CAR T-Cell Therapy: A Healthcare Professional's Guide - Adverse Events
What is CAR T Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a form of gene therapy now FDA-approved in the U.S. This novel appraoch to cancer treatment is under study in patients with relapsed and refractory malignancies; lymphomas and leukemias are the furthest along in research.
Kymriah (tisagenlecleucel), from Novartis, was the first approved CAR-T cell therapy on August 30, 2017 for pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). Typically, these patients have run out of standard options for cancer treatment, which include surgery, radiation, chemotherapy, or bone marrow transplant.
CAR T-cell therapy works with the patient's own immune system to help boost the cancer-killing effects of the T lymphocyte (T-cell), a white blood cell. In one form of CAR T, a patient's T cells are separated out and engineered to express a chimeric antigen receptor (CAR) to target the tumor antigen CD19, a protein expressed on the surface of most B-cell lymphomas and leukemias. The re-engineered CAR T-cell is then re-infused back into the patient and redirects the T cells to kill the cancer. But CAR T-cell therapy is not for the faint-of-heart; side effects can be daunting and dangerous.
For an introductory review of tumor pathophysiology and CAR T-cell mechanisms, see these related slideshows:
Overview: Side Effects from CAR T-Cell Therapy
CAR T-cell therapy is a potent cancer treatment used in patients with high tumor burden. A positive response to CAR T-cell therapy leads to difficult, but often reversible, side effects of CAR T. Ironically, release of the cytokines brought on by the infusion of the CAR T-cell therapy, which shows a response to therapy, leads to many of these unique adverse reactions.
As studies continue in lymphomas, leukemias, and solid tumors, clinicians are learning how to manage these side effects, but fatalities have occurred. What are the expected adverse reactions to CAR T-cell therapy, and how are medical teams handling them?
Commonly reported adverse effects seen in CAR T-cell therapy clinical trials include:
- Cytokine Release Syndrome (CRS)
- B-Cell Aplasia
- Tumor-Lysis Syndrome
- Cerebral Edema
Cytokine Release Syndrome (CRS)
Cytokine Release Syndrome (CRS) is one of the most common, but worrisome, serious side effects of CAR T-cell therapy. On CAR T-cell drug labeling, a black box warning highlights this reaction, as well as neurologic toxicities. Because of the risk of CRS and neurologic toxicities, use of Yescarta also requires that a risk evaluation and mitigation strategy (Yescarta REMS) program be followed. Do not administer Yescarta to patients with active infection or inflammatory disorders.
How does CRS occur? After engineering, the CAR T-cells are reinfused back into the patient which leads to the release of cytokines (chemical messengers) like interleukin 6 (IL-6) and IL-15 into the bloodstream. The cytokines aid the CAR T-cells to begin tumor attack.
Due to cytokine release, very high fevers, sharp drops in blood pressure, tachycardia, and low oxygenation can occur, usually in the first week. Neurotoxicity such as delirium, confusion, and seizure may appear, as well. Patients with more extensive disease may experience more serious events. Ironically, CRS is an effect of T-cell activiation which denotes a positive repsonse to therapy. In the ZUMA-1 study of agressive B-cell non-Hodgkin lymphoma, CRS and neurotoxicity occurred in roughly 13% and 28% of patients, respectively.
CRS can be life-threatening, but is reversible in most patients. Administration of tocilizumab (Actmera), an agent that blocks IL-6, is used to manage cases of CRS, and researchers state that it does not appear to interfere with the CAR T cells' activity or proliferation. The addition of corticosteroids may be used as well. On August 30, 2017 the FDA approved Genentech's Actema to treat CRS associated with CAR-T therapy.
Neurotoxicity, which can occur in tandem with, or after resolution of cytokine release syndome (CRS), includes symptoms such as aphasia, tremor, and seizures. Other reported CNS events include ataxia and confusion. A black box warning is on Yescarta labeling for neurotoxicities.
The mechanisms leading to the symptoms are poorly understood, but active research is ongoing. Per package labeling for Yescarta, consider non-sedating, anti-seizure medicines (e.g., levetiracetam) for seizure prophylaxis for any Grade 2 or higher neurologic toxicities.
