Core Framework Identifies Early Onset of CAR T-Cell Therapy Symptoms at Home

A team of Dutch investigators curated a list of 28 possible toxicities related to CAR T-cell therapy administration which indicate that a patient needs to present to the acute care center for evaluation and proper management. Results from their research were published in JCO Oncology Practice.

The goal of this framework is to allow for safe CAR T-cell therapy toxicity monitoring in the outpatient setting. The authors outlined how each of these symptoms can be monitored and gave a measurement of when each of the symptoms have reached, what they deemed, red flag status requiring immediate attention.

According to investigators, the following red flags could be monitored via a wearable device: fever (> 38 °C), low blood pressure (< i90 mmHg), and a high heart rate (> 120 BPM).

An immune effector cell–associated encephalopathy (ICE) assessment could be used to assess encephalopathy or altered mental status. An ICE score of less than 10 would represent a red flag. The Alert, responsive to Voice, responsive to Pain, Unresponsive level of consciousness (AVPU) assessment could be used to monitor a low level of consciousness, and a red flag would be if that patient was only response to voice, pain, or if they were completely unresponsive.

Many of the parameters in the assessment would be monitored through a question to the patient or caregiver and responded to on a scale and may require demonstration to be assessed via a physical evaluation. For example, weakness of arms or legs at a 1 would be marked by the patient suddenly not being able to lift their arms or legs or being unable to stand up from a chair. Difficulty walking or a change in walking pattern is another symptom, and cause for concern would be appropriate if they were suddenly not able to walk at all, in a straight line, or unable to keep an upright posture.

Difficulty speaking or understanding language should be flagged if the patient demonstrates slurred speech, uncomprehensive speech, or difficulty speaking or understanding language. If the patient is suddenly not able to lift 1 corner of the mouth, that is also cause for concern.

New or worsening shaking or twitching limbs, acute hearing loss, vision abnormalities, memory loss, dizziness, and shortness of breath are all reasons to contact a health care provider. A severe headache (pain score > 7), which does not go away within hours or with pain medication is a red flag. Similarly, vomiting 3 or more times in 1 day, diarrhea 4 or more times in 1 day, and a cough—especially one that is accompanied by fever, blood in sputum, dyspnea, hypoxemia, or acute chest pain. Lastly, problems with intake of medications or fluids (being unable to drink at least 1 L of fluids/day), spontaneous nose bleeds, blood in urine, stool, sputum or vomit, and painful skin changes, such as blisters, should be reported to health care professionals right away.

“The core set of [a patient- and caregiver-reported outcomes] P/CROs, including specific definitions of red flags, provided in this study contributes to strategies enhancing safe outpatient monitoring and fosters wider implementation of CAR T-cell therapy,” Anne M. Spanjaart, MD, PhD, a clinical hematologist at Amsterdam University Medical Center, and colleagues, wrote in the study. “This will not only help to control costs, improving affordability and accessibility of CAR T-cell therapy, but is also believed to increase patient’s satisfaction with received care and [quality of life] QOL.”

CAR T-cell therapy has led to high complete response rates across various settings of relapsed or refractory hematology malignancies. However, it is also associated with toxicities which be potentially-life threatening if they are not promptly recognized, such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and infections. For this reason, most centers administer CAR T-cell therapy in the inpatient setting and require patients to stay in-hospital for at least 7 to 10 days postinfusion. This is usually followed by an intensive outpatient follow-up period leading up to 28 days postinfusion.

As more CAR T-cell therapy indications and products are approved, the authors noted there is a growing need to reduce the length of inpatient stays associated with infusion. Tools designed to help educate caregivers on potential complications, that can monitor and report potential toxicities that patients experience back to health care providers, are believed to be key in broadening the implementation of outpatient CAR T-cell therapy delivery. However, standardizing caregiver education, and creating clear markers for when they should present to the clinic, represent a key part of designing these health tools.

Therefore, investigators sought to compile a core set of signs and symptoms, along with red flags warranting immediate action, to include in a daily checklist for at-home use. To do so, they performed a systematic review of phase 2 and 3 trials leading to an FDA approval of CAR T-cell products, and selected all common and severe adverse events that could be transplanted into a P/CPO. The analysis included 9 clinical trials, with 457 adverse events—42 of which were identified as being applicable for use as a P/CRO. The final framework had 28 items, including 5 signs that could be measured with wearable devices, and 2 signs which could be measured through caregiver performed assessments.

Investigators noted that 1 disadvantage of this work is that all the contributing authors were Dutch; an international validation of the framework may be valuable. In addition, few patients were involved in the evaluation of the core set. However, they also noted that the framework is advantageous, as it can be implemented in numerous ways. One such way is to create a remote patient monitoring platform, such as a smartphone app connect to wearable devices—these could be used in conjunction with regular visits. The framework may also be used to help predict clinical outcomes, as well as be used to help education and guide formal caregivers who lack extensive CAR T-cell therapy experience.

“This is the first evidence and consensus- based core set of P/CROs including specific definitions of red flags providing a framework for (eHealth) tools aiming to empower patients and their caregivers to more effectively recognize and report signs and symptoms of acute CAR T-cell–mediated toxicities during the early outpatient treatment phase,” study authors concluded. “If this framework incorporated in an eHealth tool is proven to have adequate usability and feasibility, this tool could be used in studies investigating strategies to reduce hospital visits in the first month after CAR T-cell infusion and/or enable early discharge or even complete ambulatory treatment.”

Reference

Spanjaart AM, Pennings ERA, Kos M, et al. Development of a core set of patient- and caregiver-reported signs and symptoms to facilitate early recognition of acute chimeric antigen receptor T-cell therapy toxicities. JCO Oncol Pract. 2023;(3):e407-e416. doi:10.1200/OP.22.00501