The anti-CD19 CAR construct lisocabtagene maraleucel induces a rapid, high rate of durable responses in patients with relapsed/refractory large B-cell lymphoma
The recent introduction of the two CD19 directed CAR T cell constructs axicabtagene ciloleucel and tisagenlecleucel offers new hope to patients with relapsed/refractory diffuse large B-cell lymphoma. During ASH 2019, pivotal results were presented of a large phase I study evaluating a third CD19 CAR T cell product (lisocabtagene maraleucel [liso-cel]) in patients with large B-cell lymphoma. In this trial, liso-cel was associated with an overall response rate of 73%, with 53% of patients obtaining a complete response. Furthermore, the time to a response to liso-cel was short (median: 1 month) and the obtained responses proved to be very durable (54.7% ongoing responses at 12 months). At 12 months, 44.1% of patients in the trial were alive and free of progression (65.1% in patients with a complete response). Of note, meaningful activity was observed across all investigated subgroups, including rare large B-cell lymphoma subtypes and patients with poor prognostic features. Importantly, the incidence of cytokine release syndrome and neurological toxicity was low with liso-cel.
Background
Historically, patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in whom second-line therapy failed had no curative treatment options, with fewer than 50% of patients achieving a response to subsequent treatments. The outcome is even worse for patients with chemotherapy-refractory disease, where complete response (CR) rates to conventional treatment are not higher than 7% with a median overall survival (OS) of only 6 months. In recent years, the introduction of CD-19 targeting CAR T cell therapy addressed this medical need in R/R DLBCL by inducing high response rates and durable remissions. Liso-cel is a novel CD-19 directed, defined composition, 4-1BB CAR T cell product. A typical characteristic of this CAR T cell therapy is that CD8+ and CD4+ CAR T cell components are administered separately. This allows for a consistent administration of the CD8+ and CD4+ CAR T cell dose and leads to a low variability in the CD8+/CD4+ ratio. This may have an influence on the incidence and severity of cytokine release syndrome (CRS) and neurological events (NE).
In the pivotal phase I TRANSCEND NHL 001 trial, liso-cel was evaluated as a treatment option for patients with R/R large B-cell lymphoma (LBCL). Patients in the study had R/R DLBCL not otherwise specified (NOS; including transformed from any indolent lymphoma), high-grade B cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B). Patients had R/R disease after ≥2 lines of therapy and had to have an ECOG performance status 0‒2. Bridging therapy was allowed, but patients had to have PET-positive disease before lymphodepletion (LD) with fludarabine and cyclophosphamide. Liso-cel was administered at 1 of 3 target dose levels (DLs) of 50×106 (DL1), 100×106 (DL2), or 150×106 (DL3) viable CAR T cells in the dose-finding cohorts. All dose levels were expanded, and DL2 was chosen as the target DL for dose confirmation.
Results
In total, 344 patients were leukapheresed, of whom 294 received LD and CAR T cells. Twenty-five patients received a non-conforming product resulting in a liso-cel treated set of 269 patients. For the efficacy analysis, another 13 patients were excluded (no PET-positive disease before liso-cel, no PET scan after bridging, etc.). The median age of patients in the study was 63 years, 51% had DLBCL NOS, 22% of patients had transformed FL and 13%, 6% and 1% of patients in the study had HGBCL, PMBCL, or FL3B, respectively. In total, 38% of patients had a high disease burden and patients received a median of 3 prior lines of therapy (26% received 4 or more prior treatment lines). A third of patients previously underwent a hematopoietic stem cell transplantation (HSCT) and 67% were chemotherapy refractory. Overall, 44% of patients in TRANSCEND never achieved a CR with prior therapy. Bridging therapy was used in 59% of patients.
The most common adverse events with liso-cel were neutropenia (63%, 60% grade ≥3), anemia (48%, 38% grade ≥3) and fatigue (44%, 38% grade ≥3). Any grade CRS was reported in 42% of patients, but the incidence of grade 3/4 was very low (2%). The median time to CRS was 5 days and also the time to CRS resolution was 5 days. NE of any grade was reported in 30% of patients, with grade 3/4 NEs in 10% of patients. The median time to onset and resolution of NE was 9 and 11 days, respectively. In only 4% of patients, NE or CRS led to admission in the intensive care unit. Overall, 28% of patients received some form of treatment for CRS or NE (13% tocilizumab and corticosteroids). Prolonged grade ≥3 cytopenia was reported in 37% of patients, while grade ≥3 infections were seen in 12% of study participants.
In total, 73% of patients responded to liso-cel, with 53% having a CR. The time to the first CR or partial response (PR) was short at a median of 1 month. Importantly, responses were also durable with a 6- and 12-month duration of response (DoR) rate of 60.4% and 54.7%. The 12-month progression-free survival (PFS) rate in the entire study population was 44.1% (65.1% in patients with a CR). The 12-month OS rate was reported at 57.9%, while 85.5% of patients with a CR to liso-cel were still alive after 12 months. Of note, no significance difference was seen in terms of PFS between patients with or without bridging therapy. In contrast, liso-cel treated patients without comorbidities did seem to have a significantly better PFS than patients with comorbidities (median PFS: 9.5 versus 3.0 months; HR 1.5 [95% CI: 1.0-2.2]; p=0.03).
Conclusions
TRANSCEND NHL001 is the largest clinical study to date evaluating an anti-CD19 CAR T construct in patients with R/R aggressive LBCL. In this population of heavily pretreated patients, liso-cel induced a high rate of durable responses and this activity was similar across all investigated patients subgroups, including uncommon LBCL histologic subtypes (HGBCL, PMBCL) and patients with high-risk prognostic characteristics. Importantly, the incidence of high-grade CRS or NE was low and the late time of onset of these adverse events supports the use of liso-cel in an outpatient setting.
Reference
Abramson J, et al. Pivotal Safety and Efficacy Results from Transcend NHL 001, a Multicenter Phase 1 Study of Lisocabtagene Maraleucel (liso-cel) in Relapsed/Refractory (R/R) Large B Cell Lymphomas. Presented at ASH 2019; Abstract 241.
