Hematology

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Hyperleukocytosis predicts inferior clinical

outcome in pediatric acute myeloid leukemia

Lu-Hong Xu , Jing-Wen Wang , Yin Wang & Feng-Ying Yang

To cite this article: Lu-Hong Xu , Jing-Wen Wang , Yin Wang & Feng-Ying Yang (2020)
Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid leukemia,
Hematology, 25:1, 507-514, DOI: 10.1080/16078454.2020.1859169

To link to this article: https://doi.org/10.1080/16078454.2020.1859169

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HEMATOLOGY
2020, VOL. 25, NO. 1, 507–514
https://doi.org/10.1080/16078454.2020.1859169

Hyperleukocytosis predicts inferior clinical outcome in pediatric acute myeloid

leukemia
Lu-Hong Xu , Jing-Wen Wang, Yin Wang and Feng-Ying Yang
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Pediatrics, Sun Yat-Sen
Memorial Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China

ABSTRACT KEYWORDS
Objectives: Hyperleukocytosis (HL) is a laboratory abnormality commonly presented in Acute myeloid leukemia;
patients with acute myeloid leukemia (AML). However, large cohort studies on the clinical hyperleukocytosis; pediatric
significance of HL in pediatric AML are paucity. Moreover, the effect of stem cell patients; clinical outcome
transplantation in HL patients remains unknown.
Methods: The clinical profiles of 885 pediatric patients with AML were downloaded from the
TARGET dataset. HL was defined as an initial peripheral WBC count of ≥ 100 ×109/L. We
analyzed the prevalence, clinical profile and prognosis of HL in these patients.
Results: The frequency of HL among all the pediatric AML was 22.6%. FMS-like tyrosine kinase
3/internal tandem duplication (FLT3/ITD) mutation and gene fusion of NUP98/NSD1 occurred
with higher incidence in HL patients. Overall, HL was associated with a low induction complete
remission rate, and high risk of induction death. Moreover, HL predicted a significantly inferior
5-year event-free survival (EFS) (P < 0.001) and a trend of inferior 5-year overall survival (OS) (P
= 0.059). However, compared with chemotherapy, stem cell transplantation had no significant
effect on the survival of HL patients in terms of 5-year leukemia-free survival (P = 0.449) or OS
(P = 0.447). Multivariate analysis revealed that HL was an independent prognosis factor for EFS
(Hazard ratio:1.352, P = 0.013) but not for OS (Hazard ratio:1.225, P = 0.170) in pediatric AML.
Conclusion: HL might predict inferior clinical outcome in pediatric AML. SCT is an effective
therapy for AML, but it may have no better effect on the survival of patients with HL,
compared to chemotherapy.

1. Introduction in the 1980s. Recently, routine clinical care have been

incorporated with more advanced supportive care,
Acute myeloid leukemia (AML) is a heterogeneous
such as prompt transfusion of platelets, leukapheresis,
disease that accounts for about 20% of all leukemias
hydroxyurea, urate oxidase and hemodialysis [12, 13].
in children [1, 2]. Hyperleukocytosis (HL) is a laboratory
Thus, it is necessary to investigate the clinical signifi-
abnormality, commonly defined by a white blood cell
cance of HL in pediatric AML. Furthermore, the role
count of ≥100 ×109/L. HL is presented in 5% to 20%
of stem cell transplantation (SCT) in pediatric AML
of patients with AML [3]. Two main pathogenetic
patients with HL remains unclear. In this study, we
factors were reported to be responsible for the devel-
evaluated the prevalence, clinical profile, and progno-
opment of HL: first, a rapid blast proliferation leading
sis of HL in a cohort of 885 pediatric patients with AML.
to a high leukemic tumor burden; second, disruption
Our results show that HL predicts inferior clinical
in normal hematopoietic cell adhesion leading to a
outcome in pediatric AML. However, SCT does not sig-
reduced affinity to the bone marrow [3, 4]. Thus, HL
nificantly benefit HL patients.
may result in 3 main complications: leukostasis,
tumor lysis syndrome and disseminated intravascular
coagulation. Pulmonary and central nervous system 2. Methods
injuries are the major issues associated with HL
2.1. Data Sources
patients [5, 6]. Many adult studies showed that HL pre-
dicted poor prognosis [7–10]. However, studies on the Data on patients with complete clinical data from the
clinical significance of HL in pediatric AML in a large therapeutically applicable research to generate
cohort are paucity. effective treatment (TARGET) dataset were downloaded
Bunin et al. [11] found that pediatric AML with HL (https://ocg.cancer.gov/programs/target/data-matrix).
was associated with higher frequency of early death In total, 885 pediatric patients younger than 18 years

