Methods
Study design
This study targeted patients who underwent induction chemotherapy for
ALL at the Department of Hematology/Oncology for Children and
Adolescents, Sapporo Hokuyu Hospital, between April 2007 and December
2019. Children and AYAs were defined as < 15 years of age and
≥ 15 years of age, respectively. Analyses were conducted based on all
data obtained up to February 31, 2020.
A total of 115 patients were treated at our institution according to the
Japanese protocols for ALL, which are based on the
Berlin-Frankfurt-Münster (BFM) regimen [19]. Two protocols were
adopted to treat the patient with precursor B-cell ALL (BCP-ALL), and
all of the enrolled patients underwent 7 days of prephase with steroid
and one intrathecal dose of methotrexate, followed by the induction
therapy. The patients then received 4 chemotherapeutic agents consisting
of vincristine, daunorubicin, L-asparaginase, prednisolone, and
intrathecal chemotherapy during the induction. In the protocols used
until December 2012, the patients stratified into the intermediate-risk
(IR) or high-risk (HR) groups were given an additional dose of
cyclophosphamide (1,200 mg/m2/dose). Similarly, those
who were classified into IR or HR after 2013 received two additional
doses of daunorubicin (25 mg/m2/dose). The treatment
regimens for IR and HR were the same in each protocol. As for the
risk-stratifying method during the induction therapy, the two protocols
in this analysis applied the same approach conventionally used in the
BFM-typed regimen, in which patients with ALL were stratified according
to National Cancer Institute criteria [20], cytogenetic
abnormalities, response to the prephase and blast counts of bone marrow
at day 15. In addition, patients with T-cell ALL and mixed-phenotype ALL
were treated with the same regimen as the IR/HR protocol for BCP-ALL
during the induction therapy. Details of the protocols are shown in
Table I.
Of the enrolled patients, 5 infant patients with ALL, one patient with
mature B-cell ALL, and one patient with Philadelphia chromosome-positive
ALL who received different types of chemotherapy were excluded from this
study. Furthermore, one patient with trisomy 21, one patient who started
tyrosine kinase inhibitor (TKI) during induction therapy, 3 patients who
had already been administered prednisolone at the time of
hospitalization, and 4 patients who had not completed all scheduled
anti-cancer agents for the induction were excluded. Additionally, two
patients who died during induction chemotherapy and two patients who did
not achieve complete remission before starting an early intensification
therapy were also excluded. Therefore, a total of 95 patients were
defined as eligible for the present analyses. Of these, 81 were children
and 14 were AYAs. The median age of the children at diagnosis was 5.7
years old (1.3−14.7 years old), and that of the AYAs was 16.9 years old
(15.1−24.0 years old). Further details regarding the characteristics of
the patients are shown in Table II. No significant differences were
found in the patients’ gender, immunophenotypes, or cytogenetic
abnormalities except for WBC counts at diagnosis and M3 marrow at day
15.
The neutropenic episodes (neutrophil counts < 0.5 ×
109/L) of the analyzed patients were retrospectively
investigated, and the D-index was calculated from the duration and depth
of the neutropenia. Then, the D-index and the duration of neutropenia in
the induction course were then statistically compared between children
and AYAs.
Finally, the incidence rates of FN, bacteremia, and IFI were surveyed in
the eligible patients and were compared between children and AYAs. The
incidence rate was defined as the number of newly identified infectious
complications per whole number of accomplished induction chemotherapies.
Blood cultures were always conducted whenever patients experienced FN at
the institution, and any positive result from the cultures was
considered to be bacteremia. IFI was defined according to the
standardized definitions of the European Organization for Research and
Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the
National Institute of Allergy and Infectious Disease Mycosis Study
Groupconsensus group [21]. Antibacterial agents were not
administered until the patients exhibited fever or some sign of
infection, and granulocyte colony-stimulating factor was not used in all
analyzed patients. In terms of the method to prevent infections,
trimethoprim-sulfamethoxazole for Pneumocystis jiroveciipneumonia, and oral fluconazole at 10 mg/kg/day was used for all
enrolled patients.
The present study was approved by the Institutional Review Board of
Sapporo Hokuyu Hospital.
Definition and calculation of the D-index
The D-index is derived by plotting the absolute neutrophil count during
neutropenia (< 0.5 × 109/L) and calculating
the area over the curve, which is the difference of the expected
neutrophil area (Ae) minus the area under the curve or
A0. Ae is calculated as the product of
500 and the number of days during which neutrophil counts are at or
below the level of neutropenia. For instance, if a patient experienced 6
days of neutropenia, Ae is 3,000 (6×500) days ・
neutrophils/μL. A0 is calculated using the trapezium
rule, as follows:
\begin{equation}
A_{0}=\sum_{\mathbf{i}=2}^{n}\begin{matrix}{(t}_{i}-t_{i-1})\frac{\begin{matrix}N_{i-1}+N_{i}\\
\end{matrix}}{2}\\
\end{matrix}\nonumber \\
\end{equation}Here, (ti–ti-1) is the time interval
(days) between two consecutive neutrophil counts, and Niand Ni-1 are the respective neutrophil counts (per
microliter) at times ti and ti-1. All
available neutrophil counts are included in the calculation of the
D-index, where the total number of neutrophil counts is n[17].
Statistical analyses
Fisher’s exact test was used to compare categorical variables of the
patients’ baseline characteristics, and the incidence of infectious
complications.
The
Mann-Whitney U test was used to compare continuous variables of the
D-index and the period of neutropenia. A p- value of 0.05 or less
was considered statistically significant. All statistical analyses were
performed with EZR, which is a graphical user interface for R (The R
Foundation for Statistical Computing). More precisely, it is a modified
version of the T commander designed to add statistical functions
frequently used in biostatistics [22].