Liso-Cel Prolongs Responses, PFS, and OS in Pretreated, High-Risk, R/R CLL

Lisocabtagene maraleucel (liso-cel; Breyanzi) generated durable responses and extended survival in patients with heavily pretreated, high-risk, relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who had previously progressed on a BTK inhibitor and venetoclax (Venclexta), according to updated follow-up data from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198) presented at the 2024 ASH Annual Meeting.1

At a median on-study follow-up of 23.8 months (range, 0.4-59.6), among efficacy-evaluable patients in the primary efficacy analysis set (n = 50) who received liso-cel at 100 x 106 CAR T cells, the rate of complete remission (CR)/CR with incomplete hematologic recovery (CRi) was 20% (95% CI, 10%-34%). The median time to first CR/CRi was 2.1 months (95% CI, 0.8-18.0).

Additionally, the overall response rate (ORR) was 44% (95% CI, 30%-59%). Best responses of partial remission (PR)/nodular PR (nPR), stable disease (SD), progressive disease (PD), and unevaluable responses (NE) were reported in 24%, 42%, 8%, and 6% of patients, respectively. The median time to first response was 1.2 months (range, 0.8-17.4). Furthermore, the rates of undetectable minimal residual disease (uMRD4) in the blood and marrow were 64% (95% CI, 49%-77%) and 60% (95% CI, 45%-74%), respectively.

“These data confirm the sustained clinical benefit and favorable benefit-risk profile of a single treatment of liso-cel in patients with relapsed/refractory CLL/SLL,” the study authors wrote in a poster presentation of the data.

TRANSCEND CLL 004 Trial Design

The open-label, multicenter TRANSCEND CLL 004 trial enrolled patients at least 18 years of age with relapsed/refractory CLL/SLL who had previously progressed on or were ineligible for BTK inhibition. Patients needed to have progressed on at least 2 (high-risk) or 3 (standard-risk) prior lines of therapy; have an ECOG performance status of 0 or 1; have adequate bone marrow, organ, and cardiac function; and have no Richter transformation nor active central nervous system involvement from the malignancy.

After screening, patients underwent leukapheresis, after which liso-cel was manufactured and patients received optional bridging therapy. At the end of liso-cel manufacturing, trial eligibility was reconfirmed, and eligible patients received lymphodepleting chemotherapy with fludarabine at 30 mg/m2 plus cyclophosphamide at 300 mg/m2 for 3 days. Patients received liso-cel 2 to 7 days after lymphodepletion, and the first disease assessment occurred at day 30. Liso-cel was administered at 1 of 2 dose levels: 50 x 106 CAR T cells (dose level 1) or 100 x 106 CAR T cells (dose level 2). Dose level 2 was identified as the recommended phase 2 dose.

Follow-up was conducted on the TRANSCEND CLL 004 study for 24 or 48 months; or in the phase 2/3 long-term follow-up trial (NCT03435796) for up to 15 years after liso-cel infusion.

In the primary efficacy analysis set at dose level 2, the primary end point was the CR/CRi rate per International Workshop on CLL 2018 criteria by independent review committee assessment. Key secondary end points in this population included ORR and the rate of uMRD4 in blood. Post hoc analyses assessed efficacy outcomes in patients with prior BTK inhibitor exposure who had not received prior venetoclax.

Previously reported data from the primary analysis of TRANSCEND CLL 004 showed that, among patients in the primary analysis set who received liso-cel at dose level 2 (n = 49), the CR/CRi rate was statistically significant, at 18% (95% CI, 9%-32%; P = .0006).2

Patient Characteristics

At a data cutoff of January 12, 2024, 22 patients in the full population (n = 118) were ongoing in the study; 35 patients had completed the study; and 61 patients had discontinued the study due to death (n = 36), withdrawal of consent (n = 16), PD at month 24 (n = 5), and other reasons (n = 4).1 Additionally, 19 of 60 eligible patients had enrolled to the long-term follow-up trial. The median age was 65.0 years (range, 49-82), and 83% of patients had high-risk cytogenetic markers. Patients had received a median of 5 prior lines of therapy (range, 2-14), and 86% of patients had received prior chemoimmunotherapy.

In the primary efficacy analysis set (n = 71), treatment was ongoing in 17 patients at the data cutoff. Thirteen patients had completed the study, and 41 had discontinued the study due to death (n = 23), withdrawal of consent (n = 12), PD at month 24 (n = 3), and other reasons (n = 3). Among these patients, the median age was 66.0 years (range, 49-78), and 86% of patients had high-risk cytogenetic markers. Patients had received a median of 5 prior lines of therapy (range, 2-14), and 89% of patients had received prior chemoimmunotherapy.

The subset of patients who had prior BTK inhibitor exposure and were venetoclax naive (n = 23) was less heavily pretreated, having received a median of 3 prior lines of therapy (range, 2-11); all patients in this group had received prior chemoimmunotherapy.

