Predicting and Managing Toxicities of Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma

A 68-year-old man with relapsed stage IIIA diffuse large B-cell lymphoma (DLBCL) without comorbidities is referred for consideration of chimeric antigen receptor T-cell (CAR-T) therapy. Molecular profiling of a pathological specimen at diagnosis demonstrated germinal center double-hit lymphoma. He received six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for initial therapy, followed by progression at six-month restaging. He then received two cycles of R-ICE (rituximab, ifosfamide, carboplatin, etoposide) as second-line therapy, with plans for consolidative autologous hematopoietic stem cell transplantation. Now, his positron emission tomography/computed tomography scan demonstrated bilateral involvement of the axillary, inguinal, retroperitoneal, and para-aortic nodes, the largest conglomerate, which measures 3 cm in its largest dimension. Autologous transplantation is deferred, and the patient is referred for consideration of salvage CAR-T therapy. Vital organ test results included a negative respiratory viral swab, normal pulmonary function, adequate left ventricular ejection fraction on echocardiogram, and a low-risk psychosocial profile showing strong caregiver support. Laboratory studies, including C-reactive protein (CRP), are normal except for elevated lactate dehydrogenase. He reports some fatigue and decreased exercise tolerance; however, he continues to walk three miles daily.

No patient should expect to go through CAR-T therapy without some bumps in the road. The treatment timeline and steps must be described in detail, both verbally and via robust written material, by the treating physician and a care coordinator. This includes vital organ testing, the apheresis procedure, fludarabine and cyclophosphamide conditioning chemotherapy, infusion of the cells, and the monitoring and likelihood of toxicities. The two most common toxicities after CAR-T therapy are CRS and neurotoxicity, now called “immune effector cell–associated neurotoxicity syndrome” (ICANS).¹  High fevers are the hallmark of CRS, which is associated with elevation of cytokines and chemokines after adoptive transfer of CAR-Ts. Hypotension, hypoxia, and resultant organ failure occur in more severe cases. ICANS is a constellation of signs and symptoms that can range from mild confusion to severe aphasia, obtundation, or seizures. The incidence of CRS and ICANS is approximately 58 and 21 percent, respectively, with tisagenlecleucel, and roughly 93 and 64 percent with axicabtagene ciloleucel, which are the two currently approved agents available for third-line DLBCL treatment.^2,3  Regulatory approval for lisocabtagene maraleucel, with CRS and ICANS rates of approximately 42 and 30 percent, respectively, in DLBCL, is expected in 2021.⁴  Even “mild” cases of CRS can involve prolonged high fevers of 40°C and severe constitutional symptoms. Severe CRS occurs in one to 13 percent of patients, while severe ICANS occurs in 10 to 37 percent of patients, with incidence varying across the different agents.

Both CRS and ICANS are typically transient, with almost all cases resolving within two weeks of CAR-T treatment. The chance of a patient dying from the treatment itself as opposed to progressive DLBCL is approximately 3 percent, with infections or rare complications associated with CRS (e.g., multiorgan dysfunction) or ICANS (e.g., cerebral edema) as likely causes. While the toxicity rates may impact the decision as to which CAR-T therapy to select, differences in the pivotal trial designs preclude direct comparisons of not only toxicity rates but also efficacy of the therapies; therefore, physician and center preference play a large role.

The care team is composed of numerous clinicians including infectious disease specialists, nocturnists, psychologists, nurses, pharmacists, and social workers.⁵  A multidisciplinary tumor board allows for discussion of patients at consult and again immediately prior to proceeding with CAR-T therapy, with a goal of consensus recommendation for therapy. Essential points of discussion include confirmation of diagnostic testing, the prior lines of therapy, clarification of comorbidities, elucidation of social support, and consideration of performance status. Not only must the patient meet the label approved indication or clinical trial eligibility for CAR-T therapy, but the team must be sure that the patient can benefit without undue risk of death or comorbidity. Several of the same features associated with high rates of toxicity are also associated with decreased opportunity for prolonged disease-free survival (DFS).⁶  The common and easily identifiable clinical features are a poor performance status and high disease burden.⁷  Patients with poor performance status often have elevation of proinflammatory markers such as CRP, ferritin, and IL-6, which are also independently associated with higher CRS and ICANS rates and lower opportunity for durable response.⁸  High tumor burden, when measured by a multidimensional approach or by metabolic tumor volume, is also associated with worse clinical outcomes.⁹  However, the opportunity for prolonged DFS following CAR-T therapy remains even in patients with these poor prognostic baseline features. Older patients without comorbidities can expect efficacy and toxicity outcomes similar to those of younger patients, though older patients who develop severe CRS or ICANS may require a longer recovery period owing to deconditioning brought on by a prolonged bed-bound state.¹⁰ 

In our clinical practice, the presence of several of the following features typically preclude selection of CAR-T therapy as a treatment option: dynamic rapidly progressing disease (daily measurable growth or significant growth between cycles of salvage), poor performance status (Eastern Cooperative Oncology Group performance status, 2-4) that cannot be expected to improve with bridging therapy, or extreme elevation of ferritin or CRP. Early referral to a CAR-T treatment center is key to avoid these situations, with referral consideration at first relapse after frontline therapy.

Conditioning chemotherapy before CAR-T infusion is typically administered in the outpatient setting. Most patients treated on the pivotal clinical trials were then admitted for CAR-T therapy infusion to allow for close monitoring and management of toxicities. In real-world practice, many centers are infusing tisagenlecleucel on an outpatient basis. Axicabtagene ciloleucel is rarely infused as an outpatient due to high rates of CRS-associated fevers, accompanied by neutropenia associated with the conditioning chemotherapy, within a few days of infusion. Beyond the safety profile of the CAR-T therapy, other factors must be considered before selecting a patient for outpatient infusion, including 24-hour caregiver availability and capability, performance status, comorbidities, and distance to the treating center. Patients with extremely high tumor burden or proinflammatory markers are generally poor candidates for outpatient infusion.

The ability to give CAR-Ts as an outpatient should not be confused with ease of setting up and managing a CAR-T program. The infrastructure necessary to safely administer CAR-Ts on an outpatient basis is greater than that needed to treat patients in the hospital. Requirements include additional caregiver training, 24-hour on-call staff trained on CAR-T therapy adverse effects, easy admission procedures and bed availability if CRS/ICANS develop, lodging within minutes of the treating center, and a robust outpatient treatment facility to allow for frequent visits and potential intravenous treatments.

A decision is made to proceed with axicabtagene ciloleucel. The patient receives fludarabine and cyclophosphamide conditioning without incident and is admitted for CAR-T therapy infusion. On day +2, the patient is found to have a temperature of 39.8°C and low blood pressure, which responds to intravenous fluid infusion and does not require vasopressor support. The patient does not have signs or symptoms of ICANS.

The patient is placed on broad spectrum antibiotics in the face of neutropenia and fever. His temperature and blood pressure normalize after a single treatment of tocilizumab and dexamethasone. In the absence of other new symptoms, he is discharged on day +10 following neutrophil count recovery. On day +30 and again on day +90, his restaging scans show complete remission.