Differentiation syndrome and coagulation disorder - comparison between treatment with oral and intravenous arsenics in pediatric acute promyelocytic leukemia

Abstract

Realgar-Indigo naturalis formula (RIF), with A₄S₄ as a major ingredient, is an oral arsenic used in China to treat pediatric acute promyelocytic leukemia (APL). The efficacy of RIF is similar to that of arsenic trioxide (ATO). However, the effects of these two arsenicals on differentiation syndrome (DS) and coagulation disorders, the two main life-threatening events in children with APL, remain unclear. We retrospectively analyzed 68 consecutive children with APL from South China Children Leukemia Group-APL (SCCLG-APL) study. Patients received all-trans retinoic acid (ATRA) on day 1 of induction therapy. ATO 0.16 mg/kg day or RIF 135 mg/kg·day was administrated on day 5, while mitoxantrone was administered on day 3 (non-high-risk) or days 2-4 (high-risk). The incidences of DS were 3.0% and 5.7% in ATO (n = 33) and RIF (n = 35) arms (p = 0.590), and 10.3% and 0% in patients with and without differentiation-related hyperleukocytosis (p = 0.04), respectively. Moreover, in patients with differentiation-related hyperleukocytosis, the incidence of DS was not significantly different between ATO and RIF arms. The dynamic changes of leukocyte count between arms were not statistically different. However, patients with leukocyte count > 2.61 × 10⁹/L or percentage of promyelocytes in peripheral blood > 26.5% tended to develop hyperleukocytosis. The improvement of coagulation indexes in ATO and RIF arms was similar, with fibrinogen and prothrombin time having the quickest recovery rate. This study showed that the incidence of DS and recovery of coagulopathy are similar when treating pediatric APL with RIF or ATO.

Keywords: Acute promyelocytic leukemia; Arsenic compounds; Children; Coagulation disorder; Differentiation syndrome.

Fig. 1

The dynamic changes of median WBC during induction treatment for ATO and RIF arm. The WBC counts at different time points were compared using Mann–Whitney U test, all p > 0.05. The mixed linear model was used to analyze the overall dynamic trend of the two arms, p = 0.539

Fig. 2

The comparison of dynamic changes of median WBC count and median WBC normalized value between ATO and RIF arm by risk stratification. a In NHR arm: There were statistical differences in WBC count between the ATO and RIF arm at five time points. They are D0, days 6–8, days 12–14, days 15–17, and days 18–20 (p = 0.047, p = 0.034, p = 0.035, p = 0.044, and p = 0.031, separately). Using mixed linear model to analyze the overall dynamic trend of ATO and RIF arms, p = 0.004. b In HR arm: The overall dynamic trend between ATO and RIF arm was compared by mixed linear model, p = 0.404. Using Mann–Whitney U test to compare the WBC count at different time points, all p value > 0.05 between ATO and RIF arm. c In NHR arm: Comparison in the dynamic trend of WBC normalized value between ATO and RIF arms by mixed linear model, p = 0.480. Mann–Whitney U test was used to compare the WBC normalized value at different time points, p > 0.05. d In HR arm: The overall dynamic trend of WBC normalized value was compared between ATO and RIF, p = 0.379. WBC normalized values at different time point were compared using Mann–Whitney U test, all p value > 0.05

Fig. 3

The dynamic trend of coagulation data in ATO and RIF arm. All coagulation data in figure are showed as median with interquartile range. a, c, d Mann–Whitney U test was used to compare the difference of PLT, PT, and Fbg between the two arms at each time point, all p > 0.05. Using the mixed linear model to compare the recovery trend between ATO and RIF arms, the p values of PLT, PT, and Fbg were 0.352, 0.277, and 0.353 respectively. b d-Dimer on days 12–14 (p = 0.033) showed slower recovery in RIF arm. However, the p value of the dynamic trend calculated by mixed linear model was 0.285. e Even in normal range, APTT on days 6–8 (p = 0.040) recovered slower in ATO arm. f Survival analysis comparing the time to platelet recover (PLT > 30 × 10⁹/L) between ATO and RIF