CONTACT Lu-Hong Xu xulvhong@126.com

Supplemental data for this article can be accessed https://doi.org/10.1080/16078454.2020.1859169.
© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrest-
ricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
508 L.-H. XU ET AL.
old with AML were included in our study. Year of diag-
nosis ranged from 1996 to 2010. Year of last follow up
ranged from 1997 to 2015. The diagnosis of AML as
well as risk group stratification were done according
to the Children’s Oncology Group (COG) guidelines
[14]. Subtype classifications of AML were assigned
according to the French–American–British (FAB)
classifications. Treatment protocols for AML included
AAML03P1, AAML0531 and CCG-2961. All these treat-
ment protocols consisted of a remission induction
phase followed by an intensification phase. Stem cell
transplantation (SCT) was considered for patients in
the first complete remission. HL was defined as an
initial peripheral WBC count of 100 ×109/L or over.
2.2. Statistical analysis
The clinical and biological characteristics of patients
were summarized by descriptive statistics. To
compare categorical variables, we used χ2 analysis
and Fisher’s exact test in case of small numbers. The
nonparametric Mann–Whitney U-test was applied for
continuous variables. To assess outcome, the following
parameters were used: complete remission (CR, defined
as a normocellular BM containing fewer than 5% blasts)
rate, event-free survival (EFS, defined as time between
diagnosis and first event, including induction failure,
relapse or death of any cause), overall survival (OS,
defined as time between diagnosis and death from
any cause), leukemia-free survival (LFS, defined as survi-
val without leukemia relapse or progression). EFS, OS
and LFS were estimated by the Kaplan–Meier method,
and compared using the log-rank test. Prognostic
factors were examined by multivariate Cox regression
analysis. Hazard ratios (HR) were presented with 95%
confidence intervals. A two-sided P-value < 0.05 was
considered statistically significant for all statistical ana-
lyses. The data were analyzed with the Statistical
Package for the Social Sciences (SPSS®) version, 24.0
(IBM Corporation, Armonk, NY, U.S.A.).
3. Results
3.1. Patient characteristics
Overall, among 885 pediatric AML patients, 200
(22.6%) had HL at diagnosis. As shown in Table 1, no
correlation was found in median age between HL
group and non-HL group. However, the age under
one year was associated with an increased risk of HL.
The median of WBC count was 182.1×109/L in HL
group and 19.6 ×109/L in non-HL group. Moreover,
patients with HL had higher percentage of blasts in
peripheral blood (P < 0.001) and in bone marrow (P <
0.001) compared with those in patients without HL.
The FAB subtypes in HL group were mainly M1, M4
and M5. The percentage of high risk in HL group was
higher than that in non-HL group (22.0% vs 12.0%, P
= 0.001). Notably, the FMS-like tyrosine kinase 3/
internal tandem duplication (FLT3/ITD) mutation was
substantially higher in HL group (26.5%) compared
with non-HL group (13.9%) (P < 0.001). However, no
significant difference was found in the median of
FLT3/ITD allelic ratio and nucleophosmin (NPM1)
mutations between HL group and non-HL group. In
addition, SCT and the treatment protocols for pediatric
AML were equally distributed between the two groups.
Though there was no significant association
between HL and cytogenetic status, we found distinc-
tively different distribution of abnormal cytogenetics
in the two groups. As shown in Table S1, HL occurred
more frequently in patients with inv(16) (P < 0.001) and
MLL (P = 0.046), but less frequently in patients with t
(8;21) (P = 0.001) and del 9q (P = 0.001). We further ana-
lyzed gene fusion data available in 429 cases. As shown
in Table S2, HL patients had significantly higher inci-
dences of CBFB-MYH11 (P = 0.005) and NUP98-NSD1
(P < 0.001), but lower incidence of RUNX1-RUNX1T1
(P < 0.001) than those without HL.
3.2. Clinical outcomes
We examined the CR rate in the pediatric patients with
AML. At the end of the first course of therapy, 142
(71.4%) of the 199 patients with HL achieved a CR com-
pared with 528 (78.1%) of 794 patients without HL (P =
0.048). Moreover, the death rate at the end of first
course of therapy was significantly correlated with HL
(4.0% vs 1.2%, P = 0.015). At the end of the second
course of therapy, low CR rate (P < 0.001) and high
death rate (P = 0.032) were found in HL group.
Next, we analyzed survival data in all the 885 pedi-
atric patients. The median follow-up time for the survi-
vors was 5.62 years (5.90 years for HL patients and 5.58
years for non-HL patients, respectively, P = 0.873). As
shown in Figure 1(A), HL patients had a markedly
worse 5-year EFS (37.4 ± 3.5%) compared with non-
HL patients (49.7 ± 1.9%; P < 0.001). HL patients also
had a trend of worse 5-year OS (57.4 ± 3.6%) compared
with non-HL patients (64.3 ± 1.9%) (P = 0.059) (Figure
1B). In the subgroup of normal cytogenetics, HL
patients showed a significantly lower 5-year EFS
(36.6 ± 7.5% vs 50.5 ± 4.1%, P = 0.010) and a trend
towards reduced 5-year OS (54.2 ± 8.0% vs 64.6 ±
3.9%, P = 0.076) (Figure 1C, D). In the subgroup of
abnormal cytogenetics, HL was associated with poor
clinical outcome in term of EFS (P = 0.007), but not
OS (P = 0.403) (Figure 1E, F).
3.3. Stratification analysis of FLT3/ITD and
NUP98-NSD1
We further investigated the prognostic impact of FLT3/
ITD and NUP98-NSD1 in AML patients by stratification
 HEMATOLOGY 509

