Summary
Patients with high-risk, relapsed or refractory large B-cell lymphoma showed a low incidence of cytokine release syndrome (CRS) or neurologic events when treated with lisocabtagene maraleucel (liso-cel), according to results from the TRANSCEND NHL 001 trial presented at the 2020 ASCO Annual Meeting (Abstract e20046).
Only 2 percent of participants developed severe CRS, while 10 percent developed severe neurotoxicity. Among patients who developed these adverse events, most symptoms were low-grade at presentation and had a late-onset.
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Original Article
Mostly Low-Grade, Late-Onset Toxicity With Liso-Cel in R/R Large B-Cell Lymphoma
Oncology Times
By Veronica Hackethal
Patients with high-risk, relapsed or refractory large B-cell lymphoma showed a low incidence of cytokine release syndrome (CRS) or neurologic events when treated with lisocabtagene maraleucel (liso-cel), according to results from the TRANSCEND NHL 001 trial presented at the 2020 ASCO Annual Meeting (Abstract e20046).
Only 2 percent of participants developed severe CRS, while 10 percent developed severe neurotoxicity. Among patients who developed these adverse events, most symptoms were low-grade at presentation and had a late-onset.
“Notably the majority of the 269 subjects on trial had no CRS or neurotoxicity,” principal investigator Jeremy Abramson, MD, told Oncology Times. Abramson is Director of the Lymphoma Program at Massachusetts General Hospital and Associate professor at Harvard Medical School.
Liso-cel is an investigational CAR T-cell therapy directed against the CD19 gycloprotein expressed on normal and malignant B cells. It is under development for the treatment of relapsed-refractory large B-cell lymphoma.
Study Details
The TRANSCEND NHL 001 study is an open-label, multicenter, non-randomized phase I study investigating the efficacy and safety of liso-cel among patients with relapsed/refractory B-cell non-Hodgkin lymphoma.
An analysis of 256 TRANSCEND NHL 001 participants presented at the 2019 American Society of Hematology (ASH) Annual Meeting suggested that liso-cel is associated with a high rate of durable response and low incidence of CRS and neurologic events.
To provide additional information on toxicities, researchers performed an analysis of 269 patients from the TRANSCEND NHL 001 trial. Included patients had undergone at least two prior lines of therapy and had a median age of 63 years. Thirty-eight percent had a high tumor burden and/or high levels of inflammation (sum of perpendicular diameters ≥50 cm2 on PET scan or lactate dehydrogenase ≥500 U/L). Participants received liso-cel after lymphodepletion with fludarabine and cyclophosphamide. Those with PET-positive disease were allowed bridging therapy, which was received by 59 percent. Researchers graded CRS according to 2014 Lee criteria, and neurological events according NCI CTCAE v4.03 criteria.
Overall, 42 percent (n=113) of participants experienced CRS of any grade and 30 percent (n=80) experienced neurologic events of any grade. Participants showed a low incidence of severe events (grade 3 or higher), with severe CRS occurring in 2 percent (n=6) and severe neurologic events occurring in 10 percent (n=27). No participants experienced grade 5 CRS or neurologic events. Four percent of patients required ICU care for CRS and/or neurologic events.
Both CRS and neurologic events showed delayed onset (median 5 days [1-14] and 9 days [1-66], respectively). Median time to resolution was 5 days (1-17) for CRS, and 11 days (1-86) for neurologic events. CRS most commonly developed before neurologic symptoms and was mild (grade 1/2) at onset in all but two patients.
The most common CRS symptoms included pyrexia (40%), hypotension (20%), and tachycardia (18%). The most common neurologic symptoms were confusional state (11%), tremor (9%), and aphasia (8%).
Tocilizumab and/or corticosteroids were used to treat CRS in 20 percent and neurologic symptoms in 17 percent of patients (see Table for details).
| CRS | Neurologic Events | |
|---|---|---|
| Tocilizumab only | 10% | <1% |
| Corticosteroids only | 2% | 13% |
| Both tocilizumab and corticosteroids | 8% | 3% |
| Vasopressors | 3% | <1% |
A prior analysis of 102 patients in the TRANSCEND NHL 001 study also showed low incidence of severe CRS or neurologic events (J Clin Oncol 2019;37(15 suppl). However, severe grade 3-4 toxicity was associated with a 328 percent increase in costs compared to milder toxicity, with costs driven mainly by hospitalizations.
Abramson discussed ways to prevent severe CRS and neurologic events. “One way to reduce health care cost is to consider the rates of severe CRS and neurotoxicity when selecting among available CAR T-cell products, and select a product that is associated with less severe toxicity,” he noted. “This could mean selecting a 4-1 BB co-stimulated product like lisocabtagene maraleucel or tisagenlecleucel, relative to a CD28-costimulated product like axicabtagene ciloleucel.”
Another strategy could be earlier use of corticosteroids when managing CRS.
“Administering steroids at the time of grade 1 CRS instead of grade 2 or higher appeared to reduce the progression to severe CRS in a study with axicabtagene ciloleucel, which would be a favorable result in patients due to decreased severe toxicity, and to the healthcare system by decreasing costs,” he added.
Veronica Hackethal is a contributing writer.