Absolute lymphocyte count is predictive of response to salvage therapies for post-CAR T failure

Abstract

Abstract Introduction: Most patients with relapsed or refractory large B-cell lymphoma who undergo CD19-directed CAR T-cell therapy ultimately develop progressive disease. Identifying biomarkers to guide prognosis and post-relapse management is paramount. Absolute lymphocyte count (ALC) is a readily available immune parameter that may reflect host immune competence and predict treatment outcomes. We sought to assess the prognostic and predictive value of ALC in patients with relapsed/refractory disease following CAR T-cell failure, aiming to identify its potential role in guiding post-CAR T therapeutic strategies. Methods: We conducted a retrospective study in a database of 352 consecutive LBCL patients who received CAR T-cell therapy following ≥2 prior therapies and subsequently received salvage therapies post-CAR T relapsed/refractory disease [RT alone, systemic therapy (ST) alone, or combined modality therapy (CMT)]. All three categories were defined at the time of the first salvage therapy following CAR T failure. ALC counts were evaluable in 116 of the 131 patients who received salvage therapies. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: 131 patients received salvage therapies (RT, 24 patients; CMT, 16 patients; ST, 91 patients). The median follow-up after CAR T-cell infusion was 14.5 months [interquartile range (IQR): 6.3-45.3 months], and the median follow-up after post-CAR T salvage therapy was 7.3 months (IQR: 2.7-26.2 months). The median overall survival (OS) was significantly higher among patients with late relapse after complete remission post-CAR T-cell therapy (>6 months, n = 32; median OS = 28.6 months) compared to those with early relapse (≤6 months, n = 32; median OS = 5.4 months) or primary refractory disease (n = 67; median OS = 7.2 months) (p = 0.037). Analysis of patterns of failure revealed that the majority of patients (n=98, 75%) had a component of failure in previously involved sites pre-CAR T. The best overall response (complete response [CR] + partial response [PR]) to the first salvage regimen was 46% (n = 60). There was no significant difference in OS or progression-free survival (PFS) based on the class of first salvage therapy. Among 62 patients who received a second salvage regimen, 48% (n = 30) achieved a response (CR + PR). Patients with ALC > 1.0 x 10⁹/L at best response after first-line salvage therapy had significantly improved OS (p = 0.03) and PFS (p = 0.01) compared to those with ALC ≤ 1.0 x 10⁹/L. ALC at best response after CAR T or at the time of CAR T failure was not significantly associated with OS or PFS. There was no significant difference in ALC at best response after CAR T between responders (CR/PR) and non-responders (SD/PD) (p = 0.37); however, ALC at best response after first-line salvage therapy was significantly higher in responders compared to non-responders (p = 0.002). On multivariable analysis, age ≥60 at time of diagnosis (HR 1.86, 95% CI 1.07–3.25, p = 0.03), bulky disease ≥5 cm at time of first salvage therapy (HR 1.78, 95% CI 1.02–3.12, p = 0.04), stage III/IV at time of first salvage therapy (HR 2.20, 95% CI 1.27–3.80, p = 0.005), elevated LDH at time of first salvage therapy (HR 1.64, 95% CI 1.01–2.66, p = 0.04), number of lines of therapy pre-CAR T >2 (HR 2.10, 95% CI 1.18–3.73, p = 0.012), and ALC > 1.0 x 10⁹/L at best response after first-line salvage therapy (HR 0.50, 95% CI 0.26–0.96, p = 0.037) were independently associated with OS. For PFS, stage III/IV at time of first salvage therapy (HR 2.18, 95% CI 1.37–3.47, p = 0.001), elevated LDH at time of first salvage therapy (HR 1.74, 95% CI 1.15–2.61, p = 0.008), late relapse (>6 months) after complete remission post-CAR T (HR 0.58, 95% CI 0.34–0.99, p = 0.045), and ALC > 1.0 x 10⁹/L at best response after salvage therapy (HR 0.47, 95% CI 0.27–0.82, p = 0.008) were independent predictors of PFS. Conclusions: We report, for the first time, the association of ALC post-CAR T-cell failure with clinical outcomes and its utility in predicting response and survival in patients with relapsed/refractory LBCL. Higher ALC may reflect improved immune recovery and functional T-cell reserve, which could enhance responsiveness to subsequent treatments and support its role as a simple, accessible biomarker to guide risk stratification in this setting.