CAR Therapy Yields High Complete Response Rates in Adults with B-cell ALL in Phase I Trial

Jae H. Park, MD

Infusion with 19-28z chimeric antigen receptor (CAR) modified T-cells led to complete response (CR) rates of 77% to 90% and minimal residual disease (MRD)—CR rates of 68% to 70% in adult patients with relapsed or refractory B-cell acute lymphocytic leukemia (B-ALL). Lead investigator Jae H. Park, MD, an assistant attending physician at Memorial Sloan-Kettering Cancer Center, presented the phase I trial results, the largest dataset of its type, at the 2016 ASCO Annual Meeting.

“It’s important to note that we observed high CR and MRD-CR rates regardless of patients’ pre-infusion disease burden. And patients with minimal disease at the time of 19-28z CAR T-cell infusion experienced significantly less severe CRS and neurological toxicities,” Park said. “These findings support the use of 19-28z CAR T-cells in earlier lines of ALL treatment, such as in a frontline setting.”

The single-center trial focused on adult patients whose B-ALL was relapsed or refractory (n = 51). Patients who relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) were allowed, as were those with isolated extramedullary disease. Exclusion criteria were active central nervous system disease, active graft-versus-host disease that required immunosuppressants, and serious cardiac disease (myocardial infarction within the previous 6 months or an ejection fraction less than 40%).

The study began with leukapharesis in preparation for T-cell modification. If necessary, patients received salvage chemotherapy during T-cell production. All patients underwent bone marrow biopsy at the time of CAR T-cell infusion and were divided into 2 cohorts based on disease burden. Patients who had 5% or more blasts were considered to have morphologic disease (n = 31, 61%). Those with less than 5% blasts were characterized as having minimal disease (n = 20, 39%).

The median patient age in the morphologic disease group was 40 (range 24 to 73), while it was 38 (range 22 to 74) in the minimal disease group. The morphologic disease group had a median of 3 (range 2 to 7) prior lines of therapy, and a median of 2 (range 2 to 4) in the minimal disease group. Notably, 15 patients with morphologic disease (48%) had received 4 or more lines; only 3 patients with minimal disease (15%) had received 4 lines. A similar discrepancy was seen regarding previous blinatumomab use: 11 patients with morphologic disease (36%) compared to only 1 patient (5%) with minimal disease.

In the morphological disease group, 13 patients (42%) had received prior allogeneic HSCT, while only 5 patients (25%) with minimal disease did. Seven patients with morphological disease (23%) were Philadelphia chromosome-positive, while 8 (40%) with minimal disease were positive.

Patients then received lymphodepleting conditioning chemotherapy followed by 19-28z CAR T-cell infusion. Patients with morphologic disease received 1 x 10⁶CAR T-cells/kg. Those with minimal disease received 3 x 10⁶CAR T-cells/kg.

“One recent change we made was to redefine conditioning chemotherapy as more data come out how important lymphodepletion is to CAR T expansion and persistence,” said Park. “Therefore, for the last 9 patients on the study, we added fludarabine to the cyclophosphamide conditioning.” All previous study patients received conditioning chemotherapy with cyclophosphamide alone (n=42). Disease reassessment occurred between 28 days and 35 days post-infusion.

Park explained that to date all 51 patients were evaluable for toxicity assessment, and 50 patients were evaluable for response assessment with follow up of at least 1 month. With a data cutoff of May 2, 2016, the median follow-up was 8.5 months (range 1 to 54 months). Twenty-nine patients (58%) have had at least 6 months of follow-up, and 17 (34%) have had 1 year or more of follow-up.

In the morphologic disease group, 23 patients (77%) achieved a CR, as did 18 patients (90%) in the minimal disease group. The MRD negative CR rate was 19 of 21 (90%) in those with morphologic disease and 14 of 18 (78%) in those with minimal disease. The mean time to CR was 20 days for the morphologic group and 25 days for the minimal group. Park also presented CR rates for various subgroups, such as disease burden and age groups, but most did not impact the CR rates.

In examining the post-CAR T-cell infusion clinical course, Park reported that 16 out of 41 patients (39%) who achieved CR proceeded to allogeneic HSCT. The morphologic disease cohort accounted for 9 patients out of 23 (39%), while 7 patients out of 18 (39%) in the minimal disease cohort.

Fifteen patients of 33 (45%) with MRD-CR relapsed; 4 of 15 relapses (27%) were CD19 negative/undetectable. Around one-fourth of the study population (n = 9, 27%) remained disease-free for more than 1 year.

Among all patients, the median OS follow-up was 13.0 months. In the morphologic disease cohort, the median OS was not reached; it was 9.0 months in the minimal disease group (P= 0.25). OS among MRD-CR patients was 17.0 months for the morphologic disease cohort, while the minimal disease group did not reach their median OS (P= 0.16).

In looking at the OS among MRD-CR patients and post-CAR T-cell HSCTs, Park reported that 7 patients with morphologic disease did require transplantation, while 12 did not. For those with minimal disease, 6 patients did require transplantation and 8 did not. Durable responses and survivals were observed in a subset of patients who did not require subsequent transplantation in both cohorts.

19-28z CAR T-cells were measured in peripheral blood cells and bone marrow by quantitative PCR[DL1](qPCR) and flow cytometry. The maximum T-cell expansion occurred between days 7 and 14, and correlated with occurrences of cytokine release syndrome (CRS). The T-cells persisted for 1 to 6 months following infusion, as measured by qPCR.

Among adverse events, CRS was of course the most concerning. Not surprisingly, more patients in the morphologic disease cohort experienced CRS compared to those in the minimal disease group: 13 patients (42%) versus 1 patient (5%). When CRS did occur, 12 patients received tocilizumab, 11 received steroids, and 10 received both. According to Park, these treatments had no impact on relapse free survival (RFS) or OS. Three patients with morphologic disease died due to grade 5 toxicity; none of the minimal disease cohort patients did.

Park JH, Riviere I, Wang X, et al. Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL.J Clin Oncol34, 2016 (suppl; abstr 7003).

A multicenter, single-arm phase II trial of 19-28z CAR T-cell infusions in adults with relapsed B-ALL began accruing patients in September 2015. Enrollment in the trial, known as ROCKET, is ongoing, Park said (NCT02535364).