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 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 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 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.

Early‐onset venous thromboembolisms in newly diagnosed non‐promyelocytic acute myeloid leukemia patients undergoing intensive induction chemotherapy

“…However, patients were treated on an individual basis and we cannot provide systematized treatment recommendations based on our current data 47 . Although we did not observe major bleeding complications 23 in these patients, literature and current guidelines both clearly indicate a non‐negligible risk of hemorrhage 16,47–50 . In contrast, patients with solid cancers suffer higher mortality due to VTE than due to major bleeding 11 .…”

“…47 Although we did not observe major bleeding complications 23 in these patients, literature and current guidelines both clearly indicate a non-negligible risk of hemorrhage. 16,[47][48][49][50] In contrast, patients with solid cancers suffer higher mortality due to VTE than due to major bleeding. 11 Since we and others have failed to clearly detect an adverse impact of VTE on OS, whereas the adverse impact of hemorrhage in AML patients is clear, 16 a conservative approach toward the treatment of VTE may be warranted.…”

Trying to outRun‐DIC in KMT2Ar AML: It's tricky

“…In this independently validated model (development cohort [ n = 341], independent cohort [ n = 143]), platelet count ≤40 ×10 9 /L and INR‐prothrombin time (PT‐INR) >1.3 at baseline, dichotomously stratified patients into low‐ and high‐risk groups for grade 4 bleeding. Notably, high bleeding risk in both cohorts was associated with DIC and proliferative disease 7 . Identifying patients at high risk of bleeding and DIC remains an important measure to prevent early mortality from AML.…”

“…Acute promyelocytic leukemia (APL), a favorable risk AML subset marked by the translocation of chromosomes 15 and 17 resulting in PML‐RARA gene fusion, is particularly associated with hemorrhagic diathesis; however, other patients with non‐APL AML are also at risk of increased bleeding‐associated morbidity and mortality. Recently, Versluis and colleagues devised a model to predict grade 4 bleeding (per the World Health Organization bleeding assessment scale) events at day + 60 in patients with AML who are receiving induction chemotherapy 7 . In this independently validated model (development cohort [ n = 341], independent cohort [ n = 143]), platelet count ≤40 ×10 9 /L and INR‐prothrombin time (PT‐INR) >1.3 at baseline, dichotomously stratified patients into low‐ and high‐risk groups for grade 4 bleeding.…”

Early mortality in acute myeloid leukemia with KMT2A rearrangement is associated with high risk of bleeding and disseminated intravascular coagulation

“…A recent study by Versluis et al developed and externally validated a risk model for predicting major bleeding events within the first 60 days in patients with AML undergoing induction chemotherapy. 8 They identified low baseline platelet count ≤40 � 10 9 /L and elevated INR ≥1.3 as independent risk factors associated with major bleeds and developed a scoring system with these two variables to predict patients with AML at high risk for major bleeding events. We incorporated their model into our study, which predicted 52% of evaluable patients with KMT2Ar AML to be at high risk for major bleeding compared with 33% in the normal karyotype cohort, though this was not statistically significant (p = .2).…”