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Division of Medical Oncology
Department of Medicine
Harvard Medical School
Dana-Farber Cancer Institute
Caron A. Jacobson, MD, has disclosed that she has received consulting fees from AbbVie, Bluebird, Bristol-Myers Squibb/Celgene, Kite, Lonza, Nkarta, Novartis, and Precision Biosciences and funds for research support from Kite.
Although CAR T‑cells are potentially curative for many patients with high‑risk leukemias and lymphomas who lack other treatment options, both lymphodepleting chemotherapy and CAR T-cells markedly compromise the humoral immune system for 1 year or longer. Despite the potentially increased risk of severe COVID-19 infection for these immunocompromised patients, many centers—including mine—have decided not to withhold life‑saving therapy.
Below, I share my center’s experiences in overcoming the many challenges to the safe administration of CAR T-cell therapy presented by COVID-19.
Potential Concerns With COVID-19 Infection
Our currently approved CD19-targeted CAR T-cell therapies can immunocompromise patients via on‑target and off‑target effects, potentially increasing patients’ risk of severe COVID-19 if they become infected. By targeting CD19, which is present on malignant and normal B-cells, CAR T-cells can cause B‑cell aplasia that can last for 1 year or longer, in some cases. In addition, patients can be rendered T‑cell lymphopenic for some time due to fludarabine and cyclophosphamide lymphodepletion and possibly CAR T‑cell therapy itself. Although some recover within 6 months, others experience T‑cell lymphopenia for as long as 18 months after CAR T‑cell therapy.
Unfortunately, we have observed that patients in cancer remission with good blood counts (eg, CD4+ T-cells >200 cells/µL, IgG >400 mg/dL) more than 1 year after CAR T‑cell therapy can experience a protracted COVID-19 infection. Although some only develop low‑grade symptoms, others became quite ill and were unable to clear COVID-19. These are some of the sickest patients with COVID-19 I have seen.
These observations support many healthcare professionals’ concerns about the impact of CAR T‑cells on the immune system and underscore the importance of following strict precautions against COVID-19 for patients receiving CAR T‑cell therapy.
COVID-19 Screening and Quarantining
We make sure that all patients are negative for COVID‑19 both before starting outpatient lymphodepletion and before hospital admission. Those 2 negative tests make us more confident that if a patient spikes a fever, it is most likely due to cytokine-release syndrome (CRS)—a key CAR T‑cell therapy-related adverse event—and not hospital-acquired COVID-19.
A related issue is that patients who develop fever, body aches, fatigue, headaches, general malaise, and/or low blood pressure—symptoms of CAR T‑cell–related toxicities—need to be screened for COVID-19. Before the advent of rapid COVID-19 testing, they needed to be isolated in negative‑pressure rooms. Given that the vast majority of CAR T‑cell–treated patients develop these symptoms after receiving CAR T‑cells, the dilemma was whether we should move patients from their admission bed, where they were being taken care of by nurses trained in CAR T‑cell therapy and toxicities, and move them to another part of the hospital until they received their COVID-19 results. We decided that if a patient experienced symptoms within the expected window for CRS and there were no indications of COVID-19, then these patients did not need to be moved. Now that we have rapid testing, we can get an answer within an hour and avoid this complicated dilemma.
We do not know yet whether patients will respond adequately to COVID-19 vaccines after CAR T‑cell therapy, and the best timing for vaccination in these patients is unknown. Our institution is currently conducting a study where we vaccinate patients 3 or more months after CAR T‑cell therapy. For the first 20 patients vaccinated in a 3‑ to 12‑month window after CAR T‑cell therapy, we will check for COVID-19 antibodies to see if they are developing a protective immune response after vaccination.
COVID-19 has also complicated CAR T‑cell therapy for reasons related to hospital resources and general policies. For example, tocilizumab is used to treat CRS and was also used early in the pandemic to treat severe COVID-19. A sufficient supply of tocilizumab is required at all times to manage CRS in patients receiving CAR T‑cells; our institution ensured that we had an oncology supply and a nononcology supply that guaranteed we had sufficient tocilizumab for all of our patients.
Another complicating factor was bed availability and ICU volume. Because some centers reached full ICU capacity due to COVID-19, that potentially meant our CAR T‑cell–treated patients would not have an ICU bed available if they needed it. Our institution created a priority system for CAR T‑cell therapy that would allow us to delay therapy for lower-priority patients if our hospital reaches surge capacity. The priority system factored in who could wait for their CAR T‑cell therapy and also who was most likely to benefit, as we have learned from clinical trials and real‑world studies that certain comorbidities, pretreatment disease characteristics, and patient factors predict for less long-term benefit with CAR T‑cell therapy. Thankfully, we have not needed to employ that priority system.
Inpatient vs Outpatient
Another quandary faced by many centers was whether to treat patients with CAR T-cell therapy in the inpatient or outpatient setting. On the one hand, treating in the outpatient setting means that you can free up hospital beds in the event of a COVID-19 surge. On the other hand, it can be very complicated to do an unplanned admission for a patient with a fever, as we do not want to bring in patients with fevers until we know that these are related to CRS and not COVID-19. Thus, we have not been doing any outpatient CAR T‑cell therapy during the pandemic. That being said, other centers have prioritized outpatient CAR T-cell therapy because this approach decreases inpatient volume.
What challenges have you faced in administering CAR T-cell therapies during the COVID-19 pandemic? Answer the polling question and join the conversation by posting a comment in the discussion section.
To get individualized recommendations on CRS and neurotoxicity management from multidisciplinary experts, please visit CCO’s Interactive Decision Support Tool: Assessment and Management of CAR T-Cell Toxicities (update coming soon!).