Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the overexpression of cyclin D1 due to the chromosomal translocation t(11;14)(q13;q32). Despite advances in therapeutic approaches, MCL remains a significant clinical challenge, particularly in relapsed and refractory (R/R) cases. Relapse occurs when the disease reappears after an initial response to therapy, while refractory MCL refers to cases where the disease fails to respond adequately to standard treatment regimens. Both conditions are associated with poor prognosis and limited treatment options, reflecting the need for novel therapeutic strategies.

Relapsed MCL is characterized by clonal evolution and the emergence of more aggressive phenotypes, including resistance to previously administered therapies. Refractory cases, on the other hand, exhibit intrinsic or acquired resistance mechanisms, such as mutations in the B-cell receptor (BCR) signaling pathway, TP53 abnormalities, and alterations in DNA damage response genes.

Recent therapeutic advances have improved outcomes for R/R MCL patients. Targeted therapies, including Bruton’s tyrosine kinase (BTK) inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib, have demonstrated significant efficacy by disrupting BCR signaling. Ibrutinib, the first BTK inhibitor approved for R/R MCL, has shown durable responses in clinical trials, although resistance to BTK inhibitors is a growing concern. Lenalidomide, an immunomodulatory agent, and venetoclax, a BCL-2 inhibitor, have also shown promise in heavily pretreated patients. Furthermore, chimeric antigen receptor (CAR) T-cell therapy targeting CD19, such as brexucabtagene autoleucel, represents a groundbreaking approach for patients with chemorefractory disease. While these therapies offer hope, their application is often limited by adverse events, accessibility, and high costs.

Biological heterogeneity within MCL further complicates the management of R/R cases. The proliferation index (Ki-67), TP53 mutation status, and the presence of blastoid or pleomorphic variants are critical prognostic factors influencing treatment decisions. Additionally, the integration of next-generation sequencing (NGS) and molecular profiling enables the identification of actionable mutations and pathways, paving the way for personalized medicine.

Despite these advancements, challenges remain in optimizing the sequencing of therapies, managing toxicities, and overcoming resistance. Clinical trials continue to explore novel agents, including bispecific antibodies, proteasome inhibitors, and checkpoint inhibitors, as well as combination strategies to enhance efficacy and minimize resistance. Moreover, the role of minimal residual disease (MRD) monitoring in guiding treatment remains an area of active investigation.

In conclusion, relapsed and refractory MCL represents a complex clinical entity with significant unmet needs. While recent therapeutic innovations have improved outcomes, the heterogeneity of the disease necessitates a personalized approach to treatment. Future research should focus on elucidating resistance mechanisms, refining therapeutic strategies, and improving access to novel treatments to enhance the prognosis for this challenging patient population.