Table 1. Characteristics of study population according to HL status.

All patients Hyperleukocytosis (WBC ≥ 100 ×109/L) No hyperleukocytosis (WBC < 100 ×109/L) P-value
Number (%) 885 200 (22.6%) 685 (77.4%)
Age, median (year) 9.6 8.9 9.7 0.481
Age<1 year, n (%) 81 (9.2%) 34 (17%) 47 (6.9%) <0.001
1≤Age<10 years, n (%) 375 (42.4%) 72 (36%) 303 (44.2%) 0.038
10≤Age<18 years, n (%) 429 (48.5%) 94 (47%) 335 (48.9%) 0.635
Gender (% female) 47.80% 47.50% 47.90% 0.924
WBC, ×109/L, Median (range) 31.7 (0.2-610) 182.1 (100.7-610) 19.6 (0.2-99.3) <0.001
% PB blast, Median (range) 47 (0-99) 80 (0-99) 36 (0-99) <0.001
% BM blast, Median (range) 70 (0-100) 82 (0-100) 64.7 (0.4-100) <0.001
FAB classification: N (%) 0.869
M0 21 (2.9%) 6 (3.6%) 15 (2.7%) 0.596
M1 98 (13.4%) 31 (18.7%) 67 (11.9%) 0.025
M2 196 (26.9%) 20 (12.0%) 176 (31.3%) <0.001
M3 2 (0.3%) 0 (0%) 2 (0.4%) >0.999
M4 200 (27.4%) 61 (36.7%) 139 (24.7%) 0.002
M5 160 (21.9%) 46 (27.7%) 114 (20.2%) 0.041
M6 12 (1.6%) 0 (0%) 12 (2.1%) 0.078
M7 40 (5.5%) 2 (1.2%) 38 (6.7%) 0.006
Risk group: N (%) 0.017
Low risk 333 (38.9%) 67 (35.1%) 266 (40.1%) 0.213
Intermediate risk 400 (46.8%) 82 (42.9%) 318 (47.9%) 0.226
High risk 122 (14.3%) 42 (22.0%) 80 (12.0%) 0.001
FLT3/ITD <0.001
Positive, n (%) 148 (16.8%) 53 (26.5%) 95 (13.9%)
Negative, n (%) 734 (83.2%) 147 (73.5%) 587 (86.1%)
FLT3/ITD allelic ratio,
Median (range) 0.55 (0.03-9.50) 0.63 (0.05-9.50) 0.53 (0.03-5.19) 0.732
NPM1 mutation 0.226
Positive, n (%) 66 (7.6%) 11 (5.6%) 55 (8.2%)
Negative, n (%) 803 (92.4%) 186 (94.4%) 617 (91.8%)
Cytogenetic status 0.575
Normal (n, %) 198 (23.5%) 41 (21.9%) 157 (23.9%)
Abnormal (n, %) 646 (76.5%) 146 (78.1%) 500 (76.1%)
SCT in 1st CR 0.204
No (n, %) 676 (83.9%) 138 (80.7%) 538 (84.7%)
Yes (n, %) 130 (16.1%) 33 (19.3%) 97 (15.3%)
Protocol 0.202
AAML03P1 (n, %) 93 (10.5%) 26 (13%) 67 (9.8%) 0.192
AAML0531 (n, %) 737 (83.3%) 163 (81.5%) 574 (83.8%) 0.444
CCG-2961 (n, %) 55 (6.2%) 11 (5.5%) 44 (6.4%) 0.634
CR status at end of course 1 0.033
CR 670 (76.6%) 142 (71.4%) 528 (78.1%) 0.048
Not CR 189 (21.6%) 49 (24.6%) 140 (20.7%) 0.238
Death 16 (1.8%) 8 (4.0%) 8 (1.2%) 0.015
CR status at end of course 2 <0.001
CR 749 (87.2%) 148 (77.1%) 601 (90.1%) <0.001
Not CR 89 (10.4%) 35 (18.2%) 54 (8.1%) <0.001
Death 21 (2.4%) 9 (4.7%) 12 (1.8%) 0.032
Abbreviations: BM, bone marrow; CR, complete remission; FAB, French-American-British morphology classification; FLT3/ITD, FMS-like tyrosine kinase 3/
internal tandem duplication; NPM1, nucleophosmin; PB, peripheral blood; SCT, stem cell transplantation; WBC: white blood cell.

