Liso-Cel leads to rapid responses, high undetectable MRD rates in relapsed/refractory CLL/SLL
Treatment with lisocabtagene maraleucel (liso-cel; Breyanzi) elicited encouraging responses regardless of prior progression on BTK inhibition or absence of clinical benefit with venetoclax (Venclexta) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), meeting the primary end point of the phase 1/II TRANSCEND CLL 004 trial (NCT03331198). Primary findings were presented at the 2023 ASCO Annual Meeting
At a median follow-up of 21.0 months (95% CI, 17.5-26.6), the independent review committee (IRC)-assessed complete response (CR)/CR with incomplete hematologic recovery (CRi) rate was 18% (95% CI, 11%-28%) in the full study population who received liso-cel at dose level 2 (n = 87). The IRC-assessed objective response rate (ORR) was 47% (95% CI, 36%-58%), and the rate of undetectable minimal residual disease (uMRD) in the blood was 64% (95% CI, 53%-74%).
Additional findings indicated that the uMRD rate in marrow was 59% (95% CI, 48%-69%). Best overall response consisted of CR/CRi (18%), partial response (PR)/nonconfirmed PR (29%), stable disease (39%), and progressive disease (7%). Six patients (7%) were not evaluable.
The median time to first response in the full study population was 1.5 months (range, 0.8-17.4). Median time to first CR/CRi was 4.4 months (range, 1.1-17.9).
“A single administration of liso-cel demonstrated rapid, deep, and durable responses in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma,” said Tanya Siddiqi, MD, lead study author and medical director in the Division of Lymphoma at City of Hope Orange County in Duarte California.
Patients with relapsed/refractory CLL/SLL following treatment with BTK inhibitors and venetoclax have poor outcomes and experience reduced treatment efficacy with each subsequent therapy. Liso-cel is a CD19-directed CAR T-cell therapy administered at equal target doses of CD8-positive and CD4-positive CAR+ T cells.
In the full study population, the median DOR was not reached (NR), 24.0 months (95% CI, 12.3-NR), and 35.5 months (95% CI, 19.8-NR) in patients who achieved CR/CRi, PR/nonconfirmed PR, or derived any response to liso-cel. In the BTK/venetoclax-pretreated population, the median DOR was NR, 23.8 months (95% CI, 8.4-NR), and 35.3 months (95% CI, 11.0-NR), respectively, at median follow-up of 19.7 months (95% CI, 16.5-27.2). OS by best response, which was evaluated with median follow-ups of 24.2 months (95% CI, 23.3-29.7) in the full study population and 20.8 months (95% CI, 17.8-25.2) in the BTK/venetoclax-pretreated population, also showed improved outcomes among patients who achieved CR/CRi. In the full study population, median OS was NR, NR, 10.7 months (95% CI, 6.4-27.1), and 43.2 months (95% CI, 26.9-NR) in patients who achieved CR/CRi, PR/nonconfirmed PR, no response, or overall. In the novel agent–pretreated population, the medians were NR, NR (95% CI, 20.9-NR), 10.7 months (95% CI, 7.3-30.3), and 30.3 months (95% CI, 11.2-NR), respectively.
PFS by best response and MRD status in blood by next-generation sequencing at a sensitivity of 10-4 demonstrated similar trends, with the best outcomes in patients who achieved CR/CRi and uMRD. Specifically, median PFS was NR (95% CI, 30.1-NR), 26.9 months (95% CI, 18.0-NR), 6.3 months (95% CI, 4.6-12.0), 3.0 months (95% CI, 1.9-NR), and 1.0 month (95% CI, 0.8-NR) in patients who achieved CR/CRi uMRD, PR/nonconfirmed PR uMRD, stable disease uMRD, stable disease detectable MRD, and progressive disease detectable MRD, respectively.
In the novel agent–pretreated population, the medians were NR, 26.2 months (95% CI, 9.4-NR), 6.4 months (95% CI, 3.7-12.0), 2.8 months (95% CI, 1.9-NR), and 0.9 months (95% CI, 0.8-NR), respectively.
Additionally, Siddiqi stated that liso-cel expansion was associated with a reduction in CD19-positive cells in responders and patients with stable disease and uMRD. Furthermore, lower liso-cel expansion was associated with best response of stable disease and detectable MRD; this population was unable to clear CD19-positive cells over time.
Liso-cel also demonstrated “rapid expansion,” with a median time to maximum expansion of 14 days (interquartile range, 10.0-14.0) after liso-cel administration. Moreover, “persistence of the liso-cel transgene was detected up to 36 months after liso-cel infusion in at least 1 of 4 evaluable patients,” Siddiqi said.
Regarding safety, the most frequent grade 3 or greater treatment-emergent adverse effects (AEs) were neutropenia (61%), anemia (52%), and thrombocytopenia (41%). Cytokine release syndrome (CRS) occurred in 85% of patients (grade 1, 37%; grade 2, 39%; grade 3, 9%). The median time to onset and resolution of CRS was 4.0 (range, 1-18) and 6.0 (range, 2-37) days, respectively. Neurotoxicity occurred in 45% of patients (grade 1, 11%; grade 2, 15%; grade 3, 18%; grade 4, 1%). Median time to onset and resolution was both 7.0 days (range, 1-21 and range, 1-83, respectively). A total of 69% of patients received tocilizumab (Actemra) and/or corticosteroids.
"Overall, these results support liso-cel as a potential new treatment option for relapsed/refractory CLL/SLL,” concluded Siddiqi, who is also director of the Chronic Lymphocytic Leukemia program at the Toni Stephenson Lymphoma Center, and associate professor in the Division of Lymphoma, Department Of Hematology & Hematopoietic Cell Transplantation.
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