Over the past 10 years, the treatment landscape and prognosis for Chronic Lymphocytic Leukemia (CLL) has dramatically improved, even among older adults. In this video, Shazia Nakhoda, MD, Assistant Professor, Department of Hematology/Oncology, Fox Chase Cancer Center, discusses the latest best practices for diagnosing, treating and managing CLL, providing internists with a comprehensive overview of optimal therapies, cardiac risk and hypertension assessment, routine cancer screening and CDC vaccination guidelines and multidisciplinary, collaborative care.
Topics include:
Work up and diagnosis of unexplained persistent lymphocytosis
Current preferred latest treatments Venetoclax with Obinutuzumab and CLL prognosis
Multidisciplinary care to manage toxicity, recurrent infections, cytopenia, and secondary cancers
Guidance on CDC-recommended vaccinations and infection prevention
Hi, my name is Shahzinakota. I am an assistant professor in the Department of Hematology and oncology at Foxy's Cancer Center. I specialize in the management of lymphomas, particularly chronic lymphocytic leukemia. And today we're gonna talk about an internist, uh, guide to diagnosis and management of CLL. So the main objectives of this course are to review the workup of lymphocytosis and how we establish a diagnosis of CLL. We'll talk a little bit about the current treatment landscape as well as prognosis. And then we'll talk about how we can work together with interdisciplinary care to ensure these patients are well taken care of. And then finally, I'll talk about vaccinations and in infection prevention. So let's talk a little bit about the workup of lymphocytosis. So in a patient that you're seeing in clinic, the most important thing to evaluate first is the chronicity. So a patient has a new acute increase in their lymphocyte count, for example, They have normal lymphocytes, and now all of a sudden they have a new lymphocytosis. My first concern might be that they have a reactive process, such as an infection, for example. And in that scenario, I would simply repeat the CBC with a differential in a few weeks. On the other hand, if a patient has had progressive rise in their lymphocytosis, this is much more telling for a hematologic malignancy, most commonly being CLL. So the differential for an elevated lymphocyte count includes a viral or infectious issue, a hypersensitivity reaction. Smoking can often cause an increase in their lymphocyte and neutrophil count. Um, patients who've had their uh spleen removed oftentimes can have a lymphocyte elevation. And then, of course, autoimmune ideologies such as rheumatoid arthritis, um, malignancies, hyperthyroidism, and, uh, LGL lymphocytosis. So, in a patient that has progressive lymphocytosis that does not resolve on uh repeat blood testing, I do recommend those patients get a flow cytometry. It's actually very helpful when my internal medicine colleagues actually collect the flow cytometry before the patients even comes to me, because then I can guide them on whether this is a monoclonal or malignant process or pre-malignant process or more of a reactive process. And the way I recommend testing for this is through Lab Quest or LabCorp or Temple University also has an in-house lab that we use. And so that's a great thing that we can order for our patients depending on their insurance or where they're getting their labs drawn. I also recommend, recommend getting a CMP and an LDH. I'll screen these patients for hepatitis and HIV. And of course, if the patient is having recurrent infections, I'll often also get an IgG level. Now, on a flow cytometry, what we'll often see for a diagnosis of CLL is a very specific type of clonal B cell population. So typically they identify a CD5 positive, CD10 negative, these are often also CD23 positive. Um, and what we see is um uh. A percentage reported and in a patient who has um a cumulative number, so this is their um percent uh multiplied times the um absolute lymphocyte count of less than 5000, we consider that to be a monoclonal B cell lymphocytosis, which is considered a precursor to CLL. Um, and those with greater than 5000 can be diagnosed with CLL. Um, and as I mentioned, there's other, uh, B cell malignancies oftentimes that we can also see. So for example, a CD5 negative CD10 positive uh population, we worry more about follicular lymphoma, um, or large cell lymphomas for patients that have CD5 um negative CD10 negative clonal populations, we often worry about. Um, hairy cell leukemia or marginal's own lymphoma or um lymphoplasmocytic lymphoma or Waltramloinemia, and then finally, if a patient has CD5 positive CD10 negative with also a cyclin D1 mutation, overexpression, we worry about mantle cell lymphoma. So those can um often overlap, but it's important we distinguish between these. Um, so once the patient has a diagnosis of CLL based on their, uh, flow cytometry, I'll often do a physical exam to see if they have an enlarged spleen or enlarged lymph