Advances in Malignant Hematology

Additional Info

• Audio File:uf_health_shands/ufhs048.mp3
• Doctors:Al-Mansour, Zeina
• Featured Speaker:Zeina Al-Mansour, MD
• Guest Bio:Zeina Al-Mansour, MD, is an associate professor in UF Health’s Division of Hematology & Oncology in the University of Florida College of Medicine. 
  
  Learn more about Zeina Al-Mansour, MD
• Transcription:Melanie:  Welcome to USF Health MedEd Cast with UF Health Shands Hospital. I'm Melanie Cole. And today, we're exploring advances in malignant hematology. Joining me is Dr. Zeina Al-Mansour. She's an Associate Professor of Medicine in Malignant Hematology, Bone Marrow Transplant, and Cellular Therapy at UF Health Shands Hospital.
  
  Dr. Al-Mansour, it's such a pleasure to have you join us today. Tell us a little bit about the role of precision medicine in malignant hematology practice and some of the things that you've seen over the years as this field has evolved.
  
  Dr Zeina Al-Mansour: Well, thank you, Melanie, for having me today. In malignant hematology, we pride ourselves that precision medicine has really taken off particularly over the past 20 years with the increasing use of molecularly-targeted therapy and all the advances that we have witnessed lately. Precision medicine really uses a broad range of clinical practices in which genetic tests results are used to guide a patient's care.
  
  It is applied to prevention, diagnosis, and the treatment of diseases. And in malignant hematology, we mostly use it for the diagnosis and the treatment of diseases. It is used to improve medical decision-making and delivery of therapies tailored to the patient's sequence of the genetic changes that we see in their cancers. In this way, we believe that we optimize disease control and we improve the chances of curing the patient of their malignancy.
  
  Also, when we apply precision medicine basics, we avoid exposing the patient to medications that have lower efficacy toward their cancer and we also reduce exposure to medications that may expose them to greater toxicity. In malignant hematology, the examples of using precision medicine includes all the targeted medications that we have witnessed their approval over the past couple of decades.
  
  The first one that comes to mind is imatinib or Gleevec, which is basically a revolutionized molecularly-targeted therapy in malignant hematology. It targets the Philadelphia chromosome in chronic myeloid leukemia, which basically transformed this leukemia that used to be life-threatening or fatal within two years, the life expectancy used to be two to three years in this malignancy, to more or less a chronic disease now by blocking this driver mutation in these patients.
  
  So patients now who take this medications basically just has to stay on it, usually for life. And as long as they are tolerating that, they just continue on the medication and continue to control their leukemia in most cases. A smaller fraction of patients may require more aggressive treatments or require change of treatment. But for the most part, continuing on imatinib or some medications of the same family may control it.
  
  Likewise, other molecularly-targeted treatments have transformed the course of many of previously thought to be fatal diseases. For instance, we have the FLT3 pathway, is one of the driver mutations in acute myeloid leukemia. We always say that patients who have acute myeloid leukemia with this pathway, the question is not if it will come back or not, the question is when. But now, we have multiple medications that block these drivers that have changed the course of this leukemia. And by blocking these mutations with these molecules, we have significantly increased the chances of curing the patient of these leukemias.
  
  We currently have two approved medications with multiple ones that are under investigation to be approved. This pathway is known to evade growth suppression, sustain proliferation of this cancer, resist cell death of this malignancy. And blocking this pathway improves the cancer control by blocking all these mechanisms.
  
  Other pathways where we apply precision medicine basics include the JAK pathway, which is identified in multiple myleloid malignancies in terms of deregulating cellular energetics, sustaining proliferative signaling. It avoids immune destruction. It also promotes tumor inflammation and it resists cell death. So we have JAK inhibitors. Jakafi is one of them. And by inhibiting that, it also can control tumor growth by blocking these mechanisms.
  
  And there are multiple other examples from the chronic lymphoid leukemia. For instance, another example, we have in the lymphoid malignancies in which we apply the basics of a precision medicines by using molecularly-targeted therapies that inhibit these driver mutations in these malignancies. With these, we can alter tumor growth or stop it or improve ptosis or cell death to increase the chances of controlling the cancer in these patients.
  
  Melanie: That was a comprehensive answer, Dr. Al-Mansour. Thank you so much. What an exciting time to be in this field, as we're talking about immuno-oncology and the treatment of blood malignancies. Tell us about any novel immune-based therapeutics, BiTEs, CAR T-cell therapy, advances in transplant. Walk us through some of these novel immune-based therapeutics.
  
