Nelarabine treatment before allogeneic stem cell transplantation was associated with an increased risk of neurological adverse events in patients with T-ALL/lbl: A retrospective study of the kanto study group for cell therapy.

Abstract

Abstract [Introduction] Nelarabine (NEL) is an agent approved specifically for T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). Although increasingly incorporated into modern treatment protocols, NEL is associated with severe neurotoxicity. The impact of NEL treatment on the safety and efficacy of subsequent allogeneic stem cell transplantation (SCT), particularly regarding neurotoxicity, has not been clarified. [Methods] This retrospective study included patients with T-ALL/LBL who received SCT from 2010 to 2023 at 11 institutions participating in KSGCT. Neurologic adverse events (NAEs) included both peripheral and central nervous system events. Invasion of tumor cells, cerebrovascular disease, and infections were excluded. NAEs were graded based on CTCAE version 5.0. The primary end point was the cumulative incidence (CI) of ≥ grade 3 NAEs. Key secondary endpoints were overall survival (OS), CI of relapse (CIR), and CI of non-relapse mortality (NRM). All endpoints were calculated from the date of SCT. The Mann-Whitney U test was used for continuous variables, and the chi-square test was used for categorical variables. OS was calculated by Kaplan-Meier method and CI was estimated by Gray's test. Cox proportional hazards regression and Fine-Gray proportional hazards regression with a stepwise selection based on p-values were used in multivariate analysis for prognostic and risk factors, respectively. Significant factors identified in these analyses, along with NEL-treatment status, were then assessed in the final models. Statistical significance was defined as p < 0.05 (two-tailed). [Results] Of the 175 patients included in this study, 52 received NEL treatment before SCT (the NEL group) and 123 did not (the control group). Significant baseline differences were observed between the NEL and control group in disease status at SCT (CR1: 17% vs. 60%; CR2/CR3: 33% vs. 15%; not in remission: 50% vs. 25%; p < 0.001), donor type (matched related: 23% vs. 20%; unrelated: 15% vs. 43%; cord blood: 44% vs. 29%; haploidentical related: 17% vs. 8%; p = 0.003), conditioning intensity (myeloablative: 56% vs. 30%; reduced-intensity: 44% vs. 70%; p = 0.002), and number of SCT (first: 60% vs. 90%; second or more: 40% vs. 10%; p < 0.001). Median follow-up durations of survivors were 441 days (range, 168-4,382) for the NEL group and 2022 days (range, 168-5,284) for the control group. In the NEL group, the median cumulative NEL dose was 4,500 mg/m2 (range: 3,250-45,000 mg/m²). Nelarabine was administered at a dose of 1,500 mg/m²/day in 72% of patients, and 11% received it in combination with other chemotherapeutic agents. The CI of NAEs was significantly higher in the NEL group (14% vs. 4% at 1 year after SCT; p = 0.006), and NEL treatment prior to SCT was identified as the sole independent risk factor for NAEs in multivariate analysis (hazard ratio [HR] = 3.6; p= 0.021). Eight patients (19%) in the NEL group developed NAEs (median age: 37 years, range: 16–58). The median time from SCT to the onset of NAEs was 35 days (range, 5-1830). Types of NAEs included encephalopathy in 38%, posterior reversible encephalopathy syndrome in 38%, peripheral sensory neuropathy in 13%, and altered consciousness in 13%. A cumulative NEL dose of >4,500 mg/m² was associated with a significantly higher incidence of NAEs (29% vs. 3% at 1 year after SCT; p = 0.041). Despite various interventions, including corticosteroids and tapering of immunosuppressive agents, neurological symptoms resolved in only 3 patients. SCT outcomes were assessed in 80 patients undergoing first SCT in CR1 (7 in the NEL group and 73 in the control group). The OS rates and the CI of NRM had significant differences between the 2 groups (OS: 57% vs. 86% at 1 year after SCT; p = 0.041; NRM: 43% vs. 6%; p = 0.002), while no significant difference was observed in the CIR (0% vs. 14%; p = 0.258). In multivariate analysis, NEL treatment was identified as an independent risk factor for NRM (HR = 5.7; p < 0.001) besides age at transplant (≤50 vs. >50 years) (HR = 3.2; p = 0.023), but not for OS (HR = 2.9; p = 0.055).[Conclusion] These findings suggest that NEL treatment before SCT might be associated with a higher risk of clinically relevant NAEs in T-ALL/LBL patients. Further investigation is warranted to elucidate the risk factors for NAEs following SCT in patients treated with NEL, and to better define the impact of NEL on transplant outcomes in a larger cohort.