Liso-Cel Achieves High MRD Negativity Rate in High-Risk CLL/SLL

Tanya Siddiqi, MD

Chimeric antigen receptor (CAR) T-cell therapy with lisocabtagene maraleucel (liso-cel) led to rapid and durable responses in patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). Updated results of the ongoing TRANSCEND CLL 004 study (NCT033311980) also showed that a high degree of undetectable minimal residual disease (uMRD) was achieved, according to findings presented at the 2020 ASH Annual Meeting.

The phase 1/2 trial examining liso-cel, the investigational, CD-19 directed, defined composition, 4-1BB CAR T-cell product, enrolled a total of 23 patients with R/R CLL or SLL. All were evaluable for safety, while 22 were evaluable for efficacy. The median age was 66 years, all patients had undergone a median of 6 prior therapies, and 83% of patients had high-risk disease. All 23 patients had previously received ibrutinib (Imbruvica). Ninety one percent (n= 21) patients were refractory to, or relapsed on, ibrutinib and 9% (2) were intolerant to ibrutinib. Forty eight percent (n= 11) were refractory to both a prior BTK inhibitor and venetoclax (Venclexta).

Clinicians administered the liso-cel treatment after 3 days of lymphodepletion with fludarabine and cyclophosphamide, at one of two dose levels: 50 × 106 (DL1) or 100 × 106 (DL2) CAR+ T cells. Treatment with liso-cel produced an overall response rate (ORR) of 82% (n= 18) with a complete response rate of 45% (n= 10).

At the 15-month follow up and the 18-month follow up, researchers found responses were maintained at 53% (n=10/19; 6 CRs) and 50% (n=7/14; 5 CRs) respectively. However, at a median follow up of 18 months, the median duration of response was not reached in patients who had initially responded to liso-cel, and median progression-free survival (PFS) was 18 months.

“For patients who had failed both BTK inhibition and venetoclax prior to enrolling onto our study, the baseline disease characteristics of those 11 patients were fairly similar to the monotherapy total cohort of 23 patients,” explained lead author Tanya Siddiqi, MD, in a presentation at ASH.

MRD was assessed in the patient’s blood by flow cytometry, with 20 of the 23 patients being MRD evaluable. Fifteen patients had uMRD in the blood while 13 had uMRD in their bone marrow. Sixty percent of patients achieved uMRD by day 30 of treatment with liso-cel.

Siddiqi, a hematologist oncologist at the City of Hope, went on to note that lico-cel therapy elicited rapid, deep and durable responses and highlighted how, after a 24-month follow up, all 7 patients who completed the 2-year study maintained their response.

“These responses appear to be durable over time. At the 12-month mark, 50% of patients were in response and only 2 of these responders progressed beyond the 12-month mark,” Siddiqi said in her presentation.

Additionally, researchers found the safety profile of liso-cel to be in line with that previously reported, with no late or delayed adverse events emerging during the 2-year follow-up. The most common treatment emergent adverse events (TAEAs) were grade 3/4 and included thrombocytopenia (70%, n= 16), anemia (78%, n= 18), neutropenia (57%, n- 13), and leukopenia (43%, n= 10).

Overall, patients in this heavily pretreated, high-risk population who were treated with liso-cel had a high rate of uMRD, which was even seen in patients who were refractory to both a BTK inhibitor and venetoclax.

Siddiqui concluded by noting that the phase 2 monotherapy expansion of the TRANSCEND CLL 004 study is currently enrolling.

_Reference

_{Siddiqi T, Soumerai J, Dorritie K, et al. Updated Follow-up of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Treated with Lisocabtagene Maraleucel in the Phase 1 Monotherapy Cohort of Transcend CLL 004, Including High-Risk and Ibrutinib-Treated Patients. Presented at: 2020 ASH Annual Meeting & Exposition. Abstract 546.}