S260: IMMUNE EFFECTOR CELL ASSOCIATED HEMATOTOXICITY (ICAHT) FOLLOWING CAR T-CELL THERAPY: INTERNATIONAL SURVEY AND CONSENSUS GUIDELINES ON ITS GRADING, DIAGNOSIS, AND MANAGEMENT ON BEHALF OF EHA AND EBMT

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Hematological toxicity represents the most common grade ≥3 toxicity after chimeric antigen (CAR) T-cell therapy and is qualitatively unique. However, its underlying pathophysiology is incompletely understood and its grading and management remains ill-defined. Aims: We sought to unify grading and develop consensus guidelines for the diagnosis and management of a novel toxicity category of CAR-T therapy, termed Immune Effector Cell Associated Hemato-Toxicity (ICAHT). Methods: A joint EBMT/EHA-wide group was formed to produce a framework for grading and risk-stratification, and to suggest practical clinical recommendations for ICAHT following CAR-T therapy. As a first step, we undertook a survey of experienced clinicians using an online survey focusing on (1) grading, (2) risk-stratification and diagnostic work-up, (3) short-term and (4) long-term management of ICAHT. Results: There were 81 survey respondents across 18 countries. A high degree of variability was noted for cytopenia grading in regards to depth, duration, and time from CAR-T infusion. The majority of experts favored pre-CAR-T bone marrow studies, especially in case of a high-risk profile (80%). Most respondents felt that the work-up for patients with severe hematotoxicity should rule-out viral infections (96%), substrate deficiency (80%), or coincident sHLH/MAS (serum ferritin: 92%), and should include bone marrow aspiration (86%) and/or biopsy (61%) (Fig. 1A). Clinicians were divided as to whether the occurrence of coincident immunotoxicity should influence the decision to apply G-CSF, and when to initiate G-CSF support. The majority of experts (57%) noted that the occurrence of severe neurotoxicity (or CRS), defined as grade ≥3, would result in deferral of growth factor application. Notably, a wide range of answers was provided in regards to the optimal time point to start growth factors, with the most popular choice being “only in case of severe or prolonged grade ≥3 neutropenia” (47%), though a significant fraction of survey participants also favored routine use (Fig. 1B, top). In terms of the management of prolonged thrombocytopenia, most survey participants favored TPO agonists such as eltrombopag or romiplostim (86%), followed by autologous stem cell boost, if available (43%). Conversely, autologous stem cell boosts represented the preferred choice for immune effector cell associated neutropenia (63%), followed by TPO agonists (43%), immunosuppressive agents (20%), and allogeneic stem cell transplantation as a last resort (16%). Despite the popularity of autologous stem cell boosts, they were frequently not available even when they were considered (Fig. 1B, bottom). For example, 20% of respondents reported never finding an available autologous back-up in a patient with a prior history of autologous stem cell transplantation, while 41% of respondents identified a suitable autologous product in <30% of cases. Furthermore, no consensus was reached regarding the optimal trigger point for stem cell boost. Prophylactic collection in high-risk candidates and/or pre-emptive application of an available stem cell boost was not a common practice (<10% of respondents). Summary/Conclusion: These findings underline the current heterogeneity of practice patterns regarding ICAHT and invite the development of consensus guidelines, which may harmonize grading, establish standard operating procedures for diagnosis, and set management guidelines. For this purpose, an international expert panel will meet in Lille in March 2023. The resulting consensus guidelines will be presented together with the survey results at the EHA meeting.Keywords: Side effects, CAR-T, Lymphoid malignancy