Rapid Undetectable MRD (uMRD) Responses in Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated with Lisocabtagene Maraleucel (liso-cel), a CD19-Directed CAR T Cell Product: Updated Results from Transcend CLL 004, a Phase 1/2 Study Including Patients with High-Risk Disease Previously Treated with Ibrutinib

Background: The advent of oral-targeted drugs has improved treatment outcomes for patients (pts) with CLL. Nonetheless, some pts prove intolerant or resistant to therapy and/or fail to achieve complete response (CR) with uMRD. Liso-cel is an investigational, anti-CD19, defined composition, 4-1BB CAR T cell product administered at a target dose of CD4+ and CD8+ CAR T cells. TRANSCEND CLL 004 is an open-label phase 1/2 study of liso-cel in pts with R/R CLL/SLL (NCT03331198).

Methods: Eligible pts with CLL/SLL had received at least 3 (standard-risk disease) or at least 2 (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) prior lines of therapy, including a Bruton's tyrosine kinase inhibitor unless contraindicated. Pts with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter's transformation were excluded. After 3 days of lymphodepletion with fludarabine/cyclophosphamide, pts received liso-cel infusion; 2 dose levels (DLs) were tested: DL1=50×10⁶ and DL2=100×10⁶ CAR+ T cells. Dose-limiting toxicities (DLTs) were evaluated for 28 days postinfusion. Responses were assessed by 2018 International Workshop on CLL criteria. MRD was assessed at a sensitivity of ≤10^-4 in blood and/or bone marrow (BM) lymphocytes. Liso-cel CAR T cells were monitored by flow cytometry of blood cells from treated pts over time. Serum cytokines and chemokines were assessed via an electrochemiluminescence platform.

Results: At data cutoff, 23 pts were evaluable for safety and 22 for efficacy. Median age was 66 (range, 49‒79) years; 83% (19/23) of pts had high-risk disease. Pts had a median of 5 (range, 2‒11) prior therapies. All pts had received prior ibrutinib; 56.5% (13/23) had progressed on ibrutinib and received therapy with venetoclax; 91% (21/23) were refractory to, or had relapsed on, ibrutinib; and 9% (n=2) were intolerant to ibrutinib. Liso-cel was successfully manufactured in 96% of pts, with the established process. Nine pts were treated at DL1 and 14 pts at DL2. Two pts had DLTs (all at DL2: grade 4 hypertension in 1 pt; grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome in 1 pt). The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia, 70%; anemia, 96%; neutropenia, 56.5%; leukopenia, 43.5%. Two pts had grade 3 cytokine release syndrome (CRS); 5 pts had grade ≥3 neurological events (NEs), including encephalopathy (n=3). Median time to onset of CRS and NE was 4 (range, 1-10) days and 4 (range, 2-21) days, respectively. The median duration of CRS and NE was 5 (range, 2-30) days and 21 (range, 6-169) days, respectively. To manage CRS and/or NE, 61% (n=14) of pts received tocilizumab and 48% (n=11) received corticosteroids. Lymph node tumor burden correlated with NE (P=0.025). Additional disease distribution correlates are being evaluated and will be presented. Cytokine analyses revealed that NE onset was preceded by elevated TNFα and IL16 early after liso-cel infusion (P<0.01). The table shows best responses at median follow-up of 9 months. Among evaluable pts, the best overall response rate was 82%; the best CR/CRi rate was 45.5%. Sixty-eight percent (15/22) of pts achieved objective response by Day 30; 78% (7/9) of responders with ≥9 months of postdose follow-up have remained progression-free. In 6 pts, responses deepened over time (3 from partial response [PR] to CR, 2 from stable disease [SD] to PR, and 1 from SD to CR). Among 20 pts evaluable for MRD, most achieved blood and/or BM uMRD (Table); 60% (12/20) achieved BM uMRD by Day 30. All pts who achieved blood and/or BM uMRD have remained uMRD to date.

Conclusions: In this population of heavily pretreated pts with R/R CLL/SLL (all received prior ibrutinib and half failed both prior venetoclax and ibrutinib), liso-cel toxicities, including CRS and NE, were manageable at both DLs tested. Objective responses, CRs, and uMRD were rapidly achieved, with durable responses past 6 months. Updated safety, pharmacokinetic, and efficacy results from the phase 1 monotherapy part of the study will be reported. The phase 2 portion of the study is currently enrolling at DL2.

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