CAR T-Cell Immunotherapy Induces Complete Remissions in Patients with Refractory DLBCL

Interim analysis of Zuma-1 study shows nearly six-fold higher rate of complete remission compared to historical data

A late breaking abstract presented during the 58th American Society of Haematology (ASH) Annual Meeting and Exposition in San Diego, US (3-6 December, 2016) demonstrates that chimeric antigen receptor (CAR) T-cell therapy is a promising option for treatment of refractory diffuse large B-cell lymphoma(DLBCL). From a practice perspective, it could be implemented in a variety of real-world clinical settings. The study, which involved 22 institutions and tested anti-CD19 CAR T-cells, is the first multicentre trial of this cellular immunotherapy-based treatment approach for lymphoma. 

The study focused on patients with DLBCL that does not respond to chemotherapy or recurs after autologous stem cell transplant. Such chemorefractory patients have a poor prognosis; median overall survival is just over six months and only about 8% achieve complete remission with existing therapies. There has been no new treatment for these patients for over 20 years.

In the first phase of ZUMA-1 study, which was conducted in four institutions, 43% of patients have ongoing complete remission at 12 months. To test the treatment’s real-world feasibility, the second phase of ZUMA-1 expanded the study to involve 22 institutions, most of which had no prior experience with CAR T-cell therapy.

The new findings report positive results from a pre-specified interim analysis of 51 patients with DLBCL. Following anti-CD19 CAR T-cell treatment, these patients had an overall response rate of 76% (47% complete remission and 29% partial remission) with most responses noted within the first month. By the end of month three, the overall remission rate was 39% (33% complete remission and 6% partial remission). 

According to the researchers, led by Dr Sattva Neelapu of The University of Texas MD Anderson Cancer Center in Houston, the results are encouraging from an efficacy standpoint and also show that CAR T-cell manufacturing, treatment logistics, and the management of adverse events can be successfully implemented across multiple sites.

Serious adverse events reported in the total DLBCL cohort of 73 patients that were related to anti-CD19 CAR T-cells included neurologic events (25% of patients; typically temporary confusion or disorientation) and grade three or higher cytokine release syndrome (14%). The most common symptoms of cytokine release syndrome were fever, hypotension, and dyspnoea. The researchers reported that one patient died as a result of overactivation of the immune system. 

Recent studies of CAR T-cell therapy have improved the ability to manage side effects. There are now guidelines on how to recognise and grade these side effects and how to manage the symptoms.

The team has also separately analysed results from 20 patients in ZUMA-1’s second cohort, which include patients with primary mediastinal B-cell lymphoma or transformed follicular lymphoma, two lymphoma types that are less common than DLBCL. The overall response rate in this second cohort is 80% with a complete remission rate of 55%.

The researchers will continue to track patient outcomes in these cohorts for 15 years. 

References

LBA-6. Neelapu SS, Locke FL, Bartlett NL, et al. Kte-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1.  Presented at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, US (3-6 December 2016).

998. Locke FL, Neelapu SS, Bartlett NL, et al. A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL):  Interim Results From ZUMA-1. Presented at the 58th American Society of Hematology (ASH) Annual Meeting and Exposition, San Diego, US (3-6 December 2016).