Prediction of life-threatening and disabling bleeding in patients with AML receiving intensive induction chemotherapy

Abstract

Bleeding in patients with acute myeloid leukemia (AML) receiving intensive induction chemotherapy is multifactorial and contributes to early death. We sought to define the incidence and risk factors of grade 4 bleeding to support strategies for risk mitigation. Bleeding events were retrospectively assessed between day-14 and day +60 of induction treatment according to the World Health Organization (WHO) bleeding assessment scale, which includes grade 4 bleeding as fatal, life-threatening, retinal with visual impairment, or involving the central nervous system. Predictors were considered pretreatment or prior to grade 4 bleeding. 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 × 109/L compared with >40 × 109/L, and baseline international normalized ratio of prothrombin time (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- vs low-risk (development: 31 ± 7% vs 2 ± 1%; P < .001; validation: 25 ± 9% vs 7 ± 2%; P = .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 the development of rational risk mitigation strategies to improve early mortality of intensive induction treatment.

Graphical abstract

Figure 1.

Bleeding events WHO grade 2 and higher in the development and validation cohorts. This plot shows bleeding events by location, as labeled on the left. Bleeding events are depicted by the colored bars, and each column represents 1 of the 168 patients with a WHO grade 2 bleeding or higher. Colors reflect the bleeding grade, as labeled on the top.

Figure 2.

Development and validation of grade 4 bleeding score. (A) Variables and their assigned points of the grade 4 bleeding score result in 2 subgroups of low and high risk for grade 4 bleeding. (B) Frequency of grade 4 bleeding by risk score in the development and validation cohort. The number of patients by bleeding score is shown in the table below. (C) Cumulative incidence of grade 4 bleeding by risk group of the bleeding score, with death considered a competing event. Time is measured from the first day of induction chemotherapy, whereas events occurring in the 14 days prior to the start of induction treatment are counted at day zero.