Axicabtagene Ciloleucel Moves to Acute Lymphocytic Leukemia

Axicabtagene ciloleucel, which in October 2017 became the first chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of B-cell lymphoma, showed “promising efficacy” in patients with relapsed/ refractory, CD19-positive acute lymphocytic leukemia (ALL), according to results from the ZUMA-3 trial.

The results were seen independent of prior exposure to blinatumomab, a CD19/CD3 bispecific T-cell engager that is considered a standard of care for patients with relapsed/refractory ALL, lead author and presenter Bijal D. Shah, MD, from the Moffitt Cancer Center in Tampa, Florida, noted. These findings update ZUMA-3 data that were presented at the 2017 ASH Annual Meeting, in which 71 percent of patients treated with the anti-CD19 CAR T-cell therapy experienced a complete response (CR) or CR with incomplete hematologic recovery (CRi).

“An important question emerged during the conduct of [ZUMA-3]: How would prior blinatumomab influence T-cell quality, T-cell function, and – secondarily – safety and efficacy with this product?” Dr. Shah said. “We don’t know the mechanisms of resistance to blinatumomab, but we can infer that perhaps these patients might be at higher risk of treatment failure.”

To answer this question, the investigators evaluated the safety and efficacy of axicabtagene ciloleucel among 23 adults: 11 patients had prior blinatumomab exposure, and 12 were blinatumomab-naïve. The authors observed that patients who received blinatumomab appeared to have worse performance status (Eastern Cooperative Oncology Group stage 0 = 27% vs. 44%), were more heavily pre-treated (relapsed/refractory to second-line treatment = 55% vs. 28%) and had a higher blast cell burden at enrollment (median blasts at screening = 85 vs. 66; p values not reported).

As of July 31, 2017 (data cutoff) and a median follow-up of 2.7 months (range = 0-10.6 months), 23 patients were evaluable for safety and 18 were evaluable for efficacy.

Following low-dose conditioning chemotherapy (fludarabine 25 mg/m2 and cyclophosphamide 900 mg/m2), patients received axicabtagene ciloleucel at doses of 0.5×106 cells/kg, 1×106 cells/kg, and 2×106 cells/kg). Those with prior blinatumomab exposure were excluded from the 2×106 dosing group.

As with clinical trial experiences of axicabtagene ciloleucel in lymphoma, cytokine release syndrome (CRS) and neurotoxicity were common adverse events (AEs) among these patients:

  • CRS: 21 (91%) any-grade and 5 (22%) grade ≥3 AEs
  • Neurotoxicity: 18 (78%) any-grade and 12 (52%) grade ≥3 AEs

The researchers did not observe any significant differences in CRS rates between blinatumomab-naïve and blinatumomab-exposed groups, and “all [of these events] resolved, and the two patient deaths, one in each group, were related exclusively to disease progression,” Dr. Shah reported.

Among the efficacy-evaluable population, 13 patients (72%) had CR or CRi. Blinatumomab exposure did not appear to affect CR/CRi rates: 63 percent (n=5/8) and 80 percent (n=8/10) among those with and without blinatumomab, respectively (p value not reported).

Overall, 17 patients (94%) achieved undetectable minimal residual disease (MRD) and, again, this did not appear to differ based on blinatumomab exposure (88% with and 100% without).

“Among six evaluable patients who did not respond to prior blinatumomab, five had undetectable MRD response to axicabtagene ciloleucel,” Dr. Shah noted. He also reported that there were no major differences in CAR T-cell manufacturing success or CAR T-cell expansion between the two groups.

“These results are reassuring [and] show we can be less apprehensive with our sequencing of these therapies,” Dr. Shah concluded. However, he added that the findings were limited by the small patient population and potentially confounded by the fact that CAR T-cell dose infusions differed between patients with and without blinatumomab exposure.

The authors report financial relationships with Kite Pharma and Amgen, the manufacturers of KTE-C19 and blinatumomab, respectively.

Reference

Shah BD, Oluwole OO, Baer MR, et al. Outcomes of patients (pts) treated with prior blinatumomab (Blin) in ZUMA-3: A study of KTE-C19, an anti-CD19 chimeric antigen receptor (CAR) t cell therapy, in adult pts with relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Abstract #7006. Presented at the 2018 ASCO Annual Meeting, June 2, 2018; Chicago, IL.

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