Meet the Author: Miguel-Angel Pareles, MD, FASTCT — ASTCT Consensus Grading for Immune Effector Cell-Associated Toxicities 2026 Update
Miguel-Angel Perales, MD, FASTCT, is the senior author of “ASTCT Consensus Grading for Immune Effector Cell-Associated Toxicities 2026 Update.” In this Q&A, he discusses the collaborative effort behind updating ASTCT's consensus grading criteria, the emerging toxicities driving the need for revision, and how the updated framework will support clinicians, researchers, and clinical trial teams as immune effector cell therapies continue to evolve.
Read on for his perspective, and then visit Transplantation and Cellular Therapy, the official journal of ASTCT, for the full article.
NUCLEUS: What prompted ASTCT to revisit and update its consensus grading criteria for immune effector cell therapy toxicities, and why was now the right time for this effort?
Miguel-Angel Perales, MD (MP): The ASTCT consensus grading guidelines for IEC toxicities published in 2019 by Lee et al have become the standard in the field and have been adopted worldwide both in the clinical trial setting and in clinical practice. Having a uniform grading system represents a critical advance in the field. Since 2019, several new CAR T-cell products have been approved by the FDA or under clinical investigation. Several new toxicities have been reported in association with these novel products that had not been included in the Lee 2019 paper. As a result, the ASTCT leadership in collaboration with the Committee on Cellular Therapy decided it was necessary to update the 2019 criteria. I want to take this opportunity to highlight that this was a significant collaborative effort and recognize all the authors who participated in the in-person meeting and contributed to the manuscript. Special recognition to my co-authors Drs. Marcela Maus and Fred Locke, Anna Hawkshead, Operations Manager at ASTCT, and medical writer Jennifer Motl.
NUCLEUS: What changes in the field made updating the grading framework necessary?
MP: The most significant change in the field, as noted above, has been the recognition of toxicities associated with novel CAR T-cells, including BCMA-targeted CAR T-cells, that were not observed with CD19 CAR T-cells. As noted in the paper, these include IEC-associated hematotoxicity (ICAHT), IEC-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), non-ICANS neurotoxicities (NINTs) IEC-parkinsonism, IEC-cranial nerve palsies, IEC-polyneuropathies, and tumor inflammation-associated neurotoxicity (TIAN), IEC-enterocolitis; local IEC-associated toxicity syndrome (LICATS).
NUCLEUS: What were some of the most important challenges the expert panel encountered when working toward consensus recommendations across differen T-cell therapy platforms and toxicity profiles?
MP: We intentionally convened a large group of experts with different areas of expertise to ensure we had broad representation. This ensured robust discussions and inclusion of various viewpoints. One of the main areas of challenge is how the grading system is used in the context of clinical trials. The panel was very careful to stress the point that these should be used for determination of dose-limiting toxicities.
As noted in the conclusions: “We expressly do not recommend that such grading scales be adopted as criteria for dose-limiting toxicities without careful consideration of the target patient population and disease-specific risk tolerance for a given disease. We recognize that attribution of toxicities plays a critical role in the setting of clinical trials and that many of the toxicities described after IECs or T-cell engagers can be multifactorial in etiology and not solely related to the “drug.”
Why is this important? If we automatically use the grading system in a DLT context, we may incorrectly assign the toxicity to the CAR T and this could results in drugs being abandoned because of safety concerns. A specific example in acute lymphoblastic leukemia where many patients are pancytopenic at time of treatment with CAR T and would therefore meet criteria for grade 3-4 N-ICAHT and T-ICAHT before even receiving the CAR T-cells. The clinical trial would essentially end before it started if these were considered CAR T related toxicities.
NUCLEUS: How do these updated grading recommendations help clinicians more accurately assess and manage toxicities such as cytokine release syndrome and neurotoxicity in everyday practice?
