In Practice

Patient Selection: The Key First Step to Successful CAR T-cell Therapy

In the In Practice column, Cell Therapy Next will work with members of the Peer Perspective Board to break down the practical knowledge needed to implement and offer CAR T-cell therapy to patients in everyday clinical settings.

In this installment, Ryan D. Cassaday, MD, of the University of Washington and Fred Hutchinson Cancer Research Center, answers straightforward questions about how to select patients and discuss this new treatment with them. Consider this a primer for the first steps of CAR T-cell therapy.

In our next installment, the question-and-answer format will focus on toxicities of CAR T-cell therapy and management of those toxicities. If you have specific questions for that installment or suggestions for upcoming In Practice topics, please email us at CellTherapyNext@Healio.com.

Q: When do you know that a patient is ready to move into CAR T-cell therapy?

With two approved treatments on the market, a lot of what dictates whether a patient is ready to move toward CAR T-cell therapy is dictated by their labeled indication. Potentially, if there are investigational options available, physicians should consider the criteria for those.

Ryan D. Cassaday, MD
Ryan D. Cassaday

Generally, for the two products that are approved for aggressive lymphoma, they have specific indications for use (See Table 1 below). It’s generally patients that have relapsed after or are ineligible for autologous stem cell transplantation. Those are granular pieces of information that will help identify when it might be appropriate to start thinking about it.

Beyond that, it comes to more subjective aspects of the patient’s situation, such as comorbidities, willingness to travel to another institution and long-term goals of care (See Table 2 below). For example, are we looking at long-term care for this patient or are we looking for more palliative care? CAR T-cells would not be given with palliative intent.

The risks for side effects from these therapies are real and legitimate so patients have to be in pretty good shape. They should be relatively fit and without serious medical comorbidities. If it’s someone who is frail and elderly with congestive heart failure and COPD, then CAR T-cells are not going to be a viable option. But if someone is in good medical condition and otherwise fit, then these become an option.

In many respects, when considering a patient’s overall condition and medical comorbidities, it’s similar to determining whether a patient would be medically fit for stem cell transplantation. Some of the same ideas or thoughts that we have about using that therapy, which has been around for decades now, are the same general principles that we would use to determine if a patient is eligible for CAR T-cell therapy.

Table 1
Table 2

Q: How do you broach the subject with your patient?

In my experience, because there is so much out there in the popular press and social media and various other points of access that people have for medical information about CAR T-cell therapy, it’s usually the patient who is asking about it rather than the physician broaching the subject.

But, again, if you are broaching the subject, it is similar to discussing stem cell transplantation. We have to discuss patient selection and whether each individual patient is truly a candidate for CAR T-cell therapy. If a patient is a candidate, then the physician must be honest that this is a relatively involved, aggressive and intense therapy approach that’s newly available. I acknowledge that CAR T-cell therapy does have encouraging data behind it and it can be effective, but that it will take some work on both our parts and there are some very legitimate and serious risks. That’s usually a good branching point to get more into the nitty gritty details of things like cell collection and lymphodepletion.

But, again, unlike many other therapies, at least in my experience, people are usually coming to the physician to ask for this. It’s not something you will often need to broach, especially if it’s a patient with a relatively high level of sophistication about their disease.

Q: How do you talk to a patient who is not a candidate but requested this therapy?

It’s of utmost importance to have a good understanding of the contraindications and side effects as well as labeled indications of the therapies so you can best address a patient who is interested but where it is not in his or her best interests.

For example, sometimes it’s straightforward. If it’s somebody with relapsed/refractory ALL and they’re 56 years old, the reality is we are probably not going to be able offer that patient tisagenlecleucel (Kymriah, Novartis) because it’s only approved for patients up to age 26. Now there may be investigational options available that a patient like that could pursue, but as far as the approved options, they won’t be available and you should know exactly why.

Having concrete objective information to explain why a patient may not be a candidate makes it easier to convey the message. It gets a lot harder if we are concerned on some of the more subjective points. For example, maybe we think their performance status is not good enough or we are concerned about their ability to tolerate toxicity either because of age or comorbidities.

Not to sound like a broken record, but in a lot of ways, these discussions are like the conversations we’ve had with patients regarding stem cell transplantation. Although stem cell transplantation and CAR T-cell therapy are clearly not the same and each have their own specific issues, a lot of the general principles regarding fitness and candidacy particularly as it relates to their medical comorbidities, previous knowledge of stem cell transplantation gives a pretty good framework within which to work. Physicians can draw on those more comfortable conversations and their experience in that arena to explain why we don’t think some patients are candidates for CAR T-cell therapy.

