Liso-Cel Demonstrates Durable Efficacy in Relapsed/Refractory CLL/SLL

Nirav N. Shah, MD

A single administration of lisocabtagene maraleucel (liso-cel; Breyanzi) elicited rapid responses in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that have proven to be deep and durable with longer follow-up, according to findings from the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198).¹

Data presented during the 2024 Transplantation & Cellular Therapy Meetings, and previously shared at the 2023 ASH Annual Meeting, showed that at a median follow-up of 23.5 months, the CAR T-cell therapy elicited an independent review committee (IRC)–assessed complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 20% (95% CI, 10%-34%) when given at the recommended phase 2 dose (RP2D) of 100 x 106 CAR-positive T cells (dose level 2 [DL2]) in the prespecified subset of patients (PEAS) who had progressed on BTK inhibition and failure with venetoclax (Venclexta; n = 50).

In this group, the IRC-assessed objective response rate (ORR) was 44% (95% CI, 30%-59%). Moreover, 64% (95% CI, 49%-77%) of patients achieved undetectable minimal residual disease (uMRD) in the blood; the uMRD rate in the marrow was 60% (95% CI, 45%-74%). The median time to first response and time to first CR/CRi was 1.1 months (95% CI, 0.8-17.4) and 2.1 months (95% CI, 0.8-18.0), respectively.

At a median follow-up of 22.4 months (95% CI, 20.9-23.6), the median duration of response (DOR) with liso-cel was 35.3 months (95% CI, 12.4-not reached [NR]). When broken down by best overall response, those who achieved a CR/CRi experienced a median DOR that was NR, and those who achieved a partial response or remission (PR)/nodular PR (nPR), the median DOR was 12.4 months (95% CI, 8.4-NR).

Additionally, at a median follow-up of 24.2 months (95% CI, 23.6-25.2), the overall median progression-free survival (PFS) was 11.9 months (95% CI, 5.7-26.2). In responders, the median PFS was 38.1 months (95% CI, 13.4-NR) vs just 3.7 months (95% CI, 2.4-6.1) in nonresponders. When examining PFS by best overall response, those who achieved a CR/CRi or a PR/nPR experienced a median PFS of NR and 26.2 months (95% CI, 10.3-NR), respectively. At a median follow-up of 24.3 months (95% CI, 23.6-25.1), the total median overall survival (OS) was 30.3 months (95% CI, 15.0-NR). The median OS in responders was NR vs 10.7 months (95% CI, 7.3-30.3) for nonresponders. When broken down by best overall response, those who achieved a CR/CRi or PR/nPR experienced a median OS that was NR.

“Overall, these results support liso-cel as a potential new treatment option for relapsed or refractory CLL/SLL,” Nirav N. Shah, MD, lead study author and an associate professor at Medical College of Wisconsin in Milwaukee, and colleagues, wrote in a poster on the data.

The open-label, multicenter, phase 1/2 TRANSCEND CLL 004 study enrolled patients with relapsed/refractory CLL or SLL who were at least 18 years of age, an ECOG performance status of 0 or 1, and had experienced failure with or were not eligible for BTK inhibition. In total, patients must have experienced failure with 2 or more or 3 or more prior lines of therapy. They were required to have acceptable bone marrow, organ, and cardiac function and could not have Richter transformation or active central nervous system involvement by malignancy.

After being screened, participants underwent leukapheresis with optional bridging therapy as liso-cel was being manufactured. After their eligibility was reconfirmed, they went on to receive lymphodepletion comprised of 30 mg/m2 of fludarabine and 300 mg/m2 of cyclophosphamide for 3 days. Two to seven days after chemotherapy was completed, they were given a single infusion of liso-cel at DL1, which was 50 x 106 CAR-positive T cells, or DL2/RP2D.

The primary end point of the study was CR/CRi rate per iwCLL 2018 criteria and IRC assessment in the PEAS given liso-cel at DL2. Important secondary end points were ORR and uMRD rate in the blood in this patient subset.

Of the 137 patients who underwent leukapheresis, 118 went on to receive the CAR T-cell therapy; these patients comprised the safety set. A total of 97 patients were found to be evaluable for efficacy; 9 patients received liso-cel at DL1 and 88 received it at DL2. Fifty-four patients comprised the PEAS, with 4 patients having received liso-cel at DL1 and 50 having received it at DL2.

The median patient age in the PEAS was 66.0 years (range, 49-78). Most patients had high-risk cytogenetics (86%) and almost half (46%) had bulky lymph nodes. The median number of prior lines of systemic therapy received was 5 (range, 2-14). All patients had prior exposure to BTK inhibition, and all were refractory to these agents. All patients also previously received venetoclax; 96% were refractory to the agent and 4% were intolerant. Most patients (79%) received bridging therapy.

In the full study population (n = 88) given liso-cel at DL2, the median patient age was 65.0 years (range, 49-82). Eighty-three percent of patients had high-risk cytogenetics and 45% had bulky lymph nodes. The median prior lines of systemic treatment received was also 5 (range, 2-14). All patients previously received BTK inhibition, with 88% refractory, 2% relapsed, and 10% intolerant only. Eighty-one percent of patients had prior venetoclax; 76% were refractory to the agent and 3% were intolerant only. Seventy-six percent of patients received bridging therapy.

“Efficacy outcomes were similar in the full study population, [those with] relapsed or refractory CLL or SLL after prior BTK inhibition, demonstrating a clinical benefit of liso-cel in this broader population,” the study authors wrote.