analysis. As shown in Figure S1, FLT3/ITD conferred
poor clinical outcomes in AML patients with decreased
5-year EFS (P < 0.001) and OS (P = 0.004). As shown by
the survival curves of pediatric AML patients grouped
based on HL and FLT3/ITD status (Figure 2), HL in
FLT3/ITD negative patients was associated with poor
prognosis in 5-year EFS (40.7 ± 4.1% HL vs 51.7 ±
2.1% non-HL; P = 0.009). However, HL showed no
impact on 5-year OS (61.7 ± 4.1% HL vs 65.7 ± 2.0%
non-HL; P = 0.308) in FLT3/ITD negative patients. Simi-
larly, HL in FLT3/ITD positive patients also had negative
impact on 5-year EFS (P = 0.036) but not on 5-year OS
(P = 0.218).
As shown in Figure S2, NUP98-NSD1 gene fusion
conferred poor clinical outcomes in AML patients in
term of 5-year EFS (P < 0.001) and OS (P = 0.029). The
survival curves of pediatric AML patients according to
the combined HL and NUP98-NSD1 status are shown
in Figure 3. When restricted to no NUP98-NSD1
group, HL was correlated with worse 5-year EFS (40.6
± 4.6% HL vs 51.8 ± 2.6% non-HL, P = 0.018) but not
5-year OS (60.3 ± 4.7% HL vs 68.2 ± 2.4% non-HL, P =
0.142). However, when restricted to NUP98-NSD1
group, HL showed both significantly worse 5-year
EFS (11.8 ± 7.8% HL vs 40.3 ± 12.1% non-HL, P =
0.004) and OS (22.1 ± 10.9% HL vs 75.5 ± 10.7% non-
HL, P = 0.002).
3.4. The association between HL and SCT
To evaluate the association of HL and outcome of SCT,
patients with induction failure or death without remis-
sion were excluded from our analysis. As shown in
Figure 4(A, B), when restricted to SCT, HL had no sig-
nificant impact on SCT outcome in term of 5-year LFS
(51.5 ± 8.7% HL vs. 63.0 ± 5.0% non-HL, P = 0.255) or
510 L.-H. XU ET AL.

Figure 1. Survival curves of pediatric AML patients according to hyperleukocytosis (HL) status. (A) Probability of EFS for all
patients. (B) Probability of OS for all patients. (C) Probability of EFS for patients with normal cytogenetics. (D) Probability of
OS for patients with normal cytogenetics. (E) Probability of EFS for patients with abnormal cytogenetics. (F) Probability of OS
for patients with abnormal cytogenetics.