In the ZUMA-1 trial, Kite Pharma's pivotal trial for axicabtagene ciloleucel (Yescarta), grade 3 or higher neurological adverse events occurred in 28% of patients, and encephalopathy was noted in 21% of participants.
Somnolence, agitation, and delirium are other specific neurotoxic side effects reported to occur with CAR T-cell therapy.
Cerebral edema (brain swelling) is another very serious and sometimes fatal adverse event encountered with CAR T treatment.
Several cerebral edema-related deaths have been reported. Five deaths due to cerebral edema came from the now shelved JUNO JCAR015 - ROCKET study of adult ALL patients. Two deaths were from the JUNO JCAR014 trial. One death was reported in a Kite ZUMA-1 Phase 2 safety study on May 8th, 2017.
Axicabtagene ciloleucel (Yescarta) was submitted for FDA approval in March 2017 as treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL) who are ineligible for autologous stem cell transplant (ASCT). The FDA approved the agent on October 18, 2017.
The currently approved preconditioning lymphodepleting regimen in the product label for Yescarta is a regimen of cyclophosphamide and fludarabine before infusion of Yescarta.
Previously, it was suggested the chemotherapy drug fludarabine, part of this pre-conditioning treatment given to patients before CAR T-cell infusions, was to blame for cerebral edema. Some manufacturers removed fludarabine from their pre-conditioning regimens, but this was proven incorrect when there were still patient deaths.
Severe neurological side effects can occur with fludarabine treatment, even in the absence of CAR T-cell therapy. In addition, many patients that develop serious side effects such as cerebral edema are already high-risk patients with an extremely high tumor burden; they are out of treatment options.
Using tolicizumab (Actemra) earlier to head off CRS is now approved by the FDA. Researching ways to "turn off" CAR T-cell therapy when needed is ongoing.
B Cell Aplasia
One of the advantages of CAR T-cell therapy that targets the C19 tumor antigen is that C19 is not found on other cells except B cells, sparing other healthy tissues.
B cell aplasia occurs due to "on target-off tumor" toxicity, where the CAR T-cells destroy normal B cells. B cell aplasia is defined as low or absent B cells and is an expected side effect of CAR T. Depletion of B cells is near universal in patients treated with CAR T-cell therapy. Due to B cell depeletion, antibodies are not produced as readily and can lead to an elevated infection risk. B cell aplasia is managed with intravenous immunoglobulin (Ig) infusions.
CAR T-cells can persist in a patient after infusion, and this effect can augment prolonged remissions, but also lead to prolonged B cell depletion. It is not not known if B cell aplasia will be an ongoing or reversible effect over time. Researchers are still learning about the length of B cell aplasia due to CAR T, reported to last from months to years.
Tumor Lysis Syndrome
Tumor lysis syndrome (TLS) is another known and expected side effect of CAR T-cell therapy. TLS occurs due to cell death and subsequent release of content into the bloodstream. Multiple metabolic and electrolyte complications ensue. Hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia may occur. Complications such as renal insufficiency, cardiac arrhythmias, seizures, and death due to multiorgan failure are possible.
The onset can begin one month or more after CAR T-cell treatment, and is a common complication in hematologic cancers. It's effects can be life-threatening. Treatment is typically standard supportive therapy.
ZUMA -1: Other Adverse Events
- Anemia (43%), thrombocytopenia (24%)
- Neutropenia (39%), febrile neutropenia (31%), decreased neutrophil count (32%)
- Decreased WBC count (29%), decreased lymphocyte count (20%)
- Cytokine release syndrome, CRS (13%)
Three deaths were reported; 2 deemed related to therapy. One case was reported as hemophagocytic lymphohistiocytosis, where the immune system damages the patient’s own tissues and organs, and one cardiac arrest in the setting of CRS.
In addition, in May 2017 a death due to cerebral edema in a Phase 2 portion of ZUMA-1 was also reported. The patient had explosive, refractory non-Hodgkin lymphoma. According to the company, this was the first grade 5 cerebral edema event recorded in approximately 300 patients treated with axicabtagene ciloleucel. The sponsor noted that all axicabtagene ciloleucel development studies will continue as planned.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - Adverse Events
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