Reduced Intensity Stem Cell Transplantation in Children With Relapsed Neuroblastoma After Autologous Transplantation

• tumor response, overall survival, event-free survival [ Time Frame: from 1 year after reduced-intensity allogeneic hematopoietic stem cell transplantation ] [ Designated as safety issue: No ]
  

Procedure: Reduced-intensity allogeneic hematopoietic stem cell transplantation

Treatment Scheme

• Enrollment - Pre-RIST treatment - RIST
• 4 cycles of conventional chemotherapy will be given prior to RIST.
• Surgery will be done whenever possible prior to RIST.
• Local radiotherapy will be applied whenever possible prior to RIST.
• topotecan + cyclophosphamide) regimen will be used for pre-RIST conventional chemotherapy.
• Cyclophosphamide/Fludarabine (CyFlu) regimen will be used as conditioning regimen for matched related or unrelated SCT. CyFlu-ATG regimen will be used as conditioning regimen for mismatched related SCT.

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.