What are the side effects of CAR T-cell therapy? For patients receiving CAR T-cell therapy, we normally expect two major side effects for which we monitor them very closely. The biggest one which we are always concerned about is this massive inflammatory response in the body called cytokine release syndrome, which we call as CRS. CRS comprises of the patient developing fever, low blood pressure, elevated heart rate, and generally feeling unwell. The key to treating CRS is early identification because if we do not identify it early, the patient can go into what we call hemodynamic instability and they could get worse and worse. The treatment for CRS is usually giving an early administration of steroids and a monoclonal antibody called tocilizumab or another medication called anachyndra. These are very time sensitive medications which we have to institute at least within zero to two hours in which we identify CRS, which is why it's of paramount importance that we capture patients going into CRS as early as possible. That is the first and most important side effect that we can expect from CAR T-cell therapy. The second which we are always concerned about and we test patients on a daily basis is for the development of neurotoxicity. Neurotoxicity manifests in the form of losing the ability to identify people, losing the ability to count a little bit, like you take more time to count from one to ten than you would normally do. We ask you every day to write something in the paper and we see that sometimes the handwriting changes but these are changes that when treated again with steroids at the right time are reversible but it's crucial that we identify them as early as possible to give the treatment within two hours as early as possible. The long term effect of CAR T-cells are yet to be known, it's still being studied. However, we do see that patients who come back to clinic do take a longer time to recover their blood counts. So when those CAR T-cells go after the cancer cells, the way they do the tumor killing is mostly by releasing chemicals called cytokines. And cytokines can cause some systemic reactions and I like to discuss those in two separate headings. Patients would be feeling like a bad flu and often they start with fever, unrelenting at some times and if that continues patients can develop low blood pressure, low oxygen and if that is not promptly recognized or treated, patients can be very sick and may go to intensive care unit and requiring high dose of pressures to maintain the blood pressure and sometimes even they cannot breathe on their own. Thankfully, most of the patients, 70 to 80% of them develop the early stage mild reactions but if they progress, we have medicines available to counteract those cytokine storm. This is called cytokine release syndrome. We use Tocilizumab, which is an anti-intellucine 6 to counteract these cytokine release syndrome symptoms and if that is not sufficient, we often use early but prudent use of dexamethasone, which is a steroid and by doing this, most of the patients are controlled well. They do not usually go beyond grade 2 or grade 3 and many of the patients are able to be discharged from the hospital within 7 to 10 days. The other side of the cytokine would be affecting the brain, encephalopathy and often there are changes in the mental status. Sometimes there is increase in the pressure in the brain, patients could be forgetful and again it's very, very important for early recognition. So CAR-T patients are taken care by multidisciplinary specialists where we have neurologists see the patients, our nurses are certified to take care of the patients and monitor and in the earliest sign and symptom of encephalopathy, we institute therapy. If the patient does not have cytokine release, then we do not usually use Tocilizumab, dexamethasone is the only way to go but sometimes they have combined CRS as well as encephalopathy, then we use both Tocilizumab, anti IL-6 treatment as well as dexamethasone. And with that again majority of the patients resolve symptoms within 10 to 14 days and they are discharged and then monitored very, very closely within the first few weeks in the clinic and after day 30 when the symptoms abate, they can go back home and follow up with their community oncologists. So recognition early, taking care by a multispecialty group, having algorithm and SOPs available and CAR-T being done in an experienced center where they have done CAR-T both in clinical trials as well in commercial aspect is very, very important. It's an active area of research of mine is how best to counsel patients or caregivers about CAR-T therapy because the side effects are so new that patients don't understand them or haven't heard of them, let alone half of our doctors don't understand these side effects. There are three, used to be two, now they're kind of what I call the big three side effects that I tell my patients about after CAR-T therapy, CRS, ICANS and immunocompromised. So in plain English, CRS, a cytokine release syndrome, I think of that as mainly fevers, feeling sick, feeling crummy. We'll talk about why that is, but in brief it's your body is revved up very inflamed, almost like you have the flu, you don't, but all of a sudden your immune system is recognizing all these foreign myeloma cells and so that syndrome of inflammation that often causes fevers and more is called CRS. The second one is ICANS or neurotoxicity. I used to use the two terms synonymously. Neurotoxicity just means anything that's wrong with the nervous system, with how we think or how we move our arms and legs and so forth. ICANS is specifically referring to the term we use for neurotoxicity. Generally speaking with regards to a cephalopathy or confusion, I think it's worth noting that neurotoxicity after CAR T therapy isn't just about confusion or difficulty speaking. Also patients can have difficulty moving, again, certain muscles. For example, there have been cases of facial nerve palsy or unable to really move your mouth properly after CAR T therapy. They get better obviously over time. It's something to keep an eye out for. And the newest one, specifically with stiltocaptogen or stiltacell or carvicti, manifestation of neurotoxicity is this idea of these Parkinsonian type side effects that we're still learning more about where patients sometimes have difficulty moving, not because they can't move their arms or legs, but because they have difficulty with big muscle movements, similar symptoms of Parkinson's disease, difficulty writing in a normal font and not too small, those kinds of things, rigidity, difficulty really just getting a motion started. That could be neurotoxicity. So again, CRS, neurotoxicity or ICANN is number two. Number three is low immune system or immunocompromise. And that can manifest in two points. One is that patients after CAR T therapy can quantitatively have low numbers of immune cells, period. And we've noticed a lot of our patients, sometimes up to a third, can go a month or two when their immune system is quantitatively low. Sometimes and increasingly we're getting more comfortable giving growth factors to these patients. All of you who are leading this have probably heard of neupogen or something similar, filgrastem or growth stimulating factors that can help boost the immune system quantitatively. We used to be nervous about those. We're starting to use those more to help quantitatively help the immune system recover. And then qualitatively, even if the numbers look okay in terms of the absolute number of white blood cells, the cells might not be functioning as well as they need to be. And we've gotten more experience with understanding what that practically means. One part of the immune system, B cells, make antibodies that fight infections. Earlier I alluded to, for example, how recipients of CAR T therapy often for months or if not years may have difficulty mounting a response to vaccines or fighting common infections off. And that's because our B cell antibody immunity is lowered. The other word people may hear about that is low IgG. IgG is a synonym for the main type of antibody against everything that our body makes or hypergammaglobulinemia, which is a mouthful. But again, all the same principle that it's not that the number of cells is low, but basically the quality and their functioning is low and that the cells that need to make those antibodies that help fight off normal infections and help mount a response to vaccines are qualitatively not doing their job. And the numbers of antibodies are low as a result. So those are kind of the big three that I tell my patients about. And then we go through strategies to kind of figure out if it's happening one, figure out how bad is happening, if it's happening, and then manage it if it is occurring. Do you lose hair with CAR T cell therapy? So we use low much lower doses of chemotherapy. And although there is a chance of hair loss with these doses of chemotherapy, the majority of patients in my experience do not lose their hair. Certainly not completely. They may have some hair loss, but not significantly.