OS (59.4 ± 8.7% HL vs. 66.9 ± 4.9% non-HL, P = 0.582). to HL patients, compared with chemotherapy (no
In addition, we evaluated the impact of SCT on HL SCT), SCT had no significant impact on the clinical
patients. As shown in Figure 4(C, D), when restricted outcome in term of 5-year LFS (51.5 ± 8.7% SCT vs.
 HEMATOLOGY 511

Figure 2. Survival curves of pediatric AML patients according to the combined hyperleukocytosis (HL) and FLT3/ITD status. (A)
Probability of EFS for AML patients. (B) Probability of OS for AML patients.

46.1 ± 4.5% non-SCT, P = 0.449) or OS (59.4 ± 8.7% SCT 4. Discussion

vs. 68.5 ± 4.3% non-SCT, P = 0.447).
3.5. Multivariate analysis
In the Cox model (Table 2), we analyzed HL status with
other co-variables including age (utilizing 1 year as the
cutoff value), high risk, standard risk and SCT. High risk
and standard risk were significantly associated with
worse clinical outcomes. In contrast, SCT was significantly
associated with better clinical outcomes. Age affect
neither EFS nor OS. Importantly, we identified that HL
was an independent factor for EFS but not OS in pediatric
patients with AML. HL was a highly significant predictor
for inferior EFS (HR:1.352, 95% CI:1.066-1.715, P = 0.013),
but not for OS (HR:1.225, 95% CI: 0.917-1.636, P = 0.170).
The frequency of HL among the 885 pediatric AML
patients was 22.6%. Our study showed that pediatric
AML with HL was associated to the age ( < 1 year),
FAB subtypes of M1, M4 and M5, FLT3/ITD, inv (16),
MLL, gene fusion of CBFB-MYH11 and NUP98-NSD1.
However, no association was found between HL and
NPM1 mutations. These results are consistent with an
earlier pediatric study [15]. In another large cohort of
adult study, the frequency of HL among 3510 newly
diagnosed AML patients was only 10%. Moreover,
adult AML with HL was associated with higher frequen-
cies of monocytic subtype of AML, FLT3/ITD and NPM1
mutations [3]. It has been reported that monocytic leu-
kemic cells have a larger volume and markedly
increased lysozyme activities. There was a greater

Figure 3. Survival curves of pediatric AML patients according to the combined hyperleukocytosis (HL) and NUP98-NSD1 status. (A)
Probability of EFS for AML patients. (B) Probability of OS for AML patients.
512 L.-H. XU ET AL.

Figure 4. Survival curves of pediatric AML patients according to the combined hyperleukocytosis (HL) and stem cell transplan-
tation (SCT) status. (A) Probability of LFS for patients with SCT according to HL status. (B) Probability of OS for patients with
SCT according to HL status. (C) Probability of LFS for HL patients according to SCT status. (D) Probability of OS for HL patients
according to SCT status.

degree of cytoreduction in M4 and M5 than in other Studies have reported various significance of HL in
subtypes of AML after chemotherapy began, and treatment response and clinical outcome. In 1987,
massive tumor lysis caused coagulopathy and meta- Dutcher et al. [10] found that HL predicted high risk
bolic disturbance with electrolyte abnormalities [16]. of early death, low CR rate and survival rate. In the
database of the Alliance Leukemia study group, early
death in HL group was higher after 1 week and 30
Table 2. Multivariate analysis for EFS and OS in pediatric
days of chemotherapy compared with non-HL group,
patients with AML.
Outcome Variable Hazard ratio (95% CI) P-value
the 5-year OS and relapse-free survival rates were
EFS HL 1.352 (1.066-1.715) 0.013
lower in HL group [3]. However, other adult studies
Age > 1 year 0.959 (0.677-1.359) 0.815 showed that HL did not impact the clinical outcomes
High risk 3.247 (2.326-4.534) <0.001 in term of OS and disease-free survival rates [17, 18].
Standard risk 2.270 (1.789-2.879) <0.001
SCT 0.440 (0.321-0.604) <0.001 Furthermore, the clinical significance of HL on clinical
OS HL 1.225 (0.917-1.636) 0.17 outcome in pediatric patients with AML was shown
Age > 1 year 1.187 (0.776-1.816) 0.429
High risk 4.164 (2.795-6.204) <0.001 by Inaba et al. that pediatric patients with or without
Standard risk 2.971 (2.189-4.031) <0.001 HL had similar CR rates and OS rate, but those with
SCT 0.600 (0.424-0.849) 0.004
HL had a lower EFS rate [19].
Abbreviations: CI, confidence interval; EFS, event-free survival; FLT3/ITD,
FMS-like tyrosine kinase 3/internal tandem duplication; HL, hyperleuko- Our study showed that HL in pediatric patients was
cytosis; OS, overall survival; SCT, stem cell transplantation. associated with high risk of induction death,

