Determinants of Early Death and Outcomes for Acute Promyelocytic Leukemia in the Arsenic Era: A Real World Study

Objective

Early death (ED) persists as the main obstacle to cure all the patients with acute promyelocytic leukemia (APL) in all-trans retinoic acid (ATRA) era. Uncertainty remains as to whether ED rate can reduce and which markers are independent predictors for ED and outcomes in arsenic era. We conducted a real world study of APL patients to assess ED, outcomes and predictors in arsenic era.

Methods

This study includes consecutive 309 APL patients in our center between 2005 and 2013. Three treatment protocols using arsenic and ATRA as first-line treatment were adopted in our center. Protocol A was used from 2005 to 2007.Patients received oral tetra-arsenic tetra-sulfide (As4S4) (60mg/kg/day) or intravenous ATO (10 mg/day) daily with ATRA (25 mg/m2/day), until complete remission (CR) for induction therapy, whereas additional minimal chemotherapy was administered to control hyperleukocytosis (mitoxantrone 1.4 mg/m2/day for 5-10 days or daunorubicin 40 mg/m2/day for 2-3 days was added if peripheral WBC was greater than 10 × 10⁹/L or on the second day in patients with high risk). After achieving CR, most patients were administered 3 courses of consolidation chemotherapy including mitoxantrone (6-8 mg/m2/day for 3 days), daunorubicin (40mg/m2 for 3 days) ,idarubicin (6-8 mg/m2 for 3 days). Maintenance treatment included inter-mittent oral As4S4 and ATRA for 2-3 years. Protocol B was used from 2008 to 2012, which is described in our previous report (Zhu HH, et al. JCO 2013; 31:4215-4221 ).Protocol C was used since 2013, which only included non high-risk patients and was described in our previous report (Zhu HH, et al. NEJM 2014; 371:2239-41).

Results

The ED (death within 30 days of diagnosis) rate was 4.8% (n=15) and showed a trend of decrease after 2008 (3.8% vs, 8.5% p=0.053). Using multivariate Cox proportional hazards regression, the hazard ratio of ED was 19.89 (95% CI, 4.49-88) for white blood cell (WBC) count of >10×10⁹/L vs ≤10×10⁹/L (P<0.0001) and 8.70 (95% CI, 1.15-66.67) for platelet count of ≤40×10⁹/L vs >40×10⁹/L(P=0.037). Estimated 10 year cumulative incidence of relapse (CIR), disease-free survival and overall survival (OS) was 6.32% (95% CI: 3.03%-9.61%), 93.0% (95% CI: 88.7%-95.7%) and 92.0% (95% CI: 88.3%-94.6%). WBC count was only independent predictor for OS (HR 5.34, 95% CI, 2.36-12 for >10×10⁹/L vs ≤10×10⁹/L, P<0.0001) in multivariate analysis.

Conclusions

In this large cohort of APL patients under a 'real world' setting, a relative low ED and high OS could be achieved and high WBC count emerged as an independent predictor of ED and OS in arsenic era.