Even After 6 Years, Disease Progression Impacts Survival in Mantle Cell Lymphoma

A population-based study from Sweden upends conventional thinking on when patients with mantle cell lymphoma (MCL) can exhale regarding early disease progression, with data showing that even very late relapses—beyond the 6-year mark—significantly worsen patient survival.

Sara Ekberg, PhD | Image: Red Door

Collaborators from several Swedish institutions, led by Sara Ekberg, PhD, of the Karolinska Institutet in Stockholm, analyzed Swedish lymphoma registry data for 1186 patients with MCL who were diagnosed between 2006 and 2018, following them for up to 10 years. Initial data were presented during the 67th American Society of Hematology (ASH) Annual Meeting and Exposition in Orlando, Florida, in December 2025, with full data scheduled for publication in April in the International Journal of Cancer.1

The Swedish cohort received various first-line treatments, with 3 main treatment groups1:

• 33% received bendamustine rituximab (BR)
• 30% received a treatment known as Nordic MCL2, consisting of dose-escalated R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alternating with R-cytarabine for 6 courses and high-dose treatment with autologous stem cell transplantation as consolidation
• 14% received R-CHOP or similar therapies

Patients treated with other regimens, such as chlorambucil and R-CHOP/cytarabine, or ibrutinib alone, were included in the overall analyses but did not have sufficient numbers for separate analyses. The overall results also included patients who received maintenance treatment with rituximab.

The authors noted that it has long been established that early progression within 24 months of initial treatment for MCL progression is particularly devastating, and results from this analysis confirmed that finding. However, this new study also found that progression that occurs 6 to 10 years after initial treatment carried a significantly worse prognosis compared to patients remaining progression-free.

Patients with such late disease progression showed more than a 2-fold increased mortality risk (HR, 2.67), which the authors said shows the conventional 24-month cut-off as the primary prognostic marker may be inadequate. “Our results clearly emphasize large survival benefits of late [disease progression] over early [disease progression] in all treatment groups,” they write, “and even better prognosis if [disease progression] can be avoided altogether.”1

On the absolute scale, survival differences persisted remarkably long—up to 9 years after primary treatment. Among BR-treated patients who progressed at 6 years, only 38% were alive 5 years later, compared with 77% of those remaining progression free—a 39% survival deficit. For patients receiving the Nordic MCL2 regimen, the gap was 26% (62% vs. 88%).1

The negative effects of disease progression varied by treatment type. The Nordic MCL2 regimen showed the most notable impact, with patients who progressed within 12 months having a 37-fold increased mortality risk. Authors wrote that this likely reflects more aggressive disease in patients who resisted intensive therapy. Among those who progressed after 6 to 10 years, BR-treated patients faced the highest relative risk increase (5.6-fold), though the effect remained substantial among patients receiving the Nordic MCL2 regimen.

These findings have important ramifications for MCL management. As the authors emphasize, efforts should focus not only on prolonging remission but on avoiding relapse entirely. The results suggest that all progression events—regardless of timing—carry clinical significance and should inform treatment decisions.

The study highlights the potential value of maintenance therapy in preventing progression and calls for more investigation into the use of Bruton tyrosine kinase (BTK) inhibitors for this purpose, including in combinations. Combinations of rituximab and BTK inhibitors may help achieve deeper, more durable remissions. Novel first-line approaches, such as adding venetoclax, as demonstrated in the SYMPATICO trial with ibrutinib (NCT03112174), may better eradicate disease in high-risk patients.2

Combinations with second- and third-generation BTK inhibitors in MCL have demonstrated notable efficacy, with more studies ongoing:

