Discussion
The conditioning regimen used for our children with acute leukemia was
initially developed for adult transplant recipients. It included Bu
(targeted at an AUC of 3750μmol*min) and Flu (dosed at
250mg/m2 total), to which ATG was added to reduce the
incidence of GvHD.13,16 TBI at 400cGy was included in
the protocol to reduce the incidence of relapse and was noted to
significantly improve outcomes.17 Our protocol uses a
higher Flu dose compared with other centers using similar regimens.
Survival outcomes, relapse incidence and non-relapse mortality in our
cohort were similar between the subjects who had TDM and those who did
not. The number of subjects in our cohort played an important role in
the results not reaching significance levels. Previous studies that have
compared Bu based conditioning to TBI regimens in children with
malignancies have presented outcomes favouring TBI based
conditioning.8,18 This has mainly been due to higher
rates of relapse and non-relapse mortality rates in the Bu groups.
However, these earlier studies have not consistently reported
measurements of Bu serum levels.8,18,47
Recently, the results of the international FORUM study (For Omitting
Radiation Under Majority age), a multicenter randomised trial comparing
a fractionated TBI/Etoposide regimen to various chemotherapy-based
conditioning (CHC) regimens has shown conclusively that a TBI based
conditioning regimen is superior for children above four years of age
with ALL.19 In that study individual institutions were
allowed to choose between Bu and Treosulfan (Treo) as a backbone for
their CHC regimens. A potential drawback to this flexibility is the
introduction of heterogeneity.51 Therefore, despite an
overall equivalence between the Bu and Treo based regimens, data does
not allow a direct comparison across individual CHCs. Furthermore, Bu
serum level targeting was allowed but not mandated by the FORUM study
and no analysis is done to compare outcomes between the centers that
used serum targeting of Bu and those that did not.51Additionally, although cranial radiation was allowed for central nervous
system positive disease, none of the CHC regimens in the FORUM study
included TBI. For these reasons, a direct comparison of outcomes with
the regimen used in the current study is not appropriate.
In 2007, Chaudhury et al published an abstract reporting their findings
using a regimen incorporating both Bu and TBI.20Although the targets for Bu TDM were similar (4000 μmol *min/day), an
Important difference in their preparation regimen was their use of lower
cumulative doses of Flu (150 mg/m2 over five days).
They reported a one-year OS and PFS of 63% and 56% respectively. A
recent article by Rosoff et al further expanding analysis of the same
cohort, using Bu-Flu-ATG and 400cGy TBI regimen, reported a five-year OS
of 37% in their ALL cohort consisting of only nine children (one of
whom had positive MRD).21 In both studies by Chaudhury
and Rosoff the most important reason for failure was high rates of
relapse, seen in 29% and 28% of subjects
respectively.20,21 We speculate that the lower
cumulative incidence of relapse in our cohort may potentially be related
to the higher doses of Flu. Evidence for this has recently been
published in both transplant and Chimeric Antigen Receptor T-cell
(CAR-T) settings with studies showing that both lower and very high
serum Flu levels result in inferior outcomes driven by increased relapse
rates and toxicity respectively.52,53
Although the rates of aGvHD reported in this cohort are higher than
those in other studies, which quote incidences closer to
30%,18,21,23 they are similar to results reported by
Chaudhury et al who report their severe aGvHD rate as being
32%.20 A striking similarity between both studies is
the use of PBSC products, utilised in close to 90% of transplants in
the current study and in 75% of cases in the study by Chaudhury. PBSC
products have been shown to be associated with increased aGvHD in
multiple studies although the difference has not been consistently
significant.24,25,48 Six (20%) of the donor-recipient
pairs in our study were female donors to male recipients. Pulsipher et
al, have shown that the presence of aGvHD is related to a lower risk of
relapse,50 which perhaps contributed to the EFS in the
current study.
The cumulative incidence of cGvHD in our study was comparable with most
other studies. 18,20,29 It was lower than rates
reported by Rosoff et al and those in a report by Modi et al (which used
a similar conditioning regimen for adults with
AML).21,23 The reason for the low rates of cGvHD in
our study despite a higher incidence of aGvHD may be explained by our
method of giving ATG.30,31 At our institution we
follow a regimen similar to one recommended by Bacigalupo et
al.31 In their 2001 paper, they suggested all patients
receive ATG at 7.5mg/kg as this dose was not associated with increased
risk of infections and was shown to reduce the incidence of cGvHD.
The incidence and timing of viral infections seen in our cohort were
similar to those reported in literature32-34,36 with
the exception of CMV which appeared to occur earlier than some studies
have described (median of 24 days in our study compared with 33 to 41
days in some studies).34,54 There was no effect on
outcomes which is contrary to findings in other
publications,32,35 with the exception of delayed
platelet engraftment dates in those subjects receiving platelet
infusions for hematuria secondary to BK virus induced cystitis Bacterial
blood stream infection incidence, timing and the organisms grown were
also comparable to other reports.37-41 The incidence
of mucositis was 100% in this cohort which is in keeping with other
reports using a similar regimen.21
The incidence of SOS in studies using conditioning regimens including Bu
and Flu compared to other combinations have had mixed results with some
studies reporting a reduction in SOS42-44 and others
showing no difference.45 In our cohort the cumulative
incidence of SOS at d100 was 15% (three patients). Although this rate
appears higher compared with other studies, it may not be significant
owing to the small number of patients developing
SOS.20,46 In the adult study by Kabriaei et al, six
patients in their cohort of 107 patients developed SOS resulting in a
prevalence of 6%.46 Similarly, Chaudhury et al
reported a SOS prevalence of 10% (three cases).6 It
is notable that SOS was cited as a direct cause of death in only one
case in each of the two studies. The univariate analysis in our cohort
revealed no significant correlation of the occurrence of SOS with
mortality.
The limitations to our study include firstly, that this is a
retrospective chart review and therefore dependant on the quality of
data collected and stored. Data pertaining to SOS were missing for our
earlier subjects. Secondly, the number of patients, once split into the
two cohorts, was limited and this may have contributed to the lack of
significance when comparing the outcomes following Bu pharmacokinetic
targeting. Furthermore, the comparison with a historic cohort introduces
some inconsistencies as there is a possibility that improvements in
outcomes over the years were in fact due to an unidentified confounder
and not the practice of targeting Bu serum levels. It should be noted
however, that no significant changes to supportive care were introduced
during the period of data collection. Related to this, the combination
during analysis of those children who did not have any Bu monitoring
with the group that were monitored and were out of range may have
introduced a bias, as the earlier group is a heterogenous one and may
contain some children who were within acceptable serum levels. Finally,
we did not differentiate between T-cell and B-cell ALL which introduces
heterogeneity in the cohort analysed. Despite these limitations, the
paper documents outcomes following transplant in children with ALL using
a unique and previously unpublished regimen of Bu-ATG and lower dose TBI
regimen combined with a higher dose of Flu. Although previous studies
have utilized lower dose radiation in this setting, those cohorts have
been of limited size compared with the current report. We have
demonstrated similar outcomes to other conditioning regimens when serum
Bu levels are targeted suggesting this may be a substitute to consider
when lowering radiation dose is desirable.