I would favor zanubrutinib (Tam, et al. Blood Advances, 2021). The TP53 mutation may render cytotoxic chemotherapy ineffective given impaired DNA damage response, so selective Bruton tyrosine kinase (BTK) inhibition may be of benefit.
Shyam A. Patel, MD, PhD
My preferred option will be standard of care CAR T-cell therapy with brexucabtagene autoleucel, which has been approved in the U.S. for relapsed/refractory MCL since 2020. A 2020 New England Journal of Medicine study showed that 93% of the 60 patients in the primary efficacy analysis had an objective response (95% CI 84-98) and 67% had a complete response (95% CI 53-78). Additionally, 31% had blastoid phenotype and 17% had TP53 mutation, while 62% were refractory to BTK inhibition.
If brexucabtagene autoleucel is not approved in Belgium, another option is venetoclax as a single agent. According to a 2019 study in Haematologica, venetoclax monotherapy after BTK inhibition had an overall response rate (ORR) of 53% (18% complete responses; 35% partial responses). The median time to response was 48 days (range = 14-204), the median progression-free survival (PFS) was 3.2 months (95% CI 1.2-11.3), and the median overall survival was 9.4 months.
A third options is represented in the results of a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study published in the Journal of Clinical Oncology in 2014. The study showed that in patients with MCL, reduced-intensity conditioned alloHCT leads to lower progression/relapse, but non-relapse mortality was higher when compared to autologous HCT.
My colleagues and I do not think BEAM followed by autologous HCT after BEAM conditioning will offer major benefit, given that the patient is refractory to RCHOP and R-DHAX. Instead, our approach is to treat with bridging therapy such as RICE (rituximab, ifosfamide, carboplatin, and etoposide). We get a PET scan after 2 or 3 cycles. If the patient enters a complete response or a very good partial response, then our practice is to consider a non-myeloablative alloHCT with a fludarabine and cyclophosphamide‒based conditioning regimen. Based on our experience, the patient would need to respond well to the pre-alloHCT regimen to have a good outcome with the subsequent HCT. He has not been treated with ifosfamide and etoposide, so there is a small chance that he may respond to therapy.
Suman Paul, MBBS, PhD
I think the patient should receive BEAM conditioning followed by autologous HCT.
Andrea Anampa-Guzmán, MD
Based on the presence of the TP53 mutation, the patient’s disease is unlikely to respond to cytotoxic chemotherapy. I would recommend single agent venetoclax, which has a demonstrated ORR of 53% (and a complete response [CR] rate of 18%) with PFS of 3.2 months following failure of a BTK inhibitor. If the patient attains a CR, I would then proceed with alloHCT.
Reshma Ramlal, MD