AbstractAllogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome‐positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post‐HCT, but published clinical experience is primarily with the first‐generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second‐generation TKI (2G‐TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty‐six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G‐TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G‐TKI: 576.0 days (range, 72–921) versus 254.5 days (range, 3–2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5‐year overall survival and progression‐free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post‐HCT TKI maintenance in a large real‐world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.