Discussion
We conducted this retrospective study to elucidate the cause of the
higher incidence of infection-related TRM in AYAs during chemotherapy
for ALL compared with children. It has been presumed that the intensity
of myelosuppression is more severe in AYAs, resulting in a considerable
rate of infectious complications. Generally, myelosuppressive toxicity
is largely influenced by the types and doses of drugs used in the
regimen, underlying diseases, and patient condition. Therefore, this
study was limited to examining myelosuppression during induction
chemotherapy for patients newly diagnosed with ALL. Usually, AYAs with
ALL tend to have more enhanced therapies compared to children, as they
are classified into a relatively high-risk group due to their age. In
fact, all of the AYAs in this study received an additional dose of
cyclophosphamide or two doses of daunorubicin, while more than half of
the children did not receive these treatments. This difference was at
first thought to contribute to increasing the susceptibility of AYAs to
the myelosuppressive side effects to a greater extent than what is seen
in children. However, contrary to our expectations, the D-index, which
represents the state of neutropenia during chemotherapy for ALL, was
significantly lower in AYAs than in children. This indicates that AYAs
with ALL showed less profound neutropenia than children during the
induction therapy for ALL. A study conducted at St. Jude Children’s
Research Hospital showed that young age (1-9.9 years old), compared to
age ≥ 10 years old, was associated with a significantly longer duration
of neutropenia in all phases of chemotherapy for ALL [23]. Our
present results support this argument. In this respect, it should be
noted that our study has an advantage in assessing the neutropenic state
using the D-index, since the duration of neutropenia does not reflect
how neutrophil counts change during chemotherapy. Although some studies
have assessed the myelosuppressive state using neutropenic duration or
presence of anemia or thrombocytopenia, this is the first attempt to
estimate the intensity of myelosuppression using the D-index. Given that
the D-index allows an accurate evaluation of the neutropenic state, it
is highly possible that children with ALL suffer from more profound
chemotherapy-induced myelosuppression than AYAs.
One of the possible factors why AYAs experience less myelosuppressive
toxicity could be due to the maximum dose of vincristine utilized. The
enrolled patients were administered 1.5 mg/m2/dose of
vincristine, and its maximum dose was 2.0 mg. Thus, patients with body
surface area > 1.33m2, values typically
observed in AYAs, will receive a lower dose of vincristine in the
protocols. However, the myelotoxicity of vincristine is relatively weak
[24]. Therefore, the smaller vincristine dose in AYAs seems to have
a low impact on the present results. The mechanism causing differences
in the myelosuppressive state between patients is considered to be
multifactorial. In terms of body structure, children and AYAs are not
the same, and individual organs mature rapidly during puberty, possibly
affecting the distribution and metabolism of chemotherapeutic agents
[25].
The results of the present study suggested that factors other than
myelosuppression contribute to the higher incidence of infectious TRM in
AYA. We previously investigated the reduced efficacy of antibiotic
therapy for AYA neutropenic patients due to the relatively lower dose of
antibiotics per body weight [26]. Moreover, non-infectious
complications, which may subsequently lead to infection-related
mortality or morbidity, have been observed more often in AYAs than in
children [27-30]. In fact, sarcopenia during chemotherapy in
children with a hematologic malignancy was reported as a possible risk
factor for IFI [31]. Continued studies of these issues could
indicate potential approaches to reduce the infectious TRM in AYAs with
cancer.
This study has several limitations. First, the sample size of AYAs was
relatively small compared that of children. However, equal variance of
the two groups was confirmed, and the result was statistically
significant. Therefore, it is conceivable that the results would be
consistent with the present observations if the number of cases was
increased. Second, regarding the infectious complications such as
bacteremia and IFI during induction, their incidences were both
apparently higher in AYAs than in children, though no significant
differences were observed. This lack of statistical difference could be
due to the low absolute number of infectious complications in this
study. Moreover, there have been several reports that older age and
treatment intensity were risk factors for severe infectious adverse
events during the treatment for ALL [32-35].
In conclusion, myelosuppressive toxicity during induction chemotherapy
for ALL appeared to be more severe in children than in AYAs, despite the
relatively intensified treatment for AYAs. This suggests that factors
other than myelosuppressive toxicity contribute to the vulnerability of
AYAs with ALL to infectious mortality and morbidity. A similar study
with other chemotherapeutic regimens should be pursued.