Discussion
Pediatric AML patients with hyperleukocytosis, usually refers to WBC
counts greater than 100×109/L, have been reported to
have a more dismal prognosis than patients without
hyperleukocytosis.6-8 However, WBC counts below
100×109/L can also cause leukocytosis-related
complications and affect prognosis. Hyperleukocytosis has been defined
as more than 50×109/L in some studies in adults with
AML.10-12 Hyperleukocytosis has had no definitive
criteria heretofore. To the best of our
knowledge,
this study was the first report the characteristics and prognosis of
hyperleukocytosis (described as WBC count ≥50×109/L)
in pediatric AML patients. Moreover, this study was performed to further
compare the clinical characteristics and prognoses of childhood AML
patients with hyperleukocytosis with WBC count
50-100×109/L and those with WBC count
≥100×109/L in a single
institution.
In this study, we defined a WBC count greater than
50×109/L as the cut point for hyperleukocytosis. The
incidence of hyperleukocytosis in childhood AML patients at diagnosis
was 26.38% in our center, which is similar to published data
.10-12 In this study, patients with and without
hyperleukocytosis had similar CR rates, and yet patients with
hyperleukocytosis had a higher mortality rate than those without
hyperleukocytosis. We further confirmed that the 10-year PFS and OS
rates (P =.041, P =.051) between groups separated with this
cutoff were
significantly
different at our institution. PFS and OS were similar within the
subgroups.
This
fact indicates that a high leukocyte count (WBC count ≥
50×109/L) is a significant marker of poor prognosis.
Tien et al. observed that WBC counts significantly affected OS and
pointed out that hyperleukocytosis was an independent poor prognostic
factor.11 Genetic characteristics and clinical
treatment response as risk stratifications changed the clinical
prognosis. Hence, WBC count ≥ 50×109/L should be
classified as one of the risk stratification factors for pediatric
AML.
Patients with AML-M5 often present with
hyperleukocytosis,
and patients with AML-M5 may experience serious symptoms of
hyperleukocytosis.17In
this study, half of patients had the FAB M5 subtypes
in
patients with AML and
hyperleukocytosis.
In all patients with hyperleukocytosis, FAB M5 subtype patients had a
significantly inferior survival. Monocytic leukemia cells have more
large-volume active lysosomes.18During
chemotherapy, leukemia cells destroy and release a large number of
lysosomes, which caused coagulopathy, metabolic disturbance, and even
DIC and tumor lysis syndrome. It may be the main reason for the high
mortality of M5 with
hyperleukocytosis.19This may be one of the reasons for the increased mortality of children
with AML and hyperleukocytosis.
Moreover, Male predominance was noted in a multicentric study in
Brazil,20 which was consistent with our data. In
accord with our findings, pediatric AML and hyperleukocytosis were more
males, who had significantly poorer 10-year PFS and OS rates than
females. More than half of the AML-M5 patients experienced
testicular relapse without previous systemic
relapse.21 Poor prognosis may be related to
predominant acute monoblastic leukemia, extramedullary infiltration, and
the blood-testis barrier as a refuge for leukemia cells. All of the
above factors may lead to unsatisfactory chemotherapy effects, relapse
and high mortality in male pediatric AML patients with
hyperleukocytosis.
AML withRUNX1-RUNX1T1((AML1/ETO)or
core-binding
factor subunit beta- myosin heavy chain 11(CBFβ-MYH11) has been
considered a unique entity, which is collectively referred to as
CBF-AML.22Most
treatment protocols classify all children with CBF-AML as having a
low-risk disease.5 However, CBF-AML has a very high
degree of clinical and biological heterogeneity.23 WBC
count, platelet count and cytogenetic were significant prognostic
variables in CBF-AML.24 In our study, CBF-AML had a
low proportion of hyperleukocytosis in childhood AML patients. Moreover,
hyperleukocytosis
with CBF-AML had a significantly higher PFS and OS rate than
hyperleukocytosis without
CBF-AML.
This statistical difference may also be due to relatively small sample
size. More sample or experiments are needed to further confirm these
findings.
The incidence of FLT3-ITD was 8.14% (25 out of 307 patients) in
non-M3 pediatric AML in our study, which was consistent with
previous
reports.25 Our data suggested that the incidence ofFLT3-ITDmutations (n=16, 19.75%) was higher in AML patients with
hyperleukocytosis
than without hyperleukocytosis, and FLT3-ITD mutations had a high
probability of developing hyperleukocytosis in childhood AML patients.
These features were unanimous in WBC count above
100×109/L AML patients in the previous
study.8 The conformational changes in the
juxtamembrane
domain of the FLT3 receptor caused by ITD mutations activateFLT3-ITDreceptor tyrosine kinases, which causes proliferation, inhibits
apoptosis and suppresses differentiation.26,27 This
may be the cause of leukocytosis in FLT3-ITD patients. In
addition, FLT3-ITD mutation was an independent risk factor for
poor outcome in pediatric acute myeloid leukemia.28Therefore, It was expected to improve the long-term survival of these
patients by promising FLT inhibitors, Midostaurin and Sorafenib,
combined with sequential chemotherapy or as maintenance after
HSCT.29
In conclusion, more than 20% of AML patients have a WBC count greater
than 50×109/L, which is defined as hyperleukocytosis
in our
study.
Poor prognosis in terms of 10-year PFS and OS rates indicated
that
hyperleukocytosis was a critical predictive adverse factor in pediatric
AML.
In
all patients with hyperleukocytosis, male and FAB M5 subtype patients
had a significantly
inferior
survival, and the prognosis of CBF-AML with hyperleukocytosis
was
good. To exploit more accurate treatment strategies, a more extensive
range of WBC counts is needed to define hyperleukocytosis for stratify
risk in children with AML.