Having a good understanding of general principles regarding the very real serious adverse effects with these treatments and why those can sometimes be contraindications as well as the eligibility regarding the FDA labeling and black box warnings provides clinicians a good baseline from which to work.

Q: How do you discuss ongoing trials for which your patients may be eligible?

We have two approved therapies, but many more ongoing clinical trials for which our patients may be eligible.

While it’s great that we have approved products now, it may be prudent or appropriate to have patients strongly consider enrolling in clinical trials even if they would otherwise be candidates for the approved therapies. A lot of the impetus behind some of the ongoing trials is to make the CAR T-cells work better or make them better tolerated.

I like to frame it for my patients with the idea that while we don’t know that these new approaches will lead to those outcomes, this is how we continue to move the field forward and hopefully make things more efficacious and safer in the future. The reality is not everybody goes into remission after CAR T-cells and some people have very serious side effects, so there’s still room for improvement.

Depending on specific patient scenarios, trial availability, geography and options that are available at different centers, it may very well be prudent to recommend a clinical trial to your patient and discuss the risks and benefits of their participation.

Q: What are the steps for a community oncologist to take in referring a patient to a CAR T treatment facility?

It may be different at different centers, but where I work, the process is very similar to how patients get referred for stem cell transplantation. I imagine whatever center you might refer to for stem cell transplant in the past, there’s a good chance that center has CAR T available and has a mechanism in place for referrals analogous to that you’ve used for stem cell transplantation.

It gets trickier when you consider medical management of each individual patient. Unlike transplantation, where we are generally referring patients who are in remission to pursue that therapy, these patients being referred for CAR T-cells have active, relapsed, refractory disease. One of the largest challenges is ensuring the patient’s disease is under reasonable control to undergo the multiple steps involved to ultimately receive the therapeutic part of the process.

If you identify a patient in your clinic who you want to refer for CAR T-cells, it can be 4 to 6 weeks before therapy begins depending on the geography, insurance review or the bandwidth for the center to which you’re referring. Someone with out of control disease may not be able to wait that long. Physicians hoping to refer need to find the optimal timing to consider and start this process.

But additionally, one of the big challenges is trying to optimize their disease status going into CAR T-cell therapy. One of the barriers we have is that most therapies for these diseases are by their very nature lymphotoxic. Giving a patient an abundance of chemotherapy to try to control the disease to then send that patient for collection of circulating T-cells potentially compromises the actual process of cell collection, which is obviously a very critical part of this whole procedure.

This is where true co-management of the patient begins. As the site to where the patient is being referred, we often work with the referring physician to gauge how significant the disease burden is: What symptoms are they having? What laboratory abnormalities are there as a consequence of their disease?

Then we discuss what we think is the optimal management: Can we leave them alone and not risk making them sicker or compromising the T-cell collection by giving them a bunch of chemotherapy? Or do we need to give them something to put a lid on their disease to get them through this process?

That’s one of the more nuanced parts of this where you often can rely on the center where you are referring for guidance. It’s usually not a good idea to give a patient a bunch of myelosuppressive and lymphotoxic chemotherapy as he or she heads into the CAR T-cell process because that makes it hard to collect their cells.

Table 3

Q: What are your talking points when discussing cost with your patients?

As physicians, we often don’t get too caught up in the details of this, but it is important to emphasize that it very likely will take time for insurance companies and third-party payers to review this and ensure a patient meets the criteria for coverage. For example, I’ve heard rumors that some payers are expecting patients to meet eligibility requirements from the clinical trials that led to the approvals of these products and not just the indications in the FDA approval. These differences in coverage, interpretations and strict adherences can arise as potential issues that could slow up or delay the process of getting approval.

Physicians should be aware that because of the complexity and high cost, it’s unlikely to be a situation where you submit a referral and it’s approved 5 minutes later. Obviously, the patients will often come to the physician seeking guidance, but it’s often outside of our immediate scope and the best we can do is prepare patients in advance that there may be a barrier or delay.

It’s incumbent on us, as well, to be forthright about which patients we do refer. At a minimum, third party payers likely will be strict about the labeled indications for these, so physicians must ensure that you’re referring patients with conditions that are truly on-label. If you’re referring a patient with mantle cell lymphoma, for example, for a commercially approved CAR T-cell therapy, it probably won’t be covered because neither of the currently available products are approved for mantle cell lymphoma.

