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Treatment Toxicities: Present, but Manageable
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In this installment of In Practice, Frederick L. Locke, MD, Co-Leader of the Immunology Program and Director of the Immune Cell Therapy Program at Moffitt Cancer Center, discusses the side effects and toxicities of CAR T-cell treatments. Though he acknowledges they are common, he emphasizes that they should not hinder the referral of patients who are candidates for these potentially ‘lifesaving treatments.’
As many of you likely heard from ASH 2018, side effects in real-world studies are proving to be similar, if not lower, than those seen in clinical trials, further proving Locke’s point in this column.
In our upcoming installments, we are considering looking at navigating financial concerns as well as post-therapy transfer back to the community oncologist. If there is a practical concern you would like addressed, please email us at CellTherapyNext@Healio.com.
Q: How do you prepare patients and their caregivers for CAR T-cell treatment?
Beginning with the initial consult to discuss CAR T-cell therapy, once we have confirmed that the patient will potentially benefit from the therapy, we discuss the entirety of the treatment timeline and provide written educational materials and a personalized calendar. First, we set the stage for the vital organ testing, which allows identification of any comorbidities that may increase the chances of a poor outcome if complications arise or could even lead us to avoid CAR T-cell therapy. Following testing is the apheresis procedure where the T-cells are collected, which we describe in detail. We then discuss the timing of the therapy itself, which begins with possible bridging chemotherapy, given inpatient or outpatient while we await manufacture of the CAR T-cells, often under the direction of the referring oncologist. Once the cells are shipped back to our center, we begin the conditioning chemotherapy which is typically done as an outpatient, and then we typically admit our patients to the hospital for the infusion of the CAR T-cells.
We then discuss the potential toxicities that a patient may experience. The two broad categories of toxicities are the cytokine release syndrome and the neurologic toxicities, both of which are attributed to CAR T-cell therapy, but occur on different timelines in many patients. We often see cytokine release syndrome occurring early – within days – and the neurologic toxicities, if they occur, may happen a number of days after the cytokine release syndrome starts or, sometimes, after it resolves. Although these two toxicities are generally reversible, we always tell our patients about the possibility of treatment-related mortality, as with any medical therapy.
All of these steps are outlined upfront for the patient and described in detail, first by an advanced practice professional and next one-on-one by a physician. Finally, our cellular therapy nurse coordinators meet with the patient to outline the likely calendar and go over take-home materials that outline the therapy, the toxicities, and what our expectations are for them and their caregiver. We have our own internal materials but we also make use of the Leukemia and Lymphoma Society’s materials that are geared toward these patients.
Lastly, we have a class that the patient and caregiver attend so that they can understand what to expect. At our center, this class offers instruction on where to go, what numbers to call, what things to look out for if they’re offsite and if a new symptom occurs, etc. The class is typically completed during the vital organ testing period. It is modeled after our transplant class, which has a separate class for patient and caregiver, but for now, we’ve combined those into one class for our CAR T-cell recipients and their caregivers.
Our main goal during the pre-treatment period is to inform the patient and their caregiver what are the possible outcomes and side effects of CAR T-cell therapy.
Q: What are the side effects or toxicities of which new treaters should be most aware?
As mentioned, cytokine release syndrome and neurological toxicities are the most common CAR T-cell associated toxicities that we see. However, all patients first receive conditioning chemotherapy, which causes myelosuppression. Since the majority of patients have neutropenia, if a fever occurs patients must be carefully worked up for infectious sources even though statistically it may be most likely attributed to the cytokine release syndrome. Management of any patient following CAR T-cell therapy requires rapid evaluation for signs of infection and initiation of broad-spectrum antibiotics for fevers.
We monitor these patients closely and if the cytokine release syndrome starts off severe or worsens rapidly in that the patient needs oxygen or significant IV fluids, those are patients we would want to intervene quickly with the anti-IL-6-receptor antibody, tocilizumab, and if needed, with corticosteroids. We believe that the earlier use of these agents reduces the likelihood of their progression to severe toxicities.
The neurologic toxicities typically manifest a little later. We typically see an expressive aphasia, but we see everything from mild confusion, delirium, obtundation, or seizures. Often patients will have little recollection of the events and caregivers will report worse neurological side effects than the patient recalls. These neurological toxicities are primarily treated with corticosteroids and supportive care and, importantly, they are almost always reversible and end within a few weeks of CAR T-cell therapy.
CAR T-cell therapy offers a chance at durable remission for patients with little other options, however the toxicities can be severe. We take care to first educate our patients and their caregivers in depth, so they are well aware of these possible toxicities.
Q: Are there red flags that physicians should consider prior to delivering CAR T-cell therapy?
There are a number of things for which physicians should be on the lookout: overall fitness during vital organ testing, rapidly progressing disease, active infection or any other pro-inflammatory state. In these cases, we often take pause to confirm and re-assess the risks of proceeding with the treatment.
Patients with a pro-inflammatory state – at least those with lymphoma undergoing CAR T-cell therapy – appear to be the ones that have the highest risk for toxicities and also the least likely to benefit with durable responses. If there is a treatable infection, we will treat it prior to giving the cells, and in some cases, we’ll give bridging chemotherapy to reduce the tumor burden prior to delivering the CAR T-cells.
In any reassessment or hesitation, we state the facts to the patient. We want to be sensitive to their situation, but we want to give the patient the best opportunity for the therapy to work. If a patient has rapidly progressing disease, they are the least likely to benefit from infusing the cells in that state and most likely to have toxicities. If we can reduce the disease burden or treat infection to reduce the pro-inflammatory state, we will do so and hopefully give the patient better odds for success.
The light at the end of the tunnel whenever you’re discussing toxicities is that this person may have a remission that can last months and even years. The toxicities typically go away within the first month, so it’s a risk, but there’s certainly a potential reward.
Q: Are there any long-lasting effects that you are seeing from these toxicities?
There are potential toxicities that can go on beyond the first month. Those include immunosuppression, myelosuppression, low counts and also being at risk for infections. One of the on-target side effects is the disappearance of normal B cells, which fight infection.
Patients are at risk for infections and should be monitored as such. We send patients back to their local oncologist and we will give parameters for their bloodwork to be checked, infusion of growth factors and IVIG. Patients with infection after CAR T therapy need to be checked rapidly.
Q: What else do you want other physicians to know about managing toxicities with CAR T-cell therapy?
These toxicities are manageable. Doctors with expertise are able to manage these and get patients through, even elderly patients or those patients with significant comorbidities.
The biggest problem I see in the field right now is that community oncologists are not referring patients early enough or at all even though they qualify for CAR T-cell therapies. In fact, patients are missing out on the opportunity for lifesaving treatment because of misinformation about the tolerability and safety of the therapy or misunderstandings about whether the therapy would be covered by insurance.
I encourage community physicians to consider referral for their patients as early as the time of first relapse. This allows time to plan for autologous hematopoietic transplant or CAR T depending upon the response to second-line therapy. Given that it takes on average 3 weeks for CAR T manufacturing, the earlier we consider the process and plan for it, the easier it is to get the patient to the therapy. We are confident that this therapy can lead to long-term and durable remissions in some patients, but that is only if the patients are referred early.
- For more information:
- Frederick L. Locke, MD, can be reached at Moffitt Cancer Center, 12902 USF Magnolia Dr., Tampa, FL 33612; email: frederick.locke@moffitt.org.
Disclosures: Locke reports scientific advisory roles with Kite Pharma and Novartis, as well as a consultant role with Cellular Biomedicine Group Inc.