CAR T-Cell Therapy CTL019 Shows Promise in Phase II CLL Trial

David L. Porter, MD

The CD19-targeting CAR T-cell therapy CTL019 induced responses in 53% of patients with relapsed/refractory chronic lymphocytic leukemia (CLL), including complete remissions (CR) in 35% of patients, according to results from a phase II trial presented at the 2016 ASCO Annual Meeting.¹

“CTL019 clearly induced sustained remissions for some patients with advanced CLL, is a promising therapy, and deserves further study in relapsed/refractory CLL,” lead author David L. Porter, MD, Abramson Cancer Center, University of Pennsylvania, said when presenting the data at ASCO.

Of the 28 patients, 24 met their target cell dose, making them evaluable for response. Of the 24 patients, there were 19 men and 5 women. The median patient age was 62 years (range, 51-75) and the median number of prior therapies was 4 (range, 2-7). Nine patients (38%) had a p53 deletion and 3 patients (12%) had prior ibrutinib (Imbruvica).

Eighteen patients had received fludarabine/cyclophosphamide (FC) or pentostatin/cyclophosphamide (PC) lymphodepleting chemotherapy, 5 patients had received lymphodepleting bendamustine, and 1 patient had been treated with another lymphodepleting regimen.

Patients were randomized to either a lower dose of 1-5 x 10⁷ CTL019 cells (n = 13) or a higher dose of 1-5 x 10⁸ CTL019 cells (n = 11). The primary endpoint was the CR rate at 3 months. Secondary objectives included safety, manufacturing feasibility, overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and CAR T-cell expansion and long-term persistence.

There was no significant infusion-related toxicity. Hepatotoxicity and renal toxicity was all reversible and grade 3, according to Porter. Incidents of tumor lysis syndrome were reversible and manageable. Patients who responded also developed B cell aplasia and hypogammaglobulinemia, which was manageable.

Thirteen patients (54%) developed cytokine release syndrome (CRS), including 6 patients (55%) in the high-dose arm and 7 patients (54%) in the low-dose arm. “There was no dose/toxicity relationship,” noted Porter. In the majority of cases, CRS symptoms were resolved with with IL6 receptor antagonist tocilizumab.

Porter said the investigators were not surprised that they did not identify a dose/toxicity relationship. “I think this was somewhat anticipated. Since these cells can expand in vivo to very high levels, I think it has more to do with how many cells the patients end up with, rather than how many cells we infuse.”

The ORR was 42% (n = 10) in the initial 24 patients evaluated, including a CR rate of 25% (n = 6), and a partial response rate of 17% (n = 4). The ORR was 54% (n = 6) in the high-dose arm and 31% (n = 4) in the low-dose arm.

“This was never designed to be statistically robust, but there was a suggestion of more responses at the higher cell dose without a dose/toxicity relationship, and, therefore, it was the higher cell dose that we chose to move forward with,” said Porter.

Six patients were added to the higher, “optimal” dose group, to create an expanded cohort of 17 patients. This expanded cohort included 14 men and 3 women. The median age was 59 years (range, 48-75) and patients had received a median of 3 (range, 2-7) prior therapies. Eight patients (47%) had a p53 deletion and 6 patients (35%) had prior ibrutinib. Nine patients had FC/PC lymphodepleting chemotherapy, 5 had lymphodepleting bendamustine, and 3 had other lymphodepleting chemotherapy regimens.

The ORR in this expanded optimal dose cohort was 53% (n = 9), including a CR rate of 35% (n = 6) and a PR rate of 18% (n = 3). Both PFS and OS for this cohort were approximately 80%, according to Porter. “There were no relapses beyond 6 months in any of these patients. Many of these remissions remain sustained and many patients have remained alive beyond 2 years.”

In the pilot study² that preceded the phase II trial, a 5-year follow-up of the first 14 patients treated showed an ORR of 57% (n = 8), which included 4 CRs and 4 PRs.

“We concluded from this pilot study that CTL019 can eradicate—and I do mean eradicate—relapsed/refractory CLL; complete remissions were all documented to be MRD negative,” said Porter, adding that the pilot study demonstrated that “CTL019 undergoes massive expansion in vivo—up to 3 logs or more—and we now know that these cells can persist in vivo beyond 5 years in some cases.”

Porter said the outcomes he reported at ASCO were consistent with these initial pilot findings. “Similar to the pilot trial [in the phase II study] CTL019 underwent marked in-vivo expansion and exhibited long-term persistence, out beyond 3 years.”

References

1. Porter DL, Frey NV, Melenhorst JJ, et al. Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. J Clin Oncol 34, 2016 (suppl; abstr 3009).
2. Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7(303):303ra139.

The randomized phase II dose optimization study accrued 28 patients with relapsed/refractory CLL. The researchers enrolled patients aged ≥18 years who had an anticipated survival of less than 2 years. Patients had relapsed after at least 2 prior therapies and within 2 years of their last regimen.