Currently, chimeric antigen receptor (CAR) T-cell (CAR-T) therapies are approved for use in some patients with relapsed or refractory large B-cell lymphoma who have previously received 2 or more lines of therapy (and 1 of the 2 therapies in this category, tisagenlecleucel [Kymriah®], is indicated for some patients with B-cell precursor acute lymphoblastic leukemia, as well). The success of these adoptive cell therapies in the setting of hematologic malignancies has generated considerable interest in the investigation of whether administering CAR-T therapy earlier in the course of treatment would improve outcomes, in particular for aggressive LBCL. 

To that end, several trials are under way that seek to assess the efficacy of CAR-T treatments as second-line therapies. But, the phase 2, multicenter study ZUMA-12 will test the efficacy and safety of the anti-CD19 CAR-T therapy axicabtagene ciloleucel (axi-cel/Yescarta®) at the earliest time point in the course of LBCL treatment so far — and that is in patients who have persistent disease after only 2 cycles of induction chemoimmunotherapy ( Identifier: NCT03761056). The protocol was described at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting last month.

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ZUMA-12 is estimated to enroll around 40 patients, 18 years or older, that are newly diagnosed with high-risk LBCL and have a maximum Eastern Cooperative Oncology Group (ECOG) performance status of 1. High-risk patients are identified by the presence of MYC and BCL2 and/or BCL6 translocations (ie, “double-hit” or “triple-hit” lymphomas, depending on the number of translocations present) or an international prognostic index (IPI) of 3 or higher before enrollment. 

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The trial uses an additional eligibility criterion to capture high-risk patients: individuals must display progressive disease or do not a complete remission after 2 cycles of chemoimmunotherapy, as evidenced by a Deauville score of 4 to 5 assessed by positron emission tomography (PET) scan. “In general, patients who don’t achieve a complete remission on that interim PET scan are thought to have a worse prognosis,” coauthor Chaitra Ujjani, MD, an oncologist at Fred Hutchinson Cancer Research Center and Seattle Cancer Care, Seattle, Washington, told Cancer Therapy Advisor.

While the trial has been described on as a “first-line therapy,” it’s technically somewhere in between a first-line and a second-line therapy, Dr Ujjani explained. But because patients have only had 2 cycles of induction therapy, this is the earliest in the course of treatment that a CAR-T therapy would be administered.