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.