DISCUSSION
In this study, the 5-year EFS rates of all high-risk neuroblastoma
patients who underwent the double-conditioning regimen comprising
thiotepa and melphalan and of CR/VGPR/PR patients before HDC were 41.5%
and 50.0%, respectively. Considering the poor prognosis of patients who
did not undergo anti-GD2 antibody immunotherapy, the outcome of our
patients who showed CR/VGPR/PR before HDC was comparable to previous
studies.3,22 It is partly becauseMYCN -amplified high-risk neuroblastoma patients show a superior
survival rate.
Comprehensive studies have considered MYCN amplification as a
poor prognostic factor in high-risk
neuroblastoma.23,24 In contrast, in this study,MYCN amplification was a favorable prognostic factor, althoughMYCN -amplified high-risk neuroblastoma patients showed a higher
response rate after induction chemotherapy compared toMYCN -non-amplified high-risk neuroblastoma patients. This result
indicated that the double-conditioning regimen might be appropriate for
the treatment of MYCN -amplified high-risk neuroblastoma.
Some studies have shown favorable outcomes in MYCN -amplified
high-risk neuroblastoma patients after intensive treatment, including
tandem HDC.5,6 This finding suggests thatMYCN -amplified high-risk neuroblastoma might be more
chemosensitive and more likely to benefit from treatment
intensification. The double-conditioning regimen is quite unique in that
it consists of two cycles of a drug combination (thiotepa and melphalan)
for 2 consecutive weeks to safely administer the maximum dose of these
drugs.8 Therefore, this highly potent regimen could be
especially effective in MYCN -amplified high-risk neuroblastoma,
as shown in some studies using tandem HDC.
In this study, MYCN -amplified high-risk neuroblastoma patients
who showed CR/VGPR before HDC especially had good prognosis. Kushner et
al. (2014) reported that MYCN -amplified high-risk neuroblastoma
patients show extreme dichotomy in the clinical course;MYCN -amplified and MYCN -non-amplified high-risk
neuroblastoma patients who showed good response to induction
chemotherapy also showed similar good long-term outcomes, whileMYCN -amplified high-risk neuroblastoma patients who did not show
CR/VGPR developed earlier progression with a significantly poor outcome
compared to MYCN -non-amplified high-risk neuroblastoma
patients.25 The high frequency of chemosensitiveMYCN -amplified high-risk neuroblastoma in our cohort might have
led to our positive results.
Other favorable prognostic factors shown in this study, such as good
remission status (CR/VGPR) and bone metastasis negativity, were similar
to previous reports.15,26 High MSI (>1)
and older age (≥5 years), extracted as variables for risk stratification
from the analysis of the HR-NBL-1/SIOPEN study, didn’t have any
prognostic impact.25
The toxicity of the double-conditioning regimen is relatively severe. In
this study, 2 patients died of regimen-related toxicity, and 1 patient
who developed grade 4 TMA died from a pulmonary hemorrhage 1 year
post-HDC. Acute mucositis was frequently observed. The dose-finding
experience of the double-conditioning regimen for several solid tumors
showed severe gastrointestinal toxicity, microangiopathy, renal tubular
acidosis, and neurological toxcity8. Another study
also reported excessive gastrointestinal toxicity and delayed platelet
recovery.27 Okada et al. (2019) reported the
successful prevention of renal toxicity by decreasing the doses of
thiotepa and melphalan in patients less than 2 years old or in those
showing low renal function while gastrointestinal toxicity was still
severe.9 Therefore, the double-conditioning regimen
warrants special care when applied to high-risk neuroblastoma patients
who undergo intensive induction therapy.
Recently, thiotepa as a double-conditioning regimen therapeutic was
approved in Japan along with melphalan with a reduced cumulative dose
from 280 to 210 mg/m2. The feasibility of this
modified double-conditioning regimen has been confirmed in early
clinical trials.28 Further studies to confirm the
efficacy of this modified double-conditioning regimen are required.
This retrospective study had a few limitations. First, there was
selection bias of patients. Especially, the difference in the response
rate between MYCN -amplified and MYCN -non-amplified
high-risk neuroblastoma patients warrants careful interpretation.
Second, treatments other than the double-conditioning regimen were
heterogeneous. However, treatment components did not exhibit any
prognostic effects, except for second SCT. Third, we could not cover the
entire range of toxic profiles because data collection was based on only
medical records. Finally, because of a lack of a common long-term
follow-up method, this study did not report long-term toxicity.
Therefore, long-term complications in patients who underwent this potent
treatment merit considerable care.