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Hello everybody. My name is Paolo Strati. I'm an associate professor in the department of lymphoma and meeloma at the University of Texas and the Anderson Cancer Center in Houston, Texas. One point that I would like to make as we start is that when it comes to uh managing by specific associated toxicities, the management actually starts even before we start treatment, though of course it will continue uh through toxicity recognition, grading, and management, and that's because we have to make a real effort to try to prevent as much as possible any toxicity with the use of biospecifics. So of course it's always key as we plan to start treatment to have baseline blood work so that we can subsequently better understand how clinically relevant are the changes that we will see during treatment. Uh, it is important for patients that we will consider to be high risk for by specific associated complications, mainly those who have high tumor burden. To be identified as early as possible because these are the patients where we may decide no matter what's the FDA label maybe to do inpatient hospitalization and monitoring and then when it comes to risk mitigation strategies, they tend to be part of the drug label per se and I'll show you later for specific by specific antibodies the way and the type of corticosteroids that we utilize for CRS mitigation. Or anti-CD20 monoclonal antibodies that we utilize for uh the same goal are different, uh, but again they're very well detailed in the drug label. Now with that said, once we start treatment, it's very important that we are familiar with the typical acute complications of bi-specifics in large basal lymphoma and follicular lymphoma, which are currently the only two histologies in which anti-CD3, CD20, bi-specifics are formally approved by the FDA. The first one is cytogen release syndrome or CRS, and I'll show you in a second, uh, how it will present clinically. And the second one is neurotoxicity, also known as immune affector cell associated neurotoxicity syndrome or IIS. I have to start by saying that we tend to extrapolate these terms from the CRT cell experience. And many times we made the incorrect assumption that the pathophysiology and grading and measurement is the same. But very recently, uh, a new grading and management system has been developed by Doctor Crombie and a large group of farm investigators. I encourage you all to actually read up, uh, this black publication from now, a couple of years ago. That's really been critical for particularly, uh, our colleagues in the community to be able to move the utilization of bi-specific safely from academia to community oncology. Now, the rate of CRS and neurotoxicity tends to be with bi-specific much different than what we experienced with CRT. There are currently 3 anti-CD3 CD20 bi-specifics approved by the FDA for either large-basal lymphoma and or follicular lymphoma, glofetumab just for large-basal lymphoma, musulitudinum just for follicular lymphoma. And a coriamab for both in the, uh, in Europe, Odronexamab is also available for Bal and Hodgkin lymphoma, but I will focus on the three currently approved by the FDA in the United States. The point that I want to make is that differently from CART, where particularly if you're using a CART cell product with the CD28 co-simulatory domain, the chance of neurotoxicity can be really high, 60% or above. Neurotoxicity or ICAs is not really the big problem when it comes to biospecifics. But it tends to be mainly CRS and CRS happens typically during cycle one. And as you will see later, this is really crucial, particularly for non-lymphoma specialized providers who will take care of these patients to know so that they can properly address this as compared to an infectious complication. It's also important to know the typical uh time to median onset of CRS based on the product that you utilize. And as you can see, uh, can be in the order of 12 hours when it comes to products such as clopiumab, uh, but Uh, close to 24 hours or longer when it comes to products such as the Coritama. So by then patients actually may have most likely have left the infusion center and may be back home. Neurotoxicity again, while present and possible by specifics is way less common. If you look into the three main products currently approved by the FDA in the United States, no more than 5 to 8% of patients will experience neurotoxicity, and it tends to be mainly low grade, grade 1 or 2. And once again, if it happens, it typically happens during cycle one. Now keeping that in mind, how does CRS present? The typical presentation is fever. That's actually the condisio sineconon, the necessary factor for the definition of CRS. Now that can be a major compounding factor because these patients are typically patients who have been treated before with something else that have a hematological malignancy such as lymphoma. So every time they spike a fever, while we can make the assumption, particularly during cycle one and particularly within 12 to 24 hours after by specific infusion or injection that it could be a CRS, we have to keep in mind that these patients are immunocompromised. So we have to keep our differential as wide as possible and also consider infectious complications. Now when it comes to grading, this will be a low grade, grade one, if it's just fever, typically with a temperature of 100.4 or if you think in Celsius 38, as long as no hypotension and no hypoxemia are associated. But as soon as any of these additional changes in vital signs are observed, based on the depth of intervention that they require, it could be just hydration, but as, uh, severe as vasopressor utilization for hypotension and as simple as nasal cannula or as severe as ventilation for hypoxemia, the grading will go up. Now, that's where the key difference between CRS from biospecifics and CRS from CRT comes into place and where we really need to go beyond the misconception that these two have a similar pathophysiology and or management because they don't. So when it comes to CRS, about 90% of patients can actually manage over the phone at home. And less than 10% truly required to come to the hospital for uh more intensive management. And the reason is mainly that again this is tends to be mainly just fever and so most of the times we're able to tell patients to take at home Tylenol and then if the fever comes back within 8 hours they can use dexamethasone 10 mg once. And not if the fever either doesn't respond to Tylenol and or dexamethasone, or if it occurs too early within 6 to 8 hours on dexamethasone, that's a sign that even if it's just fever, they may require something more such as tosilidzumab, which is a monoclonal antibody target interleukin 6, which is one of the key mediators of CRS both for by specifics and CRT and cannot be given at home. So that of course it's a a scenario where grade 1 CRS patients will need to come to the hospital. But about 90% of patients are able to stay at home just by taking Tylenol and or dexamethasone. If, of course, when they call in addition to fever, they also have hypoxemia or hypotension and or symptoms suggestive of one of those, most of the times it's not actually safe to manage them over the phone and they do need to come to the hospital because again, tocilium might be required in addition to potentially higher doses of corticosteroids and given by me. So this brings to my first polling question. Sue calls the practice 12 hours after step up dosing with a temperature of 101 °F of more than 38 °C and new dizziness. So every time a patient reports dizziness, of course this could be a sign of associated hypoxemia and or hypotension. She's the artist lady very properly, I think, because even if we're missing the other vital signs because she may have a, a CRS grade higher than one, in, uh, through the established pathway on assessment, uh, she develops hypotension, the response to IV fluids without the need for vasopressors or supplemental oxygen requirements. How should this presentation be classified and managed? Is this grade 1 CRS? And so we just provide symptomatic treatment and continue close outpatient observation. Is this grade 2 CRS? So we initiate management according to the established CRS pathway and monitor closely for progression of CRS to a higher grade. Or is this grade 3 CRS and we need to escalate right away to ICU level care with basopressors and or advanced oxygen support. Now what, what you learn from the, from the polling question and from the prior slides is um fever alone could be a grade 1. If combined with low level hypotension or hypoxemia, so requiring just hydration or nasal cannula would be grade 2. If requiring more than that, such as vasopressors, ventilation, or uh higher intensity oxygen support would be in grade 3 or 4. So what is really crucial, every time a patient with fever presents to uh our attention during the set of dosing, so during cycle one, of course, is to collect a very thorough review system, to perform a very thorough physical examination.