NCCN Journal Publishes Guidelines Update in Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) accounts for about 4% of newly diagnosed non-Hodgkin lymphomas (NHL),¹ and for years it was treated as a hard case: incurable with conventional chemoimmunotherapy, yet more aggressive than the indolent lymphomas. The treatment picture has shifted quickly, and this month the official publication of the National Comprehensive Cancer Network (NCCN) offers the latest guidance reflecting the evolving landscape.²

In the September 2026 issue of the Journal of the National Comprehensive Cancer Network (JNCCN), the NCCN B-Cell Lymphomas panel, chaired by Andrew D. Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center, presented the MCL recommendations from Version 4.2026 of its B-cell lymphoma guidelines.² According to the authors, frontline care “has evolved in recent years with the incorporation of covalent BTK inhibitors, sensitive assays for the assessment of measurable residual disease (MRD), and predefined maintenance or continuous therapy.”²

The stated goals of therapy remain relief of symptoms, a deep response, and long-term remission, which the panel says now includes “the possibility of a functional cure for an increasing proportion of patients.”

Precision Medicine Testing at Diagnosis

The guidelines recognize 3 MCL subtypes defined by the World Health Organization (WHO) 5th edition and International Consensus Classification: (1) classic MCL, typically SOX11-positive with unmutated IGHV and an aggressive course; (2) leukemic non-nodal MCL, usually SOX11-negative and IGHV-mutated with an indolent course; and (3) in situ mantle cell neoplasia.³

The panel lists the following as “essential”diagnostic tests:

• Immunophenotyping by an immunohistochemistry (IHC) panel of CD20, CD3, CD5, cyclin D1, CD10, CD21, CD23, BCL2, BCL6, SOX11, and Ki-67, with or without flow cytometry.
• Ki-67. A proliferation index below 30% in lymph nodes is associated with a more favorable prognosis, and Ki-67 is part of the MCL International Prognostic Index (MIPI).
• TP53 sequencing. TP53 mutations predict poor outcomes with conventional therapy, including transplant. Sequencing is preferred; in the frontline setting, p53 expression by IHC can serve as an initial screen but should be confirmed by sequencing, since reports conflict on how well IHC tracks mutation status.

Tests that are “useful in certain circumstances” include LEF1 by IHC to distinguish MCL from variant chronic lymphocytic leukemia, and SOX11 or IGHV sequencing to identify clinically indolent disease. Fluorescence in situ hybridization (FISH) for t(11;14) is not required when cyclin D1 IHC is positive, but FISH for t(11;14) or CCND2 and CCND3 rearrangements can help diagnose the rare cyclin D1-negative cases (under 5%).

For patients with indolent MCL whose disease becomes symptomatic, the guidelines call for evaluating possible transformation with a repeat biopsy and repeat TP53 sequencing before choosing therapy.

MRD as a treatment decision tool. After induction, the guidelines call for MRD testing with an assay sensitive to at least 10^-6. As described below, that result now determines who goes to transplant.

BTK inhibitors move to the front line

For fit patients with classic, TP53 wild-type MCL, the guidelines list the TRIANGLE regimen as a preferred aggressive induction option: RCHOP plus a covalent Bruton tyrosine kinase (BTK) inhibitor alternating with dexamethasone, high-dose cytarabine, and platinum plus rituximab (RDHAP), followed by rituximab plus BTK inhibitor maintenance. In the phase 3 TRIANGLE trial (NCT02858258) of 870 patients younger than 66 years, adding ibrutinib to induction and maintenance produced 3-year failure-free survival of 88% with transplant and 86% without it, vs 72% for chemoimmunotherapy plus transplant alone.⁴

Citing better safety in head-to-head trials in other B-cell cancers, the panel allows second-generation zanubrutinib (Brukinsa; BeOne Medicines) or acalabrutinib (Calquence; AstraZeneca) to replace first-generation ibrutinib (Imbruvica; Janssen), now category 2A, although neither was tested in TRIANGLE.^5,6

