CAR T-Cell Therapy in CLL, DLBCL, FL, and MCL: Current Evidence and Guidance to Support Optimal Integration into Care

[00:07:37]

Introduction

Kelly Brandt (CCO): Hello, and thank you for joining us for this PCE live webinar in partnership with Clinical Care Options titled CAR T-Cell Therapy in CLL, DLBCL, FL, and MCL: Current Evidence and Guidance to Support Optimal Integration into Care. 

My name is Kelly Brandt.  And I am a Scientific Director with Clinical Care Options.  This program is provided by PACE in partnership with Practicing Clinicians Exchange and Clinical Care Options and supported by an educational grant from Bristol Myers Squibb. 

[00:08:05]

Program Chair

I am honored to introduce our faculty for today's program.  Our Program Chair, Beth Faiman, is a Nurse Practitioner at the Cleveland Clinic in Cleveland, Ohio. 

[00:08:17]

Faculty

Christopher D'Andrea is a Physician Associate at the Cleveland Clinic in Cleveland, Ohio.  And Lisa Nodzon is the Lead Nurse Practitioner at the Moffitt Cancer Center in Tampa, Florida. 

[00:08:29]

Disclosures

Their disclosures are listed here. 

[00:08:33]

Outcomes Analysis: What Did You Learn?   

Please note that we will be performing an assessment of this education with polling questions in this activity being asked twice, once before the content and then again later in the activity.  Your individual responses will not be identified and discussion of the correct answers will occur during this webinar. 

[00:08:50]

Polling and Questions

Before we get started, I would like to take a moment to review the features of our virtual player so that you may maximize your participation in today's webinar.  When a new polling or survey question pops up on your screen, please select your answer and then press submit.  Once the presenter moves on, the poll will close and you will no longer be able to answer it.  You may submit questions for our faculty by typing them in the Q&A on the bottom of the screen.  You may type in questions for our faculty at any time during the program and they will try to answer as many of your questions as possible during our panel discussion sessions. 

[00:09:21]

General Information

Also at the end of this program, please click the claim credit link in the resources at the bottom of your screen to evaluate this program and receive your credit.  If you experience any technical difficulty, please let us know via the Q&A button at the bottom of the console. 

Finally, downloadable slides are available on the PCE and CCO websites and can also be found within the resources tab. 

[00:09:40]

          Poll 1

Now let's start with a few quick polling questions.  How many people with lymphoma do you provide care for in a typical week? 

[00:09:55]

          Poll 2

Which best describes your practice setting? 

[00:10:13]

Understanding and Communicating Current Evidence for CAR T-Cell Therapy

It is now my pleasure to turn things over to faculty and Lisa will get us started with a few questions. 

Dr. Lisa Nodzon (Moffit Cancer Center): Hi.  Well, thank you everybody for joining us here tonight.  The first part of our talk will be on understanding and communicating current evidence for CAR T-cell therapy. 

[00:10:29]

Pretest 1

Pre-test question one.  What is the key difference between CAR T-cell therapy and bispecific antibody therapy? 

1. Bispecific antibodies do not cause cytokine release syndrome;
2. CAR T-cell therapies are typically administered only once;
3. Bispecific antibodies have reversal agents based on mechanism of action; and
4. CAR T-cell therapies are available off the shelf. 

[00:11:07]

          Pretest 2

Pre-test question two – sorry about that.  Pre-test question two.  Your 59-year-old fit patient with relapsed/refractory CLL harboring deletion 17p progressed on first-line acalabrutinib and is now progressing on second-line venetoclax with rituximab.  Which therapy would you recommend next? 

1. Axi-cel;
2. Brexa-cel;
3. Liso-cel; or
4. Tisa-cel. 

[00:11:54]

          Tumor Immunology: Overview

Okay.  So with that we will start.  A little bit of tumor immunology, a little background here with a simple cartoon.  As their name implies, we know that T-cells are part of the adaptive immune response, meaning they help orchestrate what we are seeing here on this simple cartoon. 

They direct the – the direct killing, if you will, of cells that are infected with pathogens.  Hence, that's the reason why they are the backbone of CAR T-cell therapy in that they are directing the cell kill of the tumor itself.  Very simplistically shown, we need three main active – three main parts for this to occur.  We need activation, we need differentiation, and we need expansion. 

So really basically what occurs is the tumor antigen is presented through the major histocompatibility complex of the dendritic cell, shown over here on the right.  This goes signaling through the T-cell receptor in concert with the CD28 for co-stimulation.  That will then turn the resting T-cell into an activated T-cell.  Once we have an activated T-cell, we can undergo differentiation just through the mediation with other chemical receptors and cytokines.  And then, of course, we want a T-cell clonal expansion. 

So as we can see here in this diagram, that is why T-cells are the backbone of CAR T-cell therapy. 

[00:13:12]

          Autologous CAR T-Cell Therapy: Underlying Principles  

When we talk about how to manufacture CAR T-cells, we recognize that they're really unique to each patient, meaning we have to collect the patient's white blood cells.  We have to isolate out the T-cells.  We will then engineer them into what's called a CAR gene or a construct.  This construct is shown over here where we've got a targeting element, in this case, the recognition of CD19, which is on the surface of the B-cells, or in the case of plasma cells, BCMA. 

The CAR construct also has to have other really important domains, the transmembrane domain, so it can span the surface of the cell, along with a co-stimulatory domain.  The CD28 helps allow for expansion of those CAR T-cells in vivo.  This contract is transfected into the patient's T-cells.  We then call them our T-cells. 

The T-cells are then expanded, then infused into the patient, and then we hope that they have their activity directing against here, for example, CD19 on the surface of B cells.  Of course, you can see a median manufacturing time is there for CAR T-cells, could be roughly on the order of 17 to 28 days.  That can vary from product to product.  It's really important that we're explaining that to our patients, that you don't get the cells overnight off the shelf, but rather they have to be manufactured, and there can be delays in that, and they obviously have to go through a quality improvement process. 

Having said that, of course, we know that we're dealing with patients that have refractory disease, and as such, while they're waiting for these cells to be manufactured, consideration has to be there for bridging therapy, or even before the whole process of leukophoresis, what about salvage therapy?  What can we give the patient really to preserve their functional status as well as stabilize the disease? 

One question we get sometimes is, well, what's the big difference between CAR T-cell therapy and bispecific antibody therapy?  CAR T-cell therapy is typically administered only once, whereas we know bispecific antibody therapy is something that the patient can get in succession.  It's given over the course of cycles for as long as the patient, you know, is tolerating or the patient is responding. 

And of course, another key difference is that CAR T is directed therapy against CD19, whereas the bispecific monoclonal antibodies have the two arms.  They're directing – you know, bringing those two cells into contact with each other, a T-cell and then that of the tumor cell. 

[00:15:34]

          What Are the Effects of Targeting CD19 by CAR T-Cell Therapy in B-Cell Malignancies? 

So a big question we typically get.  Well, what are the effects of targeting CD19 on the surface of B-cells?  There's going to be pros and cons, correct?  Pros, it's ubiquitous.  The CD19 is expressed in the early stage of the B-cell, so we can limit off-target effects.  But most importantly, by just targeting CD19, we have a lot of disease specificity for that target that we're going after, so very, very high fidelity there. 

Of course, cons, when we think about depleting the B-cell population or B-cell aplasia, this will lead to hypogammaglobulimia in a patient.  It can persist for weeks, months, if not years after CAR T-cell therapy, leading the patient open for infection risk.  So we have to consider, do we need any prophylactic antimicrobials?  IVIG might need to be on board?  Chris will talk about this a little later on in his presentation.  But really also loss of CD19, if we're going after just one target, does represent a cause for treatment failure. 

[00:16:34]

          Posttest 1

So now we'll do our post-test to see who’s – who's been listening.  What is the key difference between CAR T-cell therapy and bispecific antibody therapy? 

1. Bispecific antibodies do not cause cytokine release syndrome;
2. CAR T-cell therapies are typically administered only once;
3. Bispecific antibodies have reversal agents based on mechanism of action; and
4. CAR T-cell therapies are available off the shelf. 

So I'll give you a few seconds to answer that. 

[00:17:18]

          Posttest1: Rationale

Okay.  So here's the polling question.  So 78%, CAR T-cell therapies are typically administered only once, 78%.  And that is the correct answer.  Bispecific antibodies we know can cause CRS and bispecific antibodies do not have the reversal – do not have the reversal agents. 

So 78% got it correctly.  So good.  We've got an audience tonight that's nice and alert and ready for the rest of the presentation. 

[00:17:47]

Clinical Data and pipeline for CAR T-Cell Therapy in NHL 

So let's move into the clinical data, as well as the pipeline for what's to come with CAR T-cell therapy and not Hodgkin's lymphomas. 

[00:17:55]

          FDA-Approved CAR T-Cell Therapies in NHL        

Shown here are the four FDA approved CAR T products that are currently on the market.  You can see their indications here are for patients typically with refractory disease, right?  Indications are for patients that have received at least two lines of therapy, whether it be for the diffuse large B-cell, mantle cell, or follicular lymphoma. 

Two of the products are also approved for refractory or relapsed B-cell ALL.  We're not going to talk about ALL tonight, but just to point that out, we've got brexa-cel as well as tisa-cel.  Liso-cel has a very new indication, and that is for patients with relapsed or refractory CLL or SLL that have received at least two prior lines of treatment, including a BTK inhibitor, as well as a BCL2 inhibitor.  And that's important to note because with CLL and SLL, we don't treat those patients with chemoimmunotherapy as several lines of data and trials have shown. 

Chemoimmunotherapy is not effective in patients with CLL or SLL.  So we use the oral targeted therapy.  So for a patient to be refractory to BTKI or BCL2 inhibitor, venetoclax being the only one on the market, we term those patients to be double refractory.  And we'll talk about the TRANSCEND trial tonight leading to approval. 

[00:19:10]

          SCHOLAR-1: Outcomes with Conventional Therapy for Refractory DLBCL

So as you can see, the hunt is always on for more effective therapies for patients with refractory large cell lymphoma. 

SCHOLAR-1 was a very important pivotal study looking at a retrospective analysis between full data from two phase III trials, as well as two observational cohorts in patients that had received conventional treatment, meaning no CAR T for refractory disease or after first or second line therapy or relapse from post-transplant.  Here, refractoriness really was what defined their – their disease across the board. 

If we look at this patient population that was heavily pretreated and we look at what their responses were to our conventional regimens, what we see is very dismal responses, right?  If you look at the CR and the PR rates across the board, they're pretty low.  And the pooled analysis response rates only around 26% and CR rates of around 7% overall.  So again, dismal response for patients in the refractory settings.  So again, this – the search is on for more effective therapies for our patients. 

In this particular setting with salvage chemotherapy, median overall survival is only on the order of six months. 

[00:20:26]

          Pivotal Trials Leading to FDA Approval: NHL

An important study that was done – let me go back.

[00:20:32]

          ZUMA-1 vs SCHOLAR-1: Outcomes With Axicabtagene Ciloeucel vs SoC for Refractory DLBCL

An important study that was done by Dr. Neelapu and colleagues was looking at the comparative retrospective analysis between ZUMA-1 and SCHOLAR-1, looking at the outcomes of these patients over a two-year period using axi-cel versus the standard of care for the refractory diffuse large B-cell lymphoma. 

A little bit of background on ZUMA-1.  This is with axi-cel.  These patients were heavily pretreated and followed for about a period of two years and saw really good overall response rates in this patient population of around 83% with CR rates of 53%.  So showing a very durable and efficacious response in patients with refractory disease, as we just talked about was the previous slide, and that was with SCHOLAR-1 looking at salvage chemotherapy in refractory disease. 

We can see here right off the bat with these Kaplan-Meier curves that we already have an improved overall survival with ZUMA-1, meaning patients in refractory setting that had received axi-cel as compared to the studies of SCHOLAR-1 that we just talked about. 

So much more durable response with patients receiving CAR-T in the refractory setting as compared to the salvage chemo. 

[00:21:41]

          Pivotal Trials Leading to FDA Approval: NHL

Of course, this then led to other trials looking at CAR T cell products shown here across the board in different phase II and phase I trials with different products.  We see good overall response rates as well as high CR rates in refractory patient population setting. 

The TRANSCEND trial all the way over there to your right with CL – for CLL 004.  That was liso-cel’s newest indication for patients with relapsed/refractory CLL or SLL.  And then highlighted there is really particularly what we're going to talk about tonight, and that's the double refractory subset, those patients that had failed both the BTK inhibitor and also venetoclax. 

