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.