As Mantle Cell Lymphoma Risk Tools Advance, Access Lags Behind

Risk assessment in mantle cell lymphoma (MCL) is evolving beyond traditional clinical scores, as genomic and dynamic biomarkers may help identify high-risk disease and guide personalized treatment, though access and validation challenges remain, according to a review published in Expert Review of Hematology.¹

Expanding Risk Stratification in MCL

MCL accounts for 5% to 7% of lymphomas in Western Europe and is typically diagnosed between 60 and 70 years of age, with men making up 70% to 80% of cases. Its course ranges from indolent to rapidly progressive, making risk stratification central to care.

The MCL International Prognostic Index (MIPI) combines age, performance status, lactate dehydrogenase, and leukocyte count. Its refinement, the combined MIPI, adds the Ki-67 proliferation index. However, the authors noted that these models were developed in the chemoimmunotherapy era to predict long-term survival, rather than sensitivity to targeted agents or early progression. Among clinical markers, progression within 24 months of diagnosis remains one of the most reliable predictors of poor outcomes in relapsed or refractory disease.

TP53 alterations are consistently linked to primary resistance to chemoimmunotherapy and shorter overall survival, regardless of the detection method. The authors recommended routine TP53 assessment and said patients with these alterations should be considered for frontline trials of novel strategies. They also described an emerging ultra-high-risk subset. These patients often have blastoid or pleomorphic histology, highly proliferative disease, TP53 alterations combined with CDKN2A or NOTCH1 changes, or central nervous system involvement.

Dynamic biomarkers are adding another layer to risk assessment. Post-treatment minimal residual disease (MRD) negativity has been consistently associated with longer progression-free survival (PFS) and overall survival. Circulating tumor DNA may also enable noninvasive monitoring and earlier detection of molecular relapse.

The review examined how integrating clinical, pathological, molecular, and dynamic factors could refine the definition of high-risk MCL and inform more personalized treatment strategies as targeted therapy and cellular immunotherapy options expand. The literature search included PubMed publications, clinical trials, reviews, and international guidelines through June 2026.

Emerging Treatment Strategies for High-Risk MCL

Because TP53 alterations and other high-risk features are associated with poor outcomes with conventional therapy, treatment strategies are increasingly being evaluated in these populations, with MRD emerging as a potential tool for guiding treatment duration.

In the phase 2 BOVen trial (NCT03824483), 25 patients with untreated TP53-mutated MCL received zanubrutinib (Brukinsa; BeOne Medicines), obinutuzumab (Gazyva; Genentech), and venetoclax (Venclexta; AbbVie/Genentech). The regimen produced an 88% complete response rate and an 84% MRD-negativity rate at 24 months. When treatment was stopped after 24 cycles based on MRD, 91% of patients with undetectable MRD remained in complete remission off therapy at a median follow-up of 39 months.

Similarly, the phase 2 TRAVERSE study (NCT05951959) evaluated acalabrutinib (Calquence; AstraZeneca), venetoclax, and rituximab (Rituxan; Genentech/Biogen) in untreated patients with MCL. The trial reported a 95.4% overall response rate. Among patients with TP53-mutated disease, 64.7% achieved a complete response and 94.1% reached MRD negativity. By contrast, frontline acalabrutinib plus rituximab in older patients in the phase 2 ALTAMIRA trial (NCT05214183) produced a 1-year PFS of 86.5% overall but only 69% in TP53-mutated disease. However, the review authors cautioned that durability remains unproven and that randomized data have not yet shown chemotherapy-free combinations are superior to chemoimmunotherapy.

Chemotherapy-containing regimens are also evolving. The phase 3 ECHO trial (NCT02972840) supported the January 2025 FDA approval of acalabrutinib plus bendamustine-rituximab in older, transplant-ineligible patients with MCL.² In that trial, median PFS was 66.4 months with the combination vs 49.6 months with bendamustine-rituximab plus placebo. Separately, the EA4151 trial (NCT03267433) suggested that patients with undetectable MRD in first remission may be able to forgo autologous stem cell transplant in favor of maintenance.¹

In the relapsed or refractory setting, the researchers highlighted emerging approaches, including ibrutinib (Imbruvica; Pharmacyclics/Janssen Biotech) plus venetoclax, the noncovalent Bruton tyrosine kinase (BTK) inhibitor pirtobrutinib (Jaypirca; Eli Lilly and Company), the BCL-2 inhibitor sonrotoclax (Beqalzi; BeOne Medicines), and early-stage BTK degraders.¹

Barriers to Personalized MCL Treatment

Despite these advances, the researchers emphasized that treatment decisions in routine practice remain largely driven by patient fitness, age, and drug availability. As the number of potential biomarkers grows, they also cautioned that treatment selection could become more complex without validated models to guide how these factors should be integrated.

Translating these advances into routine care may be particularly challenging outside major cancer centers, the researchers noted. They cited the cost of and access to mutation testing, novel BTK inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and MRD assays that require specialized laboratory infrastructure. The authors argued that the field "must prioritize global equitable access to the best possible care."

Beyond access and implementation, the review also highlighted an important gap in the current understanding of MCL. The researchers explained that the lower-risk majority of patients have been largely overlooked and may harbor undiscovered determinants of outcome. Many emerging biomarkers also lack prospective validation and standardized implementation.

“Future efforts should therefore move beyond risk stratification alone and focus on integrating clinical, molecular, and dynamic biomarkers into practical decision-making models capable of guiding treatment selection,” the authors concluded. “The development of validated biological risk-adapted algorithms will be crucial to identify the most appropriate therapeutic strategy for each patient and ultimately translate biological knowledge into personalized clinical care.”

References

1. Moioli A, Carazzai E, Mion I, et al. Refining risk stratification for mantle cell lymphoma: integrating novel combination treatments and personalized approaches. Expert Rev Hematol. 2026;19(10):1159-1168. doi:10.1080/17474086.2026.2715445
2. Shaw ML. FDA grants 2 traditional approvals for acalabrutinib. AJMC^®. January 17, 2025. Accessed October 7, 2026. https://www.ajmc.com/view/fda-grants-2-traditional-approvals-for-acalabrutinib