates are certainly not as high in adults as they might be in kids. But there are many people still who can be cured just with chemotherapy. Generally, it involves combination chemotherapy, a mix of different drugs, depending on the type of leukemia somebody may have. All of these drugs are designed to kill more cancer cells than normal cells. But in truth we do not have any traditional chemotherapy that only kills cancer cells and doesn't also kill normal cells. So it is common to treat people with a combination of different types of chemotherapy. What generally happens is the leukemia cells will disappear from detection from the circulation at least temporarily, but there are common side effects. It also will kill off many of the normal blood cells. So it is common during this type of chemotherapy that people even if they start out with relatively normal blood cells, white blood cells. They will go very low for a ten day or two week period until they start growing back. The platelet count will go very low from chemotherapy. People will be prone to bleeding and they will become quite anemic. Often these people are needing blood transfusions or platelet transfusions during this chemotherapy period. The hope is though that the chemotherapy kills off more of the cancer cells than the normal cells. And what will grow back then are just the normal cells. The other side effects are killing other cells that tend to grow rapidly, and that is for instance hair. It is one of the reasons that people lose their hair during this type of therapy. Hair will grow back. Other cells that turnover rapidly that are often affected by chemotherapy may be the lining of the mouth and the GI tract. So it is very common to find people get mouth sores, for instance during this type of chemotherapy. And get infections in the mouth and the bowel. It is one of the reasons that we look so closely and work so closely with our oral medicine colleagues, because that is such a common site of infection. But the hope is then, that after two weeks, three weeks, the normal blood cells can recover, leaving a patient without leukemia cells in remission. The treatments are dangerous, they are risky, but they can be quite effective. In today's modern era, in AML 75 to 80% of patients can achieve a remission at least in ALL, it's similar, probably 80 to 90% of patients can achieve an initial remission. Chronic leukemias are treated a little bit differently. And, again, it depends on what type of leukemia. If we're talking about amyloid leukaemia or if we're talking about lymphoid. Very often, patients who present with these chronic leukemias may not need any treatment at all. We may use a philosophy of watch and wait, of observation. When they need treatment, the treatments tend to be less intensive than what we use for acute leukemia. Many of these therapies are designed to control the disease, to at least stop it from growing and causing problems, but may not be as intensive in trying to induce remission or even cures. So it does depend on the type of leukemia or the type blood cancer we're talking about. All of these treatments are non-specific, they affect, hopefully more of the leukemia than normal cells, but they affect normal cells and not just blood cells. They can damage, as we said, the lining of the mouth or the gut and hair will fall out, but they can affect the lungs, they can affect the liver. There have been tremendous advances and a great deal of energy put in trying to develop better, more effective therapies. As we have learned more about leukemias and blood cancers, there has been the development of more specific treatments. Biological therapies that aren't designed to just kill off all the cells, but they are designed to target the biological abnormality of the cancer cell, and again there are many different approaches depending of the type of cancer. But one of the things that we have been very interested in trying to develop has been targeted therapy to attack the malignant cell without effecting normal blood cells. And we have been very active in trying to develop targeted cellular therapy for B cell malignancies. B cells are lymphoid cells, and so this can be applied in particular to acute lymphocytic, or acute lymphoblastic leukemia, ALL, both in kids and children, but also some of the chronic lymphoid malignancies like CLL, chronic lymphocytic leukemia, or non-Hodgkin's lymphoma. All B cell malignancies, almost all B cell malignancies have a protein on their surface called CD19. CD19 is a molecule that defines a B cell. It's on normal B cells as well but it is on just about every B cell malignancy. If you can target this protein, you can target the B cells, the malignant B cells without affecting other parts of the body. It shouldn't affect the nuetrophils, or the platelets, or the red blood cells. Working with colleagues here, at the University of Pennsylvania, really led by Dr Carl June, who was so instrumental in developing this technology in his laboratory with a number of different people. So, what we do with this technology is we can genetically modify a patient's own immune cells, their own T cells, so that they can recognize the CD19 protein on the malignant B cells, and normal B cells in fact. The way that this works is we use a virus to bring in new genetic material into the T cell. This virus is called a Lentivirus, it is made up of, or based on an HIV virus. It uses part of the HIV that allow it to get in efficiently to a T cell, it brings new genetic material into the T cell, that genetically changes that T cell, the immune cell, so that it can now recognize and target CD19+. We then grow those genetically modified cells in the laboratory and can reinfuse them back into the patient. This can be applied to any B cell malignancy, and we have used it now to treat patients with ALL, both children and adults, and patients with CLL and other lymphoid malignancies like non-hodgkins lymphoma. I do have a animated cartoon here to show and explain how this technology works. What you see in the cartoon is a virus bringing in new genetic material into the T cell. That genetic material gets integrated into the DNA. It is affecting expression of what we call a Chimeric Antigen Receptor, which is a receptor that recognizes CD19+. You see it here being transported to the cell surface, stably integrated into the cell surface, it now allows the T cell to recognize CD19+ when it couldn't before, hopefully leaving behind a dead cancer cell. And that's really how this technology works. We have applied this initially to patients with ALL and CLL, and now non-Hodgkin's Lymphoma, and some other diseases. Some of our first trials were in acute lymphoblastic leukemia, in patients who had relapsed into refractory disease. Patients who had run out of treatment options, nothing was working, many have had a prior bone marrow transplant. And really, had no effective treatment options left. And in fact the vast majority of these patients will die of their disease without some other treatment. The initial results have been astounding. 90% of patients with ALL who get these genetically modified T cells, what we call chimeric antigen receptor modified T cells, or CAR T Cells, have gone into remission, 90% remission rate. There really was no precedent for this in leukemia therapy. We have applied this to CLL, we have gotten really exciting results, again in patients who have had refractory leukemia where nothing was working. And similarly have now started treating patients with Non-Hodgkin's lymphoma, finding that this can induce remissions in people again who were not responding to standard treatment options. This idea of using novel cellular immune therapy, really is a new frontier in medicine. Immunotherapy itself is a new frontier. And cellular immunotherapy has just been really remarkable and something we're very excited about exploring in the the future. >> So this is still in the testing phase? >> This is still in the clinical trial phase. Though, the intent there are a couple different companies who have announced plans to submit applications to the FDA, to try and get approval so that this can be an FDA-approved therapy for certain types of leukemia or lymphoma, and those applications are reportedly to go in in 2017. >> Do you foresee a situation where this type of therapy will replace chemotherapy which is so damaging to the other organs? And this will be the standard of care? >> We do not know yet, but, of course, do I foresee it? I am optimistic that that can happen, and that may happen with this type of T cell immunotherapy being more targeting and more specific. There are many other types of immunotherapy being developed for leukemias and lymphomas, drugs that target the immune system rather than the cancer cell itself, and so there are drugs that allow activation of the immune system so a patient's own immune cells can then fight their leukemia or their lymphoma. There are targeted agents directed against the genetic abnormality in the cancer cell that are being used to treat leukemias. So I absolutely envision, whether it's from this CAR T cell therapy, or other treatments that we are moving into a realm of targeted, specific therapy, where we are trying to get at the leukemia cells without the non-specific, very dangerous toxicities that we get from traditional chemotherapy. >> Right, well, thank you very much for an enlightening discussion. Appreciate you coming. >> My pleasure. [MUSIC]
