Allogeneic CD123 CAR-T Shows Some Clinical Activity in R/R Acute Myeloid Leukemia

UCART123v1.2, an investigational CD123-targeted chimeric antigen receptor T-cell (CAR-T) therapy being investigated for the treatment of patients with relapsed/refractory (r/r) acute myeloid leukemia (AML) in the phase 1 dose-escalation AMELI-01 (NCT03190278) clinical trial, demonstrated cell expansion and clinical benefit in several patients, according to data presented in an oral presentation in an oral session at the 64th American Society of Hematology (ASH) Annual Meeting, held December 10-12, 2022, in New Orleans, Louisiana.

Among the 17 patients who received UCART123v1.2, 4 showed clinical benefit with 1 patient achieving a greater than 90% bone marrow blast reduction from 60% to 5% at 28 days after infusion and another patient achieving a durable long-term minimal residual disease (MRD)-negative complete response (CR) at 56 days which has continued past 12 months. The trial divided patients into 2 arms, with patients in the FC arm receiving a lymphodepletion regimen with 30 mg/m² x 4d fludarabine and 750 mg/m² x 3d cyclophosphamide and patients in the FCA arm receiving the same regimen of fludarabine and cyclophosphamide along with 12 mg/day x 4d alemtuzumab. Both previously mentioned patients who showed clinical benefit were in the FCA arm and received UCART123v1.2 at dose level 2 (DL2), 6.25x10⁵ cells/kg. The other 2 patients who showed clinical benefit were in the FC arm and received UCART123v1.2 at DL2i, 1.5x10⁶ cells/kg. One of these patients achieved clearance of blasts by 14 days post-infusion, but experienced a rapid return of blasts by 28 days post-infusion. The other patient achieved a morphological leukemia-free state (MLFS). It was noted that patients in the FCA arm experienced prolonged lymphodepletion and a higher rate of UCART123v1.2 expansion compared to patients in the FC arm.

“We did sequential cytokine profiles and peripheral blood on these patients [in the FCA arm]...” presenter and first author David A. Sallman, MD, assistant member, Department of Malignant Hematology, Moffitt Cancer Center, noted during his presentation. “There was an IL-2 peak around 1 to 2 days after cell infusion, potentially an early biomarker for UCART123v1.2 cell proliferation. A quite similar expansion of cytokines, similar to the expansion of CAR-T cells, with increases of IL-6, interferon-gamma, and TNF-alpha [was also seen]. Although importantly, we did not see the severity of CRS correlate with the absolute increase in these cytokines, albeit these are relatively small cohorts. Additionally, in the FCA arm we saw strong correlations between ferritin levels with vector copy number, working as a surrogate for UCART123v1.2 expansion, [which]potentially could be utilizedfor early mitigation in CRS.”

In terms of safety, all patients experienced cytokine release syndrome (CRS), 4 cases of which were grade 3 or greater. Several dose-limiting toxicities occurred, including 2 cases of grade 5 CRSin the FCA arm. Among all treated patients, 2 cases of immune effector cell-associated neurotoxicity syndrome (ICANS) occurred, with only 1 case that was grade 3 or greater. Sallman mentioned that other severe adverse events that occurred in the patient population were typically related to the severity of baseline cytopenias, the critical nature of the patients’ disease, and lymphodepletion. He also noted that approximately 25% of the treated patient experienced cases of transaminitis.

The ages of the 18 patients who enrolled in the trial and received lymphodepletion ranged from 18 years to 64 years (median, 57). The group included 10 male patients and 8 female patients. All but 1 patients had an Eastern Cooperative Oncology Group Performance Score of 1. Sallman highlighted that 14 of the patients were classified as having adverse risk according to European LeukemiaNet 2017 Classification, that the patients had a median of 37% baseline bone marrow blasts, that the patients were heavily pre-treated with 3 to 9 (median, 4) prior lines of therapy, that 9 patients had previously relapsed after haematopoieticstem cell transplant, and that 33% of the patients had TP53 mutations.

Sallman concluded the presentation by noting that the FC arm of the trial will be closed due the poor cell expansion seen in this cohort. The FCA arm will continue enrolling at DL2. The trial will also add a second dose to the treatment regimen for this arm and the use of prophylactic tocilizumab to mitigate the severity of CRS.

“UCART123v1.2 expansion correlates with a reduction in tumor burden at DL2, but at this dose UCART123v1.2 cell function was not sufficient to sustain anti-leukemic activity in all patients,” Sallman noted. “As this is an off-the-shelf product, this allows the potential to give a second dose which is now going to be incorporated in the protocol with patients getting the second dose around 10 to 14 days. This will be without the need of second lymphodepletion... The hope of this is that while we see the expansion of these cells drop off that we can ideally utilize the second dose to clear residual disease.”

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REFERENCE

Sallman DA, DeAngelo DJ, Pemmaraju N, et al. Ameli-01: A phase I trial of UCART123v1.2, an anti-CD123 allogeneic CAR-T cell product, in adult patients with relapsed or refractory (R/R) CD123+ acute myeloid leukemia (AML). Presented at: ASH 2022 Annual Meeting. December 10-12, 2022; New Orleans, LA. Abstract 981