nodes. We don't have to get a bone marrow or a staging CT scan. for these patients unless there's a high clinical suspicion for bulky disease, because if a patient has adequate bone marrow function, for example, normal hemoglobin and platelet, a normal neutrophil count, we wouldn't necessarily recommend treatment in the absence of other symptoms. So next, let's talk about the current treatment landscape and the prognosis of CLL and SLL. So, the first treatment option is watch and wait. So, these are patients who are largely asymptomatic. We would recommend simply monitoring lab work and doing a physical exam. Typically when patients start to have worsening cytopenia, typically hemoglobin is less than 10, platelets counts less than 100 that continue to decline, bulky lymphadenopathy or splenomegaly, I think of patients who have worsening weight loss, early satiety, or bloating, or left upper quadrant pain. That's a great reason to start therapy. Patients with pleural effusions or other extranodal disease involvement also warrant therapy, and then of course, progressive constitutional symptoms. I like to rule. Out a transformation to a more aggressive lymphoma in patients who have unintended weight loss, major fatigue that's impairing their activities of daily living, or fevers and night sweats. And if it's confirmed to be truly driven by their CLL, that's another reason to start therapy. So one challenge with uh watching and waiting is that it can be uh difficult for patients from a psych. Psychosocial standpoint, especially when they feel like their disease is just progressing and they're not doing something about it. So oftentimes I'll counsel patients that empirically treating patients may cause more side effects related to the treatments and little benefit to the patient. And of course we don't want to create resistance mutations before the patient needs therapy. So I often try and discuss it with the patient and give as much psychosocial support as possible when we are going this route with therapy. Um, supportive measures when patients are on watching weight, of course, are routine vaccinations, um, annual skin exams because there is an increased risk for melanoma and non-melanoma skin cancers, and of course, um, optimizing their cardiovascular risk factors in case they need treatment. The future. The frontline therapy for patients with CLL are either um a covalent inhibitor such as acaibrinib and Xanrutinib, which targets the brinyrosinerosine kinase, or obittuzumabatoclax, which I'll talk about in the next slide. Acallibrinib and Xanrutinib is a continuous therapy patients will take until disease progression or intolerable side effects for the vast majority of people who tolerate these drugs, we can get 6 to 10 years of disease control, maybe even more. Um, and the perk of this therapy is it's completely oral. Patients do not have to come back and forth to the infusion room. The downside is patients need to stay on these therapies because they don't induce very deep responses initially. Really, what happens is these therapies provide long disease control. We often see a rise in their lymphocyte count when they first start because this class of drug actually pushes the lymphocytes outside of the lymph nodes into the circulating bloodstream where they slowly die off and therefore, And an initial rise in their lymphocyte count is not worrisome to us, and for the vast majority of patients, after a few months, their lymphocyte count completely normalizes or significantly decreases. The major side effect of this class of drugs is hypertension, atrial fibrillation, ventricular arrhythmias. Bleeding and bruising. So I recommend these patients really tell their other doctors and, and surgical team proceduralists that they would need to hold their therapies around a surgery that has increased bleeding risk. Arthrologists and myalgia, diarrhea, fatigue can be annoying side effects for patients. Um, and oftentimes we manage this by simply holding the therapy, trying a course of steroids, or switching between the agents. So for example, switching from a calnip to Xanbrot nib or rub calurnip is often very effective. If those adjustments aren't enough. Um, and of course, cytopenia is an infection risk is a major side effect. So if patients are having infections, I'll often check an IgG level to make sure they don't need IVIG infusions. So one of the other preferred treatment options for CLL is Venetoclax and obintuzumab. This is a particularly enticing regimen for patients because it's a fixed duration of therapy for 1 year in the frontline setting or 2 years in the second line setting and beyond. A lot of patients really value time off therapy, which is why they may select this treatment. The downside is it does require time in the infusion room. Uh, for the first cycle, it's every week for the 1st 3 weeks, and then monthly for 6 months. And the time the infusion room can be long, up to 10 hours. The Venetoclax is a