Q: How can physicians best mitigate that delay?

One of the challenges that most clinical oncologists face is we want to be able to provide therapeutic optimism about anything being delivered at that time, but we also need be realistic about the probability of that intervention being successful. For example, if you have a young adult with ALL who has relapsed multiple times and you’re giving them traditional multi-agent salvage chemotherapy, there’s a pretty good chance that person is not going to go into remission. If it’s someone with diffuse large B-cell lymphoma who relapsed 3 months after RCHOP, we might give them traditional second-line therapy, but the likelihood of that working is small.

We still hope that whatever we do as that salvage option is going to be successful and get the patient into remission and on to transplant, but the reality is that many times, that is not going to work and there are things to do on the back end to prepare.

You might want to reach out to your transplant center, to say, ‘I have a patient with relapsed DLBCL that I’d like to refer for an autologous transplant if they respond to second-line therapy, but in the event they don’t, do you have a CAR T therapy program? Do you have slots open? Do you have any trials open?’

That gives you a sense of the lay of the land, so in the event your patient does not get into remission or they start to progress through treatment, you’re not caught flat-footed.

Q: Any pointers on taking the first steps with a patient in beginning CAR T-cell therapy?

Patient selection is important as is being realistic about your patient’s disease status. You need to be confident that a patient is (or that you can treat them to be) stable enough to ultimately get through the process of collection, lympho-depletion and cell infusion.

Then do take note of the starter questions in Table 3. It’s important to have a sense of those basic things before offering this therapy to patients. You certainly don’t want to offer someone this really exciting and potentially groundbreaking and revolutionary therapy only to find out they have to travel 1,000 miles to get it or they don’t have a caregiver but the referring center requires that for participation.

Understanding those basic, practical, logistical issues in advance will help do a better job of understanding which patients to whom we can genuinely and honestly recommend this therapy, so we are never pulling this option out from under them.

Disclosures: Cassaday reports research support from Kite/Gilead, Amgen, Merck and Seattle Genetics, as well as consultant roles with Amgen, Jazz Pharmaceuticals and Pfizer.

In the In Practice column, Cell Therapy Next will work with members of the Peer Perspective Board to break down the practical knowledge needed to implement and offer CAR T-cell therapy to patients in everyday clinical settings.

In this installment, Ryan D. Cassaday, MD, of the University of Washington and Fred Hutchinson Cancer Research Center, answers straightforward questions about how to select patients and discuss this new treatment with them. Consider this a primer for the first steps of CAR T-cell therapy.

In our next installment, the question-and-answer format will focus on toxicities of CAR T-cell therapy and management of those toxicities. If you have specific questions for that installment or suggestions for upcoming In Practice topics, please email us at CellTherapyNext@Healio.com.

Q: When do you know that a patient is ready to move into CAR T-cell therapy?

With two approved treatments on the market, a lot of what dictates whether a patient is ready to move toward CAR T-cell therapy is dictated by their labeled indication. Potentially, if there are investigational options available, physicians should consider the criteria for those.

Ryan D. Cassaday, MD
Ryan D. Cassaday

Generally, for the two products that are approved for aggressive lymphoma, they have specific indications for use (See Table 1 below). It’s generally patients that have relapsed after or are ineligible for autologous stem cell transplantation. Those are granular pieces of information that will help identify when it might be appropriate to start thinking about it.

Beyond that, it comes to more subjective aspects of the patient’s situation, such as comorbidities, willingness to travel to another institution and long-term goals of care (See Table 2 below). For example, are we looking at long-term care for this patient or are we looking for more palliative care? CAR T-cells would not be given with palliative intent.

The risks for side effects from these therapies are real and legitimate so patients have to be in pretty good shape. They should be relatively fit and without serious medical comorbidities. If it’s someone who is frail and elderly with congestive heart failure and COPD, then CAR T-cells are not going to be a viable option. But if someone is in good medical condition and otherwise fit, then these become an option.

In many respects, when considering a patient’s overall condition and medical comorbidities, it’s similar to determining whether a patient would be medically fit for stem cell transplantation. Some of the same ideas or thoughts that we have about using that therapy, which has been around for decades now, are the same general principles that we would use to determine if a patient is eligible for CAR T-cell therapy.

Table 1
Table 2
PAGE BREAK

Q: How do you broach the subject with your patient?