Typically, those patients were deemed to go to transplant if eligible.  And of course, we know with median age of diagnosis for CLL, not all those patients are deemed to be eligible for – for transplant. 

So very important trials here to look at, and we'll talk about some of them in further detail tonight. 

[00:22:44]

          TRANSFORM: CAR T-cells (Lisocabtagene Maraleucel) vs SoC in High-Risk DLBCL

The TRANSFORM was also a very pivotable – pivotal phase III trial looking at liso-cel versus standard of care in high-risk diffuse large B-cell lymphoma patients.  Again, refractory disease being defined as refractory to either the front-line or relapsing within a year of front-line. 

These patients received standard of care with some salvage regimen and could go to go on to auto transplant if there was no response. 

The lymphodepletion, as we see, fludarabine and cyclophosphamide is there.  If we look at the data, if we compare liso-cel versus the standard of care for event-free survival as well as PFS and CR rates, we see a much more durable and efficacious response for those patients that receive liso-cel as compared to standard of care with really manageable grades of CRS as well as ICANS.  And then Chris will talk a little bit more about that in later subs – later slide set. 

But most importantly, the trial met its primary endpoint, that of event-free survival.  There was a recent update of this particular trial at ASCO this year, and one important point of the update was that there were no new safety signals with regard to CRS or in the neurotoxicity. 

[00:23:55]

          Phase III Trials of CAR T-Cells vs SoC: High-Risk DLBCL Refractory to or Relapsed Within 12 Mo of 1L Tx

Other phase three trials of CAR T-cells versus standard of care in the refractory large cell lymphoma population, shown here, ZUMA-7, TRANSFORM, as well as the BELINDA trial. 

We can see for the ZUMA-7, which used axi-cel and TRANSFORM, which used liso-cel, that these patients had a much more durable EFS as compared to those patients that received standard of care.  In the ZUMA-7 with axi-cel, the median being eight months versus standard of care at two months.  And in the TRANSFORM with liso-cel, median for event-free survival, 10 months versus only two months for the standard of care.  So again, beginning to see in a patient population that's very refractory, where chemoimmunotherapy is just not providing a very meaningful response, we're getting very durable – durable and efficacious response with CAR T-cell products. 

If you look at the BELINDA trial, you see those Kaplan-Meier curves are basically on top of each other, and this was with tisa-cel.  So the question, of course, was, well, why didn't the patients that received standard of care versus tisa-cel have any difference between those two arms? 

Well, one of the hypotheses that the authors had concluded was perhaps in the manufacturing time with tisa-cel was around 52 days, whereas for liso-cel or axi-cel, it's roughly on the order of 29 days. 

So as I mentioned earlier, when we think about manufacturing time for the CAR T product and you're dealing with a patient that's got refractory disease, we know the disease is not waiting for the manufacturing process.  So one thing that they concluded in the BELINDA trial is basically those two arms were kind of different in that the patients receiving tisa-cel, those patients have already begun to progress.  This does affect, obviously, their performance status as well. 

So again, thinking back to planning, which Beth will talk about in her upcoming slide set, the importance of planning when it comes to CAR T-cells with our patients based on where their disease is at and what you're thinking about with them for their later lines of therapy is really important. 

[00:26:00]

          ZUMA-2: Brexacabtagene Autoleucel (KTE-X19) for Relapsed/Refractory MCL

ZUMA-2 looked at patients with refractory mantle cell lymphoma.  This was a single-arm open-label phase II trial using brexa-cel in heavily pretreated mantle cell lymphoma patients receiving at least one to five prior lines, including a BTK inhibitor.  We have a really good overall response rate of 93%, with around 67% of those responding being complete responses.  So very efficacious, particularly for patients that are heavily pretreated. 

This translated into a PFS shown over there on that curve to the right, roughly on the order of around 23, 24 months, with very manageable toxicities of grade 3 CRS, as well as a neurotoxicity grade 3 or higher at 31%. 

And of course, tocilizumab used around 59% of those patients.  So again, showing efficacy of a CAR T product in refractory disease for mantle cell lymphoma. 

[00:26:55]

          TRANSCEND CLL 004 Update: Lisocabtagene Maraleucel in Relapsed/Refractory CLL/SLL

The TRANSCEND trial, as I mentioned earlier, this is the newest one, the newest indication for liso-cel for refractory CLL or SLL patients.  This is the first clinical trial looking at CD19 directed therapy in this refractory disease state.  It was a multi-center open-label phase I/II trial.  The dosing of the cells was based on the phase I trial, so the DL2 dosing.  Shown over there in the blue box is what was utilized and what we're going to be talking about. 

If you look on the left, those were the folks that entered into the clinical trial.  Again, high-risk patients, patients with complex karyotype, deletion 17p.  But most importantly, as I indicated earlier, these were patients that were also double refractory to a BTK inhibitor and also with venetoclax. 

For this trial, patients were enrolled.  They underwent leukophoresis.  During the liso-cel manufacturing period, bridging therapy was permitted.  Bridging therapy is what can buy the patient more time to get them over to hopefully halt and stabilize the disease and keep them with good performance status.  Once the eligibility was reconfirmed, they underwent lymphodepletion with a very typical regimen, fludarabine and cyclophosphamide.  Two to seven days after lymphodepletion, they received liso-cel. 

And primary endpoint that they were looking at in this particular study was CR or CRI, which is incomplete recovery per iwCLL criteria, as long as some key secondary endpoints of overall response rate, as well as what we call MRD rates or undetectable MRD rate in the blood.  MRD being defined as less than 10 to the minus fourth of clonal cells. 

[00:28:39]

          TRANSCEND CLL 004 Update: Efficacy at DL2

If we look at the efficacy with the DL2, as I just mentioned, that was the dose of the CAR T cells based on the phase I trial.  And if we just focus on the subset to the right, these were the double refractory patients.  These are the ones that we worry about the most, being that the mainstay of CLL therapy is either a BTK inhibitor or a venetoclax-based regimen. 

If we look at the CR or CRI rates for those patients, we see 20% of those patients achieved a complete remission.  44% of those patients also exhibited a response.  And the responses were pretty quick in that the median time to first response was around one month.  Of course, this data is really encouraging for this patient population in which we have no other treatment options really for them.  And really, mainstay has always been transplant if the patient is eligible.  And of course, all the ducks are in a row, and we know that's not really what we see in all of our patient population.  So longer time on follow-up and perhaps a larger patient population will begin to tell us in time if this response is really durable for this particular patient population.  So stay tuned on that. 

[00:29:45]

          TRANSCEND CLL 004 Update: Efficacy at DL2

If we look at other efficacy in terms of PFS and overall survival by best overall response off this trial, if we're looking at PFS or overall survival, obviously those patients that achieved a CR or a CRI fared the best for these two endpoints here as compared to the patients with a partial response or a nodal partial response. 

I'll point out here that when it comes to the iwCLL criteria for CLL responses with patients, it's based on two things.  So we have to think about the bone marrow and we have to think about the clinical, the imaging of the patient, the lymph node sizes.  CLL, SLL is a compartmental disease.  So that's something that we have to think about when we think about delivering of these CAR T products.  Can we penetrate into the spleen and can we penetrate into the lymph nodes when we think about response rates in patients with CLL or SLL? 

PFS by MRD status and the blood is shown over there on the far right.  We know that PFS is becoming a more important prognostic marker in our patients with CLL in that MRD negativity has been shown to do – has been shown to give patients a clinical benefit in terms of PFS.  So being MRD negative is better than obviously being MRD positive, but even MRD negative with a partial response is better than being MRD positive in a complete remission. 

So I know that sounds a little bit backwards, but it has to do with the sensitivity and can we actually detect circulating clonal cells.  So here we show for patients with undetectable MRD status in the peripheral blood had really enjoyed the longest PFS benefit as compared to those that were detectable with a dismal benefit roughly along the order of about three months. 

[00:31:33]

          Ongoing/Recent Clinical Trials in NHL

So as such thinking about patients with refractory disease and we know that chemotherapy doesn't really provide a meaningful response or even if they – these patients are relapsing within the first year of an auto transplant, further trials are underway looking at can we deliver CAR T perhaps in earlier lines of – earlier lines of the patient's treatment course?  The ZUMA-12 is looking at that with axi-cel in high-risk front-line large B cell lymphoma with overall response rates of 85%, CR rates of 74%. 

Because as we know with each subsequent line of therapy that we're giving our patients, we're deriving a less benefit and we know that PFS is becoming shorter, overall survival is becoming shorter and really, it's really just beating up our patients as they become – begin to become more frail for delivering a chemotherapy which is not really giving them much benefit in that salvage setting. 

[00:32:28]

          Fitting CAR T-Cell Therapy Into Current Treatment Paradigms in DLBCL

So where do we put CAR T with our current treatment paradigms for patients with diffuse large B cell lymphoma? 

Well, this is a simple diagram shown here for debate of course.  Initial chemotherapy can be given to a patient if their primary – if their primary refractory disease or they relapse within that short period of time.  Consideration could be there for CAR T-cell therapy.  Is it approved through the patient's insurance?  Can the patient meet the logistical criteria?  Beth will go through that later, or if the patient doesn't meet that giving them a salvage regimen.  If through that salvage regimen, we can get a CR or a PR, could the patient go on for an auto transplant and then at the time of relapse have consideration for CAR-T or if we don't have response for the salvage regimen go on to CAR T-cell therapy. 

So this is what clinical trials currently are looking at is can we move CAR-T up earlier in the treatment paradigm for our patients and derive perhaps a better benefit for them and not expose them to the toxicities. 

Key items to consider shown there over on your right as you can see that there are many.  With regards to referral, what regimen do we give the patient before leukophoresis to avoid T cell lymphopenia, can we get the disease burden low to have lower toxicities?  Is there CNS involvement?  When can we stop the prior therapy that they're on?  So a lot goes into the complex decision making when it comes to selecting of the patient for CAR T-cell therapy. 

[00:33:57]

          Posttest 2

So post-test question two.  Your 59-year-old fit patient with relapsed/refractory CLL with deletion 17p has progressed on first-line of acalabrutinib and is now progressing on second-line venetoclax with rituximab.  Which therapy would you recommend next? 

1. Axi-cel;
2. Brexa-cel;
3. Liso-cel; or
4. Tisa-cel. 

So go ahead and select your answers.  Perfect.  So correct.  The correct answer at 44% is liso-cel.  It's – it’s newest indication approved for patients with refractory CLL that's at least in two lines of therapy, but most importantly for those patients that are double refractory.  The other CAR T products are not approved for patients with CLL. 

[00:35:04]

          Posttest 2: Rationale

So again, that was the rationale that we just went over. 

[00:35:12]

Patient Factors and Education for CAR T-Cell in NHL

So what about factors that go into the education for CAR T-cell in our patients with non-Hodgkin's lymphoma? 

[00:35:18]

          Predictors of CAR T-Cell Response 

We can already begin to think that there's going to be a lot, right?  These patients in the refractory setting, they can be frail, they can have cytopenias, they can have high disease burden.  A lot of logistics will play into this.  So things that healthcare providers have to think about in terms of who would be eligible for CAR T, some of the items are the patient factors alone.  Do we have a low tumor burden?  Are pretreatment inflammatory markers low along with LDH?  These would be predictive of a patient's likely to have a good response. 

Obviously, medical comorbidities can certainly be exacerbated through the CAR T-cell process with just the chemo alone, from the disease itself.  How are these going to come to play?  So there's multidisciplinary management when we think about a patient going to CAR T. 

And what about a need to bridge the patient over?  If we're thinking about the manufacturing time, as we talked about earlier with what was hypothesized in the BELINDA trial, how long will it take to manufacture this CAR T product to actually deliver it to the patient as we know the disease is not going to wait? 

The T cells have a factor themselves.  What is their doubling time in vitro?  Do we have a higher CAR T-cell peak versus the tumor burden? 

And then there's the tumor biology itself.  Is there a high degree of tumor infiltrating lymphocytes?  Or do we have low tumor myeloid-derived stem cells?  So things that we have to think about when it comes to the patient factors is it's multi – it’s multifactorial, right?  And I think you're beginning to see that as we've gone through the slides tonight, but things that we, as healthcare providers, have to think about when we're educating our patients, if not other healthcare providers. 

[00:36:47]

          Key Patient and Disease Factors in Determining Candidacy for CAR T-Cell Therapy

Big indications as well when it comes to the patient is, does the insurance even approve their product?  Are we meeting FDA labels?  Some insurance companies might have preference for what's on their formulary based on another one.  So that's going to be an important consideration, the kinetics of the disease. 

