Tanya Siddiqi, MD
The CD19-directed CAR T-cell therapy lisocabtagene maraleucel (liso-cel; JCAR017) showed promising clinical activity and manageable toxicity in heavily pretreated patients with high-risk chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), all of whom had progressed on ibrutinib (Imbruvica), according to updated findings from the phase I/II TRANSCEND CLL 004 study presented at the 2019 ASH Annual Meeting.
At a median follow-up of 11 months, 18 (81.5%) of the 22 patients evaluable for efficacy had a response, including 45.5% who had a complete response (CR) or a CR with incomplete blood count recovery as best overall response, reported Tanya Siddiqi, MD, principal investigator of TRANSCEND CLL 004’s site at City of Hope.
There were 9 patients who failed both ibrutinib and venetoclax (Venclexta). Among these patients, the overall response rate was 89% (8 of 9 patients) with 67% (n = 6) achieving a CR as best response.
“Clinical responses were rapid, improved over time, and were deep and durable,” said Siddiqi.
Among the 20 patients who were evaluable for minimal residual disease (MRD), undetectable MRD was achieved in the blood in 75% of patients and in the marrow by 65% by day 30. Among the 8 patients in whom both ibrutinib and venetoclax failed and for whom MRD status was available, 87.5% had undetectable MRD in the blood and 75% in the marrow.
“CR and undetectable MRD rates remain somewhat inadequate in the relapsed setting, especially when monotherapy is used,” said Siddiqi. “Patients who progress on novel therapies have poor outcomes. So, effective therapies are still needed for patients with relapsed disease, especially those who have failed both BTK inhibitors and venetoclax.”
Liso-cel is an investigational CD19-directed, defined composition, 4-1BB CAR T-cell therapy that is given separately at equal target doses of CD8+ and CD4+ CAR+ T cells. “If you have a defined composition of product with low variability in the CD8+ to CD4+ ratio, you could potentially have not only lesser toxicity down the line but also more predictable toxicity,” Siddiqi said.
TRANSCEND CLL 004 enrolled 23 patients with relapsed/refractory CLL or SLL who were ineligible for or previously failed BTK inhibitor therapy. Patients with high-risk disease were candidates for the trial if they had failed ≥2 prior therapies. Those with standard-risk disease were required to have failed ≥3 prior therapies. All participants had an ECOG performance status of 0 to 1.
After undergoing lymphodepleting chemotherapy, 9 patients received liso‐cel infusion at 50 × 106
total CAR+ T cells (dose level 1) and 14 patients received 100 × 106
total CAR+ T cells (dose level 2). Response was assessed by International Workshop on CLL 2008 criteria. MRD was assessed by flow cytometry in blood and by next-generation sequencing in bone marrow.
The median patient age was 66 years, 47.8% were male, and 34.8% of patients had bulky disease. Almost three-fourths (73.9%) of patients received bridging treatment while the CAR T-cell product was being manufactured and 83% had high-risk features, including a complex karyotype (48%), del(17p; 35%), and/or TP53 mutation (61%). The patients had received a median of 5 (range, 2-11) prior lines of therapy, and all had received prior ibrutinib.
Both BTK inhibitor therapy and venetoclax had failed in 39% of patients. This cohort’s baseline characteristics were similar to the overall group of patients.
One patient developed Richter’s transformation before CAR T-cell administration and was excluded from the efficacy analysis. This patient achieved a CR as best response.
Fifteen (68%) of the 22 patients had a response by day 30. Six (27%) of the responses deepened over time, including 3 patients who went from a partial response (PR) to a CR, 2 of whom did not achieve a CR until 1 year. Ten (83%) of 12 patients who achieved a CR or PR at 6 months remained in response at 9 months; “now 8 are out a year or more maintaining or actually improving upon their response,” said Siddiqi. Of the 15 patients who achieved undetectable MRD in the peripheral blood, 12 (80%) maintained their responses, and the 3 who did not progressed with Richter’s transformation.