Background/Aim: The Philadelphia chromosome is found in 30% of acute lymphoblastic leukemia (ALL) patients, a distinct ALL subgroup where the BCR-ABL fusion gene is associated with poor prognosis. Treatment with tyrosine kinase inhibitors (TKIs) often induces complete remission and these patients subsequently undergo an autologous stem cell transplantation (ASCT). However, 20% of subjects experience a relapse associated with the selection of point-mutations in the BCR-ABL kinase domain. We report the clinical evolution of a Philadelphia-positive ALL patient co-expressing the e1a2 and e14a2 BCR-ABL transcript at diagnosis. Materials and Methods: Multiplex reverse transcriptase (RT)-PCR was used to detect BCR-ABL transcripts and their levels were measured by quantitative Real Time PCR. Clonal sequencing and next-generation sequencing (NGS) were used to identify mutations. Results: Although the patient underwent ASCT following treatment with multiple TKIs, he relapsed twice. The first time he exhibited the e1a2 transcript and the second time he presented only the e14a2 variant. Mutation analysis, performed by clonal sequencing and NGS, detected two alterations after the first relapse and a single mutation at the time of the second relapse. Conclusion: The observed shift from the e1a2 to the e14a2 variant and the selection of TKIresistant clones heavily contributed to the fatal evolution of the disease.The Philadelphia (Ph) chromosome, resulting from the reciprocal translocation of the ABL gene at 9q34 with the BCR gene at 22q11, is the most frequent cytogenetic abnormality in both chronic myelogenous leukemia (CML) and adult acute lymphoblastic leukemia (ALL) (1-3). At the molecular level, the t(9,22) translocation generates the BCR-ABL chimeric oncogene that may encode for a 210-kD or a 190-kD protein both displaying constitutive tyrosine kinase activity and favoring cell-cycle progression (4-7). The fusion gene is found in more than 95% of patients with CML (8), and in 20-30% of adult ALL patients, with the incidence rising to more than 50% in patients aged >50 years where it is associated with an inferior prognosis (9). Several reports have found the e1a2 transcript to coexist with e13a2 or e14a2 isoform in patients with Ph-positive ALL (10, 11).In the pre-tyrosine kinase inhibitor (TKIs) era, Allogeneic Stem Cell Transplant (allo-SCT) in first complete remission was the only potentially curative option (12) for the disease. Currently, the standard of care for patients with Ph-ALL is a combination of chemotherapy and a TKI followed by allo-SCT. However, 60-70% of Ph-ALL individuals are ineligible for allo-SCT due to their age, lack of an HLA-matched sibling, lack of a matched-unrelated donor or a suitable cord blood unit. These patients can then be considered for autologous stem cell transplantation (ASCT), although this procedure is associated with a higher incidence of relapse (13). Hence, TKIs can be used for the in vivo eradication of the malignant clone before ASCT, followed by maintenance therapy after tran...