Trial Information

Allogeneic Hematopoietic Stem Cell Transplantation With Reduced-intensity Conditioning in Children With Neuroblastoma Who Have Failed a Prior Autologous Transplantation

The prognosis of high-risk neuroblastoma (NB) after conventional chemoradiotherapy is very
poor. Therefore, a strategy using high-dose chemotherapy and autologous stem cell
transplantation (HDCT/auto-SCT) has been explored to improve the prognosis of patients with
high-risk NB. The results of randomized trials comparing HDCT/auto-SCT with chemotherapy
alone showed a better event-free survival (EFS) in the auto-SCT arm than in the continuous
chemotherapy arm. However, the overall EFS was still unsatisfactory. In this context,
investigators have examined the efficacy of double or triple tandem auto-SCT to further
improve the outcome of high-risk NB patients. George et al. carried out a single arm trial
of tandem auto-SCT as consolidation therapy, and reported improved long-term survival
(5-year progression-free survival 47%) with acceptable toxicity. Kletzel et al. also
conducted a single arm trial of triple tandem auto-SCT and reported improved survival
(3-year EFS 57%). Investigators in the present study also carried out tandem auto-SCT as
consolidation therapy, and reported improved long-term survival (5-year progression-free
survival 62%) with acceptable toxicity. However, unfortunately, tumor relapses in many
patients even after tandem auto-SCT.

The major cause of treatment failure following auto-SCT remains relapse of the underlying
disease. Additional chemotherapy after relapse in these patients have been ineffective, and
therefore, new treatment strategies are warranted. In this context, allogeneic stem cell
transplantation (allo-SCT) has been tried as salvage treatment in patients with NB who have
failed a prior auto-SCT. Allo-SCT would theoretically be preferable in term of relapse-free
survival because this has an antitumor effect due to a graft versus tumor (GVT) effect which
is absent in auto-SCT. The graft versus leukemia (GVL) effect represents a widely accepted
major component of allo-SCT, and there is emerging evidence also for a GVT effect in solid
tumor. GVT effect was also demonstrated in patient with advanced NB who received HLA
haplo-identical allo-SCT.

Generally, allo-SCT carries a lower risk of relapse, However, it has a much higher early
treatment-related mortality (TRM) compared to auto-SCT. TRM rate in allo-SCT is especially
high in patients who have failed a prior auto-SCT. The 1-year TRM rate following a
conventional (ie myeloablative) allo-SCT in adult recipients of a prior auto-SCT has been
reported as high as 50-85%. In children, transplantation-related toxicity was also one of
the major obstacles in conventional allo-SCT because they had been already heavily treated
prior to allo-SCT. Therefore, this salvage strategy has showed a limited success in the
majority of children with relapsed NB who have failed a prior single or tandem auto-SCT,
although allo-SCT is supposed to be the only curative treatment in patients. Only a small
proportion of these patients have the opportunity to successfully undergo this treatment.

In recent years, several groups of investigators have developed non-myeloablative
reduced-intensity conditioning (RIC) regimen, which lead to engraftment of donor lymphoid
and hematopoietic stem cells without the extra-hematopoietic toxicities of traditional
myeloablative transplantations while conserving the GVL or GVT effect after transplantation.
This reduced toxicity may make these RIC regimens especially suitable for patients with
high-risk of TRM, in particular recipients of second or third transplantation.