ASCO Treatment Framework for Management of Mantle Cell Lymphoma Calls for Individualized, Risk-Adapted Therapy

The annual meeting of the American Society of Clinical Oncology (ASCO) starts May 29, 2026, which means articles from the group’s annual educational book have started to appear. This week, Tobias Tix, MD; Anita Kumar, MD; Toby A. Eyre, MBChB, MRCP; and Martin Dreyling, MD, have published a framework for stratification and management of mantle cell lymphoma (MCL), offering clinicians a roadmap for individualized strategies.¹

Tix and Dreyling are from LMU Hospital of Munich, Germany; Kumar from Memorial Sloan Kettering in New York, New York; and Eyre is from Oxford University Hospitals NHS Foundation Trust, United Kingdom.

They describe MCL as “a biologically and clinically heterogeneous B-cell malignancy with variable prognosis, ranging from indolent, asymptomatic forms to aggressive subtypes with early treatment failure.”¹ Indeed, this complexity calls for personalized therapeutic strategies, which can complicate things for patients as they navigate prior authorization protocols that may not recognize distinct patient needs.

Risk Stratification Has Become the Foundation of Treatment Selection

The first step, the authors write, is an accurate risk assessment. The MCL International Prognostic Index (MIPI), which incorporates age, ECOG performance status, lactate dehydrogenase, and leukocyte count, remains a cornerstone of clinical staging. The related combined MIPI, or MIPI-c, integrates the Ki-67 proliferation index to improve prognostic precision.

Beyond these tools, specific molecular and pathologic features further refine risk by including blastoid or pleomorphic morphology, whether Ki-67 is greater than 30%, and TP53 mutations, which consistently predict inferior outcomes and early treatment failure even with intensive chemoimmunotherapy. As a result, guidelines from the European Hematology Association now recommend routine assessment of Ki-67 and TP53 mutational status at diagnosis and relapse.² Minimal residual disease (MRD) monitoring, increasingly performed by next-generation sequencing, adds a layer of risk stratification that allows physicians to adjust treatment decisions in real time.

Chemoimmunotherapy Is First-Line Choice for Most Younger, Fit Patients

For patients 65 years and younger, cytarabine-based chemoimmunotherapy has long anchored induction, with regimens such as alternating between R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin). This is followed by autologous stem-cell transplantation (ASCT).

The landmark phase 3 TRIANGLE trial (NCT02858258), which Dreyling led, redefined this standard by demonstrating that adding the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica; Janssen) to immunochemotherapy significantly improved 3-year failure-free survival from approximately 75% to 86%-88%, establishing BTK inhibition as a key component of frontline therapy in fit younger patients.³ Critically, the TRIANGLE data also challenged the universal role of ASCT: outcomes with ibrutinib-containing chemotherapy without transplantation were noninferior to ASCT-containing regimens, while carrying excess toxicity. Real-world data from over 4000 patients corroborated this finding, showing ASCT offered no significant survival benefit over optimized maintenance alone.

“These data suggest that improvements in long-term outcomes in contemporary practice may be driven more by optimized maintenance strategies than by routine use of ASCT,” the authors wrote.

The ECOG-ACRIN EA4151 trial (NCT03267433) further supports MRD-guided consolidation, suggesting that MRD-negative patients gain nothing from ASCT, while MRD-positive patients may still benefit from intensification.⁴ ASCT may retain a role in carefully selected patients with very high-risk biology, including blastoid morphology and p53 overexpression. Rituximab maintenance for 3 years post ASCT has demonstrated clear progression-free survival (PFS) and overall survival benefits and remains a standard recommendation, the authors state.

For Older and Transplant-Ineligible Patients, Things Are More Complex

In patients over 65 years of age or for those with significant comorbidities, treatment selection integrates fitness, comorbidity burden, and biological risk. Bendamustine-rituximab (BR) has become the preferred chemoimmunotherapy backbone over R-CHOP, given the superior PFS and tolerability. The addition of acalabrutinib (Calquence; AstraZeneca) to BR, supported by the phase 3 ECHO trial (NCT02972840), earned FDA and EMA approval and extended median PFS from 50 to 66 months.⁵ However, the question of whether upfront combination therapy is meaningfully superior to sequential BR followed by BTK inhibition at relapse remains unresolved and requires individualized assessment.

