The potential for chemotherapy-free strategies in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) may be 1 of the few cancers for which multiple chemotherapy and nonchemotherapy regimens are considered as standard. Despite the significant activity of chemotherapy in the first-line setting and beyond, its limitations are reflected in the relatively poor ultimate outcomes of patients with MCL treated in the real world. Patients with highly proliferative MCL and those with TP53 mutations tend to respond poorly despite intensive cytotoxic therapies. Patients with comorbidities and those who are geographically isolated may not have access to the regimens that may appear most promising in clinical trials. Thoughtfully directed, nonchemotherapy agents might overcome some of the factors associated with a poor prognosis, such at TP53 mutation, and might resolve some of the challenges related to the toxicity and deliverability of standard chemotherapy regimens. Several clinical trials have already demonstrated that combinations of nonchemotherapy plus chemotherapy drugs can impact outcomes, whereas data with nonchemotherapy agents alone or in combination have suggested that some patients might be well suited to treatment without chemotherapy at all. However, challenges including chronic or unexpected toxicities, the rational vs practical development of combinations, and the financial acceptability of new strategies abound. The nonchemotherapy era is here: how it unfolds will depend on how we meet these challenges.

Current trials for frontline therapy of mantle cell lymphoma

“…In order for CAR-T cell therapies to be more widely adopted in chemorefractory RRMCL, either they will have to demonstrate an ability to safely induce responses in patients who would not be eligible for allogeneic stem cell transplantation due to comorbid conditions or rapidly progressing disease or they will need to be associated with a relatively superior efficacy and tolerability profile. Moreover, the toxicities associated with CAR-T cells at present, including neurologic issues related to cytokine release syndrome [ 21 ], may limit applicability to MCL patients who are commonly older and have comorbid conditions [ 22 ].…”

The Novel TORC1/2 Kinase Inhibitor PQR620 Has Anti-Tumor Activity in Lymphomas as a Single Agent and in Combination with Venetoclax

“…The anti-tumor activity of PQR620 was particularly high in the MCL cell lines. This observation is interesting, since MCL is the histotype in which first generation mTOR inhibitors have been mostly clinically developed [3,4,8,37,38] with the European Medicines Agency (EMA) approval of temsirolimus for patients with relapsed/refractory disease [6,8]. Additionally, although they could not be defined as resistant, two groups of lymphomas presented reduced sensitivity to PQR620.…”

“…These compounds are also known as rapalogs since they are chemically derived from rapamycin and maintain the same mechanism of action [3,4]. Rapalogs have shown preclinical and clinical anti-lymphoma activity [3,4,5,6]. In particular, temsirolimus demonstrated a higher response rate and progression free survival than investigators’ treatment choices in relapsed or refractory mantle cell lymphoma [7,8] and was approved by the European Medicines Agency (EMA) for patient populations [6].…”

“…Rapalogs have shown preclinical and clinical anti-lymphoma activity [3,4,5,6]. In particular, temsirolimus demonstrated a higher response rate and progression free survival than investigators’ treatment choices in relapsed or refractory mantle cell lymphoma [7,8] and was approved by the European Medicines Agency (EMA) for patient populations [6]. However, the clinical activity of first generation mTOR inhibitors remains relatively limited and their use comes with side effects, as also demonstrated in two recently reported phase III clinical trials.…”

G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Mantle Cell Lymphoma Growth in Preclinical Models

“…Additional genomic alterations, which are involved in cell cycle, DNA damage, signal transduction, and apoptosis (2,3), are also found to contribute to MCL progression and Abbrevations: MCL, Mantle cell lymphoma; GPER, G-protein-coupled estrogen receptor; BTK, Bruton's tyrosine kinase; EGFR, epidermal growth factor receptor; ROS, reactive oxygen species; g-H2A.X, phospho-H2A.X; NOX, NADPH oxidase; NF-kB, nuclear factor kappa-B; NAC, N-Acetyl-L-cysteine; H2DCFDA, 2′,7′-dichlorofluorescin diacetate; DSB, doublestrand break. resistance to conventional chemotherapy (4,5). Recent advances in cytostatic drugs, including the development of immunomodulatory imide drugs such as lenalidomide and the Bruton's tyrosine kinase (BTK) inhibitor such as ibrutinib, have established chemo-free regimes as a promising new direction of MCL therapy (5)(6)(7).…”