Findings Support Early Use of CD19 CAR T-Cell Therapy in Relapsed B-cell ALL

Jae Park, MD

Low disease burden prior to treatment with CD19-specific chimeric antigen receptor (CAR) T-cell therapy appears to be a positive prognostic factor for long-term survival outcomes of patients with relapsed B-cell acute lymphoblastic leukemia (ALL), according to retrospective results of a phase I trial. Additionally, the use of allogeneic stem cell transplant posttreatment did not appear to have an effect. The authors concluded that these findings support early use of CD19 CAR T-cell therapy prior to morphologic relapse in patients with B-cell ALL.

Previous prospective phase I findings with the 19-28z CD19-targeted CAR T-cell therapy had shown impressive responses in patients with relapsed B-cell ALL (NCT01860937). However, researchers were unable to define what clinical characteristics were associated with durability of response, leading to the initiation of the analysis, results of which were presented at the 2017 AACR Annual Meeting.

“Adult patients with relapsed or refractory ALL have extremely poor outcomes, with the 5-year survival rate being less than 10%. Therefore, there is a clear need to develop effective therapy for these patients,” lead study author Jae H. Park, MD, an assistant attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center, said in a prepared statement during the meeting.

“To this end, we and other groups have developed and tested CD19-specific CAR T-cell therapy [19-28z CAR T-cell therapy] and have reported encouraging results, with high initial complete response rates in patients with B-ALL,” Park continued. “However, relapses are common, even after achieving seemingly deep remission, and severe toxicities have been observed in some patients.”

Fifty adult patients with relapsed or refractory B-cell ALL were infused with autologous T cells that expressed the 19-28z CAR following failure of 1 or more conventional chemotherapy regimens. Researchers assessed disease burden via a bone marrow biopsy immediately prior to T-cell infusion. Patients were then separated into 2 cohorts based on disease burden, which included minimal residual disease (MRD) with <5% blasts in bone marrow (n = 20) and morphologic disease (≥5% blasts; n = 31). The median duration of follow-up was 18 months (range, 0.2-57.3).

Results showed that the complete response (CR) rates were comparable in both the MRD and morphologic cohorts at 95% and 77%, respectively, and were found to not be statistically significant.

However, the median event-free and overall survival (OS) rates differed between the 2 groups. In the MRD cohort, the event-free survival (EFS) was not reached (95% CI, 4.2-NR) as well as the median OS (95% CI, 15.3-NR), as most patients were reported to still be disease-free and alive. In the morphologic disease cohort, the median EFS was 6.3 months (95% CI, 4.8-9.0; P = .0005) and the OS was 17 months (95% CI, 8.5-36.2; P = .0189).

Moreover, subsequent allogeneic hematopoietic stem cell transplant (HSCT) in either of the 2 cohorts was not associated with an improvement in survival (P = .8).

“While more patients and longer follow-up will be needed to adequately address the significance of HSCT, the result of this analysis raises a question as to whether 19-28z CAR therapy can be considered as a definitive, curative therapy rather than a bridge to stem cell transplant, at least in a subset of patients,” Park said in his statement.

Despite the comparable initial CR rates between the 2 cohorts, the authors stated that the durability of 19-28z CAR T-cell mediated remissions and survival in adult patients with relapsed B-cell ALL positively correlated to a low disease burden and do not appear to be enhanced by allogeneic HSCT. The findings additionally support the early incorporation of CD19 CAR T-cell therapy before patients with B-cell ALL experience morphologic relapse.

“Our data suggest that incorporation of 19-28z CAR T cells at the time of MRD following first-line chemotherapy will maximize the durability of CAR T-cell mediated remissions and survival and can potentially spare these high-risk patients from HSCT, rather than waiting until they relapse morphologically and then trying CAR T-cell therapy when it is less likely to achieve a durable long-term outcome,” Park added.

Patients in the MRD cohort did develop substantially less severe cytokine release syndrome (CRS) and neurotoxicity, both of which correlated with peak CAR T-cell expansion (P = .0326 and P = .0001, respectively), the authors noted. Five percent and 15% of patients in the MRD cohort experienced CRS and neurotoxicity, respectively, while the adverse events occurred in 42% and 58% of the morphologic patients. There were no reports of cerebral edema in either cohort.

Park JH, Rivere I, Wang X, et al. Impact of disease burden and transplant on long-term survival after CD19 CAR therapy in adults with relapsed B-cell acute lymphoblastic leukemia. In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT078.