Although chimeric antigen receptor (CAR) T-cell therapy has been a life-saving treatment for some patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and other hematologic malignancies, additional therapies may be able to perform equally well in select patients, according to Andrew D. Zelenetz, MD, PhD, Medical Director, Quality Informatics, Memorial Sloan Kettering Cancer Center, New York City. Dr Zelenetz spoke at the National Comprehensive Cancer Network (NCCN) 2020 Virtual Congress: hematologic malignancies.
CAR T-cell therapy can be lifesaving for some patients, but because CAR T-cells are genetically engineered through a laborious process, the treatment is very expensive. Furthermore, CAR T-cell therapy is associated with serious adverse events, including cytokine release syndrome (CRS) and neurologic toxicities.
So far, the FDA approved 3 CAR T-cell therapies, including tisagenlecleucel (Kymriah) for relapsed or refractory B-cell precursor acute lymphoblastic leukemia and for relapsed or refractory DLBCL, axicabtagene ciloleucel (Yescarta) for relapsed or refractory DLBCL, and most recently, brexucabtagene autoleucel (Tecartus) for relapsed or refractory mantle-cell lymphoma. A fourth CAR T-cell therapy, lisocabtagene maraleucel, has recently been submitted for FDA approval for relapsed or refractory large B-cell lymphoma.
The approval of axicabtagene ciloleucel was based on the findings of ZUMA-1, a phase 1/2 clinical trial that included 108 patients with refractory DLBCL, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma.
“These patients were in bad shape. Twenty-six percent were primary refractory, and 53% were refractory to 2 prior lines of therapy. Almost 70% had at least 3 prior lines of therapy,” Dr Zelenetz emphasized. “Updated ZUMA-1 data show a plateau in progression-free survival and overall survival. We would expect a plateau in the range of 5% to 10%, but the range is approximately 40%,” he added.
The JULIET study included 111 patients with relapsed or refractory DLBCL who received tisagenlecleucel. The patients received at least 2 previous lines of therapy, the same as the patients in ZUMA-1.
“This therapy [tisagenlecleucel] was somewhat better tolerated than axicabtagene, with less neurologic toxicity. The survival plateau is similar to what we saw in ZUMA-1, around 30% to 35%,” Dr Zelenetz said.
Lisocabtagene maraleucel is a new CD19-directed CAR T-cell therapy that was studied in the TRANSCEND trial in patients with relapsed or refractory heavily pretreated DLBCL (Abramson JS, et al. Lancet. 2020;396:839-852). In contrast to the findings of the ZUMA-1 and JULIET studies, adverse events with lisocabtagene maraleucel were low compared with the previous 2 studies, with 2% grade 3 or grade 4 CRS and 10% neurologic toxicity.
The overall response rate was 73%, with activity across all the subgroups. The survival plateau was in the range of 40%.
“Lisocabtagene appears to be the safest of the 3 CAR T-cell products,” Dr Zelenetz suggested. “Studies show that all 3 CAR T-cell agents represent a new treatment for relapsed or refractory DLBCL. This includes transformed follicular lymphoma and transformed marginal-zone lymphoma.”
Transplant Outcomes
“Some patients achieve partial response from high-dose chemotherapy and stem-cell transplant. The thinking now is that if the patient is not in complete response, you can go on to CAR T-cell therapy,” Dr Zelenetz noted.
A recent study that included 67 patients with DLBCL who had no response to late (<12 months) chemotherapy evaluated the outcomes of patients who were positron emission tomography (PET)-positive and had a partial response after second-line chemotherapy before they underwent autologous hematopoietic stem-cell transplant (ASCT). The mortality rate not linked to disease relapse was low. Disease progression was reported in approximately 50% of the patients. The progression-free survival and overall survival plateau was approximately 45%, which was similar to the outcomes achieved with third-line CAR T-cell therapy.
“This raises the question of whether you have to go on to CAR T-cell, or can you continue with high-dose chemotherapy and stem-cell transplant,” Dr Zelenetz said. “A randomized trial is needed to compare CAR T-cell therapy to ASCT before CAR T-cell replaces transplant” in patients with relapsed or refractory DLBCL.
“For chemosensitive patients, it’s not clear that CAR T-cell is superior to high-dose chemotherapy and stem-cell transplant if the patient is PET-positive after chemotherapy. Additional randomized trials are needed, and they are ongoing as we speak,” Dr Zelenetz concluded.
