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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, Bristol-Myers Squibb/Celgene, Bluebird Bio, Kite, Lonza, Nkarta, Novartis, and Precision Biosciences and funds for research support from Kite.
Although CAR T‑cell therapies can offer significantly improved outcomes for many patients with high‑risk leukemias, lymphomas, and myelomas who lack other treatment options, these products can be associated with a unique spectrum of toxicities that physicians and nurses must be adept at managing. The most worrisome adverse events of CAR T‑cell therapy—cytokine-release syndrome and neurologic toxicity—tend to occur in the first 1‑4 weeks following infusion. This is typically when the patient is still in close proximity to the CAR T‑cell treatment center and able to seek care from experienced physicians and hospital staff. But, as patients transition from their CAR T‑cell treatment center back to their local and community oncology clinic, there are notable potential delayed adverse events that their oncologists need to keep in mind.
In clinical trials, approximately one quarter of patients who received CAR T‑cell therapy had delayed or prolonged cytopenias (neutropenia, anemia, or thrombocytopenia). Cytopenias associated with CAR T-cell therapy can be severe enough to necessitate intermittent granulocyte colony-stimulating factor (G-CSF) for neutrophil support, blood transfusions, and/or platelet transfusions.
Some patients experiencing cytopenias will have had a blood count nadir with their lymphodepleting chemotherapy that recovers by the approximately 2‑week mark, with blood counts then falling again; other patients will have never recovered their counts.
Although cytopenias can occur for several reasons (including underlying bone marrow disorders or diminished bone marrow reserve after heavy pretreatment), most commonly, we find no clear cause and assume cytopenias occur as an immunologic class effect related to CAR T‑cell therapy. Cytopenias have been observed with CAR T-cell therapy across B-cell malignancies and with BCMA-targeted and CD19-targeted CAR T-cells.
Many patients will recover their blood counts after experiencing cytopenias, but it may take months. For the 25% of patients who have recurrent cytopenias, blood counts should be routinely monitored in the outpatient setting to identify the need for both G‑CSF and transfusional support. If blood counts remain low for longer than 6‑12 months, I typically recommend getting a bone marrow biopsy to look for other causes of cytopenias.
B‑Cell Aplasia and Hypogammaglobulinemia
Other important adverse events that can occur specifically with CD19-targeted CAR T-cell therapy are B‑cell aplasia and hypogammaglobulinemia. These are off‑tumor, on‑target effects of the CAR T-cells on the healthy B‑cell compartment. It is not clear whether prophylactic infusions of intravenous immune globulin (IVIg) for hypogammaglobulinemia are necessary or protective for patients, and practice varies globally. Some healthcare professionals follow IgG levels and give patients an infusion of IVIg if IgG drops <400 mg/dL. Others only recommend infusions for patients with recurrent or serious infections. Both practices can be considered, and we don’t know which one is best.
Immune Suppression and Infections
Of importance, the immune suppression associated with CAR T-cell therapy can persist past that initial 4‑week window. Physicians need to be mindful of the fact that not only can CAR T-cell therapy cause B‑cell aplasia, but also preinfusion lymphodepletion with fludarabine and cyclophosphamide can lead to T‑cell lymphopenia that can last for 12‑18 months, often with CD4+ cell counts well below 200 cells/μL. At my institution, we do prophylax our patients with sulfamethoxazole/trimethoprim for Pneumocystis jirovecii pneumonia (PJP) and with acyclovir for herpes zoster and other herpes virus infections. We continue this prophylaxis from the time of lymphodepletion through 6 months after the CAR T‑cell infusion. We check CD4+ cell counts starting at 6 months, and only stop antiviral and antibiotic therapies when a patient’s CD4+ cell count rebounds to >200 cells/μL. There have been cases of breakthrough PJP in patients whose cell count has recovered. Therefore, it is important to be mindful and to continue to be on alert for atypical infections in a patient with pulmonary symptoms following CAR T‑cell therapy.
Approximately 50% to 60% of patients treated with CAR T‑cells will develop infections. Most are bacterial infections and are not serious enough to require hospitalization. Patients can also develop viral infections. For patients who receive prolonged steroids to help manage acute toxicities related to CAR T‑cell therapy, namely cytokine-release syndrome and neurologic toxicities, we do worry about fungal infections as well as cytomegalovirus reactivation. In our clinic, we continue to monitor patients for these infections for at least 1 month after their last dose of steroids.
The optimal timing of vaccination after CAR T‑cell therapy remains unclear. At my institution, for one-time vaccines like the shingles vaccine, we typically wait 12 months after therapy. Likewise, if a patient receiving posttransplantation vaccines relapses before they finish the vaccination course and starts CAR T‑cell therapy, we will wait 1 year before reinitiating the vaccine(s). For vaccines like the influenza vaccine that are only effective for 1 year, we tend to vaccinate patients as long as they are at least 3 months out from their CAR T‑cell therapy.
Similarly, with COVID-19 vaccination, we typically vaccinate patients who are at least 3 months out from CAR T‑cell therapy. However, we have found that many do not appear to produce antibodies against the spike protein; we don’t know if the production of antibodies represents the full measure of immunity with COVID-19 vaccination but suspect that these patients may have had a less-vigorous immune response to the vaccine. Hopefully, the optimal timing to vaccinate patients after CAR T-cell therapy will become clear, including timing for a probable COVID-19 booster shot.
Have you encountered delayed adverse events in patients who have received CAR T-cell therapy? If so, how did you manage these? Answer the polling question and join the conversation by posting a comment in the discussion section.
To get individualized recommendations on cytokine-release syndrome and neurotoxicity management from multidisciplinary experts, please visit CCO’s Interactive Decision Support Tool: Assessment and Management of CAR T-Cell Toxicities. Also, download a PDF with key considerations for assessing and managing adverse events that can occur in patients being treated with CAR T-cell therapy.