As I mentioned, can the patient wait during that manufacturing time?  Or what do we have to consider for the salvage regimen to even get them to CAR T?  And then do we have to bridge them?  So that alone has to – that alone, we have to think about when it comes time for selection of the CAR T product itself, there could even be provider preference for the CAR-T product based on data for that patient and individualized to that patient's disease state. 

That immediate prior therapy matters because affecting T-cell lymphodepletion, can we even harvest cells from the patient based on that prior therapy as well? 

And then the concomitant immunosuppressive therapy, can we stop this prior to a patient's collection?  Because what's going to be important there is, are we going to cause any issues again with the harvesting or collection of those T-cells?  Active infection, we knew – we know in our patients with hematologic malignancies, infection is always of important consideration, but particularly in our heavily pre-treated patients. 

Infection is a big concern.  These patients might already have an infectious history of opportunistic infections.  So we have to have infectious disease involved in our patients, thinking about what do they need to be on prophylactically?  Is the infection that they're on currently controlled?  Can we safely proceed as well too, as we move through the process? 

And also the non-disease related comorbidities.  We know our patients typically, when they could come into this diagnosis, could be a median age of 50s or 60s, depending upon that disease state.  So how about the reserve organ function?  What do the kidneys look like, the cardiac, the pulmonary status?  These are all important considerations that, again, we really have to individualize for our patients when it comes to product selection. 

[00:38:53]

          Patient Eligibility for CAR T-Cell Therapy: General Criteria

So the way that we view our patients is really in terms of traffic lights.  There's green lights, there's yellow lights that give you caution, and there's red lights that say absolutely a no-go.  But when we think about things that make patients appropriate for CAR T-cell therapy shown here on this table, obviously life expectancy greater than six weeks, a good performance status.  We have to have adequate organ function.  The kidneys have to be good.  The liver has to be good. 

Can they tolerate the lympho-depleting chemo-immunotherapy that we're going to get to them, as well as the process in and of itself?  If we worry about the risk for CRS, is the patient too frail for that based on the organ dysfunction?  Any current active or serious infections?  But really also importantly, things that we have to think about when educating our patients, and Beth will touch on this, is what does the social support look like for our patients?  Can they make it to and fro from the clinic visits?  Do they have support at home?  Do they have someone to help take care of them, help feed them, help dress them, help look out for them with regard to their nutrition status and maybe any infectious signs the patient may be exhibiting or neurotoxicities? 

[00:40:00]

          Patient Eligibility for CAR T-Cell Therapy: General Criteria

Yellow flags, things that give us pause, where multidisciplinary management can really come to play here.  Sometimes these patients have to be presented at tumor board to kind of take a closer look at, are there any flags that may preclude them, such as pulmonary dysfunction, cardiac, transaminitis?  Do they have CNS disease?  Are the patients on immunosuppressive therapy?  Are they taking prednisone or an equivalent daily HIV? 

These are all things that we can certainly exacerbate as we put the patient through the CAR T process.  So it's really important that we have – we do a very thorough medical history with our patients as we go through this. 

And educating the patient.  I know – I know a lot of our patients that come to our center and they say, I'm here for CAR T.  It's kind of a quick – quick, timeout, timeout.  Where are we?  Where have you been?  And where we think are we going to be going with this?  So education is really important.  A lot of patients, you know, when they're seeing things on the news that they're getting cures with CAR T cell therapy and the success they've had with pediatrics doesn't always apply as we know to the adult population. 

Red flags, things that would deem the patient ineligible for CAR T and perhaps the need to look for alternative therapies, primary CNS disease, or the patient still requires greater than 10 milligrams of prednisone daily. 

[00:41:19]

          Patient Education: Salvage and Bridging Therapy

So other educations we have to talk about when we explain what is salvage versus bridging therapy.  Salvage therapy is what we give the patient to stabilize their disease.  What are we going to give the patient from the time that we say to them, let's consider CAR T and the time that they actually get to the referral center and get the consult and the – and the apheresis?  What can we give the patient?  So a lot's going to go into selection here.  What haven't they seen before?  What's their performance status?  Obviously hematologically, how are they holding up?  How much bone marrow suppression do we have? 

So I think that's a really important piece.  If you're beginning to think about a patient for your future for CAR T, what's coming down the rows, particularly we have to think about these patients very early on when it comes to sequencing of the therapies that we give them. 

Bridging therapy can be very complex as well in our patients, thinking about manufacturing time.  Is there something that we can give this patient while the CAR Ts are actually being manufactured?  And if so, what can we give the patient to stabilize their disease?  And if so, what about the functional reserve?  Can we maintain that during the manufacturing period?  You know, obviously there's nothing worse than sending a patient to CAR T and, you know, harvesting their cells and sending them off to – to be manufactured. 

But during this time period, the patient begins to progress, CNS relapse, or they become very bulky with their disease burden.  They're very symptomatic.  So things that'll start to up their red flag from being a green flag to a yellow, maybe to a red flag.  So these are things that have to go into the planning process with the patient.  It's important that the patient understand this along with their patient's primary support team to make sure that the patient knows when they can – when they have to be there, the importance of the appointments, and then what they should be doing in the meantime. 

You know, we don't want our patients out partying on a Friday night while they're waiting for a CAR T therapy, running their risk for infection, and – and other things to happen as well too.  So this is very complex when it comes to their bridging therapies, trying to choose something to stabilize that patient really during their manufacturing period. 

[00:43:25]

          Bridging Therapy Indications for CAR T-Cell Therapy in NHL

So what are the indications then?  When would we decide to give a patient bridging therapy?  Obviously for a patient that's having very bulky symptomatic disease, the kinetics of the disease is very aggressive.  It's growing very fast.  We're getting organ involvement or organ obstruction, or in fact, something is going on with the CAR T cell product – product itself.  Maybe it didn't pass quality assurance, and so it's going to take longer time. 

So anything that would delay a patient that would – that – anything that would really cause a delay in getting that product, bridging may need to be considered.  Obviously, it's going to be complex at this point, what regimen could we put the patient on?  We have to do consideration for what's going to be the least toxic to the patient to preserve their functional status. 

Some choices are shown over here to the left.  You can see really we're looking at monoclonal antibody therapy, if not looking at lenalidomide or BTKI or even venetoclax during this time period to kind of just palliate the patient over and control their disease status while maintaining good performance status. 

Regimen selection, we're going to base that on, well, what did they receive in the past?  How did they tolerate?  Are the kidneys as such that they're going to tolerate what we want to give them for bridging?  What about their cell counts?  Are they really pancytopenic?  But now we want to give them something like a BTK inhibitor, let's say.  BTK inhibitors can increase risk for bleeding.  So again, a lot of dynamics goes into this.  So again, a lot of education to the patient and their caregivers, Beth will go through, will come to play. 

It's not as easy as harvest my cells, put them in me and I'm going to do great based on this trial data that we're talking about. 

[00:45:06]

          Considerations for Selecting CAR T-Cell Products

So when it comes time for selecting CAR C – CAR T-cell products, how do we do it, if we have choices that are on the market? 

Sometimes this just comes down to what is the insurance approved for the patient so that we're on the FDA label.  CAR T is not cheap.  We need insurance to pay for this.  So that's obviously going to be one limitation for this as well.  What about antigen loss?  If we're directing these CAR T's against CD19, does the patient still have CD19?  We know these tumor cells are smart.  They can definitely lose their CD19 flag along the way. 

How urgent is the treatment?  When should we have referred the patient?  How long do we think it's going to take from the time that we're thinking about we want to give you this CAR T therapy?  Oh, this might take more time to manufacture versus this.  We have an insurance fold-off waiting on authorization.  So again, timing becomes really important when it comes to planning out the CAR T product the patient's going to receive.  And this typically goes through a process. 

And then the high risk for toxicity, what is the tumor burden looking like in this patient?  So what do we expect with regard to looking out for CRS as well as the neurotoxicities?  And then who's going to manage those comorbidities when we deliver the product?  Is the patient at a referral center that is certified to give CAR T?  What do we have on staff?  Do we have cardiology?  Do we have a nephrologist?  Do we have an infectious disease?  Who can help us manage this patient?  Do we have a good neurology team that can also come in to help us manage the patient for any comorbid issues that may be exacerbated or things that we definitely can cause while we're delivering CAR T? 

[00:46:48]

Panel Discussion and Audience Q&A

So with that, it's a lot of data I know all at once, but we can go into a panel discussion and answer some of the audience questions that you may have. 

Dr. Beth Faiman (Case Comprehensive Cancer Center): Absolutely.  Thank you so much, Lisa.  You did a great job.  I was just wondering – let's do one question.  And I think we have a case study that you wanted a case presentation set in this section.  Yes. 

[00:47:09]

          Case: 67-Yr-Old Man With Rai Stage 0 CLL

Dr. Nodzon: Yeah, we can go into the case study. 

Dr. Faiman: For the case presentation, and then we'll go to ours. 

Dr. Nodzon: Perfect.  So for our case study, we have a 67-year-old man, Rai Stage 0 CLL.  He was diagnosed in 2008.  He had intermediate risk, 13q by FISH, IGHV un – IGHV unmutated.  He had received prior lines of therapy, which is what we had back in the day before oral targeted agents.  He got fludarabine, cytoxan[?], and rituxan[?]. 

He then went on to a clinical trial with ofatumumab and lenalidomide for high-risk relapse/refractory CLL in the setting of a newly identified deletion 17p, which renders him chemorefractory.  He then progressed on that to receive ibrutinib, which is a BTK inhibitor.  He then developed resistance and went on to receive venetoclax. 

So again, a patient that we talked about earlier that's double refractory.  He went on to receive liso-cel.  In 2024, he had grade 3 CRS and grade 2 peripheral neuropathy, both of which were managed very effectively.  He achieved a complete response with undetectable MRD status in the bone marrow, so showing a very good durable PFS benefit. 

So when we see these patients now in our clinical practice in the outpatient setting, we have to be really cognizant of them, this – cognizant of what's going on with these patients, meaning the worry is not over.  This patient presented with low grade fevers, Tmax of around 100.  He had been having them off and on for a few weeks, along with some sweats, a nonproductive cough, and just generalized malaise. 

Obviously, at first glance, we're thinking, oh, high risk patient.  Is this a CLL patient that's perhaps now relapsed, a patient that's going on to Richter's transformation, just based on the fevers and the sweat?  So you can begin to see overlap with how relapsed disease might present.  But one thing we have to always be cognizant of in our patients once they go through CAR T is that B-cell aplasia that Chris will talk more about. 

So this particular gentleman, obviously, we have to rule out, in this case, relapsed disease, but also we have to do a very good infectious workup where we co-partner with infectious disease.  And we go back and take a look at what infections the patient may have experienced during CAR T.  Is the patient taking his prophylactic antimicrobials as prescribed that he should be on?  What are his contacts look like?  Has he been traveling?  And get that infectious workup done in this patient. 

IVIG becomes a mainstay for a lot of these patients as well, due to hypogammaglobulinemia to help prophylact them against serious infection risks as well. 

Dr. Faiman: Yeah, absolutely.  So this is a great case to illustrate all that you talked about, about the selection.  One of the questions we had, though, was how do you decide which product to give to patients with so many different options, right? 

Dr. Nodzon: Yeah.  So, so many different options.  So when I ask our – when I ask the physicians at work, well, why would you choose that one versus that one?  A lot of times the quick answer is always, well, that's what their insurance approved.  And we know we can get this product quicker than that product.  So there's some preference that's going to go on, maybe some bias that might go on there, or it's just the – the comfortability that that – that the CAR T – the physician has with that product and knowing that maybe there's going to be a less CRS with that product based on trial data or less neurotoxicity based on trial data. 

So there's different selective processes, but you're right.  We have products to choose from, but at the very top, we know it always starts with insurance and then it can come down to, can we individualize that if we do have product to choose from between like axi-cel or liso-cel for these patients? 

Dr. Faiman: Absolutely.  And Chris is going to go through a lot of the different details that kind of surround this case as well.  Chris, do you have anything to add, any thoughts about this case or any thoughts about Lisa's presentation before we go to our next slide, commitment to change? 

Dr. Christopher D'Andrea (Cleveland Clinic): First of all, great job, Lisa.  I think you – you covered a lot and did so in a lot of depth with – with tremendous organization and explanation.  So I – I think very, very well done. 

My initial read on this case is that this sounds – I mean, the current presentation with low grade fevers, night sweats, non-productive health and generalized malaise, that sounds to me more infectious.  I would kind of be leaning in that direction in this case because of the data Lisa showed showing that the patient did achieve a complete remission with undetectable MRD in the bone marrow.  So best of both worlds in this case. 

