Determinants of Fatal Bleeding during Induction Therapy for Acute Promyelocytic Leukemia in the ATRA Era
Authors: Mantha Simon , Goldman Debra , Devlin Sean M. , Lee Ju-Whei , Zannino Diana , Douer Dan , Iland Harry J , Litzow Mark R. , Stein Eytan M. , Appelbaum Frederick , Larson Richard A. , Rowe Jacob M. , Tallman Martin S. 
Published: October 2019

Abstract
Background Acute promyelocytic leukemia (APL) is commonly complicated by complex coagulopathy. The early use of all-trans retinoic acid (ATRA) appears to have reduced induction mortality; however, with modern regimens the risk of early hemorrhagic death remains at about 5-10% in clinical trials and up to 30% in population-based studies. Previously identified as markers of bleeding risk in this setting are: white blood cell count (WBC), peripheral blood blast count, platelet count, fibrinogen, prothrombin time (PT), activated partial thromboplastin time (aPTT) and creatinine. Nonetheless, uncertainty remains as to which ones are independent predictors.
Materials and Methods The database for study was from APL patients enrolled on three large clinical trials that used ATRA for induction: APML3 (single arm of ATRA + idarubicin ± prednisone), APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone) and ECOG 2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA). Known determinants of bleeding were assessed at baseline and considered as potential predictors of hemorrhagic death in the first 30 days of induction. In univariate analysis, using Wilcoxon Rank Sum and Fisher’s exact test, we looked at the association of the parameters mentioned above with hemorrhagic death within 30 days of induction.
Results A total of 619 patients were enrolled: ECOG 2491 (intergroup I0129) - 394, APML3 - 101, and APML4 -124. Among these, thirty (4.8%) deaths from bleeding during the first 30 days (early deaths, ED) following induction were recorded. Baseline characteristics of the patients are shown in Table 1 and Table 2. Initial coagulation parameters (PT, aPTT and fibrinogen) were not available for the ECOG trial. Parameters with significant differences between the ED cases and the remaining of the cohort included WBC (median: 7.4 vs 2.4 /Kmcl respectively, p<0.001), peripheral blood blast count (median: 1.0 vs 0.2 /Kmcl respectively, p=0.049) and platelet count (median: 20 vs 33 /Kmcl respectively, p=0.002).
Conclusions In this large cohort of approximately 600 APL patients enrolled on 3 large clinical trials, higher WBC, peripheral blast count and lower platelet count emerged as univariate predictors of early hemorrhagic death. Surprisingly, age, PT, aPTT, fibrinogen and creatinine clearance did not differ between the patients who died from bleeding and the remaining of the cohort. Multivariate analysis will clarify the relative strength of the significant predictors in assessing ED, and will be available, along with coagulation parameters for ECOG, at the time of presentation. These data hopefully will allow us to build a clinical prediction rule to identify patients at the highest risk of early hemorrhagic death. Such a stratification tool could prove useful in future trials testing novel approaches to treat the coagulopathy associated with APL.
: Abstract 948. Table 1 Baseline Characteristics of Patients, Continuous Variables Variable Total Death from Bleeding within 30 days No Yes N Median (IQR) N Median (IQR) N Median (IQR) p-value Age (years) 619 40.0 (26.0 - 54.0) 589 40.0 (26.0 - 54.0) 30 47.0 (26.0 - 63.0) 0.15 White Blood Cell Count (K/mcL) 611 2.5 (1.2 - 8.2) 582 2.4 (1.1 - 7.6) 29 7.4 (3.1 - 20.7) <0.001 Peripheral blood blast count (K/mcL) 581 0.2 (0.0 - 2.2) 552 0.2 (0.0 - 1.9) 29 1.0 (0.1 - 5.7) 0.049 Hemoglobin (g/dL) 615 9.3 (8.0 - 10.5) 585 9.3 (7.9 - 10.5) 30 9.4 (8.2 - 10.7) 0.75 Platelets (K/mcL) 615 31.0 (17.0 - 56.0) 585 33.0 (17.0 - 57.0) 30 20.0 (13.0 - 34.0) 0.002 Prothrombin time (s) 184 16.0 (13.3 - 18.2) 179 16.0 (13.3 - 18.1) 5 16.7 (16.5 - 144.3) 0.15 Activated partial thromboplastin time (s) 225 29.0 (26.0 - 32.0) 216 29.0 (26.0 - 32.0) 9 31.2 (29.0 - 38.0) 0.07 Fibrinogen (mg/dL) 217 1.8 (1.3 - 2.6) 208 1.8 (1.3 - 2.6) 9 2.3 (2.0 - 2.5) 0.36 Creatinine Clearance (mg/dL)* 225 389 (261.2 - 511.6) 216 392 (264.9 - 512.4) 9 262 (219.2 - 432.0) 0.15 *calculated using the Jelliffe formula
: Table 2 Baseline Characteristics of Patients, Categorical Variables. Variable Total Death from Bleeding within 30 days No Yes N % N % N % p-value ECOG Performance Status 579 93.54 552 93.72 27 90.00 0.50 Good(0-2) Poor(3-4) 36 5.82 33 5.60 3 10.00 Missing 4 0.65 4 0.68 0 0 FAB Classification 248 40.06 239 40.58 9 30.00 >0.95 M3 M3v 67 10.82 65 11.04 2 6.67 Missing 304 49.11 285 48.39 19 63.33

Disclosures
No relevant conflicts of interest to declare.