For low-risk or frail patients, chemotherapy-free doublets combining a second-generation BTK inhibitor with rituximab offer an effective, well-tolerated option. For higher-risk patients, triplet regimens pairing a BTK inhibitor, BCL2 inhibitor, and anti-CD20 antibody have demonstrated response rates exceeding 90% and are particularly important for TP53-mutated disease, where conventional chemotherapy offers limited benefit. This has been demonstrated in BOVen trial (NCT03824483), led by Kumar,⁶ which combined zanubrutinib (Brukinsa; BeOne Medicines), obinutuzumab (Gazyva; Genentech) and venetoclax (Venclexta; AbbVie/Genentech); as well as the TrAVeRse trial (NCT05951959), which combined acalabrutinib, venetoclax, and rituximab. This latter triplet offers patients a fixed-duration option, which may be advantageous from a cost perspective.⁷

What to Do for Relapsed and Refractory Disease

Treatment sequencing in relapsed/refractory MCL is increasingly guided by patients’ prior BTK inhibitor exposure. For patients who are covalent BTK inhibitor-naive and relapse after receiving chemotherapy, covalent BTK inhibitors remain the standard second-line approach, with superior outcomes at first relapse compared to later lines. If patients progress after treatment with covalent BTK inhibitors, options include pirtobrutinib (Jaypirca; Eli Lilly), which is a noncovalent BTK inhibitor approved following the BRUIN trial (NCT03740529), for which Eyre led the evaluation of the MCL arm.⁸ Other options cited include next-generation BCL2 inhibitors, such as sonrotoclax, an investigational therapy from BeOne Medicines; anti-CD19 chimeric antigen receptor (CAR) T-cell therapies, which are brexucabtagene (Tecartus; Kite) and lisocabtagene autoleucel (Breyanzi; Bristol Myers Squibb); and bispecific T-cell engagers such as glofitamab (Columvi; Genetech).

Because sonrotoclax “is thought to be a more selective and potent inhibitor than venetoclax with a shorter half-life and no drug accumulation,” it is seen as an excellent potential partner to combine with zanubrutinib, and indeed this pair is being studied in the phase 3 randomized double-blind CELESTIAL RR MCL trial (NCT06742996).

“The optimum management for patients with R/R MCL after [covalent BTK inhibition] remains to be clearly defined. T-cell–redirecting therapies are associated with the highest initial responses but are associated with immune-related and infectious toxicities, delivery, and logistical challenges and are not widely accessible,” the authors write. “Oral small-molecule inhibitors delivered as monotherapy result in modest efficacy but have a good tolerability profile that may enable more widespread adoption. The therapeutic efficacy, toxicity, disease biology, patient comorbidities, and preferences will ultimately help individualize decision making in this complex and ever evolving space.”

References

1. Tix T, Kumar A, Eyre TA, Dreyling M. Modern management of mantle cell lymphoma. Am Soc Clin Oncol Educ Book. 2026;46(3):e517468. doi:10.1200/EDBK-26-517468
2. Jerkeman M, Aurer I, Campo E, et al. EHA Guidelines Committee and the European MCL Network. EHA-EU MCL network guidelines for diagnosis and treatment of mantle cell lymphoma. Hemasphere. 2025;9(10):e70233. doi:10.1002/hem3.70233
3. Dreyling M, Doorduijn J, Giné E et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3
4. Timothy S. Fenske, Xin Victoria Wang, Brian G. Till, et al. Lack of benefit of autologous hematopoietic cell transplantation (auto-HCT) in mantle cell lymphoma (MCL) patients (pts) in first complete remission (CR) with undetectable minimal residual disease (uMRD): initial report from the ECOG-ACRIN EA4151 phase 3 randomized Trial. Blood. 2024;144(suppl 2):LBA–6. doi:10.1182/blood-2024-212973
5. Wang M, Salek D, Belada D, et al. for the ECHO Investigators. Acalabrutinib plus bendamustine-rituximab in untreated mantle cell lymphoma. J Clin Oncol. 2025;43(20):2276-2284. doi:10.1200/JCO-25-00690
6. 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
7. Hawkes E, Romejko-Jarosinska J, Jurczak W, et al. Acalabrutinib plus venetoclax and rituximab in patients with treatment-naive (TN) mantle cell lymphoma (MCL): Results from the phase 2 TrAVeRse study. Blood. 2025;146(suppl 1):884. doi:10.1182/blood-2025-884
8. Eyre TA, Shah NN, Dreyling M, et al. BRUIN MCL-321: phase III study of pirtobrutinib versus investigator choice of BTK inhibitor in BTK inhibitor naive mantle cell lymphoma. Future Oncol. 2022;18(36):3961-3969. doi:10.2217/fon-2022-0976