CAR T Cell Meeting 2019 | CAR T-cell therapy in lymphoma

On Thursday 14 February 2019, a session on the use of chimeric antigen receptor-modified T (CAR T) cell therapy took place at the 1^st European CAR T Cell Meeting, Paris, France. A talk was presented by Marie José Kersten, Department of Haematology, Academic Medical Center, Amsterdam, Netherlands, on when to use CAR T in lymphoma.

Professor Kersten began her talk by outlining the current treatment landscape of diffuse large B-cell lymphoma (DLBCL):

• First-line of therapy: 4 x R-CHOP
• Second-line or later-line of therapy: salvage chemotherapy
• Patients in PR or CR: autologous stem cell transplantation (auto-SCT)

Then Professor Kersten continued her presentation by introducing the SCHOLAR-1 analysis by Michael Crump, from the Canadian Cancer Trials Group at Queen’s University, Kingston, Ontario, Canada, and colleagues. SCHOLAR-1 is the first patient-level analysis of outcomes of refractory DLBCL from two large randomized trials and two academic databases:

• Initially, 861 patients were included, of which 636 met the defined refractory criteria for inclusion in the analysis set of this study
• Pooled overall response rate (ORR) = 26% (20–31)
• Pooled CR rate = 7% (3–15)
• Median overall survival (OS) in refractory DLBCL = 6.3 months (95% CI, 5.9–7)
• One-year OS = 28%, two-year OS = 20%

The SCHOLAR-1 analysis demonstrated consistent poor outcomes for patients with refractory non-Hodgkin lymphoma (NHL), and showed that effective treatments for refractory NHL represents a significant unmet need.

Professor Kersten then summarized how the treatment of B-cell malignancies has evolved in recent years and highlighted that adoptive immunotherapy with CAR T cells is a rapidly growing therapeutic approach to treating patients with B-cell malignancies.

CAR T therapy similarities and differences:

• Axi-Cel, also known as YESCARTA, was approvedfor the treatment of relapsed/refractory (R/R) adult B-cell lymphomas including DLBCL, primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL) by the US Food and Drug Administration based on the findings of the ZUMA-1 trial
• Tisagenlecleucel, also known as KYMIRAH, was the first CAR T therapy to be approved in the United States; in May 2018, tisagenlecleucel was approved by the US Food and Drug Administration for adult patients with DLBCL after 2 or more lines of therapy. The approval was supported by data from the JULIET study
• Liso-Cel is a CD19-directed CAR T cell product administered with a defined composition and induced durable responses in high-risk patients with relapsed, refractory aggressive NHL and showed encouraging durable response rates at six months and beyond in DLBCL patients according to the TRANSCEND NHL 001 trial

Best responses in multicenter CD19 CAR T trials in adult DLBCL:

• ZUMA-1
  • N = 108
  • Best ORR: 83%
  • Best CR rate: 58%
• JULIET
  • N = 111
  • Best ORR: 52%
  • Best CR rate: 40%
• TRANSCEND
  • N = 65
  • Best ORR: 80%
  • Best CR rate: 55%

Durability of responses in multicenter CD19 CAR T trials in adult DLBCL:

• ZUMA-1
  • N = 108
  • Durable ORR: 39%
  • Durable CR rate: 37%
• JULIET
  • N = 46
  • Durable ORR: 37%
  • Durable CR rate: 30%
• TRANSCEND
  • N = 38
  • Durable ORR: 47%
  • Durable CR rate: 42%

Axi-Cel real world experience:

• 17 US centers
• N = 274 patients
• Patients received Axi-Cel at a dose of 2 x 10⁶ CAR T cells/kg
• Median follow-up: 3.9 months
• 30-day ORR: 191 (80%)
• 30-day CR: 113 (47%)

ZUMA-7: A randomized phase III trial of Axi-Cel versus standard-of-care therapy in patients with R/R DLBCL (NCT03391466):

• Planned enrolment: 350 patients
• Eligible patients must have R/R DLBCL after first-line therapy and intend to proceed to transplantation if they respond to second-line therapy
• Exclusion criteria: prior SCT, prior CD19-targeted therapy, or active infection
• Patients randomized to Axi-Cel will undergo leukapheresis, then lymphodepleting chemotherapy (fludarabine [30 mg/m²/d] and cyclophosphamide [500 mg/m²/d] for three days), followed by a single infusion of Axi-Cel at 2 × 10⁶ CAR T cells/kg
• Corticosteroid bridging therapy is allowed for patients with high disease burden at screening
• Patients in the standard-of-care arm will receive investigator’s choice of second-line salvage therapy (R-ICE, R-DHAP, R-ESHAP, or R-GDP)
• Patients who respond after 2–3 cycles will receive high-dose therapy and transplant
• The primary endpoint is event-free survival defined as time from randomization to disease progression, start of new lymphoma therapy, or death; secondary endpoints include ORR, OS, progression-free survival, duration of response, safety, and patient-reported outcomes

Professor Kersten concluded her talk by stating that CAR T cell therapy in DLBCL has been shown to lead to durable remissions. Currently, there is no curative treatment option for this patient population and, thus, it is encouraging that real-world experiences showed that CAR T therapy is a feasible treatment option for patients with DLBCL.