Liso-Cel Highly Active in Relapsed/Refractory Chronic Lymphocytic Leukemia

The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

SAN DIEGO — In heavily pretreated patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), trial results revealed that treatment with lisocabtagene maraleucel (liso-cel; JCAR017) spurred complete responses (CRs) and “undetectable” minimal residual disease (MRD) in patients with both high-risk and standard-risk disease who had previously received ibrutinib. The preliminary results were presented at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California, by Tanya Siddiqi, MD, City of Hope National Medical Center, Duarte, California.¹

Although there are various therapies in the pipeline that address the treatment of CLL, and B-cell receptor inhibitors have helped some patients achieve MRD, the cancer is still considered incurable, and patients generally relapse and/or become refractory to available medications. According to Dr Siddiqi, with monotherapy, MRD rates remain inadequate and patients who progress on these therapies have poor outcomes in general. Because CLL is an indolent disease, the focus for CAR-T has historically been in multiple myeloma and lymphoma, noted Dr Siddiqi — and as a result, many researchers have considered CAR-T to be too harsh a treatment for patients with CLL.

In this open-label, phase 1/2 study — TRANSCEND CLL 004, funded by Juno/Celgene — Dr Siddiqi and colleagues had a dual goal: testing the safety of their investigational cell therapy, a single-dose cell therapy treatment for relapsed/refractory (R/R) CLL, and identifying an optimal dose for phase 2 trials. They focused on 2 different doses to evaluate: DL1=5 × 10⁷ CAR-T cells; and DL2=1 × 10⁸ CAR-T cells. Exploratory objectives included antitumor activity and pharmacokinetic profile.

A total of 16 patients were then enrolled, with 6 patients assigned to treatment with DL1 and 10 patients scheduled to receive DL2.

Patients were eligible for the trial if they had CLL/SLL and received 3 or more standard-risk prior therapies or 2 or more high-risk [del(17p), TP53 mutation, unmutated IGVH, or complex karyotype] prior lines of therapy. There was a median of 4.5 prior lines of therapy (range, 2-11). They needed to have failed on or become refractory to a B2K inhibitor, and have received ibrutinib previously (13 of the patients had actually progressed on ibrutinib). The majority of patients had advanced-stage disease and high-risk cytogenetics.

Patients undergo enrollment into apheresis while liso-cel is being manufactured (to date, the manufacturing of liso-cel has a 100% success rate). Once cells are ready, patients undergo restaging. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, participants received the liso-cel infusion. Bridging therapy was allowed — in fact, 13 of 16 patients received bridging therapy of some sort.

Strikingly, only after 30 days postinjection, 12 of 16 pts had an objective response (75%), including 5 CRs (31.3%). Best overall response was 81.3%, with 43.8% of patients achieving CR. Eleven of 15 patients (73.3%) who were evaluable for MRD had undetectable disease (assessed by flow cytometry) at day 30, and “all continue to remain undetectable at follow-up,” Dr Siddiqi remarked. At 6 months following the first dose of JCAR017, there were 5 patients who had an ongoing response (4 CRs, 1 PR) and undetectable MRD. One enrollee progressed with Richter’s transformation.

One reason patients may have been evaluable for response so quickly could be related to the short median time to peak expansion for the product, which was 16 days (range 4-30). She added that by day 90, a majority of patients still have measurable CAR-T cells.

There were low rates of grade 3 cytokine release syndrome (CRS) cases (6.3%) and neurologic events (18.8%). Although treatment-related adverse events were reported in 20% or more of patients, there were no grade 5 events reported during the study, and all of the grade 3 or higher events were reversible.

By way of a correlative biomarker analysis, the researchers determined that IL-16 and TNF were elevated before the onset of grade 2 or grade 3 neurologic events in 3 of 4 patients who experienced these reactions — with the levels being elevated as early as day 1 or day 2 postinfusion — suggesting that these cytokines may be predictive for adverse events.

Dr Siddiqi said following an analysis of the dose escalation data and selection of RP2D, the phase 2 portion of the trial was open for accrual, which she said she expects will be during the first half of 2019.

“In the future, we may be talking about [CAR-T] in the second-line, third-line — earlier phases of treatment, to see if we can get people to a cure,” she noted, but added that toxicity needs to be carefully watched, and long-term remission should be confirmed.

“I think ultimately we are all looking for a cure—and maybe CAR-T cells will be that.”

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. For a complete list of disclosures, please refer to the original abstract.

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Read more of Cancer Therapy Advisor‘s coverage of the ASH 2018 meeting by visiting the conference page.

Reference

1. Siddiqi T, Soumerai JD, Wierda WG, et al. Rapid MRD-negative responses in patients with relapsed/refractory CLL treated with Liso-Cel, a CD19-directed CAR T-cell product: preliminary results from Transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 300.