ZUMA-8: Brexucabtagene Autoleucel in CLL

Treatment with brexucabtagene autoleucel appeared safe but resulted in limited CAR T-cell expansion in a phase 1 trial of patients with relapsed/refractory CLL who had 2 or more previous lines of therapy (ClinicalTrials.gov Identifier: NCT03624036).5

A total of 15 patients received brexucabtagene autoleucel in this study. Their median age at baseline was 63 years, 12 patients had received 3 or more prior lines of therapy, and 13 had received bridging therapy between leukapheresis and conditioning therapy.


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The median follow-up was 30.3 months. Notable CAR T-cell expansion occurred in 4 patients, including all 3 patients with low tumor burden.

The ORR was 47%, with 2 patients achieving a CR and 5 achieving a partial response. All 3 patients with low tumor burden had a response, and both CRs occurred in this group. These 3 patients had responses lasting at least 14 months and were still in response at the data cutoff.

No new safety signals were reported. However, all patients experienced grade 3 or higher adverse events, with 33% of patients experiencing serious grade 3 or higher adverse events. There was 1 patient who experienced dose-limiting toxicities.

This study was discontinued due to suboptimal CAR T-cell expansion, and there are “currently no plans” to further study brexucabtagene autoleucel in patients with CLL/SLL with low tumor burden, according to study presenter Matthew S. Davids, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts.

“Studies with other CAR T-cell products may examine whether combination approaches with agents that improve T-cell function enhance CAR T-cell expansion,” he said.

Cell Death Rates Can Predict Remission Depth in CLL

Long-term follow-up of a clinical trial (ClinicalTrials.gov Identifier: NCT01752426) to assess CLL/SLL cell kinetics in patients treated with ibrutinib has revealed a correlation between initial cell death rates and the probability of achieving deeper long-term remissions.4

Researchers used deuterated water to track cancer cell death and proliferation in previously untreated patients with CLL/SLL during long-term treatment with ibrutinib monotherapy. Previously published research showed that ibrutinib induces high rates of CLL/SLL cell death and blocks proliferation.6

Long-term follow-up data on 30 patients revealed a 5-year PFS rate of 80.6%, overall survival rate of 90%, and ORR of 97%.

Peripheral blood MRD was assessed in 18 patients after 54-60 treatment cycles. Researchers found that high CLL cell death rates earlier on in treatment were associated with lower peripheral blood MRD levels 5 years after treatment initiation.

The researchers also found higher CLL cell death rates in patients without IGHV mutations. This suggests IGHV-unmutated clones are more dependent on BCR signaling, which results in deeper responses, according to the researchers.

“This study was relatively small and not designed to answer questions that may change clinical practice,” said study presenter Ekaterina Kim, PhD, of The University of Texas MD Anderson Cancer Center in Houston. “However, we believe that this provides a mechanic explanation of clinical observations that patients with IGHV-unmutated CLL seem to have better chances of achieving undetectable MRD status on ibrutinib-based regimens compared with mutated CLL.”

Disclosures: The ALPINE trial was supported by BeiGene. The triplet trial was partly supported by Genentech and Acerta Pharma, LLC. The trial of brexucabtagene autoleucel was supported by Kite, a Gilead company. The cell death trial was partly supported by Pharmacyclics LLC. Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original references for full lists of disclosures.

References

  1. Brown JR, Eichorst B, Hillmen P, et al. Zanubrutinib demonstrates superior progression-free survival (PFS) compared with ibrutinib for treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma (R/R CLL/SLL): Results from final analysis of ALPINE randomized phase 3 study. Presented at ASH 2022. December 10-13, 2022. Abstract LBA-6.
  2. Ryan CE, Lampson BL, Tyekucheva S, et al. Updated results from a multicenter, phase 2 study of acalabrutinib, venetoclax, obinutuzumab (AVO) in a population of previously untreated patients with CLL enriched for high-risk disease. Presented at ASH 2022. December 10-13, 2022. Abstract 344.
  3. Davids MS, Kenderian SS, Flinn IW, et al. ZUMA-8: A phase 1 study of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory chronic lymphocytic leukemia. Presented at ASH 2022. December 10-13, 2022. Abstract 3319.
  4. Kim E, Sivina M, Vaca A, et al. High cell death rates at start of ibrutinib therapy predict for deeper remissions in patients with chronic lymphocytic leukemia (CLL). Presented at ASH 2022. December 10-13, 2022. Abstract 1801.
  5. Davids MS, Lampson BL, Tyekucheva S, et al. Acalabrutinib, venetoclax, and obinutuzumab as frontline treatment for chronic lymphocytic leukaemia: A single-arm, open-label, phase 2 study. Lancet Oncol. 2021;22(10):1391-1402. doi:10.1016/s1470-2045(21)00455-1 z
  6. Burger JA, Li KW, Keating MJ, et al. Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib. JCI Insight. 2017;2(2). doi:10.1172/jci.insight.89904

This article originally appeared on Hematology Advisor