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Lymphoma Diagnosis & Management | Prof Manali Kamdar

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Summary

This on-demand medical session with Professor Candar will cover the diagnosis and management of lymphoma, a common blood cancer that includes over 100 different subtypes. Learn from a world expert on the clinical parameters of the lymphoreticular system, risk factors for the disease, and current cutting-edge therapies for different types of lymphoma. Take part in lively and interactive discussion, covering etiologic factors for the disease, treatments with minimal side effects, and promising therapies that are approved in the US and elsewhere. Whether you are medical student or a practicing clinician, get your questions ready to interact with Professor Candar.
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Description

Professor Kamdar is a well respected hematologist oncologist specializing in lymphomas. As an Associate Professor at the University of Colorado Cancer Center, she has made significant contributions to the field through her research and clinical work. Professor Kamdar’s expertise lies in cellular therapies, particularly CAR-T cell therapy targeting CD19. Her studies have demonstrated the effectiveness of CAR-T cell therapies in improving outcomes for patients with relapsed or refractory diffuse large B-cell lymphoma. She has presented her research findings at prominent conferences and is highly respected for her contributions to lymphoma treatment.

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Needs Assessment

Clinical Need and Patient-Level Data

Lymphoma is a group of hematological malignancies with distinct clinical presentations and pathological characteristics. According to global data, lymphoma comprises 5% of hematologic malignancies and has a substantial impact on healthcare systems [1].Despite numerous advances, lymphoma remains largely incurable, with relapse or refractoriness posing significant challenges in its management [1].

Diagnosis Gap

The timely and accurate diagnosis of lymphoma is crucial for appropriate management and improved patient outcomes. However, there are challenges in diagnosing lymphomas due to their varied presentations and overlapping symptoms with other conditions. A study published in 2015 found It took a median of 8 weeks for a non-haematology physician to diagnose Diffuse B cell lymphoma and refer to a haematologist [2]. A median of 3 weeks elapsed between specialist consultation and chemotherapy initiation [2]. Common presenting symptoms can be vague and include fatigue, bone pain, anemia, skeletal lesions, hypercalcemia, and elevated serum creatinine levels. This makes it important to close the diagnostic gap in lymphoma crucial to facilitating early detection and enabling timely intervention to improve patient outcomes.

MedAll aims to develop educational initiatives that focus on providing HCPs with the necessary knowledge and skills to effectively diagnose, and manage lymphoma patients. The goal is to bridge this gap to enhance early diagnosis and treatment to enhance the overall experience and outcomes for lymphoma patients.

  1. Jamil, A., & Mukkamalla, S. K. (2023). Lymphoma. StatPearls. StatPearls Publishing.
  2. O'Donnell, K., & O'Connor, M. K. (2023). Lymphoma: An overview. British Journal of Haematology, 191(1), 1-11. doi:10.1111/bjh.13150

Declared conflicts of interest

Prof Kamdar has received research funding from Novartis and consultancy fees from AbbVie, AstraZeneca, Celgene/ Bristol-Myers Squibb, Adaptive Biotechnologies, ADC therapeutics, Beigene, Genentech, Syncopation, and Caribou biosciences. She is on the SeaGen speaker's bureau and the data monitoring committees at Celgene and Genentech.

Learning objectives

Learning Objectives: 1. Understand the epidemiology and risk factors of lymphoma diagnosis. 2. To be familiar with the different subtypes of lymphomas. 3. To be aware of the signs and symptoms of lymphoma. 4. To acquire the knowledge to assess the different options for treatment and management options for lymphoma. 5. To have an understanding of the latest developments in the diagnosis and management of lymphoma.
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Computer generated transcript

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The following transcript was generated automatically from the content and has not been checked or corrected manually.

