Clinicopathologic features of relapsed CD19(−) B-ALL in CD19-targeted immunotherapy: Biological insights into relapse and LILRB1 as a novel B-cell marker for CD19(−) B lymphoblasts

Introduction: The mechanism of relapsed CD19(−) B-ALL after anti-CD19 immunotherapy (Kymriah [CART-19] and blinatumomab) is under active investigation. Our study aims to assess LILRB1 as a novel B-cell marker for detecting CD19(−) B-lymphoblasts and to analyze the clinicopathologic/genetic features of such disease to provide biological insight into relapse. Methods: Six patients (3 males/3 females, median age of 14 years) with relapsed CD19(−) B-ALL were analyzed for cytogenetic/genetic profile and immunophenotype. Results: CD19(−) B-ALL emerged after an interval of 5.8 months following anti-CD19 therapy. Five of six patients had B-cell aplasia, indicative of a persistent effect of CART or blinatumomab at relapse. Importantly, LILRB1 was variably expressed on CD19(−) and CD19(+) B lymphoblasts, strong on CD34(+) lymphoblasts and dim/partial on CD34(−) lymphoblasts. Three of six patients with paired B-ALL samples (pre- and post-anti-CD19 therapy) carried complex and different cytogenetic abnormalities, either as completely different or sharing a subset of cytogenetic abnormalities. Conclusion: LILRB1 can be used as a novel B-cell marker to identify CD19(−) B lymphoblasts. The emergence of CD19(−) B-ALL appears to be associated with complex cytogenetic evolutions. The mechanism of CD19(−) B-ALL relapse under anti-CD19 immune pressure remains to be explored by comprehensive molecular studies.