The case reported presents a rare CD19− phenotype shift of an acute lymphoblastic leukaemia clone during relapse/refractory ALL in a paediatric patient. We explore possible reasons for the promotion of CD19-negative cell selection, including discrete mutations and anti-CD19 treatment, which is gaining importance as targeted therapies such as blinatumomab enter standard treatment protocols. A 9-year-old male patient was diagnosed with B lymphocyte acute lymphoblastic leukaemia. Initial standard genetic analysis did not show significant chromosomal aberrations, and the patient underwent chemotherapy in line with the intermediate-risk protocol. After initially achieving remission, the disease relapsed, and the patient required hematopoietic stem cell transplantation (HSCT). In-depth retrospective microarray analysis performed at this point revealed additional risk factors, particularly a loss of function TP53 V173L mutation. A second recurrence was diagnosed which prompted targeted treatment application (blinatumomab) and subsequent HSCT. The third leukemic relapse, diagnosed shortly after the second HSCT, limited treatment options to last-resort CAR T-cell therapy in Germany. Subsequent immunophenotyping revealed insufficient CD19 expression by ALL clones and disqualified the patient from treatment. The patient died in October 2019 from disease progression. The case highlights the importance of in-depth molecular diagnostics and monitoring of relapse/recurrent ALL cases to identify and manage risk factors during treatment.