Good evening, everyone and uh good morning. Good afternoon, good day. Wherever you're joining us from today, it is a real pleasure to have you join us. And it's a real pleasure to have professor join us this evening on what's going to be a really exciting session on lymphoma diagnosis and management. And we're really going to hear from a world expert this evening. Professor Candar is from the University of Colorado Cancer Center and she's going to be discussing uh diagnosis and management of lymphoma. The session is relevant to medical students, but also to practicing clinicians who are really wanting to become more knowledgeable and, and think about how we can improve patient outcomes in this space. Professor Kadar is a highly respected clinician in this field and has made significant contributions in the form of research and clinical work in lymphoma. We're really excited to have her join us this evening and to um learn together in lymphoma. We're going to have time for questions at the end. So if you do have questions, please pop them into the chat at the end during the session. And at the end, we'll go through as many as we possibly can. So let's make this lively and as interactive as, as we possibly can. Professor Candar, it is wonderful to have you join us and I'm going to hand straight over to you. Thank you so much Phil for this kind introduction and hello everyone. It's my pleasure to talk to you today about lymphoma. Um The focus is going to be on diagnosing it. The focus is going to be providing a broad overview of everything that's happening in this field. Um I do lymphomas day in and day out. I'm a clinical trialist by trade. So of course, um I am going to talk to you about all the cutting edge things that are happening within lymphoproliferative disorders. Um But first off, let's look at the overview of what we are going to talk. We're of course going to focus on the main topic which is diagnosis and management options. And then I'm going to give you a sneak peek into all the promising therapies that are FDA approved here in the United States. Um But they also hold a lot of promise to be approved elsewhere. Um And also some of the other therapies that are in clinical trials which will hopefully get approved um pretty much all over the world. So as a way of background and I understand that we have a disparate group of colleagues today from learners to practitioners. Um So at this point, let me tell you what I know about lymphomas. And I'll start with the basic uh lymphoma is one of the most common blood cancers. Um It encompasses nearly more than 100 different subtypes. And if you were to look at it and I did do the counting one day, it's 108 subtypes of lymphomas. So, lymphomas are basically cancers that originate from the lymphoreticular system that includes lymph nodes that includes spleen, thymus, tonsils, bone marrow, um a lot of times spleen is always considered as a separate entity, but I will say spleen is a giant lymph node. So when we look at lymphomas, we want to see what's nodal meaning what's in the lymph nodal system versus what's extranodal, extranodal meaning outside of the lymph node circuit. So usually extranodal would be organs. So involvement of lymphomas in the lung or the stomach or the interstim that would be extranodal. With regards to lymph nodes. It's important to understand that the basic function of these lymph nodes is to serve as filters to destroy microorganisms. And it's primarily comprised of lymphocytes which are subtyped further into B cells, cells and NK cells. So when any of these cells go rogue because of a switch that gets turned on the wrong way. You can imagine you can either have a B cell lymphoma, you can have a T cell lymphoma or you can have an NK cell lymphoma. In terms of the incidence rates, I'm going to focus on the most common ones I will say, with regards to non hodgkin lymphoma, the incidence rate reflects what we see within United States and it does mimic everywhere else. But with regards to a specific incidence, it typically increases with a ID when it comes to non hodgkin lymphoma. So I think it's important to consider some of these clinical parameters because initially when a general practitioner who specializes in internal medicine gets a patient who's 18 years old with a new lymph node. But that has not regressed. Despite antibiotic treatment, you want to assess what's the possibility of that patient having lymphoma. And if that is so, would it be non hodgkin or hodgkin's? So with regards to non-hodgkin lymphoma, it really just speaks off somewhere between 60 80. On the other hand, when we look at Hodgkin lymphoma, and this is something that a lot of medical students do know because it surfaces all the time is the bi modal predisposition. The bi modal predisposition basically relates to the fact that there is one peak that happens in patients who develop hodgkin lymphoma between the years 2040 then the second peak that actually sets off after the ages of 70. And I think both of these entities present unique challenges because Hodgkin lymphoma as you may have known is a highly curable malignancy. But in younger patients, we wanna make sure that they don't have over toxicities, not just short term, but also long term on the other hand, with the older cohort, it gets slightly difficult to administer chemotherapy that can be toxic as a result, the complete completion of treatment regimen can sometimes be compromised in the older cohorts as a result. With all the tools that we have. Now our plan with regards to managing hodgkin lymphoma is to make sure the efficacy is high but not at the cost of over toxicity. Now, a lot of patients when they see you, they might ask why did lymphoma happen to me? And I will say that there is not one reason like for example, in a smoker, if they develop lung cancer, you know that the etiologic agent could be smoking. We don't have that kind of an association with regards to clinical factors. Similarly, with regards to genetic traits, you know, BRCA predisposes someone to getting breast cancer. Now, we don't have those kind of genetic issues in terms of lesions that can predispose someone to lymphoma. But there are possible risk factors that can increase the association of lymphoma although a direct cause and effect relationship is yet to be understood. So where do we typically see and who are these risk groups? I will say that we see this a lot in patients who are farmers by occupation because they typically handle pesticides, herbicides. Um patients who have undergone previous chemotherapy or radiation therapy. Lymphoma can be a risk factor. Patients who have had chronic inflammation of some sort including autoimmune diseases. So, autoimmune diseases like Sjogren's lupus, rheumatoid arthritis, patients who have gone through organ transplants. Um So that's actually called post transplant lymphoproliferative disorders, PTLD. Um that is something that we always watch for. There are certain medications that can put somebody at risk for developing lymphomas, for example, um Humira uh that is used so often in patients with autoimmune conditions um that can predispose somebody to developing lymphoma. So it's really important to make sure that you look at the etiologic factors. And if identified, it will be helpful to kind of go away from it. Um Sometimes patients do have a hereditary component. For example, there is an entity called familial CLL chronic lymphocytic leukemia where you do see patients within the family have CLL. Um It was interesting, I had a patient who came to me with a new diagnosis of CLL at age 40. And then 10 years later, she continues to be my patient, but her father was diagnosed with CLL so chicken and egg story. But at the end of the day, there is a component which is hereditary and I think we that's only going to be teased out once you do a good history and exam. So this is not meant to actually be readable, but it's actually meant to really understand that there are so many entities based on the who classification of lymphomas. In fact, the most recent iteration came out last year and based on that there are 108 different types of lymphomas. However, I like it simple. And in order to explain to you what a heterogenous group of malignancy lymphoma is. I typically dey it based on this algorithm. So for me, lymphomas are either Hodgkin lymphoma or her non hodgkin lymphoma. So Hodgkin lymphoma is rather rare in the United States. 