well tolerated therapy as well, but because of the high risk of tumor lysis syndrome, the medication is given as a slow ramp up over 5 weeks, and for some patients this can be cumbersome because they need extra lab monitoring, occasionally IV hydration, and occasionally hospital admission for monitoring of tumor lysis syndrome. The downside, of course, is infusion reactions related to the bentuzumab. Um, this can cause hypogayglobu anemia and other infection risk. And of course, tumor lysis syndrome is something that can be life-threatening in certain patients, so we monitor this very closely. But overall, this is a generally well tolerated therapy as well. Now, I really want to stress that really we no longer use chemo immunotherapy for the very vast majority of patients. In fact, um, some pretty good data, even long-term follow-up data shows that those intensive chemo immunotherapies that we had previously used um over a decade ago have much higher risk of infections, secondary cancer risks like leukemia, and they actually have less favorable survival outcomes, especially for those with the high risk genetic features. And therefore, our preference is really to use those BTK inhibitors or veneta lax and Ovituzumab. We just got approval on the NCCN guidelines for a new regimen where we combine acairutiib and venetalax. So combining just the oral, um, acairuinib and then the venetalax component, which is the oral therapy with Vanetta loxovituzumab, um, which is very exciting to have an all oral fixed duration therapy for patients. We also have CART recently approved for patients with multiple relafractory disease, and of course enrollment in clinical trials is so, so important for these patients because we are developing safer, more tolerable therapies for these patients and more effective therapies in multiple relapsefactory disease, and the only way we're going to be able to get these drugs approved is by studying them in clinical trials. So it's very important we have our patients referred for this evaluation. Um, and of course I think partnering with our multidisciplinary team is so crucial for patients with CLL. CLL is a diagnosis of older adults. In fact, most patients, most patients are not diagnosed till their 70s. Many patients start treatment in their 80s, so these are patients who often have multiple medical comorbidities. Um, one complication that we often see are immune-mediated cytopenia, so this could be autoimmune hemolytic anemia, immune thrombocytopenia, and the treatment for this is typically steroids, rituximab um and IVIG. We oftentimes do need to start treatment for these patients with CLL-directed therapies like the BTK inhibitors or benetalaxinobintuzumab if their autoimmune cytopeniaas are refractory to these initial therapies. Secondary cancers are a risk, which I talked about before, the importance of dermatologic screening. And of course, um, the patients who develop Richter's transformation can often be quite aggressively presenting with fevers, chills, night sweats, bulky lymph nodes, and so it's very important that the patient get referred back uh for us to immediately get a PET scan and rule out Richter's transformation, which is where it turns into large cell lymphoma, or rarely Hodgkin's lymphoma. So I recommend my patients definitely get evaluated for whether their low blood counts are being driven more by an autoimmune issue or a CLL bone marrow suppression issue, and oftentimes the tiebreaker can be determined by a bone marrow biopsy for us to get a better sense of where the count destruction is happening. Other complications that we often see are infectious complications, and this can be in patients who are on treatment or haven't received treatment yet, but oftentimes a complication of a bentuzumab um and other anti-CD20 monoclonal antibodies is um reduction in their immunoglobulins, especially IGG. Uh, for which reason patients may develop frequent infections. So I do recommend, um, screening for their frequency of infections if they're needing antibiotics every couple of months. It's a great reason to start IVIG. Typically, if their IgG levels are less than 50 to 600, we do this standardly at every 4 week interval, but every now and then, patients may need adjustment of their uh frequency of infusion. And then of course, vaccination is so so important, so we'll talk about that in a couple slides. Um, last but not least, um, the, the treatment-related complications are really, really important to manage. So, of course, optimizing cardio risk factors to reduce that risk of atrial fibrillation and uncontrolled hypertension. Um, every now and then we may need to give a patient uh blood transfusions or growth factor if they have significant uh neutropenia, anemia, or thrombocytopenia. We can often manage some of those annoying side effects with BTK inhibitors, uh, such as diarrhea, myalgia. arthrologist with dose reductions, a course of steroids, um, oftentimes switching between