MP: The addition of new toxicities provides a uniform framework for clinicians to grade these toxicities, development management guidelines, and ensure uniform reporting to registries, clinical trials and in publications. In addition to including new toxicities, we also revised the grading system for CRS and ICANS. The good news is that we kept the original framework mostly unchanged and added some clarifications. These were primarily changes to ICANS grading. First we developed a modified ICE (M-ICE) tool that is more appropriate for children or individuals for developmental delays. We also removed the CAPD, which is a neurological tool used in pediatrics but is typically used in the ICU with continuous bedside monitoring. Second, we made some changed to grade 1-2 ICANS to account for patients with an abnormal baseline ICE or MICE score. We believe these updates provide benefits to clinicians at the bedside to more accurately assess CRS and ICANS.
NUCLEUS: Were there any recommendations or areas of discussion that generated particularly robust debate among the panel members or challenged existing assumptions in the field?
MP: Probably the most robust discussions were around the incorporation of hematologic toxicities as noted above. I would also point out that, at the time of the meeting, this consisted of the ICAHT tool that was only based on neutrophile recovery. There were significant discussions about the fact that many patients also had persistent thrombocytopenia. We were fortunate to count with the presence at the meeting of Kai Rejeski who had led the original EHA-EBMT work on ICAHT. Immediately after the meeting, I asked Rejeski who at the time was a visiting investigator at MSK to perform an analysis of platelet recovery post CAR T similar to the ICAHT analysis. This work, which he led with another MSK visiting investigator, Jaime Sanz, and included contributions from other non-MSK panel members, led to the development of the T-ICAHT grading that we published in 2025 and then incorporated into the ASTCT grading system.
NUCLEUS: How do you anticipate these consensus criteria influencing clinical trial design, reporting standards, and comparisons across studies moving forward?
MP: I expect the updated consensus criteria to be broadly updated in clinical trials, clinical practice and registry reporting similar to what we saw with the Lee 2019 paper. In fact, the CIBMTR is already working on the updates. This is another opportunity to stress the collaborative nature of this process as we included representation from industry and the FDA in the meeting and manuscript review. I will also be presenting the new guidelines at an upcoming FDA meeting.
NUCLEUS: What are the key takeaways you hope transplant and cellular therapy teams, including physicians, advanced practice providers, pharmacists, and nurses, will take from this publication?
MP: CAR T-cells and immune effector cells in general represent a transformational change in our therapeutic armamentarium and now provide curative options to many patients in which standard therapies have failed. They are also associated with unique toxicities. It is important to recognize these toxicities and develop effective treatment guidelines to mitigate toxicity and optimize patient outcomes. The literature clearly shows that we have become better at treating patients with CAR T-cells and that we see less high-grade toxicities than we used to. I’m convinced that having a uniform grading system has contributed to this progress and I hope that adoption of the 2026 ASTCT grading system will continue to help develop the field and improve patient outcomes.
NUCLEUS: Looking ahead, what emerging toxicities, novel immune effector cell therapies, or areas of research do you think may require further refinement of grading systems over the next five years?
MP: The Lee 2019 paper was a landmark paper in our field. However, this is a rapidly evolving field and by 2024-2025, the paper was missing key elements. We hope the 2026 update will fill many of the gaps but also recognize that we will probably calling another panel in a few years for further updates. Two areas to highlight among many is the rapid development of CAR T-cells is non-malignant indications such as autoimmune diseases as well as in vivo CAR T-cells. This may lead to knew and yet unrecognized toxicities that will be need to be graded and reported in a uniform way. I’m convinced ASTCT will continue to lead the way in these efforts.
Reference
Rejeski K, Sanz J, Fei T, Nair MS, Hashmi H, Avigdor A, Beyar-Katz O, Bücklein VL, Curran KJ, Einarsdottir S, Esensten JH, Glaubach N, Golan-Accav N, Gomez-Llobell M, Halamis I, Itzhaki O, Locke FL, Mailankody S, Marcus R, Maus MV, Palomba ML, Park JH, Pasquini M, Raj S, Rajeeve S, Salles G, Scordo M, Shah GL, Shimoni A, Subklewe M, Tix T, Usmani SZ, Valid O, Valtis YK, Zuckerman T, Shah NN, Perales MA, Shouval R. T-ICAHT: grading and prognostic impact of thrombocytopenia after CAR T-cell therapy. Blood. 2025 Aug 14;146(7):834-846. doi: 10.1182/blood.2025028833. PMID: 40258181; PMCID: PMC12783514.