8000 people per year are diagnosed with Hodgkin lymphoma. It's certainly a lot more curable with regards to nonn hodgkin lymphoma. So the effort with regards to Hodgkin is really making sure that we cover and cure 100% of patients with very limited toxicity. So with that new regimens and clinical trials are underway and some of those are already showing a lot of promise focusing on non hodgkin lymphoma. They are further divided into B cell, non hodgkin lymphomas or T cell, non Hodgkin lymphomas or NK cell. So B cell non Hodgkin lymphoma makes up for majority of the cohort. It's 85% of non-hodgkin lymphomas versus only 10 to 15% are T cell, non hodgkin lymphomas, the t-cell, non hodgkin K cell, non Hodgkin, I will say is quite an orphan entity because of the rarity of incidence of these malignancies. There is certainly a lot of research that's going on. And at this point in time, it can only be a pooled effort because in order to do clinical trials, we need to have good numbers, we want to make sure we make good um assessments in terms of data analysis and results. And that can only be based on a pooled collaborative effort, not just within one country but probably across countries in terms of B cell, non hodgkin lymphoma, which makes up for the majority of non-hodgkin lymphomas. Therefore, they divided into 45 different types, but primarily they are divided into three buckets. The first bucket is an aggressive B cell, non hodgkin lymphoma, aggressive lymphomas are typically patients who present with a lot of symptoms. They are never surprised to get that diagnosis. They're finally relieved to know why they have been feeling so crummy for so long. They usually have symptoms such as drenching, night, unintentional weight loss, lots of lumps and bumps of palpable adenopathy that they come with. Usually the first line of treatment is a combination of antibody called Rituxan plus chemotherapy. And chemotherapy is usually a concoction of four agents that we group together including predniSONE, aggressive lymphomas have a unique biology in a way that there is about at least 40% chance based on the type of aggressive lymphoma. You have, it can go up to 80% that it can be cured as a result. Whenever we design clinical trials, we want to make sure that we always enhance that cure. Now, the post child of aggressive lymphoma is diffuse large B cell lymphoma. I will say diffuse large B cell lymphoma. A lot has happened over the last decade with regards to biology assessment, with regards to understanding that not all D LBC LS are the same. There is now a molecular classification that subtypes it into five different subtypes because each triggers a different signaling pathway. And previously, about 40% of patients used to relapse after upfront chemotherapy. And there were not many options outside of a bone marrow transplant, but with a lot of clinical trial effort, now we have cellular therapies which can potentially cure 40% of those patients who have been previously, um you know, who would previously succumb to their disease. So, with regards to indolent lymphoma, which is the second bucket, indolent lymphoma is also called non aggressive lymphomas. And these are lymphomas that are very chronic, they kind of sneak in. Um, a lot of times patients are doing absolutely fine, they go for a normal blood check and the white count comes back at 60,000. And that's how they come to an oncologist's attention. With regards to non aggressive lymphomas. It's important to remember that don't break it till it's actually broken or about to be broken. That's the philosophy. So the philosophy of the care of care is very similar to somebody with chronic diseases like diabetes or rheumatoid arthritis that if lifestyle measurements or management can take care of it, then leave the patient alone. Just make sure you watch and wait. On the other hand, if patients may are having a symptom, if the blood work starts getting abnormal, then we need to start taking talking about treatments. The one thing about indolent lymphoma is that it's chronic. It's treatable treatments are very manageable and tolerated by patients. But there is a tendency that the treatments will put the patient in remission, but usually the patient will relapse and therefore, at least for now, at least for 2023. And we're making a lot of strides in research for now, I would say that this is a chronic incurable but treatable entity, then comes the third bucket which is mixed lymphomas. Um mixed lymphomas have features that have both um initially starting off as a slow growing lymphoma and then later taking up um picking up pa versus sometimes indolent lymphomas can convert to aggressive lymphomas. Those are called transformed lymphomas. First, a child for mixed lymphoma would be mantle cell lymphoma. So with that, in terms of assessing the subtypes going deeper into non-hodgkin lymphoma subtypes, what we see most in the United States is diffuse large cell lymphoma. So this makes up for the larger part of the pie. 30% of 80,000 patients with non hodgkin lymphoma have diffuse large cell lymphoma. Um followed by um chronic lymphocytic leukemia, followed by follicular lymphoma, followed by marginal zone lymphoma in the United States. We actually have only 12% of patients who have T and cell lymphoma and 2.5% of patients which have, who have Burkitt lymphoma. So that is important because if I was um treating somebody in Africa, maybe this would look different because in Africa there is a larger cohort of endemic Burkitt lymphoma. If I treated somebody in India, then I do know that TNK cell lymphomas are actually higher in India than it is in the United States. So I think based on the incidence, it also um helps us understand initially what we may be looking at in terms of clinical presentation, it can be very varied. So I will say that an indolent lymphoma setting, usually patients do not have any clinical symptoms. They're very surprised to get this diagnosis that they've been feeling so well. And how did they get a diagnosis of blood cancer? On the other hand, most of the times what they may come back with, whether it's aggressive or indolent is a palpable swelling. As you can see on this picture here, it's an enlarged lymph node associated or not. Sometimes with what we call bee symptoms. The bee symptoms are very specific. The fever has to be 100.4 or over. You cannot have just a low grade fever. It has to go on for at least a few weeks. Night sweats have to be drenching. You cannot have sweats that maybe a perimenopausal woman might get during the day and night. So the drenching night sweats are very characteristic. For lymphoma. Patients, patients are soaked in sweats at night. They're usually limited, only nocturnal sweats, typically, the pillowcases get wet, they are literally found in a pile of sweat. So that's so characteristic. And then the unintentional weight loss, you're not trying to lose weight, but still keep losing weight. And typically it's more than 10% over six months. Um in terms of the enlargement of spleen, that is something that we can see in patients. Typically in indolent lymphoma presentations like marginal zone lymphoma, sometimes CLL and usually the spleen enlarges. And that can cause early satiety fullness after meals. As a result, patients lose weight. Um external involvement can happen, for example, mantle cell lymphoma um has a predilection to involve the gut. So somebody might, you know, at age 50 goes for a routine colonoscopy, the colonoscopy resect a polyp during the procedure and that polyp comes back as mantle cell lymphoma. So it's an incidental finding, but that is one of the features or presentations of slow growing mantle cell lymphoma, elevated white count as we know can happen in patients with CLL. But it can also happen in other lymphomas in very aggressive diffuse large b cell lymphomas. Sometimes patients can present with a lymphocytosis. Um sometimes patients have a concurrent infection with a new diagnosis of lymphoma. So make sure you look at the differential in those case scenarios, neutrophils are typically elevated. Um and again, like I stated, indolent lymphoma presentations are a lot milder or to none as compared to somebody with aggressive lymphomas. I think if anything you take out from my topics today, in terms of the takeaway, I would say, make sure you have a good biopsy before you process the discussion with the patient about what this is, what the management should be. You know, sometimes, yes, I agree that we could be in dire circumstances that we just don't have the time and we just make do with small biopsies. But I do believe that there are ways to circumvent that by giving, say pre phase steroids to keep the disease stable while we get more biopsies. So, in terms of my spiel about the adequate biopsy is that fine needle aspirations are a complete no, no for a diagnosis of