The phase 1/2 TRANSCEND CLL 004 trial met its primary end point by demonstrating that lisocabtagene maraleucel elicited responses in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma.
Lisocabtagene maraleucel (liso-cel; Breyanzi) induced a high response rate in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), according to findings from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198). Further, responses were found to be consistent regardless of prior progression on BTK inhibition or absence of clinical benefit with venetoclax (Venclexta).1,2
The findings, which were presented during the 2023 American Society of Clinical Oncology Annual Meeting, showed that the trial met its primary end point. 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,” Tanya Siddiqi, MD, lead study author and medical director in the Division of Lymphoma at City of Hope Orange County in Duarte, California, said.
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.
The TRANSCEND CLL 004 trial enrolled adult patients with relapsed/refractory CLL/SLL who had previously progressed on or were ineligible for BTK inhibition. Patients had to be high risk or standard risk, which was defined by absence of efficacy with at least 2 or at least 3 prior lines of treatment, respectively. ECOG performance status of 0 or 1, adequate bone marrow, organ, and cardiac function, and absence of Richter transformation and active central nervous system involvement by malignancy was also required.
The primary end point of the study was CR/CRi by International Workshop on CLL 2018 criteria per IRC assessment. Secondary end points included ORR, uMRD in blood, duration of response (DOR), duration of CR, progression-free survival, time to response, time to CR, overall survival (OS), uMRD CR rate in blood, and safety.
On study, patients were followed for 24 to 48 months, and up to 15 years after the last liso-cel treatment off study.
The study design was such that patients underwent screening, enrollment and leukapheresis, liso-cel manufacturing in which bridging therapy was allowed, reaffirmed eligibility criteria, followed by lymphodepletion and administration. Lymphodepletion consisted of 30 mg/m2 of fludarabine and 300 mg/m2 of cyclophosphamide for 3 days. Liso-cel was administered 2 to 7 days after lymphodepletion at 50 x 106 CAR+ T cells in dose level 1 (phase 1) and 100 x 106 CAR+ T cells in dose level 2 (phase 2).
Regarding baseline characteristics in the full study population, the median age and number of prior lines of systemic therapy was 65.0 years (range, 49-82) and 5 (range, 2-12), respectively. Most patients had bulky lymph nodes (44%), high-risk cytogenetics (83%), BTK (88%)- and venetoclax (76%)-refractory disease, and prior bridging therapy (76%). Notably, 60% of patients had both BTK inhibitor progression and venetoclax failure.
In the full study population, 137 patients underwent leukapheresis, 117 were treated, and 96 were evaluable for efficacy; 87 patients were treated at dose level 2. In the BTK/venetoclax-pretreated population, 82 underwent leukapheresis, 70 received liso-cel, and 53 were evaluable for efficacy; 49 patients received liso-cel at dose level 2.
Responses were also evaluated in the population of patients who received liso-cel at dose level 2 who had disease progression on BTK inhibition and no response to venetoclax (n = 49). Here, the IRC-assessed CR/CRi rate was 18% (95% CI, 9%-32%; P = .0006). IRC-assessed ORR and uMRD rates were 43% (95% CI, 29%-58%; P = .3931) and 63% (95% CI, 48%-77%), respectively. uMRD in marrow occurred in 59% of patients (95% CI, 44%-73%).
Best responses in this population consisted of CR/CRi (18%), PR/nonconfirmed PR (24%), stable disease (43%), and progressive disease (8%). Three patients were not evaluable. The median time to first response was 1.2 months (range, 0.8-17.4). The median time to first CR/CRi was 3.0 months (range, 1.1-6.1).
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.
“Higher liso-cel expansion, with an area under the curve of 0 to 28 days, was observed in responders vs nonresponders and patients with uMRD vs those without,” Siddiqi said.
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.
Other AEs of special interest included prolonged cytopenia (54%), grade 3 or greater infections (17%), hypogammaglobulinemia (15%), tumor lysis syndrome (11%), second primary malignancy (9%), and macrophage activation syndrome (3%).
Five treatment-emergent AE–related deaths occurred, 4 of which were deemed unrelated to treatment.
“Overall, these results support liso-cel as a potential new treatment option for relapsed/refractory CLL/SLL,” 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, concluded.