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(n=9) (p = 0.806) (Data unpublished) respectively, and the trends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.