lymphoma. If fine needle aspiration is how a patient comes to you, it typically will tell you whether anything is clonal, meaning it looks like it's malignant. It'll typically stain for certain proteins called IC. I'll talk about it in a little bit, it'll give you maybe a little bit of a hint into what this lymphoma may be, but usually FNA S are useless. So they will tell you that you're dealing with the lymphoma, but usually that needs to be followed. I prefer excisional biopsies. So it's of course, a surgical biopsy where you take out a whole lymph node. But if it is in a region where patients may have to undergo undue surgical issues because of their age or other comorbid illnesses, they're not anesthesia candidates in those case scenarios I may do with the core biopsy and make sure that you at least get four good cores. Um because we need to do a lot more testing and you can see the reason for this is really the kind of cells we see under the microscope. So with final aspiration, we only see these cells, we know they are large, we know they are staining abnormally, but that's it With core biopsies, we look at the architecture definitely much better. But the final I would say is an excisional. Sometimes you can be dealing with a transform lymphoma where if I do do a core biopsy, I might just see the indolent lymphoma cells there. I might miss the of lymphoma cells. But again, between a core biopsy and excisional, I prefer excisional, but you don't want to do an excisional. If that lymph node is sitting on the aorta, you don't want to do an excisional if you know a good core is available. So again, adequate biopsy is key, do not stop therapies um outside of certain emergent cases without having a complete understanding of what you're dealing with. And the reason for that is because we do so many tests to make sure what lymphoma we are dealing with. So with regards to biopsies, um we talked about my preference, bone marrow biopsies are kind of going in the background. We don't do a lot of bone marrow biopsies anymore. We certainly do not do bone marrow biopsies for patients with aggressive B cell, non hodgkin lymphomas. If a pet is available, a pet actually upstages the disease. A pet can find bone involvement, marrow involvement much better. Sometimes a marrow may not actually do it. Um So we do not do bone marrow biopsies for aggressive large cell lymphomas outside of a few case scenarios. For example, if I have just one lymph node and it's a limited stage disease, but the patient has cytopenias. And then I don't know if the bone marrow is involved with another process. So I definitely say that bone marrow usage is going down including in patients with indolent lymphomas like follicular lymphoma. Uh because typically the management doesn't change um where it may make a difference is making sure that you truly are dealing with stage one and stage two lymphomas with regards to what I'm really looking at to make the diagnosis. I'm looking at assessing what the cells look like. Are they small? Are they diffused? Are they cleaved? Are they non cleaved? Because that gives me a hint as to what I'm looking at. Am I looking at a small cell lymphoma? Am I looking at a large cell lymphoma that's usually morphology. Then we talk about flow cytometry, flow cytometry and immuno histochemistry. This is part of something called immunophenotyping and these are basically fluorescent labeled flow panels that we do. And each of these basically we run the cells through it, the lymphoma cells have CD markers on it, cluster differentiation markers and each lymphoma stays stains differently on the flow. And then you typically do further testing by implementing immuno histochemistry which are basically enzymatic reaction based proteins that we stain for. Um And how does it help to make a diagnosis? For example, patients who have CLL, they are usually CD five positive CD 23 positive and they are CD 10 negative. They are CD 20 dim follicular lymphoma patients, they are CD 20 bright, they are CD 10 positive. They are CD five negative marginal zone. Lymphomas are typically CD 20 bright, but they are CD five and CD 23 and CD 10 negative. So these are basically the broad strokes but of course, immuno histochemistry, they can do certain additional staining to also rule out other things such as um EBV. So there is a stain for uber. Um there are certain malignancies that can be driven by EBV such as Hodgkin lymphoma, sometimes even some of the T cell and NK cell lymphomas. So we absolutely look for that. Then comes cytogenetics, fish karyotyping. This is where we are looking at chromosomal translocation. So there are certain chromosomal translocation that seal the deal with regards to diagnosis. Follicular lymphomas express a chromosomal translocation translocation 14 and 18 where chromosome 14 shares material with 18 and then that expresses an aberrant protein called BCL two. The same happens with mantle cell lymphoma with the translocation. 11 14 is what we look for. 11 14, basically expresses an aberrant protein called Cyclin D one, which is responsible for cell cycle dysregulation. And that plays a huge role in making mantle cell lymphoma happen. Um The molecular part of this is basically looking at certain molecular mutations. For example, we really are paying a lot more attention to something called TP 53. Um So TP 53 mutations typically make cancers more aggressive because they are chemo less chemo sensitive. And as a result, we need to think of better tools to manage those lymphomas. So let's talk about initial evaluation history and a complete physical examination. Absolutely is important even in the day and age of finer examination tools like pet scans. I think it's important to know your patient. It's important to know what the patient wants. What is the physical examination looking like? And I think here, I will say that for patients in the geriatric age group, um I will say it's important to start doing some of the geriatric assessments to understand that the patient is truly um not functioning well because the lymphoma is is gathering pace or just because of the comorbid conditions, the patient is truly frail at baseline because that will help us understand what therapy to give the patient. Um Lab evaluation will typically entail a complete blood count. A CBC with differential complete um comprehensive metabolic panel that includes a renal function a hepatic function. We typically do serum electrolytes, calcium, uric acid, calcium, uric acid comes in handy to make sure the patient is not auto tumo izing. It also comes in handy when therapy gets started. Because if a uric acid just suddenly shoots up after therapy gets started, then you know that the patient is tumor izing and you wanna make sure that they get treated appropriately. Bone marrow biopsy, we talked about it. It can absolutely be omitted. In certain lymphomas, I still tend to do it in indolent lymphomas. It helps me with um just understanding the extent of disease burden for that patient. Um But if the treatments have been started, then I typically don't get a post treatment, bone marrow biopsy for my indolent lymphoma patients unless I'm in a quandary in terms of response. Um with regards to radiographic studies, I think a lot has changed previously, they used to be just an x-ray and that's how patients were diagnosed. Typically hodgkin lymphoma patients were diagnosed based on chest x-rays and biopsies. Then came the era of CT scans, which of course are very good with regards to understanding the actual size and the morphology of a lymph node. But at the end of the day, it's really important to know how hot is your lymph node because that really helps me assess the site of biopsy. That helps me assess what I may be looking at. Usually indolent lymphomas like marginal zone lymphomas they are not as avid on a pet scan. When I say avid, it basically means black. Now on pet scan, there are certain areas that normally look black, your brain, your tonsillar area, the heart and the kidneys, typically the ureters as well as the bladder outside of that. Anything else is actually abnormal. So right here, you can see that there is an abnormal thoracic mass sitting here and that is what needs to be targeted for biopsy. The other utility of pet is that it upstages a CT scan finding. So usually CT scans are not that good for extraoral sites like the bone marrow or the skin and pets are excellent for that. I do get a lot of questions especially from um general practitioners about, hey, I know you're taking care of this patient with lymphoma. She just had a pet scan, but she's also due for her colonoscopy and her mammogram. Um