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To the Editor:
Although T-cell engager therapies, including bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapy, have revolutionized treatment of hematological malignancies, immune effector cell-associated Hematotoxicity (ICAHT) remains a significant clinical challenge [1, 2]. Effective ICAHT management requires a proactive strategy beyond reactive monitoring that integrates initial bone marrow capacity with post-infusion hematological trends to categorize patient risk [3, 4–5].
A critical first step is to use the CAR-HEMATOTOX score before lymphodepletion. While this model excels in identifying patients at high risk for prolonged neutropenia (Score ≥ 2), its clinical utility is primarily its high negative predictive value. Rather than serving as an absolute mandate for prophylactic intervention, a high CAR-HEMATOTOX score should be viewed as an indicator for intensified surveillance to ensure timely therapeutic intervention [3] (Table 1).
Management of neutropenia (N-ICAHT) underscores the principle that “faster recovery is not always better.” While short-acting granulocyte colony-stimulating factor (G-CSF) allows for tighter control of myeloid recovery, prophylactic use of long-acting G-CSF before CAR-T infusion has been shown to significantly increase the risk of Grade ≥ 2 cytokine release syndrome (CRS) (HR 2.15, P = 0.02) [6]. We thus advocate a personalized, neutropenia-driven approach. While short-acting G-CSF can be initiated in response to the patient's immediate hematologic status, long-acting G-CSF should be strictly deferred until inflammatory safety is ensured following resolution of active CRS/ICANS [4] (Table 1).
Our focus must expand to include thrombocytopenia (T-ICAHT) as a primary prognostic driver. In a core cohort of 744 patients with B-NHL, severe early T-ICAHT (Grade 3—4) was a powerful independent predictor of poor survival. Specifically, grade 3—4 T-ICAHT was associated with a 2-year overall survival (OS) of only 35%, compared with 67% in grade 0 (p < 0.001). This survival deficit is driven by a 60% relapse rate rather than by non-relapse mortality. We hypothesize that severe thrombocytopenia serves as a surrogate for bone marrow reservoir exhaustion, reflecting a compromised immune microenvironment that fails to maintain long-term immunosurveillance [5] (Table 1).
In conclusion, optimizing CAR-T cell therapy outcomes necessitates a three-fold strategy: forecasting risk via CAR-HEMATOTOX, avoiding premature G-CSF intervention in N-ICAHT, and prioritizing T-ICAHT monitoring as a sentinel for relapses and long-term prognosis. Successful implementation of this framework will require establishing a robust nationwide registry to systematically collect and analyze real-world ICAHT data. Such a national-scale platform will serve as an essential foundation to validate these risk-adapted approaches and represent a cornerstone of balanced and effective patient care in this era of CAR-T cell therapies.
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