In my experience, because there is so much out there in the popular press and social media and various other points of access that people have for medical information about CAR T-cell therapy, it’s usually the patient who is asking about it rather than the physician broaching the subject.

But, again, if you are broaching the subject, it is similar to discussing stem cell transplantation. We have to discuss patient selection and whether each individual patient is truly a candidate for CAR T-cell therapy. If a patient is a candidate, then the physician must be honest that this is a relatively involved, aggressive and intense therapy approach that’s newly available. I acknowledge that CAR T-cell therapy does have encouraging data behind it and it can be effective, but that it will take some work on both our parts and there are some very legitimate and serious risks. That’s usually a good branching point to get more into the nitty gritty details of things like cell collection and lymphodepletion.

But, again, unlike many other therapies, at least in my experience, people are usually coming to the physician to ask for this. It’s not something you will often need to broach, especially if it’s a patient with a relatively high level of sophistication about their disease.

Q: How do you talk to a patient who is not a candidate but requested this therapy?

It’s of utmost importance to have a good understanding of the contraindications and side effects as well as labeled indications of the therapies so you can best address a patient who is interested but where it is not in his or her best interests.

For example, sometimes it’s straightforward. If it’s somebody with relapsed/refractory ALL and they’re 56 years old, the reality is we are probably not going to be able offer that patient tisagenlecleucel (Kymriah, Novartis) because it’s only approved for patients up to age 26. Now there may be investigational options available that a patient like that could pursue, but as far as the approved options, they won’t be available and you should know exactly why.

Having concrete objective information to explain why a patient may not be a candidate makes it easier to convey the message. It gets a lot harder if we are concerned on some of the more subjective points. For example, maybe we think their performance status is not good enough or we are concerned about their ability to tolerate toxicity either because of age or comorbidities.

Not to sound like a broken record, but in a lot of ways, these discussions are like the conversations we’ve had with patients regarding stem cell transplantation. Although stem cell transplantation and CAR T-cell therapy are clearly not the same and each have their own specific issues, a lot of the general principles regarding fitness and candidacy particularly as it relates to their medical comorbidities, previous knowledge of stem cell transplantation gives a pretty good framework within which to work. Physicians can draw on those more comfortable conversations and their experience in that arena to explain why we don’t think some patients are candidates for CAR T-cell therapy.

Having a good understanding of general principles regarding the very real serious adverse effects with these treatments and why those can sometimes be contraindications as well as the eligibility regarding the FDA labeling and black box warnings provides clinicians a good baseline from which to work.

PAGE BREAK

Q: How do you discuss ongoing trials for which your patients may be eligible?

We have two approved therapies, but many more ongoing clinical trials for which our patients may be eligible.

While it’s great that we have approved products now, it may be prudent or appropriate to have patients strongly consider enrolling in clinical trials even if they would otherwise be candidates for the approved therapies. A lot of the impetus behind some of the ongoing trials is to make the CAR T-cells work better or make them better tolerated.

I like to frame it for my patients with the idea that while we don’t know that these new approaches will lead to those outcomes, this is how we continue to move the field forward and hopefully make things more efficacious and safer in the future. The reality is not everybody goes into remission after CAR T-cells and some people have very serious side effects, so there’s still room for improvement.

Depending on specific patient scenarios, trial availability, geography and options that are available at different centers, it may very well be prudent to recommend a clinical trial to your patient and discuss the risks and benefits of their participation.

Q: What are the steps for a community oncologist to take in referring a patient to a CAR T treatment facility?

It may be different at different centers, but where I work, the process is very similar to how patients get referred for stem cell transplantation. I imagine whatever center you might refer to for stem cell transplant in the past, there’s a good chance that center has CAR T available and has a mechanism in place for referrals analogous to that you’ve used for stem cell transplantation.

It gets trickier when you consider medical management of each individual patient. Unlike transplantation, where we are generally referring patients who are in remission to pursue that therapy, these patients being referred for CAR T-cells have active, relapsed, refractory disease. One of the largest challenges is ensuring the patient’s disease is under reasonable control to undergo the multiple steps involved to ultimately receive the therapeutic part of the process.

If you identify a patient in your clinic who you want to refer for CAR T-cells, it can be 4 to 6 weeks before therapy begins depending on the geography, insurance review or the bandwidth for the center to which you’re referring. Someone with out of control disease may not be able to wait that long. Physicians hoping to refer need to find the optimal timing to consider and start this process.