And despite the high risk features, it seems that those patients tend to do – to do very well.  And again, as I'll talk about in my – my portion, a number of patients are – who undergo CAR T therapy remain at – at risk for infectious diseases for long, even – even long after their CAR T has been – has been given.  So that's my initial thought on – on this particular case, given what Lisa presented. 

[00:52:05]

Reflection and Commitment to Practice Change 

Dr. Faiman: Absolutely.  And we're going to go over how we can protect our patients in the next section and what to look for.  I'm looking – let's do one more audience question.  How long from the time you see the transplant team to treatment?  So like the CAR T team.  And that's actually probably going to be answered more so in my section when I talk about coordination of care.  So stay tuned, that person who asked the question, I'm not going to say your name out loud unless you want me to call out your name, Anna[?]. 

We'll answer your question later.  So at this point, I'd like to go over just two slides.  This is our reflection and commitment to practice change section. 

[00:52:46]

          Poll 3

The first is just a poll.  Do you plan to make any changes to your clinical practice for lymphoma based on what you've learned today from this part of the program?  You can say yes, it's okay.  And the next one's going to be just a write-in question. 

[00:53:15]

          Poll 4

The write-in question is, please take a moment to enter one key change that you plan to make in your clinical practice for lymphoma based on this education?  And it can be short, like really short.  But you have 500 characters, so if you really want to get to the 500 characters, you can.  And we'll give you a moment, and then we're going to transition over to Chris D'Andrea, who's going to share with us some more clinical pearls about understanding and communicating safety evidence.  This is really great. 

Dr. D'Andrea: All right. 

Dr. Faiman: All right.  I think you're up, Chris. 

[00:54:01]

Understanding and Communicating Safety Evidence

Dr. D'Andrea: Sounds good.  Thank you very much, Beth and Lisa.  So again, I'm Chris D'Andrea.  I'm a Physician Assistant in Hematology Oncology at the Cleveland Clinic Taussing Cancer Center in Cleveland, Ohio.  And I will be talking about the toxicities and side effect profile when it comes to CAR T products. 

[00:54:17]

          Pretest 3

So we will begin with our pre-test question, pre-test question number three.  Which of the following statements is correct regarding potential toxicity of CAR T-cell therapy?  So one choice:

1. The occurrence of CRS or cytokine release syndrome is rare, but life-threatening;
2. When CRS does occur, it typically occurs after ICANS, ICANS being immune effector cell associated neurotoxicity;
3. Tocilizumab is essential for treating both CRS and ICANS; or
4. Continued risk of infectious disease and cytopenias should be considered in these patients even greater than one year after treatment. 

All right.  I presume you've made your selection. 

[00:55:14]

          Adverse Events, Toxicities, and Safety of CAR T-Cell Therapy  

Hey, good looking pre-test numbers.  All right.  We'll see.  Let's go into the – to the topic of adverse events, toxicities and safety of CAR T-cell therapy.  Here's a general overview of what I'm going to cover.  Again, we're going to cover what the most common adverse events related to CAR T-cell therapy, those being cytokine release syndrome or CRS, ICANS.  And we'll touch a little bit, it's not terribly common, but we'll talk a little bit about HLH or hemophagocytic lymphohistiocytosis and macrophage activation syndrome.  If you want to sound really smart, say that to your friends and family very quickly. 

We'll talk about the long-term adverse events such as cytopenias, B-cell aplasia, hypogammaglobulinemia and infectious diseases. 

Finally, I thought it pertinent to mention that the FDA did issue recently a black box warning of second – the risk of secondary malignancies post-CAR T.  So we'll – we’ll get into some of the data on that and sort – sort through it. 

[00:56:14]

          Cytokine-Release Syndrome  

Initially, beginning with cytokine-release syndrome.  This is the most common toxicity with CAR T-cell therapy.  It is a syndrome resulting from immune activation correlating with CAR T-cell expansion and elevations of serum inflammatory markers and cytokines.  So as I'm talking to that – to patients about the risk of CRS, I certainly don't go into the depths of different inflammatory markers and cytokines.  However, I tend to emphasize that this is a hyper-stimulation of this – this T-cell expansion and it's sort of causing your immune system to freak out. 

And so we – we know that this can present as a non-infectious flu-like syndrome that can show up as fever, malaise and myalgias.  But in more serious cases, it can certainly progress to life-threatening vasodilatory shock, capillary leak syndrome, hypoxia and – and multi-organ failure if not identified and – and managed appropriately. 

[00:57:13]

          CRS Grading: ASTCT Recommendations  

The American Society for Transplant and Cellular Therapy has created this grading system that I think is pretty universally accepted as how to grade cytokine release syndrome.  As you can see, starting on the left of the graphic, moving right, grade 1 is the presence of a fever, that being 38 degrees or greater Celsius or 100.4 degrees or greater Fahrenheit.  So just simply having a fever is grade 1 CRS in patients who are post-CAR T therapy. 

Grade 2 is the patient has a fever plus some evidence of either hypotension and/or hypoxia.  And to further define that, so I think hypotension, the true definition would be a systolic pressure of 90 with a diastolic over 60. 

I would say that in practice, it's probably looked at as a diet – excuse me, a systolic of 100 or – or less.  Or I think it's also relative to consider to the patient's baseline to see what was their – what are their history of blood sugar, or excuse me, blood pressures going into CAR T-cell therapy and then sort of looking at that change. 

I think that is just good practice as a clinician when you're trying to evaluate for these patients developing – developing CRS is to identify that delta change.  And as I said, hypoxia may be present and – and that could manifest as a patient basically requiring oxygen via a – a nasal cannula.  So either of those would then prompt a – a grading of two.  If the patient were to clinically worsen to where they would require a vasopressor to manage their hypotension or – and/or requiring some form of, let's say, positive airway pressure respiratory support, then that would be a grade 3. 

And then in worst cases, a grade 4 would include all of those requiring multiple pressors and possibly even things like intubation and mechanical ventilation for – for maintaining respiratory support. 

[00:59:13]

          ICANS: Immune Effector Cell-Associated Neurotoxicity Syndrome  

We'll touch on ICANS here.  So again, this is the immune effector cell-associated neurotoxicity syndrome.  And these manifestations can vary.  First off, you typically see some sort of waxing and waning of symptoms.  They may be quite mild at first, such as a minor headache, maybe some diminished attention or an inability to focus.  Patient seems a little disoriented or – or distracted. 

It can present as mild aphasia or even movement disorders.  And then in more severe cases, you might see focal neurological deficits, seizures, coma, intracranial hemorrhage, or – or cerebral edema.  We're going to get into the discussion on how to manage these – not only how to recognize them.  That's kind of the point of introducing you to the grading system and to some of these things, but then we'll get into kind of management and then even do a real life kind of case scenario that – that we have here.  

[01:00:10]

          ASTCT Guidelines for Grading of ICANS: ICE Score  

Again, just like CRS, the ICANS is graded.  So one of the ways that is done by – is by using this called the ICE score.  And the ICE score, as you can see, is sort of like a mini mental status exam where you're trying to identify the patient's neurocognitive function by starting with orientation.  The patient is assigned or is given a point for each correct response when it comes to identifying year, month, city, and hospital. 

The same is true when asking the – the patient to identify objects such as pointing to a pen, a clock, or a button.  Each of those correct responses gives the patient a point.  And following commands is one point, the ability to write a standard sentence is one point, and the ability to count backwards.  So then you add up all the points and you see, again, what is their score? 

The scoring in the lower left-hand corner, you can see, is a perfect 10 out of 10, is no impairment.  A score of seven to nine is a grade 1 ICANS.  A score of three to six is a grade 2.  A score of zero to two is a grade 3.  And basically, if you're unable to assess or unable to arouse the patient, then that would be a grade 4. 

[01:01:22]

          Neurotoxicity Grading: ASTCT Recommendations  

If we take it a step further using the ICE scores, you can see that it's also graded then, again, using 1, 2, 3, and 4 system, I think, to similarly equate that to the CRS grading.  So you can see that is an ICE score of seven to nine would be a grade 1.  This is a patient who is able to awaken spontaneously and does not have any of the other more serious symptoms. 

A grade 2 would be an ICE score of three to six.  Perhaps they require a little more stimulation but will awaken to voice.  A grade 3 or – or severe ICANS would be that the patient awakens only to tactile stimulus, has an ICE score of zero to two.  If imaging is done, there's some focal edema on neuroimaging and any seizure or EEG findings that do not resolve with – with intervention. 

Finally, a grade 4, again, would be the – the most serious, in – in which case those patients may not be – be aroused and require, you know, vigorous stimuli in order to elicit some – some response.  You may see imaging changes such as diffuse cerebral edema, intracranial nerve palsies, papilledema, and, of course, life – life-threatening prolonged seizures, deep focal motor weakness, and hemiparesis or – or even paraparesis. 

[01:02:49]

          Overview of CRS and Neuroogic Events After CAR T-Cell Therapy  

So kind of summarizing that, the – the overview of CS and – CNS and – excuse me, CRS and neurological events after CAR T therapy.  Again, you can see those symptoms on the side there for – for CRS, common being fever, hypotension, tachycardia, hypoxia, and chills, and then a more serious presentation being those cardiac arrhythmias can affect the kidney function, capillary leak syndrome, as we talked about before in – in more serious CRS gradings, hypotension not responsive to, let's say, fluid boluses requiring vasopressors one or more, and even the HLH or macrophage activation syndrome. 

The neurological events, again, common would be some confusion, disorientation, delirium, which, of course, can be due to lots of different factors, but we want to be on the lookout for that, potentially serious being seizures, cerebral edema, and aphasia or uptendation. 

The timeframe at which these symptoms generally present is – is sort of identified in the graphic to the right.  You can see that as – as CAR-T cell is infused on day zero, that the median onset for cytokine release syndrome is – it begins on day two, and it typically resolves within that first week by – by day eight as the median resolution. 

And if we compare that to – to ICANS or any neurological event, the median onset is day four, with the resolution being the median day 17.  So you can see that there is some overlap, and we haven't mentioned this yet, but certainly any of these symptoms, such as fever, hypotension, tachycardia, confusion, all of that could manifest as a – as a possible underlying infectious disease.  So there's a lot of overlap, but the – the point here is to note that CRS generally occurs first, does not typically last as long compared to ICANS or any neurological event that tends to occur later on and can – can linger a little bit longer relative to – to CRS and – and the day zero of CAR T infusion. 

[01:05:07]

          CRS Incidence by CAR T-Cell Product  

So here's a graphic identifying the CRS incidents by – based on the CAR T-cell product.  As you can see in the axi-cell, the brexa-cell, and the tisa-cell, as we're talking about lymphomas, the cilta-cell and the ide-cel are for other – for multiple myeloma.  But you can see in the axi-cell liso-cel, and tisa-cel, with vast majority of patients did experience cytokine release syndrome to some degree. 

The darker bar – the darker portion of the bar graph on the top indicates any grade CRS, while the lighter portion of each respective color on the bottom part of the bar graph indicates if they had the CRS occurring at a grade 3 or higher.  So you can see that most patients did experience CRS, however it was grade 1 or grade 2 for the majority with the minority experiencing more severe symptoms that would categorize them as a grade 3 or higher. 

The liso-cel product tends to be more gentle in that respect where CRS does not occur as frequently.  You can see in less than half of patients who – who underwent – who received liso-cel experienced CRS with very few actually receiving or experiencing it as a – as a grade 3 or higher. 

So going back to – to the question I think Beth – Beth asked and Lisa discussed about which products are sometimes selected, this is another factor of consideration when evaluating the patients.  For example, I know in our practice patients who are perhaps more on the frail side, maybe have more comorbidities, or are elderly, that might be a reason where you might consider liso-cell versus axi-cel in treating relapsed/refractory diffuse large B cell lymphoma. 

So that's just one example and here's the data to support that it – it does tend to – to occur less frequently in that product compared to – to axi-cel. 

[01:07:04]

          ICANS Incidence by CAR T-Cell Product  

If we go on to ICANS, looking at that by CAR T-cell product, similar story.  You can see that the axi-cel, brexa-cel, and – and the tisa-cel products tend to occur – ICANS tend to occur in the majority of those patients who did receive it.  And again, liso-cel tending to be – again I'll use the word gentle or more – more gentle in that respect in that less – less of those patients did experience ICANS, but again most of those patients did so at a grade 1 or 2 with far fewer in comparison experiencing it at a grade 3 or 4. 

