DISCUSSION
We used the WBC normalized value to evaluate the trends of WBC and compare the WBC values at each time points because WBC at day 0 varied between patients. Our study shows that there is no significant deference in the trends of WBC between the RIF and ATO groups, either of NHR or HR patients. In our dada, only high WBC counts or percentage of promyelocytes in peripheral blood at diagnosis is associated with the development of differentiation-related hyperleukocytosis, and the cut off values are 2.61 ×109/L and 26.5%, respectively.
Wang et al. reported that adult patients treated with RIF had a significant higher peak WBC compared to those treated with ATO during induction treatment.8 This is not confirmed in our cohort. The dose of RIF they used was 60 mg/(kg·d) which was lower than 135 mg/(kg·d) we used. The median plasma trough concentration of arsenic at steady-state ( day 7 ) in their patients treated with RIF (0.33 μmol/L) was lower than that in those treated with ATO at 0.16 mg/(kg·d) (0.75 μmol/L)(p = 0.0048).2 It has been reported that arsenic at relatively high concentration (0.5 μmol/L or more) mainly induced apotosis while at low concentration induced differentiation of APL cells.16 Therefore, it can be explained that higher peak WBC occurs in patients treated with low dose of RIF at 60 mg/(kg·d) than in patients treated with ATO at 0.16 mg/(kg·d). In our cohort, patients received ATO at 0.16 mg/(kg·d) or RIF at 135 mg/(kg·d). The plasma trough concentrations of arsenic are similar between the two groups on day 7, which were 0.51±0.16μmol/L (n=10) and 0.48±0.25μmol/L (n=9) (p = 0.806) (Data unpublished) respectively, and the trends of WBC were similar between the two groups. Our data show that WBC of NHR patients from both groups slightly increased in the first week of induction treatment, even though MA was administrated on day 3. The WBC of HR patients decreased significantly with more intense cytotoxic treatment including hydroxyurea administrated on day 0 and MA on day 2-4. It could be speculated that WBC might obviously increase during induction treatment without cytotoxic therapy.
An important question is raised based on our findings mentioned above. NHR APL in adults has been recently reported that can be successfully treated with a chemotherapy-free combination of ATRA and arsenic compound (RIF or ATO).15 However, there is concern that the use of the two differentiating agents without chemotherapy may result in an increasing risk of leukocytosis and DS.17Previous studies indicated that the incidence of leukocytosis in pediatric patients with NHR APL treated on chemotherapy-free induction therapy was 84%-100% and much higher than 35%-47% in adult counterpart.10-15 Recently, two multicenter clinical trials in pediatric APL, CCLG-APL2016 and SCCCG-APL, have been reported.1, 18 One of the main differences of induction therapy between the two protocols is that the former used chemotherapy-free induction treatment with ATRA and arsenic in NHR patients while the latter used an additional dose of MA besides ATRA and arsenic. The incidence of DS was 6.8 times higher in CCLG-APL2016 group (41%) than in the SCCCG-APL group (6%). However, this difference cannot be explained by the difference in the proportion of HR patients between the two groups which is only 1.3 times more in the former than in the latter. Therefore, it strongly suggests that the safety of chemotherapy-free induction proved in adult with NHR APL is questionable in pediatric counterpart because of much higher incidences of leukocytosis and DS in pediatric patients. A randomize clinical trial is on the way comparing the incidences of leukocytosis and DS between chemotherapy-free induction with RIF + ATRA and RIF + ATRA + one dose of MA in children with NHR APL (ChiCTR200003887).
In addition, the present study showed that the recovery of coagulopathy was not statistically different between the ATO and RIF groups except for higher values of D-Dimer on day 12-14 in the RIF groups. Our findings also support the view that Fbg and PT are the early and sensitive indicators of improvement in coagulopathy.19There was no statistical difference in the incidences of bleeding and thrombus events as well as the consumption of blood components between the two groups.
In conclusion, this study demonstrated the feasibility of replacing ATO at 0.16 mg/ (kg·d) with RIF at 135 mg/ (kg·d) in terms of the management of two main critical adverse events, DS and hemorrhage, in induction treatment in pediatric APL. Our findings also suggest that induction treatment with low-dose CHT such as anthracyclines may be important in pediatric APL, which may decrease the risk of differentiation-related hyperleukocytosis and DS during induction treatment. Patients with higher WBC counts or percentage of promyelocytes in peripheral blood tended to develop differentiation-related hyperleukocytosis, with the cut-off values of 2.61 ×109/L and 26.5%, respectively.