Can those tests be avoided? And the answer is no, uh we cannot avoid a dedicated mammogram when it's needed, we cannot avoid a colonoscopy just because a patient has had pet. Um and therefore the annual surveillance studies need to be done. Of course, depending how the patient is doing during treatment. So with regards to recommendation, pet scan is absolutely considered gold standard and it is the routine scan for patients with all lymphomas, especially nodal lymphomas. Um It is not typically recommended for patients with CLL. It's not recommended for patients with marginal zone, lymphoma, plasmacytic lymphoma. But um in follicular lymphomas, because some of the follicular lymphoma, lymph nodes can be large and sometimes indolent lymphomas can present with a transformation. So, typically transform lymphoma sites are very hot on pet. Um So that way it helps you gauge which site you want to biopsy. Um Overall, I can say that the FDG avidity of lymphomas are high. If you're looking at Hodgkin's diffuse large cell lymphoma or rather any aggressive lymphoma, um mostly FDG avid are going to be your follicular and mantels. Therefore, we do use pets in them, but typically low FDG adity is going to be the indolent lymphomas like CLL SLL marginal zone lymphoma. The one thing I also want to say that I think that's a misnomer out in the community that CLL is different than SL CLL and SL are basically synonyms. It's chronic lymphocytic leukemia if the white count is elevated and the lymphocytes are clonal. Uh it's small lymphocytic lymphoma if the same subtype of lymphoma manifests in the lymph nodes, most of the times patients present with a white count and they eventually then develop lymph nodes. So typically we say it's CLL SLL L. Um So that's what it means. Um overall, I can say this is what it means to be hot on pet and not hot on pet or high avidity and variable avidity or low avidity. So, with hot skin with diffuse large B cell lymphoma. You can see that it's really black right here with follicular lymphoma, I typically see it to be moderately abd avid. And then with sl you can see that the patient has lymph nodes right here in his armpit, but they are not as jet black as we see with these lymph nodes right here. So this basically gives you a flavor of what pet looks like for individual subtypes of lymphomas. Then comes response assessment. For the longest time we use CT scans to know if the patient responded or if the patient did not respond to treatment. And as a result, we did well, but we ended up overtreating a lot of patients because end of treatment, ct every lymph node had to be under 1.5 centimeters to be called a complete response. As a result, there were lymph nodes out there that were at two centimeters, but the patient still got the designation of partial response. I think that went away when we started using pet scans because we were looking at the avidity if the avidity normalized to blood pool uptake in the mediastinum or to po uptake in the liver or no uptake at all that now became called the complete metabolic remission as a definition. And this is where we now have what we call, you know how we have the TNM classification for solid tumors just like that. We now have what we call the five point system. Dove Lugano classification for assessing how the patient is doing in between treatments and at the end of treatments for patients with lymphoma. So if somebody has 12 and three at interim or end of treatment pet, it's called a complete metabolic remission. If someone has a do four or do five at interim scan without any new lesions, that is called a partial response. If a patient has do four or five at the end of treatment, then that is called progression of disease or persistent disease. The one thing I will say anytime we worry that therapies have not worked, we are never going to just attribute it based on the do system on a pet scan. Therefore, biopsies are gold standard, not only at diagnosis, but they are also gold standard at relapse without doing a biopsy. Just moving forward with second line treatment is a huge disservice to patients because sometimes patients may finish treatment, they might go into a complete remission and there's one lymph node that remains there that may be shining bright. If you assume that to be lymphoma, the next line of treatment could be a bone marrow transplant sometimes or could be cellular therapies like car B cell therapy. It's very important to document that the patient has relapsed. I cannot tell you the number of times patients may have granulomatous reactions. People from developing countries especially can have granulomatous reactions. At the end of treatment. People from developing countries who may have been exposed to TB. You absolutely need to rule out O TB in them. So, moving forward, let's talk about staging. So we follow Ann Arbor staging for patients with um lymphoma. I will say that the stage does not matter actually for a prognosis discussion. It's not akin to somebody with um lung cancer where stage one is curable. Stage four is not, that does not apply to lymphomas for lymphomas. Whether something is curable or not actually depends on the biology of the disease. So, aggressive lymphomas are potentially curable, non aggressive lymphomas are treatable but they are not curable. They are more chronic entities. Staging is done only to understand where am I seeing lymph nodes and how much treatment do I need to give? Can I safely watch this patient? Even if patients have lymph nodes above and below the diaphragm, that would make it stage three. But if somebody has follicular lymphoma with very minimal tissue burden, then I'm going to watch that patient. On the other hand, if somebody has stage one, hodgkin lymphoma, which is an aggressive lymphoma versus stage three, hodgkin lymphoma, the therapies are radically different for stage one, it's only two cycles of chemo with radiation with stage three. It's usually six cycles of chemotherapy. So this is all that really helps me do when I do staging for patients with lymphoma. So I think for the audience here, it's very important that sometimes patients just stop hearing everything. The minute you say stage four and I will say 85% of patients with lymphoma are a stage four because it's a blood cancer, blood is everywhere. Um But I think you need to let them know that staging in lymphoma does not matter. Staging rarely comes in handy just to plan treatments. It does not really talk about prognosis. So with regards to modifiers, you may have seen in patients who may have lymphoma, their primary oncologist, say stage four BSX. That basically tells me at the outset what these patients may come with for. So for example, does the patient have a B have B, does the patient have an extra nodal site like a lung that also has lymphoma in it? Um Is the spleen involved. Uh X means bulky and typically based on which lymphoma you're looking at bulky could be more than 10 centimeters. That's usually the norm versus 7.5 sometimes for certain lymphomas. So what is the prognosis? What do we actually look at in order to tell patients, what is your prognosis? Um I will say we use something called the international Prognostic Index, also called IP. And that is consistent of um that is actually that consists of certain variables. And when you plug in those variables, it comes up with a scope. So for diffuse large cell lymphoma, we follow something called IPI IPI contains age over 60 poor performance status, elevated LDH presence of extranodal sites or what the stages. And that basically gives you a number and that number then helps you identify what is my prognosis. So, for diffuse large cell lymphoma, the IPI can go from anywhere from 0 to 5. If someone has an IPI of zero, that means it's a young, healthy, limited stage DL BCL patient probably has a cure rate of 80% versus if someone has an IP I of five, that means they are older, they are frailer, they have uh lab markers that are abnormal. They are um stage three, stage four patients. And I think it's important that those patients either get um you know, uh clinical trials or these are the patients that definitely need chemotherapy. But that's for aggressive lymphomas, indolent lymphoma patients. The prognosis basically helps me understand um how long can I typically keep the patient watch and wait vers versus when can I start treatment? What is the outcome once I start the patients on therapy? So this is a broad summary of the basic categories of lymphoma and what the therapies are in terms of the tools. So moving forward, when I talk about tools for treating lymphomas, these are usually the seven things I have in