Novel Approaches Gain Ground in Diffuse Large B-Cell Lymphoma

Kristi Rosa
Published: Friday, Feb 28, 2020

Craig Moskowitz, MD, physician in chief, Oncology Service Line, Sylvester Comprehensive Cancer Center, and professor of medicine, University of Miami Health System Miller School of Medicine

Craig Moskowitz, MD

Despite advances made in the treatment of patients with diffuse large B-cell lymphoma (DLBCL), investigators are on a quest to move more novel agents through the pipeline, said Craig Moskowitz, MD, in a presentation during the 24th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma.

Following first-line chemotherapy comprised of an anthracycline and rituximab (Rituxan), patients with DLBCL will typically achieve an overall response rate (ORR) of 60% and a long-term event-free survival of 50%. Despite this initial promise, 30% to 40% of patients will eventually relapse, and 10% are primary refractory.1

Although these patients have the option to receive salvage chemotherapy, including autologous stem cell transplant (ASCT) and monoclonal antibodies, the prognosis of these patients remains poor. Furthermore, only half of patients with relapsed/refractory disease are able to proceed to ASCT.

Although these patients are eligible for clinical trials, they do not tend to perform well. The emergence of CD19-targeted CAR T-cell therapies into the treatment paradigm, however, has led to high response rates and generated excitement within the space.

CAR T-Cell Therapy Offers Hope in Relapsed/Refractory Disease

CAR T-cell therapy is a "designer-treatment," and their use will largely be restricted to transplant centers, said Moskowitz, physician in chief, Oncology Service Line, Sylvester Comprehensive Cancer Center, and professor of medicine, University of Miami Health System Miller School of Medicine. "Each center is convinced that their CAR T-cell therapy is the "'best.'"

Currently, 2 CAR T-cell products are approved for use as third-line treatment in patients with relapsed/refractory DLBCL: axicabtagene ciloleucel (axi-cel; Yescarta) and tisagenlecleucel (Kymriah).

Axi-cel received approval from the FDA in October 2017 for use in adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after ≥2 prior lines of therapy. The product has been found to induce a median overall survival (OS) of 25.8 months for patients with refractory large B-cell lymphoma, according to data from a 3-year analysis of the pivotal phase II ZUMA-1 trial.2

At a median follow-up of 39.1 months, axi-cel boasted a 3-year OS rate of 47%, with approximately 60% of patients having relapsed or progressed. Prior findings from a 2-year analysis of the trial showed that treatment with the agent led to an ORR of 83% and a complete remission rate of 58%. At 2 years, the OS rate was 51% with axi-cel and the progression-free survival (PFS) rate was 39%.

Tisagenlecleucel received approval from the FDA the following year, in May 2018, for use in adult patients with relapsed/refractory large B-cell lymphoma after ≥2 lines of systemic therapy, including DLBCL not otherwise specified, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The regulatory decision was based on data from the pivotal phase II JULIET trial, which showed that treatment with the product led to an ORR of 50% (95% CI, 38%-62%) in those with relapsed/refractory DLBCL.3

Updated data from the trial, which were published in the New England Journal of Medicine, showed a best ORR of 52%, with 40% of patients achieving complete responses (CRs) and 12% achieving partial responses (PRs).4 The estimated rate of PFS at 12 months with the product was 83% among those who had experienced a CR or PR at 3 months. Moreover, the estimated probability of survival at 12 months was 40%.

The ongoing phase III ZUMA-7 trial (NCT03391466) is evaluating whether treatment with axi-cel will improve the clinical outcomes for patients with relapsed/refractory DLBCL compared with standard-of-care second-line therapy, which is comprised of platinum-containing salvage chemotherapy followed by high-dose therapy and ASCT in responders.5

Despite the promise seen with CAR T-cell products, more work is needed to improve outcomes with this approach, according to Moskowitz. For one, smarter, more controllable CAR T cells must be developed. Additionally, pairing these products with additional agents, such as checkpoint inhibitors or BTK inhibitors, might boost responses in patients. More research should also be dedicated to the development of universal CAR T cells-potentially available off-the-shelf products, which would allow treatment to be more convenient for patients.

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