For patients who are not candidates for aggressive therapy, preferred options are now acalabrutinib plus bendamustine and rituximab (BR), acalabrutinib plus rituximab, and BR. In the phase 3 ECHO trial (NCT02972840) of 598 patients aged 65 or older,⁷ adding acalabrutinib to BR extended median progression-free survival (PFS) from 50 to 66 months, which led to FDA approval. The panel did not endorse ibrutinib plus BR: in the SHINE trial (NCT01776840), a PFS gain did not translate to overall survival because of excess deaths from adverse events.⁸

MRD now shapes the role of transplant. High-dose therapy with autologous stem cell rescue (HDT/ASCR) has long followed intensive induction for younger patients, but the guidelines say its role “is lessening.” In the phase 3 ECOG-ACRIN EA4151 trial (NCT03267433),⁹ patients in complete response with undetectable MRD (below 10^-6) after induction had a 3-year PFS of 76.6% with transplant vs 77.4% without. The resulting recommendations:

• Complete response with undetectable MRD at 10^-6: no HDT/ASCR; proceed to maintenance with rituximab with or without a covalent BTK inhibitor.
• Complete response with detectable MRD: HDT/ASCR is an option, followed by maintenance.
• Partial response: additional chemoimmunotherapy to reach complete response, or a covalent BTK inhibitor (preferred) if the patient has not had one.

After less aggressive induction, rituximab maintenance every 8 weeks for 2 to 3 years is recommended (category 1 after RCHOP). The panel cautions that combining rituximab maintenance with a continuous BTK inhibitor has carried a significant risk of infection in trials.

A Separate Path for TP53-Mutated Disease

In younger patients, TP53 mutations are linked to Ki-67 above 30%, blastoid morphology, and poor responses to both chemoimmunotherapy and transplant. The panel strongly recommends a clinical trial for these patients. Outside a trial, it lists 3 BTK inhibitor-based options:

• The BOVen regimen of venetoclax (Venclexta; AbbVie;Genentech), zanubrutinib, and obinutuzumab (Gazyva; Genentech) for all patients, regardless of fitness. In a phase 2 trial of 25 patients (NCT03824483), the regimen produced a 96% overall response rate (88% complete response) and a 2-year PFS of 72%.¹⁰ Undetectable MRD at 10^-6 was reached in 84%, and treatment stopped after 24 cycles for those in MRD-negative complete response. The authors say long-term follow-up is needed to confirm that MRD-guided discontinuation works.
• The TRIANGLE regimen for patients suitable for aggressive induction.⁴
• Acalabrutinib plus rituximab for patients who are not. In a phase 2 trial in patients aged 65 or older, 12 of whom had TP53 aberrations, the 2-year PFS was 94%.¹¹

Relapsed Disease: Sorting by BTK Inhibitor Exposure

The guidelines now split relapsed or refractory MCL into 2 pathways based on prior BTK inhibitor exposure and timing.

BTK inhibitor-naive or late relapse (more than 24 months) after a covalent BTK inhibitor regimen. Continuous covalent BTK inhibitor therapy is preferred, with acalabrutinib and zanubrutinib the preferred agents; ibrutinib, with or without rituximab, moves to “other recommended” on safety grounds. Lenalidomide plus rituximab is also preferred. Venetoclax-based regimens, including ibrutinib plus venetoclax from the phase 3 SYMPATICO trial (NCT03112174),¹² are useful in certain circumstances, notably for high-risk features such as TP53 aberrations.

Early relapse. When there is progression on a covalent BTK within 24 months, options include the noncovalent BTK inhibitor pirtobrutinib (Jaypirca; Eli Lilly) and CD19-directed chimeric antigen receptor (CAR) T-cell therapy, either brexucabtagene autoleucel (brexu-cel/Tecartus; Kite Pharma), or lisocabtagene maraleucel (liso-cel/Breyanzi; Bristol Myers Squibb). Acalabrutinib and zanubrutinib have not been shown to work in ibrutinib-refractory disease with BTK C481S mutations, since they share ibrutinib's resistance mechanism.

