Risk Stratification Drives Cellular Therapy Recommendations for MCL in the BTK Inhibitor Era

Patient risk factors based on biomarkers form the framework for using cellular therapy to treat mantle cell lymphoma (MCL) in an updated set of recommendations from the European Bone Marrow Transplantation Harmonisation and Guidelines Committee, published July 9, 2026, in Bone Marrow Transplantion.¹

The recommendations were developed following an international expert workshop held in Berlin, Germany, in September 2025, and a structured literature review, with the resulting guidance focusing on 3 modalities—autologous hematopoietic cell transplantation (auto-HCT), allogeneic HCT (allo-HCT), and CD19 chimeric antigen receptor (CAR) T-cell therapy. According to the authors, the guidance reflects the field's rapid shift toward regimens based on Bruton tyrosine kinase (BTK) inhibitors—and they wrote that much has changed in the year since their last guidance. The authors noted that the rise of BTK inhibitors is causing considerable debate on the role of transplant modalities—and pointing out the need for more research.

The authors first establish a risk framework: high-risk disease MCL is defined by TP53 mutation, TP53 deletion, high Ki-67, blastoid/pleomorphic histology, high MIPI-c, and early progression, which is defined as progression within 24 months. Meanwhile, asymptomatic, non-nodal, low-proliferation MCL is considered low-risk. This stratification underpins nearly all subsequent recommendations.

CAR T-cell Therapy

Brexucabtagene autoleucel (brexu-cel, Tecartus; Kite/Gilead) and lisocabtagene maraleucel (liso-cel, Breyanzi; Bristol-Myers Squibb) are the only approved CD19 CAR T products for MCL, indicated after 2 prior lines including a BTK inhibitor. First-line CAR T-cell therapy is considered experimental and limited to clinical trials, even in high-risk disease. For patients who relapse following exposure to a BTK inhibitor, CAR T-cell therapy is a reasonable second-line option; beyond second line it becomes standard of care for CAR T-naïve patients, though repeat CD19 CAR-T is not supported.

Response durability appears reduced in those whose disease progresses within 24 months and other high-risk patients, and the CAR-HEMATOTOX score is the only validated tool for predicting hematologic toxicity and non-relapse mortality (NRM) in this setting.

Autologous HCT

Auto-HCT consolidation has long anchored first-line therapy in younger patients, but the TRIANGLE² (NCT02858258) and ECOG-4151³ (NCT03267433) trials now question its added value when BTKi is incorporated into induction or when MRD clearance (10⁻⁶ level) is achieved. The panel recommends considering omission of auto-HCT in standard-risk, MRD-negative patients receiving BTK inhibitor-containing induction, while high-risk or MRD-positive patients still warrant consolidation. There is no recommended role for auto-HCT in the relapsed/refractory salvage setting given the availability of CAR T-cell therapy, the authors state.

Defining the role of first-line auto-HCT in the BTK inhibitor era was a topic of considerable debate. “This is a research topic of urgent priority,” the authors wrote. “With novel pathway inhibitors, bispecific antibodies, antibody-drug compounds and their combinations, but also innovative CAR T platforms, the role of auto-HCT is expected to fade, while allo-HCT will move further downstream in the treatment algorithm.”

“Nevertheless, allo-HCT remains the only modality with proven curative potential in MCL to date, making further optimization of the efficacy-safety profile of this procedure an important research priority.”

Allogeneic HCT

Allo-HCT has no role in first-line treatment given its toxicity relative to modern outcomes, the guidance says. It has moved further down the treatment algorithm, positioned mainly after the failure of CAR T-cell therapy or where such therapy is inaccessible, since ZUMA-2 data (NCT02601313) show CAR T recipients have better survival than matched allo-HCT recipients,⁴ driven largely by lower NRM. Reduced-intensity conditioning is preferred, and allo-HCT remains the only modality with demonstrated curative potential, making it relevant for salvage-sensitive patients and select high-risk cases lacking access to CAR T-cell therapy.

Adverse Events and Quality of Life

Reported adverse events (AEs) include: higher NRM after CAR T in MCL compared with other lymphomas, with infection as the leading cause of death; cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, with liso-cel showing apparently lower neurotoxicity than brexu-cel in registration trials, a finding the authors said had not yet been confirmed with real-world safety data. Prolonged cytopenias and infectious complications had been captured by the CAR-HEMATOTOX score. For allo-HCT, 12-month NRM ranged from roughly 19% to 24% across EBMT cohorts, rising further in patients over 60, alongside standard graft-versus-host disease risk. Ibrutinib maintenance after auto-HCT in TRIANGLE produced more non-fatal toxicity than ibrutinib alone without transplant. Beyond these toxicity data, the review does not report patient-reported outcomes, symptom burden, or functional quality-of-life measures for any modality.

More Research Needed

The authors acknowledged the evolving nature of MCL treatment as well as the limitations of their guidance. “Since our preceding recommendations paper on cellular therapy in MCL, additional innovations have entered routine MCL care, e.g. extension of the acalabrutinib and liso-cel labels to MCL, and ibrutinib in combination with chemoimmunotherapy to the first line,” they wrote. “This illustrates the dynamic speed of transformation in the MCL management landscape—with obvious impact on the role and use of cellular therapies in this entity, necessitating steady adaptation of clinical practice recommendations to the evolving authorization framework and scientific state-of-the-art.”

The authors acknowledge that many recommendations in their 2026 update rely on expert opinion rather than evidence, which they say demonstrate the need for additional research, “such as defining the optimum timing of CART and allo-HCT in the different risk settings, and the role of second CART treatments and bispecific antibodies in MCL.”

References

1. Dreger P, Iacoboni G, Robinson S, et al. Cellular therapy in mantle cell lymphoma: recommendations from the EBMT practice harmonisation and guidelines committee. Bone Marrow Transplant. Published online July 9, 2026. doi: 10.1038/s41409-026-02963-5
2. 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.
3. 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 dsease (uMRD): initial report from the ECOG-ACRIN EA4151 phase 3 randomized trial. Blood. 2024;144 (suppl 2): Abstr LBA-6 doi:10.1182/blood-2024-212973
4. Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382(14):1331-1342. doi: 10.1056/NEJMoa1914347