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Investigational CAR T-cell therapy induces durable responses in pretreated leukemia subtypes

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Tanya Siddiqi

CHICAGO — Heavily pretreated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma and prior ibrutinib treatment achieved rapid and durable responses with the investigational chimeric antigen receptor T-cell product lisocabtagene maraleucel, according to data from the ongoing phase 1/phase 2 TRANSCEND CLL study presented at ASCO Annual Meeting.

“This CAR T-cell study in CLL, funded by Juno Therapeutics, evaluates liso-cel, which is a CD19-targeting CAR T-cell product,” Tanya Siddiqi, MD, director of City of Hope’s Chronic Lymphocytic Leukemia Program within its Toni Stephenson Lymphoma Center and associate clinical professor in the department of hematology and hematopoietic cell transplantation at City of Hope, said in an interview with HemOnc Today. “We treated patients who had failed two or three lines of therapy, depending on their risk category, and all of them had to have had prior treatment with a Bruton tyrosine kinase inhibitor like ibrutinib. All of the patients had progressed on ibrutinib [Imbruvica; Pharmacyclics, Janssen], and more than half had progressed on venetoclax [Venclexta; AbbVie, Genentech] when they came on to this study.”

Siddiqi and colleagues evaluated the safety, efficacy and pharmacokinetics of lisocabtagene maraleucel (JCAR017; Celgene, Juno Therapeutics) among 23 patients (median age, 66 years; range, 49-79) with CLL or small lymphocytic leukemia who received a median of five (range, 2-11) previous lines of therapy, including ibrutinib, and had ECOG performance scores of 1 or lower. Most patients (82.6%) demonstrated high-risk features such as TP53 mutation (60.9%), complex karyotype (47.8%) or chromosome 17p deletion (34.8%).

After undergoing lymphodepleting chemotherapy with cyclophosphamide and fludarabine, patients received lisocabtagene maraleucel, administered as a defined composition of CD4-positive and CD8-positive CAR T cells, at either 50 x 106 (dose 1; n = 9) or 100 x 106 (dose 2; n = 14) total CAR-positive T cells. The researchers monitored patients for dose-limiting toxicities and evaluated response by International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. They used flow cytometry to evaluate minimal residual disease (MRD) in blood (10-4) and next-generation sequencing to assess MRD in bone marrow (10-6).

Determining the recommended dose and safety served as the primary objectives. Exploratory objectives included antitumor activity and pharmacokinetics.

Median follow-up was 9 months.

Two patients in the dose 2 cohort experienced dose-limiting toxicities, including one patient with grade 4 hypertension and one patient with grade 3 encephalopathy, grade 3 muscle weakness and grade 4 tumor lysis syndrome. Cytopenias were the most prevalent grade 3 or higher treatment-emergent adverse events and included anemia (dose 1, 77.8% vs. dose 2, 78.6%); thrombocytopenia (44.4% vs. 85.7%); neutropenia (44.4% vs. 64.3%) and leukopenia (44.4% vs. 42.9%). Grade 3 cytokine release syndrome occurred in two patients in the dose 2 cohort, and five patients experienced grade 3 neurological events.

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Best overall response rate among 22 evaluable patients was 81.8% (95% CI, 59.7-94.8), with best ORR of 77.8% in the dose 1 group and 84.6% in the dose 2 group. Researchers reported a 46% rate of complete response with or without complete blood count recovery.

Seventy-five percent of patients achieved undetectable MRD in blood by day 30, and 65% attained undetectable MRD in bone marrow.

More than a quarter (27%) of patients demonstrated deepening responses over time. Six months after treatment, researchers observed high rates of maintained objective responses (67%) and undetectable MRD (64%). MRD-negative complete remissions occurred among patients who failed prior Bruton tyrosine kinase and venetoclax therapy.

Five of six patients (83%) who achieved complete response at 6 months maintained that response at 9 months, with three complete responses continuing beyond 12 months.

“The exciting part of this study has been that about 75% of patients achieved a response at the 30-day mark, which is the first response assessment,” Siddiqi told HemOnc Today. “Over time, it looks like most of these responses are durable; in fact, some patients went from partial response to complete response over the next few months.”

Siddiqi said although the long-term implications of these findings are not yet clear, the durable response rates attained in TRANSCEND CLL may represent another step toward curing CLL.

“CLL is an incurable disease, but here we are trying to find a cure without having to go through a transplant,” Siddiqi told HemOnc Today. “We want to show that not only are we bringing the disease into long-term remission, but we’re prolonging patient lives. Right now, we’re looking at patients who failed the best new drugs out there, but as we test it in more and more patients at an earlier time point, maybe we’ll see that we can further prolong patients’ lives meaningfully.”

Reference:

Siddiqi T, et al. Abstract 7501. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure s : Siddiqi reports consultant/advisory or speakers bureau roles with or travel accommodations from AstraZeneca, BeiGene, Juno Therapeutics, Pharmacyclics/Janssen and Seattle Genetics and research funding to her institution from Acerta Pharma, BeiGene, Celgene, Juno Therapeutics, Kite Pharma, Oncternal Therapeutics, PCYC and TG Therapeutics. Please see the abstract for all other authors’ relevant financial disclosures.