[01:07:43]

          Principles of Toxicity Management  

Now let's talk about some of the management of these toxicities.  CR – I mean overall there's – there’s no, I suppose, universally accepted guideline on this is how you have to do this.  I think there are universal approaches such as using tocilizumab for the management of cytokine release syndrome and you can see that it's typically suggested to use it for severe CRS, that being either a grade 2 or higher.  That does not mean you can't use it in the grade 1 setting. 

I have seen it used, we actually have a case that we'll talk about a little bit later where it was used as – as a grade 1 intervention or an intervention with grade 1 CRS, but you – you really – you really want to consider your institutional protocol as that might vary or your institution probably has some policies developed to managing CRS, whether that can be done outpatient versus all patients should be – should be triaged and managed inpatient. 

We do want to consider other causes.  You'd want to get baseline labs and consider anti-epileptic drugs, especially for those patients who have higher risk of ICANS or who maybe are experiencing some – some of those ICANS related symptoms. 

We want to consider infectious diseases and we tend not to use corticosteroids just for the management of CRS and that's kind of opposite to what we talk about when managing neurotoxicity where we do start with – with corticosteroids in the management of that condition.  And the reason being is because we know that tocilizumab actually can cause some neurological symptoms and even mimic or even exacerbate an underlying immune cell effector neurotoxicity syndrome. 

So, you say, well, all right, so if we're given – if we know that CRS and ICANS tend to overlap a little bit and we're giving tocilizumab to treat the CRS, are we actually then contributing to – to the patient developing more of the neurotoxicities and I suppose that's possible.  Sure, but the – the point being is that with CRS, it's generally managed using cyto – excuse me, using tocilizumab as a first-line intervention with corticosteroids being reserved for more refractory or – or severe cases. 

There's another drug called siltuximab, which binds directly to IL-6, therefore doesn't increase the – the IL-6 levels and that's something that we think is associated with the increased neurotoxicity.  So again, therefore, that's the concept of trying not to give toci right up front to patients with just CRS. 

However, again, there's to be some overlap, as I showed on the previous slide, relative to the timing of these – these conditions and relative to the frequency at which we have seen on the bar graph that most patients probably get some form of – of each of these side effects. 

[01:10:30]

          Principles of Toxicity Management  

And so again, this is just sort of highlighting what I said.  So, toci can lead to increased neurotoxicity and it should – should still be used in patients with concurrent ICANS and higher grade CRS. 

[01:10:47]

          Principles of Toxicity Management by Grade

This is a table looking at – at – at that sort of trying to – trying to structure and organizing the management of CRS neurotoxicity and the two combined.  So, as I said before, grade 1, supportive care plus or minus toci.  Again, it's not an absolute no-no in grade 1.  You can – you can do it and there’s – your institution probably has a policy on this, but it is a mainstay throughout the different grading of tocilizumab with steroids being reserved for more severe cases. 

For neurotoxicity, supportive care plus or minus a steroid, the idea being is that steroids, you could, or in theory, affect the – the efficacy of the CAR T product.  And so you try to minimize that.  But again, steroids would be a sort of staple for treating neurotoxicity. 

And in the overlap syndrome, the two are used – are used together.  We always want to rule out other causes, such as infectious diseases.  And in the lower left corner, you can see that bullet point that says patients with neurotoxicity should receive AED.  That's anti-epileptic drugs.  That's not defibrillators.  So make – want to make that point clear.  And appropriate CNS imaging and EEG monitoring. 

[01:12:05]

          Should We Not Be More Proactive and Prevent CRS/NE Before It Starts? 

So if we know that most patients are going to get cytokine release syndrome or a neurotoxicity event, should we consider doing something proactively to – to prevent that?  And there have been several exploratory safety management cohorts that were added to the ZUMA-1 study.  Specifically, cohort six looked at this to say, well, if we treat with a prophylactic dose of corticosteroids and tocilizumab, is there an opportunity there to mitigate CRS and neurotoxicity? 

And those are the two primary endpoints is the severity and the incidence at which those two adverse effects occurred. 

So in this cohort, 40% of patients that received – 40% of patients, excuse me, were evaluated, had received axi-cel.  On day zero, so this would have been pre-CAR T infusion or that same day, but prior to the T-cell infusion, they got 10 milligrams of dexamethasone per day, day zero, day one, and day two. 

In these patients, CRS occurred in 80%.  So again, similar to the previous bar graph that showed it does occur in most patients.  However, all of the patients that experienced CRS did so at a grade 1 or grade 2.  Nobody experienced it at grade 3 or 4. 

58% had any grade neurological event with only 13% exhibiting a grade 3 or higher.  And then finally, 68% did not experience CRS or a neurological event within that 72-hour window in which dexamethasone was – was given. 

[01:13:34]

          Should We Not Be More Proactive and Prevent CRS/NE Before It Starts?   

So, in summary, prophylactic corticosteroids and early – early corticosteroid or tocilizumab intervention have the potential to improve the benefit and the risk profile of CAR T cell therapy.  As – as – as we kind of mentioned before, the incidence was – of grade 3 or higher CRS was lower in cohort six, it was zero, than in cohorts one or two, which was 13%. 

The median cytokine release syndrome duration was shorter and time to CRS onset was delayed in cohort six versus cohorts one and two.  And there was no negative impact on axi-cel efficacy or CAR T-cell expansion. 

Overall, no impact on overall response rates, CR rates, and the ongoing response rates at a median follow-up of 8.9 months. 

[01:14:23]

          Hemophagcytic Lymphohistiocytosis/Macrophage Activation Syndrome

Actually – sorry, I want to go back and just touch on that. 

[01:14:27]

          Should We Not Be More Proactive and Prevent CRS/NE Before It Starts? 

So – but I don't know that this is actively being practiced.  I can speak to our institution and I would encourage you to identify what is your institutional practice, but our institution, we are not currently giving prophylactic dexamethasone or tocilizumab to prevent CRS or neurological events, despite this data, which seems counterintuitive. 

However, I think our – our approach is that, well, as we've – as we’ve seen before, most patients do not get grade 3 or grade 4 CRS or neurotoxicity.  And the idea being too, that if you're exposing the patients to more immunosuppressive therapy, such as steroids, then is – are you increasing the risk for complications like infectious diseases or potentially having an impact on the CAR T product itself? 

Now, this – this cohort analysis did not show that, but again, we're talking about 40 patients versus, you know, many more that we are treating with CAR T cell these days.  So I know what our protocol is still to do it as a – as an as-needed basis, but I would encourage you to check with – with your team on the protocol for managing CRS and – and neurotoxicity as a preventative or prophylactic measure versus a, you know, reactive or as-needed measure. 

[01:15:43]

          Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome   

A little bit about hemophagocytic lymphohistiocytosis for the macrophage activation syndrome.  This is felt to be a severe progression of cytokine release, although it is not fully understood.  The diagnostic criteria for HLH still applies.  Patient needs an elevated ferritin of greater than 10,000 nanograms per milliliter.  And two or more organ toxicities, evidence of hemophagocytosis in the bone marrow or the organs, and then transaminitis, renal insufficiency, or – or pulmonary edema. 

[01:16:18]

          Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome  

I would say as you're evaluating patients, think of a sepsis or a DIC-like picture, disseminated vascular coagulopathy.  These patients can have fever, hypotension.  They can hemorrhage.  That would be, I would say, the hemorrhaging or somebody who is actively bleeding.  Certainly, if – if it's not related to – to cytopenias or other potential causes, that could be a tip-off that this is HLH. 

We talked about fever and hypotension being very much sort of hallmark signs of cytokine release syndrome, lab abnormalities, pancytopenia, but again, specifically coagulopathies, hypofibrinogenemia – hypofibrinogenemia, sorry about that, elevated D-dimer, your inflammatory markers like D-dimer and LDH.  They may also have lymphadenopathy or hepatosplenomegaly, but certainly can all – all of this can mimic disease progression as well too. 

But this should also be on your radar.  How it's treated is etoposide and dexamethasone plus or minus intracranial therapy for those with CNS involvement. 

[01:17:22]

          Managing Long-term CAR-T Toxicities

Lisa started to talk about this in her – her patient, but one of the major long-term CAR T-cell toxicities is B-cell aplasia and hypogammaglobulinemia.  This occurred in up to 30% adults with relapsed/refractory large cell lymphoma, mantle cell, or ALL who received these approved agents. 

And immunoglobulin levels, it underscores that need to monitor those levels frequently.  As we know, hypogammaglobulinemia doesn't always lead to infection, and there's not one typical cutoff where you say this person's going to do well if they're better than that, or they're going to – they’re going to get sick with an infection if they're lower than that, but it underscores the concept of needing to monitor for that. 

I tend to tell patients that sometimes that do have this, it's almost like your CAR-T product works too well, and that we know that the product is designed typically to target CD19 on the B-cell surface, which is what the malignant cells are expressing.  However, we know that healthy cells also express that, and so that's how I explain it to patients and saying, it worked, it worked really well.  It just worked too well, and now we're getting this off-target effect affecting healthy immune cells in addition to – to potential malignant cells, and so that's where this – this sort of developed from, or that's a risk that you want to discuss with them going into – you know, going into this treatment. 

We should monitor for cytopenias.  I think that's probably a given.  Anytime these patients are coming back in for follow-up, they're – they’re going to have basic blood work drawn, and – and their CBCs are going to be evaluated, and you're going to need to do transfusion support.  There is some increasing data on the safety and efficacy of use of growth factor earlier post-CAR T-cell therapy rather than – rather than waiting.  So if you start to see a trend or pattern that the – the neutrophil pound is trending down, that might be something to – to act on as an early intervention to potentially mitigate these – these serious infections. 

And then the last point on the bottom of this slide says that it occurred in about 38% to 70% of patients who received approved agents in pivotal trials.  That's a pretty wide margin there, 30% to 70%.  All right, well, I think it just underscores that we should – we should have this on our radar with every patient we are seeing post-CAR T therapy.  Assume that they will be at risk for infections, particularly nowadays, I think, as – as we are seeing increasing COVID cases this summer.  Hopefully, that's not a sign of things to come. 

[01:19:48]

          B-Cell Aplasia/Hypogammaglobulinemia  

I kind of talked about this just a moment ago, but again, the risk of B-cell aplasia and hypogammaglobulinemia is – is very much significant.  Monitor IgG levels and consider IV immunoglobulin replacement for those that are maybe more critically deficient or have a history of reoccurring respiratory illnesses. 

[01:20:16]

          Timeline for Delayed Toxicities With CAR T-Cells  

I like this graph because it really articulates the potential not only for immediate but for long-term complications following CAR T therapy.  You can see at the far right the one year and beyond line that there's still this risk for late bacterial and viral infections, again, hypogammaglobulinemia, impaired B-cell and T-cell recovery, prolonged cytopenias, late neurological and psychiatric events, late immune-related adverse events, and subsequent malignancies. 

[01:20:51]

          FDA Black Box Warning  

Speaking of subsequent malignancies, so in November of ’23, the FDA issues a safety communication about reports of T-cell malignancies.  They said, based on the evaluation of data from post-marketing adverse event and clinical trial reports that they concluded there was a serious risk of T-cell malignancies, and that was applicable to all of the currently approved CAR T-cell products. 

Fast forward to April of this year, they concluded that the changes actually warranted a – a highlight on the package insert that there was this serious risk of T-cell malignancies.  It sounds very scary and definitely something to disclose to, to patients who – who may come across this on their own. 

[01:21:33]

          Proportion of Reports of Each SPM Within Each Product Relative to the Number of AE Reports per Product  

Now, I thought this was an interesting article posted in, I believe this was in – in Blood.  And they actually looked and they went and looked back at the proportion of reports of each SPM, or secondary primary malignancy, which is kind of an oxymoron, secondary primary malignancy.  Anyway, you get the point.  Secondary primary malignancy within each product relative to the number of adverse event reports per product. 

And as you can see, leukemias relative to the other potential malignancies sort of dominated, and that could be related, as we know, to previous chemotherapies, underlying bone marrow disease, things of that nature.  You can see though on the – on the y-axis of this graphic, the proportion of reports, it only goes up to 4%.  So we're talking about a – a very small population of patients that – that would be at risk for this. 

And I should have highlighted it, but in the kind of middle, just to the left, you can see lymphoma non-Hodgkin T-cell.  And when I look at the graphic, it does look pretty similar to – to the other types of malignancies that – that can occur, which again kind of makes me wonder, are we actually seeing this in practice? 