• Results from the BOVen study (NCT03824483), for newly diagnosed patients with TP53-mutated MCL treated with zanbrutinib (Brukinsa; BeOne Medicines), obinutuzumab (Gazyva; Genentech) and venetoclax (Venclexta; AbbVie), show a 2-year progression-free survival (PFS) of 72%, which compares favorably with previously reported outcomes with chemoimmunotherapy.3
• Results from BOVen presented at ASH 2025 for patients 50 years and older show a 2-year PFS of 86% and overall survival (OS) of 92%.4
• In the phase 1/2 BRUIN study (NCT03740529) among patients with relapsed or refractory MCL, 5-year data for pirtobrutinib (Jaypirca; Eli Lilly) presented at ASH 2025 show the PFS and OS for patients naive to covalent BTK inhibitors were 44.6 months and not reached, respectively.5
• In the phase 2 TrAVeRse study (NCT05951959), treatment-naive patients with MCL receive acalabrutinib (Calquence; AstraZeneca), venetoclax, and rituximab (AVR); the primary objective is to assess the rate of minimal residual disease (MRD)–negative complete response (CR) at end of induction after completing 13 cycles. Patients who achieved MRD-negative CR at the end of AVR induction were randomly assigned to continued acalabrutinib or observation. Those who progress during observation may receive retreatment with acalabrutinib.6
• Early data for 12 patients who had completed AVR induction in TrAVeRse showed all had achieved MRD-negative CR. With most of the 106 patients still on induction therapy, 95.4% had achieved MRD negativity, including 88% by the end of cycle 6. Estimated 6-month PFS was 97.1%, estimated OS was 98.1%, and estimated duration of response was 98.0%. Of the 17 patients with TP53 mutations, 15 (88.2%) achieved objective response, 11 (64.7%) achieved CR, and 16 (94.1%) achieved MRD negativity during AVR induction.7

Balancing Efficacy With Long-Term Effects

Authors of the Swedish study note that intensification of treatment, including with BTK inhibitors, must be balanced against adverse effects, such as late toxicities and secondary malignancies requiring lifelong follow-up.1 Their registry revealed that 46% of patients over 65 years of age died from MCL within 5 years (30% after disease progression), which shows that addressing the underlying disease remains the priority, whatever treatment-related risks are present.

They note that the treatment landscape in MCL is rapidly evolving; today, there are choices in BTK inhibitors along with the chimeric antigen receptor (CAR) T cell therapy, brexucabtagene autoleucel (Tecartus; Kite/Gilead). Immunochemotherapy remains the mainstay in first-line treatment worldwide, but authors suggest that more research into other options is needed.

“…[E]fforts should focus not only on prolonging remission durations but also on avoiding progression/relapse altogether. By going beyond the conventional focus on early [disease progression], we provide valuable insights into the survival outcomes of patients experiencing progression at various time points,” they write.

“Future research should continue to explore the evolving treatment landscape and the role of maintenance therapies, and further elucidate the molecular factors influencing disease progression and overall survival in MCL.”

References

1. Ekberg S, Glimelius I, Albertsson-Lindblad A, Smedby KE, Jerkeman M, Dietrich CE. Disease progression more than 6 years after treatment impacts overall survival in mantle cell lymphoma. Int J Cancer. 2026;158(7):1836-1845. doi:10.1002/ijc.70220
2. Wang M, Jurczak W, Trneny M et al. Ibrutinib plus venetoclax in relapsed or refractory mantle cell lymphoma (SYMPATICO): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2025;26(2):200-213. doi:10.1016/S1470-2045(24)00682-X
3. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood 2025;145(5):497-507. doi:10.1182/blood.2024025563
4. Kumar A. Preliminary safety and efficacy of BOVen (zanubrutinib, obinutuzumab, and venetoclax) as frontline therapy for older patients with mantle cell lymphoma. Presented at: 67th American Society of Hematology Annual Meeting and Exposition; December 6-9, 2025; Orlando, FL. Oral abstract 888.
5. Wang CM, Cohen J, Shah N, et al. Pirtobrutinib in relapsed/refractory (R/R) mantle cell lymphoma (MCL): final update from the phase 1/2 BRUIN study. Blood. 2025;146(suppl 1):Abstract 665. doi:10.1182/blood-2025-665
6. A study of acalabrutinib plus venetoclax and rituximab in participants with treatment naïve mantle cell lymphoma (TrAVeRse). ClinicalTrials.gov. Updated October 21, 2025. Accessed December 29, 2025. https://www.clinicaltrials.gov/study/NCT05951959
7. Wojtowicz MM, Hawkes E, Romejko-Jarosinska J, et al. Acalabrutinib plus venetoclax and rituximab in patients with treatment-naïve mantle cell lymphoma (MCL): results from the phase 2 TrAVeRse study. Presented at: 67th American Society of Hematology Annual Meeting & Exposition; December 6-9, 2025; Orlando, FL. Paper 0884.