New Directions for Mantle Cell Lymphoma in 2022

Abstract

Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically heterogeneous. Risk stratification at the time of diagnosis is critical. One of the most powerful prognostic indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical factors. In addition, the presence of TP53 mutation is associated with suboptimal response to intensive chemoimmunotherapy and particularly dismal survival outcomes. Given their excellent activity in the relapsed/refractory setting, increasingly, biologically targeted therapeutics—such as covalent Bruton tyrosine kinase inhibitors, lenalidomide, and venetoclax—are being incorporated into “chemotherapy-free” regimens and in combination with established chemoimmunotherapy backbones for treatment-naïve mantle cell lymphoma. In addition, risk-adapted treatment programs are increasingly being studied. These programs tailor treatment according to baseline prognostic factors (e.g., presence of TP53 mutation) and may incorporate biomarkers of response such as minimal residual disease assessment. Although still investigational, these studies present an opportunity to move beyond the biology-agnostic, historical fitness-based treatment selection paradigm and toward a more personalized, tailored treatment approach in mantle cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton tyrosine kinase inhibitor.

MYC‐induced cytidine metabolism regulates survival and drug resistance via cGas‐STING pathway in mantle cell lymphoma

“…To date, no therapeutic immunochemotherapies have been found to overcome the TP53 aberrancy in MCL patients, 36–38 despite the potential of chimeric antigen receptor T‐cell (CART) therapy that still requires more clinical validation 8,39,40 . In the present study, we found that in TP53 wild MCL cell (JVM‐2), depletion of TP53 can significantly up‐regulated cytidine metabolism, leading to the hypothesis that CTPS1 inhibition might overcome TP53 aberrancy in MCL patients.…”

How I manage mantle cell lymphoma: indolent versus aggressive disease

“…Aberrations of the TP53 gene are well established as a predictor of aggressive disease course, resistance to standard immunochemotherapy and inferior survival 33,34 . Aberrations may occur due to either deletion of 17p (del17p, detected using FISH or single‐nucleotide polymorphism array analysis) and/ or a mutation in the TP53 gene (assessed by next‐generation sequencing [NGS] or reverse transcription‐polymerase chain reaction) 35 . TP53 gene alterations promote genomic instability, cell cycle upregulation, inhibition of apoptosis and higher proliferation 36 .…”

“…33,34 Aberrations may occur due to either deletion of 17p (del17p, detected using FISH or single-nucleotide polymorphism array analysis) and/ or a mutation in the TP53 gene (assessed by next-generation sequencing [NGS] or reverse transcription-polymerase chain reaction). 35 TP53 gene alterations promote genomic instability, cell cycle upregulation, inhibition of apoptosis and higher proliferation. 36 p53 expression using immunohistochemistry (IHC) has been demonstrated to be a surrogate marker for TP53 deletion or mutation, with a series of 365 patients from the European Mantle Cell Lymphoma Network (EMCLN) demonstrating high p53 expression to be prognostic for both inferior timeto-treatment failure and OS on analyses adjusted for MIPI score and Ki-67.…”

A comparison of the International Consensus and 5th World Health Organization classifications of mature B-cell lymphomas

“…1C ), immunophenotype, proliferative index (labeling of Ki67) (Fig. 1D ) and presence of TP53 deletions/mutations since the occurrence of one or more of these variables associates with a poor prognosis [ 81 , 85 ]. Notably, TP53 deleted/mutated cases are usually resistant to chemotherapy but are sensitive to BTKi [ 82 , 83 ] or CAR-T cells [ 81 ].…”