Immunotherapy options for mantle cell lymphoma progressing after BTK inhibitor therapy

Over the past decade, Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment and management of recurrent mantle cell lymphoma (MCL
).
BTK inhibitors such as ibrutinib, acalabrutinib, and zebrutinib significantly improved the prognosis and safety profile of patients with relapsed MCL, with median progression-free survival (PFS) improving to approximately 2 years
in MCL patients.
However, almost all MCL patients treated with BTK inhibitors will eventually progress, and in addition, patients who progress after BTK inhibitor treatment have a poor prognosis, with overall survival (OS) of less than 1 year
.
Immunotherapy plays a key role
in the treatment of relapsed MCL.
Professor Jonathon B.
Cohen of Winsp Cancer Institute, USA, explained the treatment progress
of immunotherapy in MCL that relapses after BTK inhibitor treatment.

Products targeting CD19 chimeric antigen receptor T cells (CAR-T) have been approved by the FDA for recurrent diffuse large B-cell lymphoma, follicular lymphoma and MCL
。 Brexucabtagene autoleucel (brexu-cel), a product targeting CD19 CAR-T, was approved based on the ZUMA-2 pivotal trial, which showed that 68 patients with recurrent MCL who had previously received a BTK inhibitor had an overall response rate (ORR) of 93% after receiving brexu-cel, of which 67% achieved a complete response (CR); At 3 years of follow-up, the median duration of response (DOR) was 28 months and the median OS was 47 months
.
Other products targeting CD19 CAR-T have also been evaluated in recurrent MCL, such as Lisocabtagene maraleucel, which has achieved good remission rates in recurrent MCL, but has not yet been approved
.
Professor Jonathon B.
Cohen said that based on the above results, many clinicians consider CAR-T therapy for MCL patients who progress after BTK inhibitor treatment, as well as high-risk MCL patients
who are unlikely to develop a long-term response to BTK inhibitors.
In addition, allogeneic hematopoietic stem cell transplantation is rarely used for recurrent MCL, but it is still important for certain MCL patient populations, such as MCL patients with TP53 mutations who are difficult to benefit from autologous hematopoietic stem cell transplantation, but may benefit from allogeneic hematopoietic stem cell transplantation and prolong
disease-free survival (DFS).
。 The consensus of MCL cell therapy guidelines, published in the journal Transplantation and Cellular Therapy in 2021, recommends that patients with relapsed refractory MCL who relapse after CAR-T therapy or who do not receive CAR-T therapy undergo allogeneic hematopoietic stem cell transplantation
.

Targeting the ROR1 monoclonal antibody zilovertamab and the antibody drug conjugate zilovertamab vedotin (ZV) may benefit
patients with relapsed MCL.
In a trial of zilovertamab combined with ibrutinib, the ORR of 26 MCL patients reached 81%.

In a phase I trial of ZV monotherapy for non-Hodgkin lymphoma (NHL), patients with relapsed/refractory MCL had an ORR of 53%.

Professor Jonathon B.
Cohen said that the drugs are less toxic, which also suggests that monotherapy or combination therapy targeting ROR1 therapy can significantly improve the prognosis
of patients with relapsed/refractory MCL.

Bispecific antibody drugs targeting CD20 and CD3 for several B-cell NHL are under development, and such drugs have not been explored on a large scale in MCL, but they are bound to affect the treatment and management
of lymphoma.
One trial showed that glofitamab, a bispecific antibody drug targeting CD20 and CD3, administered for 7 days after treatment with obinutuzumab, resulted in an ORR of 81 percent in 29 patients with relapsed MCL who had previously received a BTK inhibitor, with 67 percent having a CR.

In addition, Epcoritamab, a subcutaneous drug targeting CD20 and CD3 bispecific antibodies, also has good efficacy in recurrent MCL, and other bispecific antibodies are still being studied
.
Professor Jonathon B.
Cohen said that whether these drugs can replace CAR-T therapy or as an additional treatment option before and after CAR-T therapy needs to be further
trialized.
They also carry a risk of cytokine release syndrome (CRS) and other immune-mediated toxicities than CAR-T therapy, but they are less
severe.

Novel immunotherapies have significantly changed the outlook for relapsed MCL and significantly improved outcomes for these patients
.
In the future, more trials will explore the role of immunotherapy in the early treatment of MCL, especially in high-risk patients; Further research is also needed to determine the appropriate treatment sequence
of BTK inhibitors, cell therapies, novel antibodies, and bispecific antibodies in MCL.

References:

Jonathon B.
Cohen.
2022 SOHO.
EXABS-205-MCL.

Typesetting: Quarter year

Execution: Quarterly year

Poke "Read Original" to see more