The advent of Chimeric Antigen Receptor T-cell (CAR-T) therapy has fundamentally transformed the treatment landscape for relapsed/refractory (R/R) hematologic malignancies. However, as clinical adoption expands and follow-up durations extend, the management of treatment-related toxicities—specifically Non-Relapse Mortality (NRM)—has emerged as a critical bottleneck for long-term patient survival. At the 2026 Annual Meeting of the European Society for Blood and Marrow Transplantation (EBMT), Dr. Charlotte Graham from London, representing the EBMT Transplant Complications Working Party (TCWP), presented a large-scale real-world study based on the EBMT registry. This analysis of nearly 7,000 CAR-T recipients provides high-granularity insights into NRM risk profiles and clinical intervention strategies.

01 Addressing the Safety Bottleneck: The Necessity of NRM Research

While CAR-T cells demonstrate potent anti-tumor activity, the resulting immune effector cell activation and cytokine cascades can trigger severe toxicities, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Although registrational clinical trials initially reported low NRM rates, trial participants are typically highly selected (e.g., robust organ function, ECOG PS 0–1).

Dr. Charlotte Graham emphasized that real-world patients often present with complex medical histories and a heavier prior treatment burden. Recently, downstream toxicities such as prolonged cytopenia and immune effector cell-associated enterocolitis have gained attention. Existing meta-analyses suggest NRM rates between 5% and 10%, yet systematic cross-comparisons between different disease types and CAR-T products remain scarce.

02 Study Design: Real-World Big Data from the EBMT Registry

This study was a large-scale retrospective cohort analysis utilizing the EBMT registry system. It included adult patients (≥18 years) who received their first commercial CAR-T infusion between January 2019 and January 2024, ensuring a follow-up duration sufficient to capture late NRM events.

  • Cohort Selection: Out of approximately 10,000 initial entries, the final evaluable cohort consisted of 6,928 patients after excluding those who were not infused, received non-commercial products, or had incomplete follow-up data.
  • Indications: The cohort included B-cell lymphoma (DLBCL, FL, etc., excluding MCL), Multiple Myeloma (MM), Mantle Cell Lymphoma (MCL), and adult B-cell Acute Lymphoblastic Leukemia (B-ALL).
  • Products: Included major commercial CD19-targeted (Tisa-cel, Axi-cel, Liso-cel, Brexu-cel) and BCMA-targeted (Ide-cel, Cilta-cel) products.
  • Definition: NRM was defined as death from any cause in the absence of evidence of disease relapse or progression.

03 Disease-Specific Outcomes: Higher NRM Burden in MCL and B-ALL

The data revealed significant disparities in NRM incidence across different malignancies.

  • Mantle Cell Lymphoma (MCL): The Most Vulnerable Population
  • MCL patients exhibited the highest NRM risk among all groups, with a 1-year NRM rate of 13.3%. Dr. Graham attributed this potentially to the older median age of MCL patients, impaired bone marrow reserve from intensive prior therapies, and the management challenges associated with Brexu-cel in real-world settings.
  • Adult B-ALL: Persistent Safety Risks
  • For adult B-ALL patients, the 1-year NRM rate was 9.8%. Notably, in the subgroup receiving Brexu-cel, the mortality curve did not plateau after the first year; the 2-year NRM rate surged to 19.0%. This indicates that for adult leukemia patients, the critical monitoring window for CAR-T safety must extend beyond 24 months.
  • B-Cell Lymphoma and Multiple Myeloma (MM)
  • The B-cell lymphoma group showed a relatively stable NRM profile. In the MM sector, the study compared two BCMA products: the Cilta-cel group had a 1-year NRM of 8.75%, which was higher than that of the Ide-cel group. However, in terms of Overall Survival (OS), Cilta-cel remained superior due to its higher efficacy in preventing relapse-related mortality.

04 Product-Specific Profiles: Subtle Differences in Safety Curves

Dr. Graham highlighted specific product performances in B-cell lymphoma:

  • Liso-cel: Demonstrated a notably low 1-year NRM (3.99%) with encouraging OS data, consistent with the lower rates of CRS/ICANS observed in its pivotal trials.
  • Brexu-cel: As noted, applications in MCL and B-ALL require heightened vigilance regarding long-term toxicity.

Multivariate analysis identified several independent predictors of NRM. For B-cell lymphoma, advanced age, male sex, pre-infusion ECOG PS ≥1, and active disease status were significantly associated with increased NRM risk. This underscores the importance of “optimal timing” and “patient selection” in clinical practice.

05 Root Cause Analysis: Infection as the “Silent Killer”

By categorizing the causes of death in 673 NRM cases, the study identified key targets for clinical management:

  1. Infection: Accounting for 35.4% of cases with a known cause, infection was the leading cause of NRM. This is closely linked to prolonged lymphopenia, hypogammaglobulinemia, and cumulative immunosuppression from prior lines of therapy.
  1. Cell Therapy-Related Toxicities: A significant proportion of NRM cases were directly attributed to refractory CRS or severe ICANS.
  1. Secondary Malignancies: These accounted for 9.5% of NRM cases. With longer follow-ups, the risk of therapy-related secondary tumors has become a top priority in hematology.

06 Clinical Implications and Management Recommendations

Based on these large-scale findings, Dr. Graham proposed several forward-looking strategies for CAR-T practice:

  • Strengthening Infection Control: Given that 35.4% of NRM is infection-related, clinicians should establish standardized prophylaxis protocols, including antiviral and antifungal agents, and timely intravenous immunoglobulin (IVIG) replacement for patients with hypogammaglobulinemia.
  • Refined Patient Selection: Patients with poor ECOG scores or high-burden active disease face significantly higher NRM risks. Clinicians must balance tumor control with treatment tolerance, utilizing effective bridging therapies to reduce tumor burden prior to infusion where necessary.
  • Establishing Long-Term Follow-Up Systems: The 19.0% 2-year NRM rate in B-ALL (Brexu-cel) serves as a reminder that safety management must extend beyond the traditional “Day 100” post-infusion. Monitoring for secondary malignancies and late-onset infections should continue throughout the patient’s life.
  • Multidisciplinary Team (MDT) Collaboration: Given the diverse causes of NRM, hematologists should maintain constant collaboration with infectious disease specialists, neurologists, intensivists (ICU), and oncologists.

Conclusion

Dr. Charlotte Graham’s research provides a comprehensive safety map for CAR-T therapy through the lens of real-world big data. It emphasizes that while pursuing “clinical cures,” the medical community must remain vigilant against the threat of non-relapse mortality. As highlighted during the conference, a joint meeting between the Infectious Diseases Working Party and the Transplant Complications Working Party in Madrid this November will further focus on the education and management of infectious complications. Identifying high-risk populations and optimizing both peri-infusion and long-term management will be key to improving the overall success rate of CAR-T therapy.

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