Michael Wang, MD,
Overcoming resistance to BTK inhibitors is the biggest clinical unmet need in the treatment of patients with mantle cell lymphoma (MCL), according to Michael Wang, MD. Patients who progress on treatment with ibrutinib (Imbruvica) and acalabrutinib (Calquence) are often incurable, challenging investigators to find a new avenue of treatment.
Chimeric antigen receptor (CAR) T-cell therapy swept through hematologic malignancies in 2017. Recent approvals in acute lymphoblastic leukemia, non-Hodgkin lymphoma (NHL), and large B-cell lymphoma have given investigators hope that patients with MCL may benefit from cellular therapy, as well.
The CD19-targeted CAR T-cell product axicabtagene ciloleucel (axi-cel; Yescarta) is currently being investigated in patients with relapsed/refractory MCL in the ongoing ZUMA-2 trial (NCT02601313).1
Axi-cel was previously approved by the FDA as a treatment for adults with relapsed/refractory NHL based on data from the phase II ZUMA-1 study. Following a priority review designation, in October 2017, Axi-cel became the second CAR T-cell therapy approved by the FDA. The first approval was with tisagenlecleucel (Kymriah) in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse. That approval was expanded in May 2018 to include adult patients with relapsed/refractory large B-cell lymphoma—including DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after 2 or more lines of systemic therapy.
ZUMA-2 is a phase II, multicenter, open-label study, with a primary outcome of overall response rate (ORR). Secondary endpoints include duration of response, best objective response, and progression-free survival.
"There are 3 major areas [of development] in MCL—targeted therapies, cell therapies, and immunotherapies," said Wang, a professor in the Department of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, and lead author of ZUMA-2. "CAR T-cell therapy is a very promising entity to deal with a drug resistance."
The trial is currently enrolling, and investigators are planning to treat approximately 70 patients. Patients must have had prior therapy with an anthracycline- or bendamustine-containing chemotherapy, anti-CD20 monoclonal antibody therapy, and either ibrutinib or acalabrutinib.
On trial, patients will receive a fixed dose of fludarabine- and cyclophosphamide-conditioning chemotherapy daily, followed by a single infusion of axi-cel, administered intravenously.
“We hope to obtain good efficacy and safety data from this CAR T-cell protocol,” said Wang. “If everything is good, we hope that we can get this therapy approved for the patients to overcome BTK inhibitor resistance.”
In ZUMA-1, investigators found that axi-cel induced an ORR of 82% and complete response rate of 54%.2
These data led to the approval in large B-cell lymphoma following 2 prior therapies, including for those with diffuse large B-cell lymphoma (DLBCL), as well as in primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL transformed from follicular lymphoma.
Similar to ZUMA-2, patients on ZUMA-1 were given a conditioning regimen of fludarabine and cyclophosphamide prior to axi-cel infusion.
Grade 3/4 toxicities observed with axi-cel in patients with lymphoma have been anemia, neutropenia, decreased neutrophil count, febrile neutropenia, decreased white blood cell count, thrombocytopenia, encephalopathy, and decreased lymphocyte count.
Additionally, there were 4 fatal events on the ZUMA-1 study, 3 of which were deemed to be related to axi-cel. In May 2017, Kite Pharma, the sponsor of ZUMA-1 and ZUMA-2, reported that a patient had died of cerebral edema in the setting of grade 3 cytokine release syndrome (CRS) with multiorgan failure. The other 2 axi-cel–related deaths were from hemophagocytic lymphohistiocytosis and cardiac arrest in the setting of CRS. These events led to a boxed warning regarding CRS. The warning also alerts clinicians of the risk of neurologic toxicities with axi-cel.
If axi-cel proves to be beneficial in patients with relapsed/refractory MCL, it could serve a population of patients with an aggressive and often incurable disease.
“We are looking forward to improving patients’ quality of life and saving patients’ lives,” said Wang. “We welcome patients to visit our center, as well as investigators to collaborate with us to cure MCL.”
According to Wang, the results from ZUMA-2 will read out at the end of 2018.
- Wang M, Locke FL, Siddiqi T, et al. ZUMA-2: A phase 2 multi-center study evaluating the efficacy of KTE-C19 (anti-CD19 CAR T cells) in patients with relapsed/refractory mantle cell lymphoma. Ann Oncol. 2016;27(6). doi: 10.1093/annonc/mdw375.40.
- Locke FL, Neelapu SS, Bartlett NL, et al. Primary results from ZUMA-1: a pivotal trial of axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphoma (NHL). In: Proceedings from the 2017 AACR Annual Meeting; April 1-5, 2017; Washington, DC. Abstract CT019.