Additional Efficacy Outcomes in the Primary Efficacy Analysis Set at Dose Level 2

Among patients in the primary efficacy analysis set who received liso-cel at dose level 2, at a median follow-up of 31.7 months (95% CI, 21.3-35.5), the median durations of response (DORs) among patients who achieved best responses of CR/CRi, CR/CRi/PR/nPR, and PR/nPR were not reached (NR), NR (95% CI, 12.4 months-NR), and 23.8 months (95% CI, 8.4-NR), respectively. The 36-month DOR rate was 61% (95% CI, 30%-81%).

At a median follow-up of 31.4 months (95% CI, 24.3-36.2), the median progression-free survival (PFS) among patients who achieved best responses of CR/CRi, those who achieved best responses of PR/nPR, and nonresponders were NR, 26.2 months (95% CI, 10.3-NR), and 3.7 months (95% CI, 2.1-6.1), respectively. The median PFS in the total population was 11.9 months (95% CI, 5.7-26.2). At a median follow-up of 31.4 months (95% CI, 24.3-36.2), the median PFS among patients with uMRD4 disease, MRD-positive disease, and unknown MRD status was 26.2 months (95% CI, 11.9-NR), 2.8 months (95% CI, 0.8-3.2), and 0.8 months (95% CI, 0.1-13.4), respectively.

At a median follow-up of 29.7 months (95% CI, 24.1-35.9), the median overall survival (OS) among patients who achieved best responses of CR/CRi, those who achieved best responses of PR/nPR, and nonresponders were NR, NR (95% CI, 20.9 months-NR), and 10.7 months (95% CI, 7.3-30.3), respectively. The median OS—incorporating long-term follow-up data—in the total population of patients was 43.2 months (95% CI, 14.5-NR).

Additional Efficacy Findings in the Full Population at Dose Level 2

Efficacy outcomes in the full population (n = 88) were similar to those seen in the primary efficacy analysis set. Among those who received dose level 2, the CR/CRi rate was 20% (95% CI, 13%-20%), and the median time to first CR/CRi was 4.4 months (95% CI, 0.8-18.0). Additionally, the ORR was 48% (95% CI, 37%-59%). Best responses of PR/nPR, SD, PD, and NE were reported in 27%, 39%, 7%, and 7% of patients, respectively. The median time to first response was 1.3 months (range, 0.8-17.4).

Furthermore, the uMRD4 rates in the blood and marrow were 66% (95% CI, 55%-76%) and 60% (95% CI, 49%-70.5%), respectively. Among MRD-evaluable patients in the full population, uMRD4 was achieved in the blood and marrow, respectively, by 100% (n = 16) and 94% (n = 17) of patients with CR/CRi; 100% (n = 23) and 100% (n = 22) of those with PR/nPR; and 59% (n = 32) and 47% (n = 32) of those with SD.

Among patients in the full population who received liso-cel at dose level 2, at a median follow-up of 30.0 months (95% CI, 22.2-35.25), the median DORs among patients who achieved best responses of CR/CRi, CR/CRi/PR/mPR, and PR/nPR were NR, NR (95% CI, 24.0 months-NR), and 23.95 months (95% CI, 12.25-NR), respectively. The estimated 36-month DOR rate was 59% (95% CI, 39%-75%).

At a median follow-up of 31.4 months (95% CI, 24.3-36.2), the median PFS among patients who achieved best responses of CR/CRi, those who achieved best responses of PR/nPR, and nonresponders were NR, 26.9 months (95% CI, 17.9-NR), and 3.7 months (95% CI, 2.4-6.3), respectively. The median PFS in the total population was 18.0 months (95% CI, 9.4-30.1). At a median follow-up of 31.4 months (95% CI, 24.3-36.2), the median PFS among patients with uMRD4 disease, MRD-positive disease, and unknown MRD status was 31.2 months (95% CI, 18.0-NR), 2.9 months (95% CI, 1.9-6.1), and 0.8 months (95% CI, 0.4-13.4), respectively.

At a median follow-up of 35.6 months (95% CI, 25.1-36.4), the median OS among patients who achieved best responses of CR/CRi, those who achieved best responses of PR/nPR, and nonresponders were NR, NR (95% CI, 31.2 months-NR), and 11.2 months (95% CI, 6.4-27.1), respectively. The median OS in the total population of patients was 52.2 months (95% CI, 30.3-NR).

Additional Efficacy Outcomes in the BTK Inhibitor–Exposed/Venetoclax-Naive Subgroup

Among efficacy-evaluable patients who had prior BTK inhibitor exposure but were naive to venetoclax who received liso-cel at dose level 2 (n = 18), the CR/CRi rate was 22% (95% CI, 6%-48%), and the median time to first CR/CRi was 9.0 months (95% CI, 3.2-15.2). Additionally, the ORR was 61% (95% CI, 36%-83%). Best responses of PR/nPR, SD, PD, and NE were reported in 39%, 33%, 0%, and 6% of patients, respectively. The median time to first response was 2.6 months (range, 0.9-6.3). Furthermore, the uMRD4 rates in the blood and marrow were both 67% (95% CI, 41%-87%).