PAGE BREAK

But additionally, one of the big challenges is trying to optimize their disease status going into CAR T-cell therapy. One of the barriers we have is that most therapies for these diseases are by their very nature lymphotoxic. Giving a patient an abundance of chemotherapy to try to control the disease to then send that patient for collection of circulating T-cells potentially compromises the actual process of cell collection, which is obviously a very critical part of this whole procedure.

This is where true co-management of the patient begins. As the site to where the patient is being referred, we often work with the referring physician to gauge how significant the disease burden is: What symptoms are they having? What laboratory abnormalities are there as a consequence of their disease?

Then we discuss what we think is the optimal management: Can we leave them alone and not risk making them sicker or compromising the T-cell collection by giving them a bunch of chemotherapy? Or do we need to give them something to put a lid on their disease to get them through this process?

That’s one of the more nuanced parts of this where you often can rely on the center where you are referring for guidance. It’s usually not a good idea to give a patient a bunch of myelosuppressive and lymphotoxic chemotherapy as he or she heads into the CAR T-cell process because that makes it hard to collect their cells.

Table 3

Q: What are your talking points when discussing cost with your patients?

As physicians, we often don’t get too caught up in the details of this, but it is important to emphasize that it very likely will take time for insurance companies and third-party payers to review this and ensure a patient meets the criteria for coverage. For example, I’ve heard rumors that some payers are expecting patients to meet eligibility requirements from the clinical trials that led to the approvals of these products and not just the indications in the FDA approval. These differences in coverage, interpretations and strict adherences can arise as potential issues that could slow up or delay the process of getting approval.

Physicians should be aware that because of the complexity and high cost, it’s unlikely to be a situation where you submit a referral and it’s approved 5 minutes later. Obviously, the patients will often come to the physician seeking guidance, but it’s often outside of our immediate scope and the best we can do is prepare patients in advance that there may be a barrier or delay.

It’s incumbent on us, as well, to be forthright about which patients we do refer. At a minimum, third party payers likely will be strict about the labeled indications for these, so physicians must ensure that you’re referring patients with conditions that are truly on-label. If you’re referring a patient with mantle cell lymphoma, for example, for a commercially approved CAR T-cell therapy, it probably won’t be covered because neither of the currently available products are approved for mantle cell lymphoma.

Q: How can physicians best mitigate that delay?

One of the challenges that most clinical oncologists face is we want to be able to provide therapeutic optimism about anything being delivered at that time, but we also need be realistic about the probability of that intervention being successful. For example, if you have a young adult with ALL who has relapsed multiple times and you’re giving them traditional multi-agent salvage chemotherapy, there’s a pretty good chance that person is not going to go into remission. If it’s someone with diffuse large B-cell lymphoma who relapsed 3 months after RCHOP, we might give them traditional second-line therapy, but the likelihood of that working is small.

We still hope that whatever we do as that salvage option is going to be successful and get the patient into remission and on to transplant, but the reality is that many times, that is not going to work and there are things to do on the back end to prepare.

PAGE BREAK

You might want to reach out to your transplant center, to say, ‘I have a patient with relapsed DLBCL that I’d like to refer for an autologous transplant if they respond to second-line therapy, but in the event they don’t, do you have a CAR T therapy program? Do you have slots open? Do you have any trials open?’

That gives you a sense of the lay of the land, so in the event your patient does not get into remission or they start to progress through treatment, you’re not caught flat-footed.

Q: Any pointers on taking the first steps with a patient in beginning CAR T-cell therapy?

Patient selection is important as is being realistic about your patient’s disease status. You need to be confident that a patient is (or that you can treat them to be) stable enough to ultimately get through the process of collection, lympho-depletion and cell infusion.

Then do take note of the starter questions in Table 3. It’s important to have a sense of those basic things before offering this therapy to patients. You certainly don’t want to offer someone this really exciting and potentially groundbreaking and revolutionary therapy only to find out they have to travel 1,000 miles to get it or they don’t have a caregiver but the referring center requires that for participation.

Understanding those basic, practical, logistical issues in advance will help do a better job of understanding which patients to whom we can genuinely and honestly recommend this therapy, so we are never pulling this option out from under them.

Disclosures: Cassaday reports research support from Kite/Gilead, Amgen, Merck and Seattle Genetics, as well as consultant roles with Amgen, Jazz Pharmaceuticals and Pfizer.