the covalent BTK inhibitors, such as switching from Xanruib to a calibrinib or a calibrid to Xanaruinib, for example, that often does the trick for most of the patients. And then of course for patients who are getting Venetoclaxinobenntuzumab, we recommend close monitoring for tumor lysis syndrome. So we'll start them on allopurinol and ensure that their labs are being closely monitored. And of course, bleeding and bruising risk is something I really stress my patients uh help uh share that they are on these BTK inhibitors with all of their doctors so that we have more checks and balances to ensure these medications get held around surgery. Now, I really rely on my primary care colleagues to help me manage these patients for their cardiovascular risk factors, routine vaccinations, and of course making sure any medications that they may be starting between my appointments um are checked with their CLL directed therapies. Um, and of course, uh, a patient may be admitted, um, especially in the hospital with new drop in blood counts, recurrent infections, um, or new progressive symptoms, which definitely warrant collaboration with our, um, oncology team here to ensure that patients manage effectively inpatient. Now, let's talk last but not least about vaccinations. I think this is a really important part of CLL management, um, because oftentimes these patients do not appear to have major um immune dysfunction. For example, they may have normal neutrophil count. And I, you know, we don't typically check IgG levels in the clinic, um, unless the patient is having major infection issues. So I do tell patients that CLL is such a heterogeneous, such a heterogeneous disease that we oftentimes can't tell a patient exactly what their immune status is, um, for example. For patients who have had multiple relapse refactory disease on several lines of therapy are going to have a perhaps more um impact in immune system than those who've never needed treatment and have very low burden disease. But I do recommend really a generic um vaccination guide for these patients. I recommend all patients get all um. Inactive vaccines, so annual flu shot, COVID-19 vaccinations, and the RSV shot if they meet criteria for that. Also, I recommend the pneumonia, shingles, T, HPV and HPV vaccines for these patients. And then I tell patients to avoid any live vaccines. Um, so the MMR varicella, yellow fever, and the intranasal flu vaccine are not recommended for patients. I've actually seen patients who get these live vaccines and have um quite extensive adenopathy as a response to this, um, and that's really not an uncommon event. So the key points I would like my colleagues in internal medicine to take away from this presentation is the importance of working up lymphocytosis. It's a very big help when patients already have a flow cytometry collected to evaluate for a. Clonal B cell population, because when they come to see me as a referral, I can already advise them on what to do based on a monoclonal process, which is typically a cancer or pre-cancer process versus a polyclonal process, which is typically more of a reactive, supportive type of of follow-up. Um, as I mentioned, routine imaging and bone marrow was not necessarily needed right away. And for many patients, they can go, um, their entire treatment course without needing a bone marrow if their disease course is uh quite well managed and, and we have a good sense of their disease burden. The treatment landscape and prognosis has drastically changed. We no longer use chemotherapy in almost every patient. We are either offering targeted agents, combination therapies, and even our older patients, even our patients with more unfavorable risk factors, tend to do quite well. Um, the important thing that I really encourage my patients to do when working with their other providers is making sure they get their cardiovascular risk factors under control. They keep up with routine cancer screening and vaccinations. As many patients with CL have a completely normal life expectancy, cancer screening for, uh, with colonoscopies, mammograms, prostate cancer, for example, are all equally important, as if someone who did not have CLL for the vast majority of patients. Um, and then, of course, uh, screening for infections, cytopenia, and progressive lymph node, um, enlargement or constitutional symptoms is something that we can always collaborate, especially in patients who are perhaps seeing their local, uh, primary care doctor or their local oncology team more frequently, um, so we can work together to ensure um prompt treatment if that's needed. Please. Contact me anytime, uh, for any of your patients. If there's questions, I'm always available. Our CLL program at Fox Chase Cancer is led by myself, Doctor Marcus Mesmer, and Zachary Frosh, um, and we're always available for you. So thank you so much for taking the time to tune in for this, uh, this presentation, and I hope to hear from you soon. Thanks.