Among responders in this subgroup who received liso-cel at either dose level 1 (n = 2) or dose level 2 (n = 11) and achieved a CR/CRi/PR/nPR, at a median follow-up of 29.8 months (95% CI, 18.2-46.7), the median DOR was NR (95% CI, 17.1 months-NR), and the 36-month DOR rate was 62% (95% CI, 26%-84%).

Among efficacy-evaluable patients in this subgroup (n = 22) who received liso-cel at either dose level 1 (n = 4) or dose level 2 (n = 18) and achieved a CR/CRi/PR/nPR, at a median follow-up of 32.8 months (95% CI, 24.0-47.6), the median PFS was NR (95% CI, 18.0 months-NR). The median OS in this population was NR (95% CI, 52.2 months-NR) at a median follow-up of 47.4 months (95% CI, 36.2-48.1).

The authors explained that the findings from this subgroup analysis indicates that “earlier treatment after fewer prior lines of therapy may lead to improved outcomes.”

Updated Safety Data

During the treatment-emergent (TE) period, 100% of evaluable patients (n = 118) had any-grade adverse effects (AEs), and 92% of patients had grade 3 or higher AEs. The most common AEs reported during the TE period were cytokine release syndrome (CRS; any-grade, 85%; grade ≥ 3, 8%), anemia (67%; 53%), neutropenia (62%; 60%), thrombocytopenia (50%; 42%), fatigue (35%; 7%), nausea (34%; 0%), diarrhea (30%; 2%), headache (29%; 1%), leukopenia (29%; 26%), hypokalemia (28%; 2%), pyrexia (28%; 1%), confusional state (26%; 9%), hypocalcemia (26%; 4%), decreased appetite (25%; 4%), and dizziness (25%; 0%).

During the post-TE period, any-grade and grade 3 or higher AEs occurred in 55% and 39% of evaluable patients (n = 107), respectively. The most common AEs reported during the post-TE period were CRS (any-grade, 2%; grade ≥ 3, 0%), anemia (11%; 6%), neutropenia (18%; 15%), thrombocytopenia (10%; 8%), fatigue (2%; 0%), nausea (5%; 0%), diarrhea (3%; 0%), headache (4%; 0%), leukopenia (11%; 8%), hypokalemia (3%; 1%), pyrexia (3%; 0%), confusional state (1%; 0%), hypocalcemia (2%; 1%), and dizziness (3%; 0%).

The study authors noted that the overall safety findings were consistent with previous reports.

Other AEs of special interest in the full study population included prolonged cytopenias (54%), including increased hemoglobin, neutrophil, and platelet counts, which recovered to grade 2 or lower by day 90 in 100%, 80%, and 74% of patients, respectively; grade 3 or higher infections (18%); and second primary malignancies (9%).

The authors explained that the incidences of CRS, neurologic effects, prolonged cytopenias, grade 3 or higher infections, and second primary malignancies aligned with previously reported data.

Grade 0, 1, 2, and 3 CRS occurred in 15%, 36%, 40%, and 8% of patients, respectively, in the full study population; no grade 4 or 5 CRS was observed. The median times to CRS onset and resolution were 4 days (range, 1-18) and 6 days (range, 2-37), respectively.

Grade 0, 1, 2, 3, and 4 neurologic effects occurred in 55%, 11%, 15%, 18%, and 1% of patients, respectively, in the full study population; no grade 5 neurologic events were observed. The median times to the onset and resolution of neurologic effects were 7 days (range, 1-21) and 7 days (range, 1-83), respectively.

In total, 46 of the 137 patients who underwent leukapheresis (34%) died after CAR T-cell infusion. One death was attributed to liso-cel–related macrophage activation syndrome per the investigators. Since the previous TRANSCEND CLL 004 data report, 1 additional patient had died due to an unknown cause of death at approximately 14.5 months post-infusion.

Evidence of Liso-Cel Persistence

Investigators detected persistence of the liso-cel transgene for up to 48 months following liso-cel infusion. At 24 months, 47% of evaluable patients who received dose level 2 had detectable levels of the liso-cel transgene; this rate was 40% at 48 months.

References

1. Siddiqi T, Gauthier J, Kenderian SS, et al. Lisocabtagene maraleucel (liso-cel) in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): updated follow-up of Transcend CLL 004. Blood. 2024;144(suppl 1):4633. doi:10.1182/blood-2024-200840
2. Siddiqi T, Maloney DG, Kenderian SS, et al. Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study. Lancet. 2023;402(10402):641-654. doi:10.1016/S0140-6736(23)01052-8