• In the phase 1/2 BRUIN trial (NCT03740529), pirtobrutinib produced a 49% overall response rate (16% complete response) and a median duration of response of 22 months among patients previously treated with a covalent BTK inhibitor.¹³
• In ZUMA-2, brexu-cel produced a 91% response rate (68% complete response) at 36 months of follow-up, with consistent responses in patients with TP53 mutations or blastoid morphology.¹⁴
• In TRANSCEND NHL 001, liso-cel produced an 83% response rate (72% complete response) in a population in which 53% had BTK inhibitor-refractory disease.¹⁵

Because response and complete response rates are higher with CAR T-cell therapy, the panel calls it “generally considered as a preferred treatment option” for eligible patients with access. Pirtobrutinib can serve as bridging therapy before CAR T-cell infusion. The 2 CAR T products have not been compared head to head, so the choice rests on clinical judgment. The panel also advises delaying bendamustine until after CAR T leukapheresis.

Later lines. The CD3 x CD20 bispecific antibodies glofitamab (Columvi; Genentech) and mosunetuzumab (Lunsumio; Genentech) plus polatuzumab vedotin (Polivy; Genentech) are recommended after BTK inhibitor-based therapy and/or CAR T-cell therapy. The panel flags higher rates of cytokine release syndrome in MCL than in diffuse large B-cell lymphoma. Because CD20 loss can cause resistance, it recommends a repeat biopsy to confirm CD20 expression before starting a bispecific.

The more selective BCL2 inhibitor sonrotoclax (Beqalzi; BeOne Medicines) is a recently approved option that can be used after least 2 prior lines, including a BTK inhibitor, based on a 53% response rate in a phase 1/2 study.¹⁶

Questions That Remain

The panel acknowledges gaps. “The optimal frequency and the use of repeat MRD assessments, and monitoring/surveillance for relapse after cessation of BTK [inhibitor] therapy, require further clarification in future studies.”

It is also unknown whether a covalent BTK inhibitor matches transplant for patients with detectable MRD after chemoimmunotherapy. With CAR T-cell therapy and pirtobrutinib available, most NCCN member institutions now defer allogeneic transplant until after multiple prior therapies, the panel notes.

References

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2. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN Guidelines: B-cell lymphomas, version 4.2026. J Natl Compr Canc Netw. 2026;24(9):e260042. doi:10.6004/jnccn.2026.0042

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9. 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: https://doi.org/10.1182/blood-2024-212973

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11. Jain P, Ok CY, Westin JR, et al. Acalabrutinib with rituximab is highly effective first line treatment for older patients with mantle cell lymphoma. Blood 2024;144(suppl 1):Abstract 3038.

12. 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;26:200–213. doi:10.1016/S1470-2045(24)00682-X

13. Wang M, 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

14. Wang M, Munoz J, Goy A, et al. Three-year follow-up of KTE-X19 in patients with relapsed/refractory mantle cell lymphoma, including high-risk subgroups, in the ZUMA-2 study. J Clin Oncol 2023;41:555–567. DOI:10.1200/JCO.21.02370

15. Wang M, Siddiqi T, Gordon LI, et al. Lisocabtagene maraleucel in relapsed/refractory mantle cell lymphoma: primary analysis of the mantle cell lymphoma cohort from TRANSCEND NHL 001, a phase I multicenter seamless design study. J Clin Oncol 2024;42:1146–1157.

16. Caffrey M. Sonrotoclax granted accelerated approval for R/R mantle cell lymphoma. AJMC. May 13, 2026. Accessed September 26, 2026. https://www.ajmc.com/view/sonrotoclax-granted-accelerated-approval-for-r-r-mantle-cell-lymphoma