my toolkit um that I typically use. Um So for example, watchful waiting, you may have heard a lot of oncologists say watch and wait, sometimes they call it active surveillance. Sometimes they call it an expectant strategy. That means we are just going to watch the patient for now, the patient's lymphoma based on where it is what it is not doing to the patients. The patient is asymptomatic. The labs are completely normal, the tumors are not bulky, the patient is completely fine. And in those case scenarios, which usually only happen in indolent lymphomas. Watchful waiting is what I would do. Um, watchful waiting is never the answer for aggressive lymphoma patients. Um It would be negligence to do watchful waiting for aggressive lymphomas. So, indication to treat when patients are on watchful waiting um would indicate a decrease in blood counts um or abnormal labs. Uh B symptoms, um quick development of bulky lymph nodes over a short period of time. Um and symptoms that are suggestive of transformation. Uh So those symptoms are actually fairly stark. It would be a large lymph node coming up over a matter of a weeks, sudden elevated LDH. Um patients are just having a huge fatigue. Um you know, that has set in that is causing them to make them literally sleep all day long. So I think these are some of the stark presentations that you absolutely need to watch for also for patients who are on watchful waiting. So the second toolkit um that I have um in my box here for treating lymphomas is antibody treatments. So you all know that B cells that we all have, they produce antibodies and they fight off germs foreign antigens including cancer. So we can technically manipulate these antibodies and make them target on certain proteins that is expressed on lymphoma cell. For example, we have antibodies that target CD 20 that are expressed B cell lymphomas. The poster child for that would be riTUXimab. Uh There are of course other newer antibodies that are now targeting CD 19 like Tafa mab that you may have heard of. There is a novel CD 20 called obinutuzumab. Um And at the end of the day, these are absolutely important. They have changed the outcomes for patients with B cell lymphomas. A lot of I will say a lot of treatments for patients with B cell lymphomas have to incorporate CD 20 antibodies for aggressive lymphomas. We typically combine antibody plus chemotherapy and together it actually improves survival versus chemo alone. So the art chops that you may have heard for aggressive lymphomas, they stem from antibody plus. So antibodies typically immunotherapy plus chemotherapy, we go a notch higher here and then we talk about adcs, ADCS are antibody drug conjugates. So if an antibody can latch on to a lymphoma cell and target death, what if the antibody is attached to a linker? And that linker has a chemo to which can then be um injected into the lymphoma cell. So that is typically an antibody drug conjugate. And I will say that there are two antibody drug conjugates that have actually changed the outcomes in patients with aggressive lymphomas for example, with Hodgkin lymphoma, we now have something called brentuximab. It sits on a protein called CD 30 that is expressed on the Hodgkin's cell. And it then only delivers the toxin called M MA E to the Hodgkin's cell. And it induces targeted cell lysis. Typically, it spares the normal cells but sometimes you can have a bystander effect. So brentuximab can sometimes cause neuropathy because of that. Similarly, there is another antibody drug conjugate called Polo Zuma, which sits on a protein called CD 79 B. Um It, it really demonstrated great responses in patients who had relapsed, diffuse large B cell lymphoma. So there was a recent study that challenged a three decade old paradigm which is our trap versus pola A chip and polar chip one. So, in patients with high risk diffuse large B cell lymphomas that are stage three stage four pola A chip is now one of the new standards. Antibody treatments of course, are given to mostly all B cell lymphomas. Um Sometimes we use it for treatment, sometimes we use it for maintenance. Um Maintenance is a concept that we typically do for patients who have indolent lymphomas. You know, we talked about the fact that they go into remission but they have a tendency to relapse. And the bigger question is if they get into a remission with an antibody, can we maintain that remission? And with that in mind, antibody treatments like riTUXimab and Obinutuzumab can be given as maintenance for those low grade lymphomas chemotherapy that we typically offer is usually a chop bendamustine. Um But as you can see, most of these chemos are always with an antibody here, riTUXimab with hodgkin lymphoma. Previously, a BBD used to be the standard. But then with brentuximab uh that got incorporated and substituted the B now called A ad, it showed overall survival benefit in the world of oncology. If there is a clinical trial, that demonstrates overall survival benefit, it becomes the standard the next day. And based on the echelon, one study which compared ABVD to a ad A ad showed an overall survival benefit as a result. A ad is now the new standard of care for Hodgkin lymphoma. I talked about diffuse large B cell lymphoma. Let's move a step further and go beyond chemotherapy. So the big question is, can we target lymphomas from any other signal pathways? And we know that there are many, many signaling pathways that the lymphoma cell can actually activate. These are different switches that can be turned on and turned off. And one of the switch that we have looked at is something called the B cell receptor signaling pathway. So basically, there is a B cell receptor right here and whenever an antigen sits on it, it targets a multitude of signaling pathways. One of the signaling pathways is called BTK Lisse and Ibrutinib or Ibrutinib is a BTK inhibitor. Um Prior to 2014 chronic lymphocytic leukemia used to only be treated with chemotherapy and it used to have dismal outcomes. Most of the times. With the advent of Ibrutinib and the clinical trials that were done in CLL, it changed the face of CLL. Um in 2023 today, um nobody treats CLL with chemotherapy based agents. Everyone starts off with a BTK inhibitor or some newer agents. But basically these are chemo free signaling pathway inhibitors. They have unique side effects. For example, Ibrutinib is the first generation acalabrutinib. Zanabin neb is the second generation. They also target not just BT K but other receptors like ITK tec egfr. Sometimes it can cause diarrhea. But I think the take home here is that most of the times it can actually cause a Von Willebrand like effect on your platelets. So the platelets don't go down in number, but in quality they are dysfunctional. So remember anytime your patient is on Ibrutinib, a Zanni and needs a procedure, you absolutely need to ask those patients to reach out to their primary oncologist because drug holes need to be done prior to a procedure as simple as a cataract surgery to as major as in back surgery. Um There is also a risk of atrial fibrillation because one of the receptors sits on the heart muscle. And therefore there is an incidence of 15% with afib for Ibrutinib to 2% with Zana Bruni. So we're getting better with regards to mitigating toxicities. But that's just something you need to be aware of. Immunomodulators are another set of drugs that we use. They are chemo free and they basically make the immune milieu conducive for lymphoma kill and they do that by activating T cells NK cells and thus induce lymphoma. Uh cytotoxic lenalidomide is one of those immunomodulators. And we use a lot of lenalidomide in patients with follicular lymphoma marginal zone. Lymphoma BCL two inhibitors or um apoptotic cascade inhibitors basically are inhibitors that target the death cascade. So BCL two is a death cascade and typically um in patients who have CLL in patients who have other lymphomas, the BCL two gets upregulated. So basically, it is a signal which tells the patient not to, which tells the cancer cell not to die. So, by inhibiting that signal, you're basically inducing apoptosis and thus tumor cell kill. We talked about immunotherapy in the form of riTUXimab, but we would be remiss if we don't talk about some of the newer immunotherapy developments that are happened, especially over the last one decade. Um Of course, we can now uh we talked about how to manipulate your own immune cells. You can manipulate them by targeting uh drugs on proteins that are expressed on B cells or um you know, we talked about Polo Zuma like CD 79 directed cytotoxic or you can make your immune therapies function in such a way that