Prediction of Life-threatening and Disabling Bleeding in Patients with Acute Myeloid Leukemia Receiving Intensive Induction Chemotherapy

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were assessed according to the WHO bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Using multivariable competing-risk regression analysis with grade 4 bleeding as the primary outcome, we identified risk factors in the development cohort (n=341), which were tested in an independent cohort (n=143). Grade 4 bleeding occurred in 5.9% and 9.8% of patients in the development and validation cohort, respectively. Risk factors that were independently associated with grade 4 bleeding included baseline platelet count [≤]40 x109/L compared with >40 x109/L, and baseline PT-INR >1.5 or >1.3-1.5 compared with [≤]1.3. These variables were allocated points, which allowed for stratification of patients with low- and high-risk for grade 4 bleeding. Cumulative incidence of grade 4 bleeding at day+60 was significantly higher among patients with high- versus low-risk (development: 31{+/-}7% vs. 2{+/-}1%, P<0.001, validation: 25{+/-}9% vs. 7{+/-}2%, P=0.008). In both cohorts, high bleeding risk was associated with disseminated intravascular coagulation (DIC) and proliferative disease. We developed and validated a simple risk model for grade 4 bleeding, which enables development of rational risk mitigation strategies to improve early mortality of intensive induction treatment. KEY POINTSO_LIRisk factors predicting grade 4 bleeding were consistent with DIC-like coagulopathy, including prolonged PT-INR and thrombocytopenia. C_LIO_LIThe grade 4 bleeding score was externally validated and allows for preventive strategies to improve early mortality in high-risk patients. C_LI