© ASCO/Brian Powers
CHICAGO—Treatment dose and schedule, as well as a patient’s tumor burden, influence the outcome of therapy with chimeric antigen receptor (CAR) T cells, according to research presented at the 2016 ASCO Annual Meeting.
One presentation suggested the dose and schedule of CTL019 can impact both complete response (CR) rates and the incidence of cytokine release syndrome (CRS).
Another presentation indicated that disease burden may determine the risk of toxicity and correlate with the efficacy of JCAR015.
Noelle Frey, MD, of the University of Pennsylvania in Philadelphia, presented results observed with CTL019 in 30 adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) treated on 2 trials (NCT02030847 and NCT01029366) as abstract 7002.*
Dr Frey noted that CAR T-cell therapies, including CTL019, have led to “unprecedented remission rates of between 70% and 90%.” However, immune activation that leads to high response rates also confers significant treatment-related toxicity—namely, CRS.
She reported that, in the 2 trials of adult ALL patients, a high dose of CTL019 led to a 100% response rate and a 100% CRS rate. Splitting the dose over 3 days led to an 86% response rate and a 66% CRS rate. A single low dose reduced efficacy to 33% and CRS to 66%.
Three of 6 patients who received a single high dose developed CRS and died within weeks. All of these patients had infections or sepsis that likely led to their deaths, Dr Frey said. She suggested clinicians aggressively monitor infections and treat with antimicrobials prior to CAR T-cell therapy.
“The infusion dose and schedule of CTL019 correlate with toxicity and response,” she observed. “A fractionated dosing scheme allows for real-time intra-patient dose modification in response to toxicity and the maintenance of high response rates. Concurrent sepsis and CRS confers a poor outcome.”
Dr Frey said future studies will determine the optimal approach to minimize toxicity while maintaining high efficacy. A fractionated dosing scheme is only one way to mitigate CRS. Other attractive approaches include inverse dosing based on disease burden and varying the timing of anti-cytokine-directed therapy.
Treatment with JCAR015 led to high CR rates and minimal residual disease (MRD)-negativity, regardless of the amount of disease at baseline. However, outcomes were superior among patients with minimal disease at baseline.
For patients with morphologic disease, 77% achieved a CR by 20 days after treatment, and 90% were MRD-negative.
For those with minimal disease, 90% achieved a CR by 25 days after treatment, and 78% were MRD-negative. These patients experienced significantly less CRS and neurotoxicity than patients with morphologic disease.
“High CR and MRD-negativity rates were observed regardless of pre-T-cell burden,” Dr Park noted. “We observed durable responses and survivals in a subset of patients with no subsequent allotransplant in both morphological and minimal disease cohorts.”
*Data in the abstracts differ from the presentations.