[01:22:47]

          Absolute Number of Reports for Each SPM in CAR T-Cell Products  

This is a graphic from that same – that same study that showed an absolute number of reports for each secondary primary malignancy in CAR T-cell products, again, leukemias being the most common for lymphoma non-Hodgkin T-cell, you can see 17 is the number that – that – of cases that were attributed to, or I should say related to, a patient who had received CAR T-cell therapy. 

[01:23:13]

          FDA Black Box Warning (Continued)

Sort of taking this a step further, this was a paper published from Stanford in New England Journal of Medicine in June of this year.  Stanford did a single institution review of 724 patients who received CAR T-cell therapy since 2016.  They found one patient to have a new primary T-cell lymphoma out of that 724, and that occurred 60 days post-CAR T-cell.  The product was axi-cell, and of course they were – they were using that to treat their relapsed/refractory diffuse large B-cell lymphoma. 

The T-cell lymphoma was found to be molecularly distinct from the original DLBCL.  So this is second – essentially looking at it as a second process rather than something that evolved out of the original diagnosis of DLBCL. 

Additionally, the T-cell lymphoma clonotype was actually first detected before infusion of CAR T-cell therapy at day minus 88, and they – they noted it was associated with EBV-positive lymphoproliferation.  So I think, again, it was – although they were unable to – to sort of definitively establish this whether this clone reflected a pre-malignant population or a mature, fully-evolved neoplasm, the presence of the clone at detectable levels before infusion would support an underlying susceptibility preceding CAR T-cell therapy. 

It's – it’s almost like, I think in this study, the T-cell clonotype was incidentally detected or perhaps detected in hindsight as they were evaluating these – these patients.  So again, nothing compelling that says, yes, the CAR T product caused this person to develop a – a T-cell lymphoma. 

[01:24:54]

          Posttest 3

All right, with that being said, let's get to our post-test question.  Again, which of the following statements is correct regarding the potential toxicity of CAR T-cell therapy? 

1. First choice, the occurrence of CRS is rare but life-threatening;
2. Second, when CRS does occur, it typically does after ICANS;
3. Tocilizumab is essential in treating both CRS and ICANS; or
4. Continued risk of infectious disease and cytopenias should be considered in these patients even greater than one year post-CAR T treatment. 

[01:25:37]

          Posttest 3: Rationale  

All right, 78% chose the last one.  Correct, absolutely.  So the occurrence of CRS is rare.  We dispelled that.  We said it actually is very common, and that's more common to have grade 1 or 2, but it is common.  We said that ICANS typically occurs after CRS, so that's why the second choice is incorrect. 

We said tocilizumab is essential for treating CRS, not necessarily ICANS.  And the fourth choice being the correct answer.  Good job. 

[01:26:05]

Panel Discussion and Audience Q&A 

Dr. Faiman: Excellent discussion, Chris.  I'm having so much fun listening to you, and I think we're doing so good on time.  We have quite a few questions in the Q&A.  You have a really nice case that you took a lot of time to put together.  Do you mind like flipping through that case and hitting the high points of that, and then we can kind of circle back to the question and answer? 

Dr. D'Andrea: Yeah, absolutely, Beth.  Thank you.  I – I thought this was cool to include because it's kind of a real timeline of a real patient who – who just was treated at our institution earlier this year. 

[01:26:38]

          Case: 68-Yr-Old Man With Stage IV MCL

So this is – of course, that's not his actual picture.  That's just a nice stock picture of a – of a very friendly, pleasant-looking man.  This is a 60-year-old patient who had stage IV mantle cell lymphoma, and his mantle cell was notable for TP53 mutation.  First-line therapy, brentuximab – excuse me, bendamustine, rituximab, and cytarabine. 

He did have a potential cerebellar toxicity due to cytarabine.  I don't think it was ever confirmed, or – or I think it was suspected.  Anyway, that was kind of noteworthy.  He did have residual disease post-induction chemo, so essentially a primary refractory.  Went on to second-line therapy, receiving acalibrutinib and venetoclax.  Unfortunately, had no response, and thus then went to CAR T, his third line being brexa-cel. 

[01:27:26]

          Case: 68-Yr-Old Man With Stage IV MCL: CAR T-Cell Therapy   

At the time he received brexa-cel.  He was symptomatic with disease above and below the diaphragm, painful bulky adenopathy.  That was a section of his PET scan.  You can see the – again, the sort of – I guess it kind of looks like fat stranding or a lot of – lot of gook in the belly. 

Yeah, let's go with that.  He was on a PCA for continuous abdominal pain.  Day zero, CAR T-cells were infused, and so then – then the evaluation process again begins for – for those adverse effects.  On day plus two, his ICE score was 10 out of 10.  Day plus three, he became neutropenic, and on day five, he developed a febrile – he developed a fever overnight, was diagnosed as grade 1 CRS, and actually did receive one dose of toci – tocilizumab with acetaminophen. 

At the time, he had no ICANS – no evidence of ICANS.  His ICE score was still 10 out of 10.  Infectious workup was initiated, and the patient was started on piperacillin and tazobactam or zosyn to cover broadly. 

[01:28:28]

          Case: 68-Yr-Old Man With Stage IV MCL: CAR T-Cell Therapy   

Then day six and seven gets a little more hairy.  He – he has an AMET call because he's acutely hypoxic with his pulse ox dropping below 90%.  He's placed on a non-rebreather.  So now we've gone essentially from a grade 1 CRS to a grade 3, because as we said, that grade 2 hypoxia would be something like nasal cannula oxygen, and – and now he's sort of leapfrogged that into – into a non-rebreather.  He's tachycardic.  He's also hypotensive, so if – if the respiratory thing wasn't enough, his blood pressure is 60 over 40.  He's given phenylephrine and fluid boluses. 

He gets between six, he gets a dose of toci on day six.  He gets a third dose on day seven.  He gets a dose of dexamethasone, not necessarily for CRS.  I couldn't define this – I couldn't definitively identify what the dex was for, but I presume it was for the acute respiratory distress syndrome, and he was transferred to the ICU.  They added vancomycin. 

And ironic – or oddly enough, he still kind of remained A&O times three, despite probably feeling pretty crummy, and he did not have any independence of ICANS. 

Day plus eight, he was normotensive, afebrile, breathing on room air now, and – and somewhat somnolent.  He was now getting scheduled dex, 10 milligrams Q6, with acetaminophen, I presume, for his – his somnolence. 

[01:29:51]

          Case: 68-Yr-Old Man With Stage IV MCL: CAR T-Cell Therapy   

And day eight and nine, now his ICE score starts to tank, so he's now noted as a five out of ten with neurotoxicity.  Dex was stopped.  He was given a bolus of methylprednisolone.  Vancomycin stopped.  His infectious workup had been negative to-date. 

So day plus nine, his ICE score improves with the methylprednisolone.  Day ten, he then crashes again from a neurotoxicity standpoint with an ICE score of zero out of ten.  A second dose of methylprednisolone is given in addition to anakinra, which is an IL receptor antagonist, because again, we talked – we talked about how toci could potentially increase neurotoxicity. 

He was started empirically on some levo – levofloxacin, and interestingly enough, his CRS is noted to resolve, so his vital signs had improved, but now his neurocognitive status, not so good. 

Day plus 11, his ICE score remains zero.  Day plus 12, his ICE score is mainly or marginally improved at – at one out of ten.  He's still getting dex.  Now it's been bumped to 20 milligrams IV Q6. 

[01:30:54]

          Case: 68-Yr-Old Man With Stage IV MCL: CAR T-Cell Therapy   

Day 12 continued.  His brain MRI showed mild diffuse parenchymal enhancement, but no – no serious cerebral edema.  His ICE score continues to not be good at day plus 13, but his vital signs are stable.  Day plus 14, a little bit of improvement.  ICE score is six out of ten.  Day 15, eight out of ten.  He did have an LP done.  It was negative for lymphoma cells.  And as you can see, he then slowly improves in his neurocognitive function. 

By day 21, his ICE score is ten out of ten.  Dexamethasone is stopped.  And by day – day 24, he is discharged home. 

[01:31:28]

          Case: 68-Yr-Old Man With Stage IV MCL

On long-term follow-up, these are his actual labs.  You can see on the immune panel, his CD – his absolute CD3 – CD19, excuse me.  His absolute CD19 count is zero, and his IgG levels are – are pretty low there as well.  So again, that has remained consistent for the, you know, three months after, or two months, excuse me, after he was discharged.  So again, underscoring the – the point I made earlier about prolonged B-cell aplasia and – and hypogamma globulinemia.  He's still at very high risk for infectious diseases.  Last I knew, he was actually doing well. 

Dr. Faiman: And that’s going to take us to – sorry, go ahead.

Dr. D'Andrea: No, no, no.  I was just adding that he was – he's – last I knew was still in a CR post-CAR T, so. 

Dr. Faiman: And he now looks like the guy in the picture again. 

Dr. D'Andrea: He's happy again.  That's right.  He's very happy again. 

Dr. Faiman: That brings us to a couple questions.  This is a really nice case.  And I like how you put in the labs.  One of the questions was, are there any specific immunoglobulin levels that are affected?  And again, it's the IgG, IgA, IgMs.  And would you start CAR T – IVIG for somebody like this with an IgG level less than 400, would you start it?  Or, you know, do you wait?  Or what's your protocol? 

Dr. D'Andrea: I think that's a good guideline.  I mean, again, this is all relative to the person sitting in front of you, but I think that's a good guideline.  And I think that often is something that insurance will – will look at too.  So I think that's another good reason to check Ig – yeah, Ig levels frequently on their follow-ups, because if you are going to do that, then you're going to need something that documents that they are in need of IVIG.  So I think trying to just sort of be proactive in anticipating the needs of the patient. 

But I think that's a reasonable consideration is that at – at 400 now, I've seen patients who they get below 500, like clockwork, they get sick.  So – so who knows?  But I think 400, you know, you start getting around like his June one, like you can see the downtrend here.  I went back to this screen and his – his IgG level in April is 300, then it goes to 231, then it goes to 183.  So clearly, if he's not sick, I'm – I’m probably giving it to him as a – as a proactive measure here. 

Dr. Faiman: And then for the CD4 count, you see it was 117, then 112, then 73, you would have them on PJP prophylaxis, right? 

Dr. D'Andrea: Correct.  Yes.  I think I – I didn't mention that.  We talked about anti-epileptic drugs as – as patients are exhibiting ICANS, or I think we even do that as a protocol, that they do that for at least a month after CAR T to mitigate seizures. 

But yes, they would also be on antivirals with typically like acyclovir, and you would cover them with – you know, we cover them for PJP pneumonia prophylaxis as well. 

Dr. Faiman: And then Lisa, maybe you can answer this one.  What about the monitoring for the CRP and ferritin during that acute phase?  So you’re – is that something you do at Moffitt? 

Dr. Nodzon: Yeah.  So there's – there’s – there’s data that surrounds and there's questions with what should we – what should we use as surrogate biomarkers with CRP and – and ferritin? 

[01:34:33]

          Reflection and Commitment to Practice Change

Maybe the – the data that surrounds it is data that's looking at, can it be predictive perhaps of severe C – CRS?  There's some other ones as well too.  Moffitt does look at some of those markers as well.  But that's really the goal of it is who – can you predict which patient that you feel may have more severe CRS versus an other if they've got high CRP levels, high ferritin levels before going into the process as well? 

But again, I mean, there can be some nuances as we know, they can be, you know, acute phase reactants and stuff and indicative of other things.  But, you know, in the ever ending search for, can we predict who's going to have severe CRS versus another? 

And then as Chris touched on earlier, the data looking – the ZUMA-1 trial with the different cohorts of, could we be more proactive in those patients perhaps that have higher levels of these surrogate markers in anticipating that the need for this patient to make sure that maybe closer monitoring of that patient might be indicated. 

Dr. Faiman: Absolutely.  Still very institution specific.  Another question we had was about plasmapheresis for CRS.  So we don't recommend – we don't usually routinely at my institution do – it's kind of like a cytokine storm type of a thing, right?  And so, you know, anakinra, if it's really severe as – as Chris's case had highlighted, dexamethasone, tocilizumab, we saw some methylprednisolone in Chris's case as well.  Any thoughts, Chris or Lisa? 

Chris, you specialize in plasmapheresis now too, that's one of your new hats that you wear. 

Dr. D'Andrea: I do, that's right. 

Dr. Faiman: Institution.  What are your thoughts on plasmapheresis for CRS? 