  Dr Zeina Al-Mansour: This is a topic that is very dear to my heart. So these immune-based therapies come from the bone marrow transplant field and bone marrow transplant is one of the immune-based therapies. In all these immune-based therapies, we are going back to the basics. We are trying to unleash the immune system that was created in the body to fight malignancies. And for some reason, something went wrong and the immune system is now not fighting the malignancy. So with these immune-based techniques, we try to reeducate the immune system, the patient's immune system, to go back and fight the malignancy, either by just changing or modulating the immune system, or by enhancing that with adding some molecules to help the immune system fight the cancer.
  
  For example, when we use what we call the BiTE techniques, BiTE stands for bi-specific T-cell engagers, these are molecules that we infuse into the patient's body. These molecules have usually two binding sites. The first BiTE that was approved was for the acute lymphoblastic leukemia. So we're going to use that for the sake of this example. This molecule has two binding sites. The first site binds the CD-19, which is a common B cell marker. The second binding side binds the CD8 cytotoxic T-cell. So when you infuse this molecule inside the patient's blood, it goes around and binds the CD-19, the acute lymphoblastic leukemia that the patient has and then goes around and binds the cytotoxic T cells that the body has normally, and usually should fight the malignancy.
  
  So when this molecule binds these two together at the same time, again, it binds the malignant cell, the CD-19 malignant cell and at the other site, binds the cytotoxic t-cell. When it brings them together, close to each other, it induces a reaction that causes cellular killing. And by doing that, it enhances the killing of the acute lymphoblastic leukemia.
  
  So this is what we call the BiTE technology, bi-specific T-cell engagers. It has been approved for, B-cell acute lymphoblastic leukemia. it is under investigation for multiple myelomas and acute myeloid leukemias as well. But we believe it's a very promising technology that uses the cytotoxic T cells in the patient's body as long as you find another target that these T-cells can bind and induce cellular killing. So this is one immune-based technology. In BALL, it has been shown to be very, very effective.
  
  The other one that uses immune-based technology is the CAR T-cells. CAR stands for chimeric antigen receptor cytotoxic T cells. And this technology, we basically use it for refractory diffuse large B-cell lymphomas. We take the T-cells from the patient's body that has the refractory lymphoma. T-cells is part of the immune system that is normally supposed to fight the malignancy. However, in that patient, for some reason, it was unable to recognize the patient's malignancy.
  
  So we harvest these T-cells by a process called apheresis. Basically, we collect them from the patient's plasma and then we send them to a specialized lab with a piece of the patient's own lymphoma. And then we re-engineer the receptors on the T-cell in a way that matches the antigens on the patient's lymphoma, so that the receptor and the antigen now can recognize each other. And after that, we culture the T cells in the lab to expand them and make them at enough numbers so that when we re-infuse them back in the patient's body, they can go and re-expand and populate in the patient's body. And then they can circulate around to find the patient's refractory lymphoma.
  
  And at that point, they can recognize the antigen because now they already engineered to recognize it. And at that point, they can interact with each other and then use cellular killing or the tumor killing and fight the malignancy. So that is the second technology, which we call CAR T or chimeric antigen T cell receptor technology. It's currently approved for refractory diffuse large B-cell lymphoma. In pediatric cases, it is approved for our refractory acute lymphoblastic leukemia. And very recently, two months ago, it was approved for refractory multiple myeloma. And it is currently under investigation for acute myeloid leukemias. And in multiple solid malignancies, it's also under investigation. So we also believe it is a very promising technology that is gaining a lot of popularity now.
  
  Melanie: What a fascinating field this is. As we wrap up, what would you like other providers to know about any clinical trials or research for hematologic malignancies that you're doing at UF Health Shands hospital and when you feel it's important they refer?
  
  Dr Zeina Al-Mansour: What I want people to remember, the hematological malignancies is a rapidly advancing field. It is a field that has a potential of a cure. These malignancies, even though they are very aggressive and potentially fatal. They have very high chances of being cured, even the refractory cases. We have multiple clinical trials at UF including BiTE trials. We do all types of cellular therapies, bone marrow transplant, and CAR T-cells at UF, as well as transplant for elderly population. That is also a very rapidly advancing field. So we are happy to see and evaluate patients for any options of treatment that we able to offer them.
  
  Melanie: What a great topic. Thank you so much, Dr. Al-Mansour, for joining us today and sharing your incredible expertise. to refer your patient or to listen to more podcasts from our experts, please visit ufhealth.org/medmatters for more information. And that concludes today's episode of UF Health MedEd Cast with UF Health Shands Hospital.
  
  Please also remember to download, subscribe, rate, and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.
  
  
• Hosts:Melanie Cole, MS
• Post Test URL:https://cme.ufl.edu/mededcast/