CAR T-Cell Therapy Yields Impressive Responses in Aggressive Non-Hodgkin Lymphoma

August 2018 Vol 11, Special Issue - Breast Cancer
Chase Doyle

Chicago, IL—Lisocabtagene maraleucel (liso-cel), an investigational CD19-directed chimeric antigen receptor (CAR) T-cell therapy, has induced durable responses in high-risk patients with ag­gressive relapsed or refractory non-Hodg­kin lymphoma (NHL), according to data presented at ASCO 2018.

The updated findings from the phase 1, multicenter TRANSCEND trial demonstrated a durable complete remission (CR) rate of 46% at 6 months for patients with high-risk diffuse large B-cell lymphoma (DLBCL), the most common type of NHL. The investigators also reported that observed acute toxicities with liso-cel were manageable at all dose levels tested, including cytokine release syndrome (CRS).

"The durable response rates in our core DLBCL data set population were very encouraging," said lead investigator Jeremy S. Abramson, MD, MMSc, Clinical Director, Lymphoma Program, Massachusetts General Hospital Cancer Center, Boston, who presented the results. "That includes 49% of patients in ongoing response at 6 months, and most of those are ongoing complete remissions. Across all dose levels, 93% of patients who achieved the 6-month time point remained in remission at last follow-up."

"Strikingly, liso-cel is showing a low and manageable toxicity profile," Dr Abramson added, "with very low rates of severe cytokine release syndrome and neurotoxicity at 1% and 13%, respectively."

Aggressive relapsed or refractory B-cell NHL represents an unmet medical need with conventional therapies. Patients with chemotherapy-refractory disease have low response rates to standard therapies and a short overall survival. In this context, noted Dr Abramson, investigators are examining liso-cel, a CD19-directed CAR T-cell drug administered in defined composition at a precise dose of CD8 and CD4 CAR T-cells. TRANSCEND is an open-label, multicenter phase 1 clinical trial focused on investigating the safety, pharmacokinetics, and antitumor activity of liso-cel in adults with relapsed or refractory DLBCL, primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, or mantle-cell lymphoma. Dr Abramson presented an updated analysis of the dose-finding and dose-­escalation cohorts.

This was a high-risk population, said Dr Abramson, adding that of the 102 patients who received liso-cel, 73% had DLBCL, 27% had DLBCL transformed from follicular lymphoma, and 22% had double- or triple-hit lymphoma. The patients were heavily pretreated, with a median of 3 and up to 8 previous treatments for DLBCL. In addition, nearly 50% of the patients had never achieved a CR, 67% had chemotherapy-refractory disease, and 38% had undergone autologous stem-cell transplant.

Outcomes "Far Superior" to Traditional Therapies

According to Dr Abramson, the most common adverse events were cytopenias, which occurred in the majority of patients. With the exception of fatigue, all other toxicities occurred only in a minority of patients and were low grade, including CRS.
"There was only a single case of severe CRS," said Dr Abramson. There were no deaths from CRS or from neurologic toxicity and no incidents of cerebral edema. "We also saw a low overall use of rescue medications," he said.

The updated response rates in the entire population showed a best overall response rate of 75% and a best CR rate of 55%, whereas the core DLBCL data set had an overall response rate of 80% and a CR rate of 59%. Moreover, these were durable remissions, pointed out Dr Abramson, emphasizing that 49% of patients had ongoing remissions at the 6-month time point.
"These remissions were seen across high-risk subsets in this trial, including double- and triple-hit lymphoma patients, patients who never achieved CR, or patients with chemotherapy-­refractory disease," he added.

Although the median duration of response has not been reached in patients in the full or the core DLBCL data set, 88% of the patients who had a response therapy at 3 months were still responding to treatment at 6 months. Among patients with a CR at the 6-month time point, 93% have remained in remission at the time of their last follow-up. The median overall survival has not yet been reached in this population, and nearly 90% of patients who achieved a CR remain alive at 1 year.

"The overall survival findings are far superior to what we might anticipate with traditional therapies in this relapsed or refractory DLBCL population. We therefore continue to evaluate this product for outpatient administration, including in the pivotal cohort," Dr Abramson concluded. 

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