In the full study population, the IRC-assessed CR/CRi rate was 19% (95% CI, 12%-29%) with liso-cel, and the IRC-assessed ORR was 48% (95% CI, 37%-59%). The respective uMRD rates achieved in the blood and marrow with the CAR T-cell therapy were 66% (95% CI, 55%-76%) and 60% (95% CI, 49%-71%). In this group, the median time to first response was 1.3 months (95% CI, 0.8-17.4) and the median time to first CR/CRi was 5.5 months (95% CI, 0.8-18.0).

At a median follow-up of 23.2 months (95% CI, 21.3-29.2), the median DOR was 35.3 months (95% CI, 24.0-NR). When broken down by best overall response, those who experienced a CR/CRi had a median DOR that was NR, and those who had a PR/nPR experienced a median DOR of 24.0 months (95% CI, 12.3-NR).

At a median follow-up of 24.3 months (95% CI, 24.0-30.2), the median PFS overall was 17.9 months (95% CI, 9.4-26.9). The median PFS in responders was 38.1 months (95% CI, 26.9-NR) vs 3.7 months (95% CI, 2.4-6.1) in nonresponders. When broken down by best overall response, the median PFS in those who achieved CR/CRi was NR (95% CI, 30.1-NR) and 26.9 months (95% CI, 17.9-NR) in those who experienced PR/nPR. At a median follow-up of 24.7 months (95% CI, 24.0-30.2), the median OS was 43.2 months (95% CI, 27.1-NR). In responders, the median OS was NR vs 10.7 months (95% CI, 6.4-30.3) in nonresponders. When broken down by best overall response, the median OS in those with CR/CRi and those with PR/nPR was NR.

“The median time to next therapy was considerably longer than that observed in a real-world study of patients with CLL/SLL after prior treatment with a BTK inhibitor and BCL-2 inhibitors, [which was] 6.6 months [95% CI, 3.6-10.1].”

In the PEAS, the median time to next therapy was 12.4 months (95% CI, 5.3-NR) at a median follow-up of 27.2 months (95% CI, 24.4-29.2). In this group, 62.0% (95% CI, 47.1%-73.8%), 51.5% (95% CI, 36.8%-64.3%), 44.5% (95% CI, 30.2%-57.9%), and 42.2% (95% CI, 28.0%-55.7%) of patients were free of next therapy at 6, 12, 18, and 24 months, respectively. In the full study population, the median time to next therapy was 18.4 months (95% CI, 9.4-NR) with a median follow-up of 27.9 months (95% CI, 25.1-32.5). At 6, 12, 18, and 24 months, 66.8% (95% CI, 55.8%-75.6%), 55.9% (95% CI, 44.7%-65.7%), 50.8% (95% CI, 39.7%-60.9%), and 46.9% (95% CI, 35.9%-57.2%) of patients, respectively, were free of their next therapy.

Regarding safety, any-grade treatment-emergent adverse effects (AEs) occurred in all evaluable patients (n = 118) with 92% of patients experiencing grade 3 or higher effects. The most common TEAEs experienced by 25% or more of patients included 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%), reduced appetite (25%; 4%), and dizziness (25%; 0%).

In the patients who experienced CRS (any-grade, 85%), 36% experienced a grade 1 event, 40% experienced a grade 2 event, and 8% experienced a grade 3 event; no grade 4 or 5 CRS events were observed. The median time to onset was 4 days (range, 1-18) and the median time to resolution was 6 days (range, 2-37). In those who experienced neurologic events (any-grade, 45%), 11% experienced a grade 1 event, 15% had a grade 2 event, 18% had a grade 3 event, and 1% had a grade 4 event. The median time to onset was 7 days (range, 1-21) and the median time to resolution was 7 days (range, 1-83). Sixty-nine percent of patients received tocilizumab (Actemra) and/or corticosteroids for a CRS and/or neurologic event.

Prolonged cytopenias that were grade 3 or higher in severity at day 30 following liso-cel administration were experienced by 54% of patients. AEs of special interest comprised grade 3 or higher infections (18%), hypogammaglobulinemia (15%), tumor lysis syndrome (11%), second primary malignancy (9%), and macrophage activation syndrome (MAS; 3%).

Five patients died due to TEAEs in the form of respiratory failure, sepsis, Escherichia coli infection, and invasive aspergillosis; 4 of these deaths were not determined by investigators to be associated with the CAR T-cell therapy. One patient who died from MAS was considered to be associated with liso-cel.

“Safety data were consistent with previous reports, demonstrating that the safety profile was manageable, with low rates of grade 3 or higher CRS and neurologic events and no new safety signals,” the study authors concluded.

In November 2023, the FDA granted priority review to a supplemental biologics license application seeking approval to expand the indication of liso-cel to include patients with CLL or SLL who had prior exposure to a BTK inhibitor and a BCL-2 inhibitor.² The sBLA is supported by data from the primary analysis of TRANSCEND CLL 004. The regulatory agency will decide on the application by March 14, 2024.

References

1. Shah NN, Siddiqi T, Maloney DG, et al. Lisocabtagene maraleucel in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: 24-month median follow-up of TRANSCEND CLL 04. Presented at: 2024 Transplantation & Cellular Therapy Meetings: February 21-24, 2024; San Antonio, TX. Abstract 483.
2. US Food and Drug Administration accepts for priority review Bristol Myers Squibb’s application for Breyanzi (lisocabtagene maraleucel) for relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). News release. Bristol Myers Squibb. November 9, 2023. Accessed February 23, 2024.