Novel targeted therapeutics for mantle cell lymphoma – What’s on the horizon?

ABSTRACT

Major advances have significantly improved the outcome of mantle cell lymphoma (MCL). Incorporation of rituximab to CHOP regimen, the adoption of high dose cytarabine with frontline autologous stem cell transplantation in young patients, maintenance rituximab or bortezomib based chemotherapy in elderly patients, improved the disease outcome. Bortezomib, lenalidomide, temsirolimus and ibrutinib have proven their efficacy and are approved for the use in refractory or relapsed MCL patients. Several other molecules are currently being evaluated such as cyclin dependent kinase 4/6 (CDK4/6), phosphoinositide 3-kinase (PI3K), B cell lymphoma-2 (BCL2) and Poly ADP-ribose polymerase (PARP) inhibitors. Unfortunately, we don’t have specific biomarkers that could reveal which of the underlying pathways or genetic alterations are mostly involved in each individual case of MCL. Efforts should be done in this field aiming to an optimal personalized therapy.

KEYWORDS:

• Mantle cell lymphoma
• targeted therapy
• chemotherapy
• cell cycle
• DNA damage response
• signaling pathways
• apoptosis

Financial and competing interests disclosure

V Ribrag is on the advisory boards of Servier, ESAI, Pharmamar, Infinity, Gilead. Research fundings: Epizyme, Bayer, Argen X. Non profit funding: Roche. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Progresses in the understanding of the cellular and molecular biology of MCL have ushered a new era of targeted therapies. The outcome has improved remarkably with achieving higher ORR in MCL patients.

• In younger fit patients, high-dose aracytine and frontline ASCT have shown a significant increase in PFS but yet there is no significant improvement in OS.

• For elderly patients or those who are ineligible for ASCT, maintenance rituximab has proven its efficacy. On the other hand, bortezomib combined with chemotherapy (VR-CAP) was also tested in MCL patients and showed an improvement in CR rate and PFS. Future studies should test the efficacy of a maintenance therapy with bortezomib that may be interesting especially in elderly people.

• In relapsed/refractory MCL cases, four targeted therapies (bortezomib, lenalidomide, temsirolimus, and ibrutinib) are currently approved in Europe.

• Emerging drugs targeting the ATM/ATR/p53 pathway with especially ATR inhibitors might be an interesting option in the near future in view of the synthetic lethality concept and the frequency of ATM and P53 mutations.

• Furthermore, sequencing revealed subclonal heterogeneity at MCL diagnosis and modulation of the initial mutational profile at the progression of the disease. This implements the role of combining conventional chemotherapeutic drugs along with newer targeted agents followed by maintenance therapy.

• Unfortunately, we still lack a standardized approach to guide our therapy, especially in the absence of specific biomarkers reflecting the involved pathways or the underlying genetic alterations. Effort should be made in this field, aiming to an optimal personalized therapy.