Treatment Delays and Hemostatic Abnormalities Predict Death in Newly Diagnosed APL

Major factors associated with early deaths in hospitalized patients with newly diagnosed acute promyelocytic leukemia (APL) included treatment delays and the incidence of hemostatic abnormalities, according to research findings published in Blood Advances.

Given these findings, early diagnosis is crucial in optimizing outcomes for patients with APL, said lead study author Harinder Gill, MD, of the University of Hong Kong. He added, “all-trans retinoic acid should be initiated at the earliest stages of APL diagnosis, and clinicians should work toward aggressive correction of hemostatic parameters.”

Intracranial hemorrhage (ICH) with comorbid hypofibrinogenemia is associated with fatal outcomes in patients with APL. Despite advances in the frontline management of APL that incorporate arsenic-based regimens, early death (ED) remains a significant challenge in the disease, explained Dr. Gill.

The investigators performed a 13-year population-based study that evaluated the clinicopathologic features and risk factors of ED in 358 patients with newly diagnosed APL who were admitted to public hospitals in Hong Kong and treated with oral arsenic trioxide (As2O3).

The median age of the study population was 47 years. Patients were categorized into the following risk groups according to the Sanz score, which uses WBC and platelet counts:

  • low (WBC ≤10×109/L and platelet count >40×109/L): 23%
  • intermediate (WBC ≤10×109/L and platelet count ≤40×109/L): 41%
  • high (WBC >10×109/L): 36%

A total of 11 patients (3%) died within the first two days following hospital admission. Deaths were due to:

  • ICH (n=6)
  • APL-differentiation syndrome (APL-DS; n=4)
  • infection (n=1)

Another 6% of patients died within three to seven days of hospitalization, primarily due to ICH (n=12), APL-DS (n=8), and infection (n=2). Additionally, 23 patients (6%) died between eight and 30 days of admission. Deaths that occurred in the later stages of hospitalization were also attributable to ICH (n=7), APL-DS (n=11), and infection (n=5).

About 33% of the early deaths reported within the first seven days were caused by APL-DS. Furthermore, 41% of early deaths within a 30-day period of hospitalization were caused by APL-DS, particularly in patients older than 50.

Early deaths, which were defined as deaths within the first 30 days of presentation, were reported in 56 patients (16%). The researchers reported that this rate is slightly lower than the approximately 20% early death rate published in population-based registries. Factors associated with early death in the study were:

  • male sex (p=0.01)
  • leukocyte count >10×109/L at presentation (p=0.03)
  • fibrinogen <1.5 g/L (p=0.02)
  • receipt of all-trans retinoic acid treatment more than 24 hours following hospitalization (p=0.001)

Administration of all-trans retinoic acid after 24 hours following hospital admission was associated with significantly worse 30-day survival in the following groups:

  • male patients (hazard ratio [HR] = 2.22; 95% CI 1.10-4.54; p=0.03)
  • female patients (HR=3.64; 95% CI 1.54-8.56; p=0.03)
  • patients with white blood cell (WBC) count greater than 10×109/L (HR=3.79; 95% CI 1.86-7.72; p<0.001)
  • patients with WBC count less than or equal to 10×109/L (HR=2.32; 95% CI 1.01-5.38; p=0.048)
  • patients with fibrinogen less than 1.5 g/L (HR=3.20; 95% CI 1.62-6.29; p=0.001)

The five- and 10-year overall survival (OS) was 68.6% and 61.2%, respectively, after a median follow-up period of 47 months. A multivariate analysis revealed associations between adverse OS outcomes and male sex (p<0.001), age ≥50 years (p<0.001), and leukocyte count ≥10×109/L (p=0.004).

The retrospective nature of this study prevented the researchers from evaluating the association between specific treatments and the risk of early death. In addition, the researchers were unable to assess the impact of oral arsenic trioxide on early deaths in this cohort.

Study authors report no relevant conflicts of interest.


Gill H, Yung Y, Chu HT, et al. Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study. Blood Adv. 2021 Jul 27;5(14):2829-38.