significantly inferior 5-year EFS and a trend of inferior
OS. Moreover, the inferior impact on EFS caused by
HL was found irrelevant of cytogenetics status. FLT3/
ITD mutation and gene fusion of NUP98/NSD1 were
characterized as adverse prognostic factors in AML
[20, 21]. We found that HL was related to higher fre-
quencies of FLT3/ITD mutation and NUP98/NSD1.
After stratifications studies, we found that HL had sig-
nificantly adverse impacts on 5-year EFS in spite of the
status of FLT3/ITD and NUP98/NSD1. Multivariate
analysis confirmed that HL was an independent prog-
nosis factor for EFS in pediatric AML. Compared with
the previous reports in 1980s [10, 11, 22], the rates of
induction death and OS in HL patients were improved.
The difference may be due to improvements in thera-
peutic protocols and dedicated intensive supportive
care.
Recently, the management of HL involves suppor-
tive care and reducing the number of circulating leuke-
mic blast cells by induction chemotherapy,
hydroxyurea, low-dose chemotherapy and leukapher-
esis. However, it is worth noted that neither hydro-
xyurea nor leukapheresis showed benefit in clinical
outcomes in patients with symptomatic HL [23, 24].
The impact of HL on SCT remains controversial in
patients with AML. In the registry of the acute leukemia
working party of the European Society for Blood and
Marrow Transplantation (EBMT), HL in 1275 adult trans-
planted AML patients was independently associated
with increased relapse rate, decreased LFS, and inferior
OS after SCT. HL retained a significant prognostic role
for adult AML undergoing SCT [25]. However, Tien
et al. found that HL patients had similar relapse rate,
OS and disease-free survival after SCT as non-HL
patients [26]. Our results showed that HL had no sig-
nificant impact on LFS and OS after SCT in pediatric
AML. On the other hand, the effect of SCT in HL
patients remains unknown. Tien et al. [26]. found that
SCT ameliorated the poor survival impact of HL, and
suggested that SCT might be beneficial for HL patients
in first CR. In our study, we found SCT was significantly
associated with better clinical outcomes for AML by
multivariate analysis. However, compared with che-
motherapy, SCT had no better effect on the survival
of pediatric AML patients with HL in term of LFS or
OS. Thus, the role of SCT in AML patients with HL
requires further investigation.
Taken together, we analyzed the impact of HL in a
large cohort of pediatric patients with AML. Our
findings showed that pediatric AML with HL was
associated with the age (< 1 year), FAB M1, M4 and
M5, as well as FLT3/ITD mutation and gene fusion of
NUP98/NSD1. HL predicted a low induction CR rate
and a significantly inferior EFS rate. SCT is an
effective therapy for AML, but it may have no better
effect on the survival of patients with HL, compared
to chemotherapy.
HEMATOLOGY 513
Data Availability
The datasets generated and/or analyzed during the
current study are available from the TARGET website:
https://ocg.cancer.gov/programs/target/data-matrix
Acknowledgements
Thanks are due to TARGET researchers as well as all study
participants for public data. This work was supported by
the Natural Science Foundation of Guangdong Province,
China (2018A030313680 to L.H. Xu) and Guangdong Basic
and Applied Basic Research Foundation (2020A1515010312
to L.H. Xu).
Disclosure statement
No potential conflict of interest was reported by the author(s).
Funding
Thanks are due to TARGET researchers as well as all study
participants for public data. This work was supported by
the Natural Science Foundation of Guangdong Province,
China (2018A030313680 to L.H. Xu) and Guangdong Basic
and Applied Basic Research Foundation (2020A1515010312
to L.H. Xu).
ORCID
Lu-Hong Xu http://orcid.org/0000-0001-7898-7720
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