you can make your T cells super active. So typically patient's lymphoma thrives because the T cell is unable to recognize lymphoma cell as foreign or it is, but it gets exhausted and it's just not able to mount a good response. So it's cellular therapy products. Um Then I'm going to talk about the, I think the first of this is an immune checkpoint inhibitor. So typically, whenever a foreign antigen sits, um it activates the T cell and after a point it basically gets hushed. Um So you have the right check on and the right check off in patients with lymphoma. For some reason, this becomes aberrant. And when it once it becomes aberrant, what you can do is typically target a protein on the T cell called PD one with an antibody called PD one inhibitor, which typically will not allow PD one to sit on PD L1, which is on the tumor as a result, the tumor cell will die. So basically, the binding will uh binding of PD one to PD L1, which happens when tumors are thriving, it inhibits the T cell activation that is needed for tumor kill. So typically, by getting antibodies that bind to P P one, it can also be designed to bind to PD L1. But PD ones, if you bind to them, this marriage is broken as a result, T cells get activated and thus you can have tumor kill. So this is a waterfall plot and anything that looks like this basically means the drug is effective. All the bars are down, which means patients are responding. And this is what we see with Nivolumab, which is a PD one inhibitor in patients with Hodgkin lymphoma. Um the most impressive significant advance of the decade has been chimeric antigen receptor T cell therapy and car T cell therapies have changed the face of how we take care of patients who have relapsed lymphomas to a point that we are bringing them ahead and ahead in the treatment paradigm. Now, what is scar T cell therapy? It's basically taking patients own T cells and manufacturing them in a lab setting with a vector derived genetic recombination method that expresses an antigen uh receptor called car in them, which now has the specificity to bind to the protein that's expressed on the lymphoma cell which that cell has forgotten to do. So a car looks like this. It has three domains. It has an antigen recognition domain that can recognize a protein on the lymphoma cell. It has a coste domain which basically makes sure that the T cell activation continues and the cars persist. And then there is a signaling pathway that induces T cell activation. So it basically is modifying your own T cells to make them super T cells or fighter T cells. So as to ward off lymphoma, but it's a logistically challenging process that entails first collection. Then lab manufacturing that takes about four weeks, followed by infusion of cars. Um It of course has changed how patients are managed with relapse refractory um lymphomas, these are the three constructs that are currently FDA approved and not just in the US, but it's also approved by other regulatory agencies in Europe as well as UK for patients with relapse refractory large cell lymphoma. You of course have to be mindful of car T cell therapy toxicities. These are unique toxicities because the idea is when I put the car product back into the patient, after the lab manufacturing these scars will unleash upon the tumor. And when that happens, it releases substances which are inflamed called cytokines, that's called cytokine release syndrome. Sometimes it can also penetrate through the blood brain barrier and cause neurotoxicity. Previously, they didn't know how to take care of these. Um We were one of the fewer centers to do some of the initial car T studies for these FDA approved agents. But as we have learned more, we now have excellent tools that can mitigate cytokine release syndromes that can tackle it much better. And there's a lot more understanding. So I will say that previously transplant eligibility was looked through the same lens as cart eligibility. That's not anymore. I cannot take an 80 year old to a, a bone marrow transplant, but I can take an 80 year old to a cart cell therapy, but it has to be at an academic center or a center that has had a well oiled machinery when it comes to logistics. Um because it takes a lot of resources to administer cart cell therapy. But it's magic. A patient with refractory diffuse large b cell lymphoma, nearly a 20 centimeter mass in his abdomen came to me nearly six years ago, got enrolled on a clinical study I had with Cart and then 30 days later, he had complete resolution of that tumor. He had previously been treated with seven lines of treatment. So clearly, the fact that the patient is still alive and kicking without any evidence of lymphoma is um amazing with this kind of cellular therapy products. These are basically the Kaplan Mayer curves of car T cell be highlighting that there is a potential for cure for patients who relapse with aggressively large cell lymphoma. About 40% of patients can now be cured with car T cell therapy who would have otherwise succumbed to their cancer. Um as a result of which previously car T cell therapy was poised to be something that would be offered if patients failed two lines of treatment of patients failed an autotransplant. So the next question to ask was, can you challenge it with an autotransplant? And the answer is yes, there were three clinical studies that were done in high risk diffuse large B cell lymphoma patients and they were all positive supporting car T cell therapy in the second line setting. Um by specific antibody treatments are basically these new antibodies that have two prongs. This is an off the shelf product. It does not require manufacturing. So it takes away that burden of waiting for the cells to get prepared. Um It has two prongs. One sits on the tumor antigen that you target the by specific antibody therapies that are currently approved are targeted against CD 20 on the lymphoma cell. And then the other prong sits on the CD three antigen on the T cell and it directs the T cell to kill the lymphoma cell. So it basically is doing what your body is supposed to do. But in patients with lymphoma, the TT cells are exhausted. So you need to retrain them. And there are many, many ways of retraining this. The next concept that is going to gain a lot of traction in the world of lymphomas is minimal residual disease assessment. Right now, we heavily depend on imaging studies to understand if the patient has relapsed, if the patient remains in a remission. But we do understand that we can find traces of lymphoma even before the disease actually manifests on imaging that's called molecular assessment of tumor. Um It may be called circulating tumor DNA CT DNA, circulating cell free DNA CF DNA. There's a lot of work that's going on and this is going to take a lot of momentum in the next five years where we are not going to wait for a relapse if CT DNA becomes after treatment finishes. We're probably going to give them some treatment to put them back into a molecular remission before they clinically relapse. So it's definitely an era where we are looking at personalized lymphoma therapy, everybody is not going to be treated the same way. Like we have previously done, it would potentially be another decade before we see this happening in real time. But there is a lot of effort that is happening. A lot of times people talk about scans and how much should we scan? Um I will say that a lot of times scans are useless. Once the patients get into a remission, I typically do one scan at the one year mark for an aggressive lymphoma patient in remission for patients with chronic lymphomas where I know that this can come back usually for the first two years, I may, I may do a scan every six months. But after that, it's a discussion between me and my patient. Um There's also significant scan anxiety called scanxiety and you need to be making sure that your patients are not really um you know, dealing with that um especially when they are in a remission. Um Typically the incidence of relapses for aggressive lymphomas goes down substantially after the 18 month mark. So be more mindful about doing scans. Um You have to be judicious, you just cannot be doing scans because there is a little bit of radiation that you do not want to expose the patients unless absolutely required. Um the utility of post therapy surveillance scan is really minimal. Uh Most of the times patients come to you with a palpable mass, most of the times the lab results are abnormal. Most of the times you detect it while physical examination is happening, just an imaging study detecting post therapy surveillance relapse is going to only be seen in patients 1.6% of the