EFFICACY AND CLINICAL OUTCOME OF PHILADELPHIA (PH) POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS TREATED WITH SECOND GENERATION TYROSINE KINASE INHIBITORS (TKIS): THE BOLOGNA EXPERIENCE

Background: Approximately 30% of adult ALL patients are characterized by the presence of the Philadelphia (Ph) chromosome, which derives from a reciprocal translocation t(9;22)(q34;q11) and results in a chimeric BCR-ABL oncogene. The prognosis for this subset of patients treated with standard therapies, including multi-agent chemotherapy, imatinib, and allogeneic stem cell transplantation, is still dismal, due to a high risk of relapse. Dasatinib and nilotinib are second generation TKIs developed to overcome resistance to imatinib in relapsed Ph+ leukemias. Here, we sought to determine the efficacy of these agents in patients with relapsed Ph+ ALL. Methods: We retrospectively evaluated the single-center experience of dasatinib, nilotinib, and experimental third-generation TKIs administered as second or subsequent lines of therapy. We evaluated the efficacy of these agents in 25 adult patients with relapsed Ph+ ALL. All patients were previously treated with imatinib.Results: The median age at time of diagnosis was 50 years (range, 18-74 years). Seventeen patients were male and 8 were female. Ten patients presented with a BCR-ABL P190 fusion protein and corresponding fusion transcript, and the remaining patients exhibited BCR-ABL P210. Nineteen patients received dasatinib, 2 patients nilotinib, and the remaining 4 patients were treated with third-generation TKIs. Fourteen patients (56%) were in first relapse, and 7 (28%), 3 (12%) and 1 (4%) were in second, third, and fourth relapse, respectively. A mutational analysis was performed twice in all the patients: before administering TKIs (9 patients with wild type BCR-ABL, 16 with mutated BCR-ABL, including T315I) and at the time of subsequent relapse. Gene expression profiling, SNPArray (6.0 Affymetrix chip), and Ikaros deletions were also analyzed. Thirteen out of 25 patients (52%) achieved a hematologic response (HR) (11 patients treated with dasatinib, 1 patient with nilotinib, and 1 patient with a third-generation experimental TKI). Ten patients also achieved a cytogenetic response (CyR) and 6 patients a molecular response (MolR). With a median follow up of 10.8 months (range, 2-29 months), median duration of HR, CyR, and MolR was 117 days (range, 14-385 days); progression free survival was 162 days with dasatinib and 91 days with nilotinib. Overall survival was 25.8 months. Interestingly, in 6 out of 9 patients with wild-type BCR-ABL treated with dasatinib, the mutational analysis showed the emergence of T315I or F317I mutation at the time of relapse. Conclusions: Second- and third-generation TKIs represent a valid approach in treating patients with relapsed Ph+ adult ALL. The subsequent relapse in Ph+ ALL patients is often associated with the emergence of mutations conferring resistance to TKIs.Acknowledgments: European LeukemiaNet, AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, Ateneo RFO grants, Project of integreted program (PIO), Programma di Ricerca Regione – Università 2007 – 2009.