The outcome of pediatric patients with Philadelphia chromosome (Ph)-positive acute lymphoid leukemia (ALL) has improved with addition of tyrosine kinase inhibitors to an intense chemotherapy. However, it is associated with high incidences of adverse effects and requires new therapeutic strategies for maximum anti-leukemic effect and reduced toxicities. We describe a challenging adolescent case with Ph-positive ALL and mechanical mitral and aortic valves due to Shone’s syndrome. The patient received reduced intensity chemotherapy and blinatumomab with dasatinib and is in deep molecular remission. Long-term anticoagulation was achieved with enoxaparin for mechanical valves and unfractionated heparin during procedures.