Understanding and identifying the unmet need of aggressive B-cell lymphomas is critical for positioning new therapies
Aggressive B-cell lymphomas are a subset of non-Hodgkin’s lymphoma (NHL) that encompass a number of neoplasms that include both precursor lymphoid neoplasms and mature B-cell neoplasms, such as diffuse large B-cell lymphoma (DLBCL), primary effusion lymphoma (PEL), mantle cell lymphoma, Burkitt lymphoma, and follicular lymphomas (grade 3).1 DLBCL is the most common B-cell lymphoma, representing 25-30% of adult NHL cases, and is characterized as fast-growing and aggressive.2,3 DLBCL is typically treated with combination chemotherapy, consisting of cyclophosphamide, doxorubicin, vincristine and prednisone.4 Upon relapse or progression, patients may be considered for autologous stem-cell transplantation. Approximately 30% of DLBCL patients will relapse,4 and the five-year overall survival ranges from 26-73%, based on prognostic factors at the time of diagnosis.5
Chimeric antigen receptor (CAR) T-cell therapy is a novel treatment option for Canadian patients with rare cancers and limited treatment options. CAR T-cell therapy combines gene therapy with adoptive cell transfer therapy and is the first gene therapy approved in Canada for limited oncology indications, including DLBCL. CAR T-cell therapy consists of harvesting T-cells from a patient’s blood, followed by genetic programming of the T-cells to target cancer cells ex vivo. The T-cells are then encouraged to multiply prior to systemic reintroduction of the engineered T-cells into the patient.6 The engineered T-cells then target and kill cancer cells.
To date, CAR T-cell therapies have achieved impressive response rates in patients with DLBCL who have failed conventional therapies as seen in the JULIET trial of tisagenlecleucel (KYMRIAH®). Patients had an overall response rate of 54% after a median of 19 months of follow-up in patients with relapsed/refractory DLBCL.7 Furthermore, in the ZUMA-1 study of axicabtagene ciloleucel (YESCARTA®), the objective response rate was 83%, while the complete response rate was 58% for patients with DLBCL.8
While tisagenlecleucel was the first CAR T-cell therapy approved by Health Canada in 2018 to treat relapsed/refractory DLBCL, axicabtagene ciloleucel for the treatment of relapsed/refractory large B-cell lymphomas is still currently under review. Recently the Canadian Agency for Drugs and Technologies in Health (CADTH) completed an Optimal Use report for tisagenlecleucel,9 which confirmed clinical benefit while acknowledging the unique administrative, regulatory, and reimbursement challenges. Most importantly, CADTH cited the current clinical evidence as insufficient, necessitating longer-term follow up studies and called for real-world data generation through patient registries.
Lisocabtagene maraleucel (Liso-Cel; JCAR017) is a CAR T-cell therapy developed by Juno Therapeutics and Bristol-Myers Squibb Company to treat aggressive large B-cell lymphoma. Liso-Cel differs from other CAR T-cell therapies by including both modified cytotoxic T-cells with helper T-cells to increase efficacy and reduce adverse events. As new gene therapies become available, understanding and identifying the unmet need of aggressive B-cell lymphomas is critical for positioning new therapies in the current treatment landscape.
1. Said JW. Aggressive B-cell lymphomas: how many categories do we need? Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 2013; 26 Suppl 1(0 1): S42-S56.
2. Sehn LH. Introduction to a clinical review series on aggressive B-cell lymphoma. Blood 2015; 125(1): 1-2.
3. Flowers CR, Sinha R, Vose JM. Improving outcomes for patients with diffuse large B-cell lymphoma. CA: a cancer journal for clinicians 2010; 60(6): 393-408.
4. Committee obotEG, Committee obotEG, Committee obotEG, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of Oncology 2015; 26(suppl_5): v116-v25.
5. Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood 2015; 125(1): 22-32.
6. Miliotou AN, Papadopoulou LC. CAR T-cell Therapy: A New Era in Cancer Immunotherapy. Current pharmaceutical biotechnology 2018; 19(1): 5-18.
7. Schuster SJ, Bishop MR, Tam C, et al. Sustained Disease Control for Adult Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma: An Updated Analysis of Juliet, a Global Pivotal Phase 2 Trial of Tisagenlecleucel. Blood 2018; 132(Suppl 1): 1684-.
8. Locke FL, Ghobadi A, Jacobson CA, et al. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. The Lancet Oncology 2019; 20(1): 31-42.
9. Tisagenlecleucel for acute lymphoblastic leukemia and diffuse large B-cell lymphoma: Recommendations. Ottawa: CADTH, 2019 Jan.