Dr. D'Andrea: I haven't seen one patient come to the apheresis department for that.  So I – I suspect it's – again, it's probably not as efficacious as you might think.  And, you know, it – I don't know that there's a lot of data behind it.  So I think, again, there's certainly more data to – to manage this in some of the other ways we've kind of touched on.  And certainly that's more convenient to give some of those medications than to – to put a central line in a patient when you're already severely immunocompromised and at high risk for infectious disease.  Is that an opportunity to introduce, you know, a sepsis by – by putting in a central line and not – and doing so where it's not maybe as efficacious.  So there's not a lot of data to drive that it is actually going to be effective in – in treating them. 

Dr. Faiman: Right.  And then the last question, and I know this section is running over a little bit, but then I’ll – I'll bring us back on – on time.  I just love listening to Lisa and Chris.  It's great, rich information. 

If a patient has only hypotension, no fever, but they do require vasopressors, what toxicity grade would this be?  So, I mean, a hallmark of CRS is fever, right?  But I think the question is what if they don't have fever, but they're hypotensive, what would you say?  Would this be CRS or would this be – we're worried about sepsis causing that or what? 

Dr. D'Andrea: I mean, both are – both have to be on your radar.  I think if they're requiring vasopressor of some sort, I think to me that elevates them to a grade 3, because again, hypotension is either none in grade 1.  It is present in grade 2, but not requiring a vasopressor.  But if we're all of a sudden considering vasopressin even, I think to me that elevates them to a grade 3. 

Dr. Faiman: Would you agree, Lisa? 

Dr. Nodzon: Yeah, I was just going to say that moved here right up – I that moved that patient right up the scale. 

Dr. D'Andrea: Yeah, they don't have to go in a stepwise fashion.  They can leapfrog on the floor. 

Dr. Nodzon: It was a leapfrog. 

Dr. D'Andrea: Yeah. 

Dr. Faiman: Exactly. 

[01:38:08]

          Poll 5

So we're going to do our commitment to change.  Do you plan to make any changes to your practice management with CAR T cell based on this discussion in today's program?  And it might have been maybe not Chris's section, but maybe you're recalling back in Lisa's section.  And it's okay to say yes.  And then the next question is going to be the typing in the one thing you're going to change based on the learnings.  And that's a short answer.  You have up to 500 characters.  You can type in two characters. 

I don't know what you type in with like two characters, but all right.  So we'll give you some time for that.  I'm going to go back and open my window.  And I'm going to go to my section, which is going to focus on the coordination of care and early referrals. 

[01:39:04]

Early Referrals and Care Coordination to CAR T-Cell Treatment Centers 

And so thank you so much for sticking with us.  And over 200 of you – 240 of you have logged in.  And for that, we're very grateful for your support.  And hopefully you'll learn something. 

[01:39:18]

          Pretest 4

For my pre-test question, when discussing CAR T cell therapy with your patient, which of the following statements would you be sure to tell them to expect after CAR T cell administration? 

1. You would be unable to drive for at least 12 weeks;
2. You are treated as an outpatient.  You need to live near the center for four weeks;
3. You will not have to worry about infection risk after the initial 12 weeks; and the last one is,
4. If you're treated as an inpatient, you'll need to be admitted for at least three days. 

So interested to see how everybody's going to answer this question.  The last time we got to see pre-test answers.  So not this time.  Oh, this time we could.  Okay.  So we have 56% said the second one, but we had a smattering of others.  So great.  So let's see if that was the right answer. 

[01:40:12]

          CAR T-Cell Therapy Patient Journey  

So this is the CAR T-cell therapy patient journey.  So one of the first questions we had received today was how long until they see the transplant team.  And so again, it's a long journey in the – the take-home point on this section.  If you remember anything.  If you're in the community, academic center, wherever earlier referrals is key because there's a long time to patient identification. 

First, they have to meet the FDA label.  And that label is changing for the different indications quite rapidly, believe it or not based on the emergence of new data from these maturing clinical trials.  So maybe your patient was a heavily pre-treated relapsed/refractory mantle cell lymphoma patient, and now we're getting new information and they might be more of a candidate earlier on.  Or like Lisa said, they come to the center requesting CAR T-cell therapy.  And she said, whoa, stop. 

Maybe there's other things available for them.  So while this discussion is on CAR T-cell therapy, maybe there's a clinical trial that might be right for them that we might have available for them.  So there is no age cutoff.  Age is just a number.  Where – whereas high dose of chemotherapy for stem cell transplantation, auto or allo, depending on your – your malignancy, we don't usually have an age cutoff.  It's usually a fitness. 

And so CAR T cell centers will have their different criteria.  They'll have groups to discuss the patient eligibility criteria.  Patients who can be CAR candidates, as I mentioned, might not be stem cell transplant candidates, but okay, your patient meets – meets the criteria, and then they get referred to a CAR T cell specialist where that institution will do all of the eligibility evaluation, including – including the insurance authorization. 

Oftentimes before they even get to the center, that appointment has to be authorized.  And then there's the consent and the education.  So once they got the drug available and they're at the center and they get this approved, then you get the CAR T-cell, the T-cell selection, and that's via the apheresis.  And then the cells are manufactured to become power cells based on the viral vector that they're given.  And then they get the lymphodepletion chemotherapy and then the T cell infusion.  So there's that monitoring. 

So they're often in the hospital for at least seven days to assess for that CRS and neurotoxicity.  And you saw Chris's case that it went way longer, about 15 days until his neural status cleared, but it can be a lot shorter or not at all.  This is just a snapshot of the process.  We also heard about the monitoring of bridging therapy.  So there's a lot of discussion in coordination of care that we'll talk about in a few moments. 

[01:42:50]

          Closer View: Collection, Manufacturing, and Infusion of CAR T-Cells  

So this is the same slide that you saw during Lisa's earlier portion.  And remember, all of these slides are free for you to download and use and share with your friends and your friends of friends.  But this is another closer view of the leukapheresis, the manufacturing to the infusion, to the expansion of those T cells so that they become warriors in the body and they have their enhanced activity to do what they do best by killing the cells. 

[01:43:17]

          Patient Journey: Physical, Financial, and Long Term  

But the patients are on a long journey.  They need caregiver support.  That's something we haven't highlighted up until now.  And that's, you know, partly because that's in my section, but they need the financial clearance.  But one of the main reasons we want a caregiver is because there’s a lot – they can't – they can't drive for four weeks.  So again, that's the answer to that question in case you didn't get it right.  They can't drive for four weeks. 

They have to live by the treatment center for four weeks.  Actually, that was the correct answer, live by the treatment center for four weeks.  And then there's the costs involved, the clearance, the lymphodepletion, the admission, and then the post-infusion monitoring.  And then we saw in Chris's section, the late effects. 

[01:43:57]

          Salvage and Bridging Therapy: Community and Academic Coordination of Care

So what about salvage and bridging therapy?  So what are the goals of salvage therapy?  So somebody who's been through one, two or three prior therapies, if not longer, then we do sometimes give salvage therapy, which might be recommended to keep the disease at bay until we can harvest the T cells, manufacture these T cells, and then re-infuse the T cells into the patient. 

The goals are balancing the, how bad is the disease?  They have this big bulky disease where we have to give them some admission for chemotherapy, or do we want to really balance that toxicity of the patient?  We want to try to avoid immunosuppressive therapy, such as the checkpoint inhibitors, blinatumomab.  And then definitely, especially if they're coming from an outside institution, we want to communicate when to stop.  So the bridging therapy might – might not be at that large CAR T cell center.  If they live two hours away, then the community practice might be administering that therapy.  So we really want to make sure that the lines of communication are open. 

[01:44:57]

          REMS Requirements and Patient Education on Acute Toxicities  

There are REMS requirements for patient education on the acute toxicities.  So we already heard some of those in Chris's talk, like the secondary malignancies, which that data have emerged in the last year particularly, but REMS stands for the risk evaluation and mitigation strategy.  So we want to reduce the risk of harm to our patients at all costs. 

So the CAR T cell therapy, anybody who undergoes this has to be enrolled in the REMS program, and not all treat – not all centers that do central transplants, for example, are cellular therapy.  They might not do CAR T cell therapy or certain types of products might not be available at that center.  But in June 2024, the REMS was just modified to minimize the burden on the healthcare delivery system.  And we do ask them to refrain from driving for four to eight weeks after the CAR T-cell therapy, but definitely, definitely stay within two hours of a REMS certified hospital for greater than four weeks – greater than or equal to four weeks.  So we just, we really say, 30 days stay. 

Patients must be provided with a wallet card.  So when they're going to the – they have to go to the emergency room, it has the manufacturer of the product that was given, the blood type, the date of the infusion, and the things to highlight.  So it has stuff like, you know, temperature of 100.4, report to your – your institution immediately, shortness of breath, chest pain, all those red flags. 

And then it should also have on that wallet card, who to contact.  So they go to an ER that's, you know, 25 minutes away from the treating center, who does that ER physician call?  So that's where we don't want patients to get lost.  We gave them this potentially a life extending therapy.  We want to make sure that they don't run into problems.  We want to make sure they have somebody to call like a fellow on call or staff or an advanced practitioner, like one of us. 

[01:46:47]

          Patient Education: In the Trenches – Clearance, LD Chemotherapy, and Admission  

In terms of the patient education, we put a lot on the patient's shoulders when we go through this, but we want to really make sure that they understand the process, this lengthy process from the clearance that we discussed before to the lymphodepletion chemotherapy.  What is a washout guidance?  When should you stop your bridging therapy in order to harvest and collect the cells?  And then when do you resume that therapy, that bridging therapy before the lymphodepletion therapy? 

A lot of this is outpatient.  We also want to make sure that the cells are on site before the lymphodepleting chemotherapy.  Many of our centers are still admitting for CAR T-cell infusion and monitoring.  It’s – a few centers across the country are doing outpatient administration.  It's just not the standard of care among most of the centers because we know that it's going to require a hospital stay.  And you don't really want the patient to have major toxicities like the CRS, which can also – you can have CRS by itself with or without the ICANS. 

Oftentimes they occur together, as we heard in Chris's section, but we want to make sure that they get the prompt treatment like with the tocilizumab, dexamethasone if it's indicated, or anakinra as well if they have that event. 

Also in terms of the infusion, it's usually given about 30 minutes depending on the product with IV gravity.  It says on this slide here it's anticlimactic to the patient because you think about it, they've gone through all these prior therapies, they now are a candidate for CAR T cell therapy, and then they go through the infusion and all this education, it's really expensive, and then they get the drug, kind of like stem cell transplant for those of you that have been involved in transplant. 

So it's like that's it, it's done.  But yeah, we monitor the vital signs and then the advanced practitioner, the nurse, whoever's at the bedside is documenting very carefully.  The post-infusion monitoring as you heard during Chris's part and somewhat in Lisa's part is for that cytokine release syndrome.  ICANs, that neurotoxicity monitoring, vital signs monitoring, looking for cytopenias.  Every institution has their own protocol in terms of infection prophylaxis.  Many institutions will start IVIG promptly if the IGG level goes below 400.  There's some specific NCCN guidelines and other guidelines for infection as well as worry about tumor lysis syndrome, especially with bulky – bulky types of lymphomas. 

And then again, the REMS requirement to stay close to that transplant, that certified center for a four-week stay. 

[01:49:22]

          Timeline for Delayed Toxicities With CAR T-Cells  

This is that nice timeline for the delayed toxicities.  Raj Chakraborty published this.  He was a fellow, now he's at Memorial Sloan Kettering.  And we worked with him, Chris and I, at the Cleveland Clinic.  I'm sure he might have had help putting the pretty colors together.  Maybe this is a CEA slide.  But regardless, bacterial and viral infections can occur throughout the trajectory, but don't forget about fungal, PJP or PC prophylaxis is important for our immunocompromised, the hypogammaglobulinemia, so make sure that you're monitoring the serum IgG levels. 

And then there will be some impaired B-cell and T-cell recovery.  Prolonged cytopenias can be seen with some people, some products.  If the A&C is less than 500 at our center, we tend to recommend levofloxacin prophylaxis.  Growth factor is okay as well. 

The neurologic and psychologic events need to be discussed with patients, the care partners, and then don't forget to work – look for the late immune adverse events and then secondary malignancies, as you heard in our case presentation about the subsequent malignancies and the New England Journal paper that Chris had shared as well. 

[01:50:34]

          Preadministration and Postadministration Patient Needs  

For the pre-administration and post-administration patient needs, education, education, education.  And you know, they're like deer in the headlight sometimes, and – and so that's really where they need the care partner with them, and maybe they don't have a dedicated care partner, maybe it's a rotating care partner group, it's a daughter, son, daughter-in-law, son-in-law, maybe the spouse isn't there, maybe they don't have a spouse.  So really discussing and supporting the patient through that so that they don't go without that effective therapy if that's right for them. 

