Bristol Myers Squibb’s Anti-CD19 CAR-T Therapy Lisocabtagene Maraleucel Demonstrates Rapid MRD-Negative Remissions in High-Risk Relapsed/Refractory CLL/SLL
Dec 10, 2019 09:28
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09:28
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December 10, 2019 /Bio ValleyBIOON/ -- The 61st Annual Meeting of the American Society of Hematology (ASH 2019) was recently held in Orlando, Florida, USA. ThisMeetingAt the conference, Bristol-Myers Squibb (BMS) announced results for lisocabtagene maraleucel (liso-cel, JCAR017), an anti-CD19 CAR-T cell therapy, in the treatment of relapsed or refractory chronic lymphocyticLeukemiaor data from the Phase I/II TRANSCEND CLL 004 study in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (R/R CLL/SLL).
At the data cutoff, 23 patients with CLL/SLL who had previously received at least three prior therapies (for standard-risk disease) or two prior therapies (for high-risk disease) were evaluable for safety, and 22 patients were evaluable for efficacy. The median number of prior therapies was 5 (range, 2–11). All patients (23/23) had previously received the BTK inhibitor ibrutinib, and the majority (21/23) were refractory to ibrutinib or experienced relapse after treatment. Nine patients (39%) had failed both a BTK inhibitor (disease progression during treatment) and venetoclax (a Bcl-2 inhibitor; no response after at least 3 months of treatment). Most patients (83%) had high-risk features, including deletion 17p (del17p; 35%, 8/23) and TP53 mutations (61%, 14/23). Patients received 50×10⁶ (n=9) or 100×10⁶ (n=14) CAR+ T cells following lymphodepletion.
With a median follow-up of 11 months, the overall response rate (ORR) among patients treated with liso-cel was 81.5% (18/22; 95% CI: 59.7–94.8), and the complete response (CR) rate was 45.5% (10/22). Among patients who had failed treatment with one BTK inhibitor and venetoclax, the ORR was 89% (8/9; 95% CI: 51.8–99.7) and the CR rate was 67% (6/9). By day 30 post-treatment, 68% (15/22) of patients had achieved an early objective response. Among the 12 patients who maintained their response at 6 months, 10 remained progression-free for at least 9 months, and 8 remained progression-free for 12 months or longer. Among 20 patients evaluable for minimal residual disease (MRD), the majority achieved undetectable MRD (i.e., MRD negativity) by next-generation sequencing in blood (75%) and bone marrow (65%). All MRD-negative patients remained in this state at the last follow-up.
The above results confirm that patients with relapsed or refractory CLL/SLL who were heavily pre-treated, including those who had failed ibrutinib and venetoclax therapy, achieved durable complete responses, including undetectable MRD (MRD-negative), after receiving liso-cel treatment.
In this study, treatment-emergent adverse events (TEAEs) of any grade occurred in 100% (23/23) of patients, and Grade ≥3 TEAEs occurred in 96% (22/23) of patients. The most common Grade ≥3 TEAEs (occurring in at least 25% of patients) includedAnemia(78%, 18/23), thrombocytopenia (70%, 16/23), neutropenia (56.5%, 13/23), leukopenia (43.5%, 10/23), febrile neutropenia (26%, 6/23), lymphopenia (26%, 6/23), and cytokine release syndrome (9%, 2/23).
The proportion of patients who experienced cytokine release syndrome (CRS) of any grade was 74% (17/23), with 9% (2/23) experiencing Grade 3 CRS. Neurological events (NE) of any grade occurred in 39% (9/23) of patients, and 22% (5/23) experienced NE of Grade ≥3. The median time to onset of CRS was 4 days (range, 1–10 days), and the median time to onset of NE was 4 days (range, 2–21 days). The incidence and severity of CRS and NE were similar among patients who had failed treatment with BTK inhibitors and venetoclax. A total of 74% (17/23) of patients received anti-inflammatory therapy with RoActemra/Actemra (generic name: tocilizumab) and/or corticosteroids. No Grade 5 events occurred.
Liso-cel was developed by Juno, which was acquired in January 2018 for $9 billion. It is a CAR-T cell therapy targeting the CD19 antigen with 4-1BB as the co-stimulatory domain, featuring a precise 1:1 ratio of CD4+ and CD8+ CAR-T cells. Liso-cel represents a potential best-in-class CD19-directed CAR-T therapy, previously approved by the U.S.FDAGranted Breakthrough Therapy Designation.
In early January this year, Bristol-Myers Squibb announced its $74 billion acquisition of Celgene. After a series of twists and turns, the massive deal was finally completed on November 21, 2019.
Liso-cel is poised to become the third CAR-T cell therapy to reach the market, following the two CAR-T cell therapies already approved.NovartisKymriah and Gilead’s Yescarta target the same antigen; however, patients receiving liso-cel undergo pre-separation of CD4+ and CD8+ T cells prior to chimeric antigen receptor (CAR) transduction. The separately transduced cells are then reinfused into the patient at a specific 1:1 ratio, resulting in a more favorable safety profile compared with other CAR-T therapies, such as a lower incidence of cytokine release syndrome. (Bioon.com)