times. So it's really not a good tool to keep letting your patients go through CT after CT after they have achieved a remission, especially from an aggressive lymphoma. These are the four parameters that are needed. I would think in terms of saying, you know what you need a scan if you have symptoms, which are B symptoms, an abnormal physical exam, an LDH that's elevated, that you can't attribute to a recent infection that the patient is going through then get a scan. So overall, I can say that with regards to conclusion that the field is just rapidly evolving, the stock has changed at least two times over the last one year, let alone what has happened over the last one decade of giving these stocks. I do believe that we are going away and away from chemotherapy. We are implementing a lot of immunotherapy tools and I do believe that huge advances still remain at some point in time. Our lofty goal is to cure 100% of the patients that walk into the door with lymphoma and that can only be possible and achievable with clinical trials. Um Anything that we do that is approved came from clinical trials. So I believe it's really important to continue to figure out and target the achilles heel of these cancers. Um What the goal to make sure that everybody gets um highly effective therapy but not that the cost of increased toxicity. So with that, I come to the end of this talk and I'm happy to take questions. I hope it was informative. Thank you so much. Uh Professor Kadar, what a wonderful overview of lymphoma diagnosis and management. We've got a few questions and I'm going to start with um a question from SVA who is asking in the United Kingdom. I believe car T cell therapy costs surpasses the quality associated life year threshold of about 30,000 lbs. What are your thoughts on the high cost of these therapies? I think it's a great question that Shiva has posed. Economic toxicity is a real concern whether the insurers or the payers pay for it or whether the patient pays for it is a society that bears the cost of it. And I think that's why there are many clinical trials that are currently underway, looking at cheaper options of manufacturing cars. I have a clinical trial on campus that we are making our own homegrown cars and the cost of delivery is way less than half a million dollars that currently, the US is slated with, with regards to all the mark up et cetera. Um but in terms of the quality of life, in terms of the actual cost effectiveness analysis, if you were to look at some of the studies that have been done, the upfront costs are high. But in terms of understanding that these patients can be cured and thus do not need the downstream for the lines of treatment. It does negate the downstream costs. So eventually it does turn out to be cost effective. But at the end of the day, it's not sustainable. We need to make sure that we design better products that are less cheaper, that are less expensive. Sorry. Uh Got another question from Panna who's asking um are there any contraindications for Brentuximab and Poliza? And what is the timeline that we can use them for in for remission? Uh So I may have to dig deeper into what the second half of the question means. But in terms of contraindications for Brentuximab and Pola Tuum Mab, in my opinion, it's primarily neuropathy. So somebody who has a grade two or higher neuropathy, I would not use Brentuximab and Poliza. So by default, it does end up being patients who have significant neuropathy from their diabetes. Um So it definitely helps to keep the rest of the diseases well controlled. Um In terms of the next question that you have posed, what's the timeline that we can use them for remission. Um we typically do not use these agents when a patient is in a remission um outside of brentuximab after an autologous stem cell transplant. So if somebody did not receive upfront, brentuximab uh for hodgkin lymphoma relapsed, went through an auto. Um and if they relapsed uh within a year of initial chemo, we typically do do maintenance, brentuximab in remission. I hope I've answered that question. Perfect. Thank you. Um And a question from undress, we've got loads of questions coming in. We're going to try and feed as much as we can, but we are pretty much at time. So um I think we've got a time for maybe one or two more. But um what are the potential long term complications and health risks that lymphoma survivors might face post treatment? Um Excellent question. I think it depends on what you have given them up front. So if you are treating somebody with just an antibody treatment like riTUXimab, then riTUXimab, you just want to make sure sometimes it can cause hypogammaglobulinemia because it attacks the B cells. And as a result, if somebody is having a lot of sinus infections, upper respiratory tract infections, you don't want to keep the riTUXimab going. Uh you want to hold it, sometimes it can happen autoimmune side effect, like 25% can have neutropenia. So you want to monitor that. Um Sometimes you may want to support them with ivig if they have recurrent infections after finishing riTUXimab, riTUXimab is in your system for six months because that's the lifespan of a B cell. So make sure that just because they took riTUXimab and jam, they come to you today with um repetitive sinus infections. You don't want to disregard that as not being related to riTUXimab. It actually may be related to riTUXimab. However, if someone has received chemotherapy, usually, chemotherapies are DNA damaging agents. Anthracycline cyclophosphamide is what we use. And if we do use that, I think the long term effects are on the DNA. Um the older the patient, the long term effects may slightly be higher. So in our survivorship clinic, we typically want to make sure that these patients don't have any new cytopenias. If that to happen, that typically happens 5 to 10 years after the initial recip of chemotherapy, you want to make sure that they don't have any early myelodysplasia. They can be at about a 10% chance of developing that. The more chemo you give, the more risk there is. So, autotransplant is nothing but more chemo patients who are autotransplant survivors. You want to rule out myelodysplasia if they come up with cytopenias. 10 years later, uh age related surveillance scans are absolutely must for patients who have gone through chemotherapy with lymphomas. Um colon cancer, prostate cancer, breast cancer, skin cancer, um CLL patients, whether you treat them or not are at a risk of a higher um incidence of prostate skin colon breast and you want to make sure that you routinely screen them. And one last question, I'm really sorry if we didn't get to your question and you ask one, but we'll try to follow up as much as we can with some more information. But one last question which is from Tusa and he's really asking about the timing of referral. So if we see patients with suspected lymphoma, do they need emergency referral? Or you don't have any acute symptoms? Can they be seen routinely at their GP or family medicine practice? Um I think it's a great question. It depends on the clinical symptoms. So I will say typically what we see is somebody says, hey, doc, I have a new lymph node that popped up um just over the last one week and I'm beginning to have drenching night sweats. I think that patient deserves a referral within a week. Uh to be able to start investigating with biopsies and imaging studies. Someone comes to you in clinic, you do their routine annual examination. White count is 12,000 and there are clonal lymphocytes are the elevated, um lymphocyte count is elevated. Uh You have to send them to a primary oncologist, of course, but the referral can potentially be two weeks down the line. I don't think there is any scenario where you have to do a referral the same day outside of Burkitt lymphoma. Burkitt lymphoma is the fastest growing cancer known to man, the doubling time is less than 48 hours. So if you have someone who says, you know what I had this lymph node, it was like the size of a pea and today it is 12 centimeters in my armpit. That patient should probably head to the er and make sure that the patient gets diagnosed, evaluated, investigated very quickly. Super Professor Candar. Thank you so much for your time today. Thank you so much for sharing so wisely with us and, and sharing your experience and thank you to everyone for, for joining us. Um I think it's safe to say that that I think we've learned a lot and we're, we're really grateful for your time this evening. Thank you so much, Professor Candar. Thank you so much for all your patient listening and thank you for the opportunity to speak with your audience. Bye.