Discussion
One or two non-treatment days are occasionally added to initial HCT conditioning regimens due to various social circumstances, such as unexpected natural adversities, abrupt deterioration of patient health, and delays in graft source arrival. Consequently, concerns pertaining to the impact of interrupted conditioning on clinical outcomes after HCT have arisen as a consequential issue.
Remarkably, in our cohorts, it was shown that the clinical outcome after HCT was not affected by conditioning interruption. The 5-year OS and EFS were the same between the groups with or without interruption of conditioning. Moreover, the cumulative incidences of relapse and NRM were not significantly different between the groups. We also found that engraftment was not affected by a few-day interruption of conditioning. In contrast, marginal differences were observed in GVHD incidence between the groups. In this study, grade II–IV aGVHD was observed less often in the interrupted conditioning group, with marginal significance. However, a significantly higher incidence of cGVHD was observed in the interrupted conditioning group, as demonstrated by the multivariate model.
Generally, it is presumed that adding one- or two-day intervals into the conditioning regimen leads to the attenuation of conditioning intensity. It is also assumed that the non-treatment days could allow malignant cells to recover from the toxicity caused by chemotherapeutic agents or TBI. However, it is noted that the capacity for toxicity recovery is likely to be decreased more in tumor cells than in normal cells and is expected to be heterogeneous in each type of cancer cell [17-20]. Moreover, it is not known if the repair capacity of tumor cells recovers in a short period of a few days [21-24]. Thus, it is challenging to determine whether the interrupted conditioning decreases anti-tumor effects. Herein, potential negative impacts of conditioning interruption on clinical outcomes, other than the incidence of cGVHD, were assessed.
It is conceivable that normal tissue would benefit from conditioning interruption because of the possibility of recovering from tissue damage and inflammation before HCT [17,25]. However, there were no differences in a transplantation-associated complications between the two groups in the present study.
Regarding aGVHD, differences in tissue damage severity and donor chimerism formation due to interrupted conditioning could be a plausible explanation for the observed lower incidence of aGVHD in the interrupted group [26-30]. It has been reported that patients with mixed chimerism experienced aGVHD less often than patients who attained donor chimerism early after HCT [31-32]. Furthermore, it has been noted that cGVHD development was delayed and of less severity when the state of mixed chimerism was prolonged [33]. Moreover, a study identified reduced-intensity conditioning as a risk factor for cGVHD [34]. In relation to this, it has been reported that a mixed chimerism state was related to high levels of pathogenic IgG autoantibody and the development of cGVHD-like lesions in a murine model. This result was explained by the persistence of host B cells after HCT [35]. Thus, changes in timing or state of donor chimerism caused by interruption of conditioning might affect the present results regarding aGVHD and cGVHD incidences between the scheduled and interrupted conditioning groups.
This study is limited by its retrospective nature and small sample size, especially the small number of patients in the interrupted conditioning group. This limitation did not permit sub-analysis stratified by graft source or donor source. Additionally, the present results would not apply to other conditioning regimens because the narrow study population only contained pediatric patients who received MAC with TBI.
In conclusion, one- or two-day interruptions of HCT conditioning appeared to have no effect on OS and EFS. However, interrupted conditioning could affect the incidence of GVHD and be a risk factor for cGVHD. The relationship between a few-day interval during conditioning and GVHD development and its mechanism requires further elucidation in future studies.