APPs can really help improve the care coordination by electronic or in-person pick-up-the-phone communication, especially if it's a referral center, making sure that the referral center knows when to stop the bridging therapy, when to stop the – before the collection, the salvage therapy before the collection or the bridging therapy before they get their cells back.  And then setting expectations for when that timeline happens. 

[01:51:31]

          Perceptions of Community Hematologists/Oncologists on Barriers to CAR T-Cell Therapy for DLBCL

And then, are people getting referred?  No, unfortunately, there was a study announced, you know, in the interest of time.  This was a study in 2019 about the community hematologists, oncologists that looked at barriers to DLBCL and going through CAR T-cell therapy.  The logistics were a big problem.  There was that, you know, cost of therapy was a problem, you can see in the blue there was a survey in November of 2019, and in the red was in the February of 2019, and we didn't get any better with the later survey. 

They were worried about toxicity, survival, and then some of the treating oncologists don't actually – didn't actually think that they had patients that would be eligible.  Unfortunately, look at that, 65% of the respondents said, you know, my patients deteriorated before the CAR T product could be administered, maybe that was a barrier for them wanting to refer them. 

So don't wait until your patient's sick enough, start that process early on.  So we know that CAR T-cell is a really good indication, there's still, again, other good products out there in the context of well-designed clinical trials, so get that network between that large referral center, that Moffitt, MD Anderson, Sloan – Memorial Sloan Kettering, wherever you are at, UCSF, any of these centers across the country, find a center that you can coordinate and collaborate with and that the patient feels comfortable getting that referral for. 

[01:52:58]

          CAR T-Cell Therapy: Best Referral Practices  

Some of the best referral practices, again, CAR T-cell therapy is incorporated into various programs in different ways.  They have a transplant model where some patients are referred to transplant, but again, when we refer them, most of the time it's within, you know, a two-week period, depending on the center, they're going to see a transplant or cellular therapy ex-specialist. 

Some people have a disease center model where all patients refer to those disease center physicians who also are cell therapists, and each institution is different.  So my institution, and I know Moffitt and others are very similar, they have this central scheduling line for referrals, so you could just call that scheduling line, and then the people behind that scheduling line, that scheduling request, I call them like the Wizard of Oz people that you never really see them, but they're – they’re there working hard behind the scenes.  They're the ones that will help you navigate. 

It can be very scary for the patients, too.  They might not want to leave their community heme/onc practice, but reassuring in that communication that care will help them feel better about that. 

We have other special considerations that are center-dependent, you know, can the patient wait?  Maybe they can't wait for this therapy and another therapy might be available for them, because remember, the manufacturing takes some time, weeks to months, depending on the product, depending on how many cells are harvested and how effective that – that viral vector or the lentiviral vector is. 

[01:54:23]

          Inpatient vs Outpatient CAR T-Cell Therapy  

Inpatient versus outpatient, there are centers across the country that do inpatient – that do outpatient administration, but many of those are equipped with 24-hour emergency care.  My institution does not have that resource currently, working on it, but there are some centers in various areas across the country in Mayo[?] Clinic and Emory are two centers, and Lisa, I'll ask you later on if – if that is something that Moffitt is doing, but there's a lot of logistical barriers, reimbursement barriers as well, but if the inpatient, oftentimes it's about a seven-day hospital stay, and then we, again, four weeks time, we want you to stay close to that center just to be on top of any side effects that you might have during that 30-day post-acute phase, such as the delayed neurotoxicity is the one that I really worry about. 

If outpatient, they have to be housed near the treating center for four weeks.  They have to take their own vital signs, record data, do the neurotoxicity scores.  We did do some cellular therapies right at the beginning of COVID that were outpatient with some ongoing monitoring in a select group of patients, but that's something that we're hopefully going to get back to many centers.  I think that would be great if many centers could. 

[01:55:35]

          Evidence for Outpatient CAR T-Cell Therapy

There are some evidence for outpatient CAR T-cell therapy and lymphomas.  Again, it’s – you have to stay generally within one hour of driving just for very acute reasons, and these data are evolving – are evolving as we speak.  You can see some of the older references on this slide.  It's just because we haven't had a lot more updated, but I think that that is where we're – we’re moving in terms of science. 

[01:56:01]

          Long-term Monitoring and Toxicities: Weeks to Months From Infusion  

So in terms of long-term monitoring and toxicity, we heard about the GCSF for prolonged cytopenias.  I – I mentioned about levofloxacin prophylaxis for A&C less than 500.  B-cell aplasia will be referenced by the IgG levels, so we recommend IVIG for less than 400.  Watch for infection.  Watch for relapse.  Watch for sepsis.  Watch for secondary malignancies. 

The vaccination schedule mirrors that of stem cell transplant in many cases.  There's various guidelines from the TCT group and – and NCCN as to what the vaccination schedule should be.  Similar in inactivated influenza, pneumococcal vaccination, as well as some others. 

[01:56:46]

          Considerations for Caregivers

In terms of considerations for caregivers, it's super important to make sure that they have a caregiver.  That is really critical because of all that the patient can experience.  I have here in the bottom, on the right, a caregiver should not be hired.  That's pretty strong language.  It's best if you could get a caregiver that's not hired, but if you have to hire a caregiver that might be from your place of worship or have a personal relationship, but yeah, you have to hire them.  That might be okay, but again, being very frank with that. 

Then we have people that we've had that say, oh, I have a caregiver, and then that caregiver leaves and goes to work all the time, and you didn't really realize that they weren't going to be present.  So again, social work support is really important.  A lot of the support exists with psychological, psychosocial, social work. 

Pharmacy is really critical in helping this, as well as the APP, the PANP as well, and really just underscoring the importance of that caregiver being there for the patient. 

[01:57:46]

          Posttest 4

So here's our post-test four.  When discussing CAR T-cell therapy with your patient, which of the following statements should you be sure to tell them to expect after CAR T administration?  I want to see 100% on this.  You'll be unable to drive for 12 weeks.  If you are treated as an outpatient, you need to live near the center for four weeks.  You will not have to worry about infection risk after the initial 12 weeks, or if you are treated as an inpatient, you'll need to be admitted for three days minimum. 

But I don't know, Lisa and Chris, it's kind of late here on the East Coast.  I'm not sure anybody's going to get all of these, right?  I just have great confidence in our group on the call.  Yay!  89%.  What? 

And look, we still had 90 people that stuck it out and answered.  Thank you so much, everybody, for – for being here.  We are towards the tail end of our program.  We have nine more minutes left. 

[01:58:44]

          Posttest 4: Rationale  

Here is the correct answer.  We talked about the four weeks.  Avoid driving for at least eight weeks.  Some people have exceeded that who've had severe neurotoxicities, and then anticipate being admitted for a minimum of seven days.  That's based on the CRS onset risk and the ICANS risks, etc. 

[01:59:02]

          Conclusion

So in conclusion, early referrals will ensure that both efficacy and safety are optimized as outcomes with patient fitness and T-cell fitness and disease burden.  And again, relationships between the referring centers and the referral centers are important.  Figure out how to best contact.  Do you pick up the phone?  Do you do electronic charts?  Do you fax things?  Do you print out a piece of paper for the patient to carry? 

And there are many different ways to – to do that, but that's really important to partner with them and build those relationships for future patients. 

[01:59:35]

Panel Discussion and Audience Q&A 

So I think with that, we're at a panel discussion.  We have a couple of questions in our chat. 

[01:59:41]

          Case: 57-Yr-Old Man With Relapsed DLBCL  

Let's see what this slide is.  57-year-old man with relapsed DLDCL.  And this is more of a discussion slide.  He lives far from the CAR T-cell treatment center.  He's in northern – northeastern Florida, and he wants to go to Moffitt because that's where his insurance covers him to go.  And so he really wants to go there, but he's like right in that panhandle, and I think that's kind of far.  How long of a drive would that be, Lisa? 

Dr. Nodzon: That's – that’s a few hours.  Yes.

Dr. Faiman: Yeah.  Well, that's far enough.  He can't ride his bike there.  So what logistical considerations?  So Lisa, what would you do to get that patient to the CAR T-cell center?  What kind of referral – what kind of support would you be able to do to get that patient there? 

Dr. Nodzon: Yeah.  So one of the early things that we would have to get involved would be our social worker, right, to start exploring the patient's benefits, maybe through their insurance, and then housing accommodations, if needed, right?  So when patients come to Moffitt, and we recognize we're really far from patients.  Moffitt has good partnerships with a lot of the local hotels where patients can come, get their consultations, stay in a hotel, take a shuttle on over to Moffitt at a reduced rate, no penalty for if they have to cancel, you know, and they'll give enough notice.  So Moffitt has that relationship with local hotels for patients coming to just visit the center. 

But for a patient that would want to come for CAR T-cell therapy, you have to get the social worker involved for that patient to – to go through insurance benefits.  One, where is the patient going to reside post-CAR T, because living four hours away post – post discharge is not going to be recommended for the patient, but keeping them nearby.  And there's some relationships with local home – local apartment complexes as well, too, to keep the patients in the vicinity. 

Dr. Nodzon: Yeah, that's a great point.  And I know some centers have hotels on site, but that can be really expensive.  Chris, what would you do?  I mean, we didn't mention in here this 57-year-old man.  Does he have a caregiver or somebody he could identify as a caregiver?  So that would be also the discussion.  What other things can you think of, Chris, that would help him as an APP to ensure he could get CAR T-cell therapy if that's something he's a candidate for and wants to do? 

Dr. D'Andrea: Yeah, I mean, certainly, Lisa, you hit on it.  I think it takes a multidisciplinary approach.  I mean, I think you enlist all hands on deck, so to speak, in – in, you know, utilizing social work, trying to explore if there are any friends or family that are – that are available, you know, trying to consider the patient themselves, I mean, their performance status, their previous – the impact of their previous treatments.  You know, is this something they want to go through? 

I mean, is this – you know, again, it's – it’s not without risk.  It’s not – clearly, as we've seen, there can be a lot of side effects.  And so I think in addition to the – to the many dozen things that you touched on, Beth, I think that's how I would kind of consider this patient in a nutshell is – is really trying to evaluate everything around them and – and to enlist a host of other specialists within your – your cancer center who – who are involved in this. 

I mean, you know, I'm sure there's others that I'm forgetting. 

Dr. Faiman: Yeah.  Yeah, absolutely.  And just to close, I think one of the questions that we got today was, you know, what does – what does the counseling look like?  You know, and then that's also one of the last bullets, what should the APPs counsel on?  I think that's the whole thing.  And again, these slides are available for you to share with your friends, your colleagues, and your friends' friends and review on your own. 

I think counseling on the short-term effects, I break it into buckets.  What are the short-term effects to worry about?  What are the long-term effects to worry about?  What's the monitoring?  So this is a one-time thing, right?  But it might not work forever.  So it's not really a one and done.  We are hoping that this might be the last therapy you're going to need for a while, but there's still that infection monitoring, regular blood work.  You have to still come and see, Chris or Lisa, in the outpatient clinic or your physician. 

So making sure that they understand that there's still continued monitoring, even though you're not going to be taking a regular IV or PO chemotherapy.  And then the – the disease monitoring with the MRD status, etc., for CLL or whatever your lymphoma of malignancy is. 

So anyhow, I think we're getting towards the end. 

[02:04:06]

          Reflection and Commitment to Practice Change  

We have three minutes left and we have the reflection and commitment to change.  And then Kelly's going to come back on and take us out.  So this is the last part. 

[02:04:14]

          Poll 7

Do you plan to make any changes to your practice based on today's program?  And this is the question I say, it's okay to say yes.  Even if you're not sure right now, you can say I'm certain.  But hopefully you took one key point away from this whole two hours you spent with us together that you might be able to change.  Early referrals.  It’s a social working call. 

[02:04:41]

          Poll 8

And then the next question is to just type in one of those things if you can.  And we'll leave this up on the screen while Kelly takes us out to – takes us out to enjoy the rest of our evening. 

[02:04:56]

          Thank You for Attending  

Kelly Gaertner Brandt: Great.  Thank you to our faculty for an excellent program and a very interesting discussion.  And thank you to the audience for being here and participating.  Don't forget to click on the claim credit link within the resources tab to evaluate this program and receive your credit.  Downloadable slides are available on the PCE and CCO sites. 

And thank you all for participating in this program and enjoy your evening. 

Dr. Faiman: Thank you all. 

Dr. D'Andrea: Thank you.

Dr. Nodzon: Thank you, everybody.

[END OF TRANSCRIPT]