Haploidentical Peripheral Blood Stem Cell Transplantation for Relapsing/Refractory Neuroblastoma.
2006
This study was aimed at evaluating the feasibility and safety of a novel therapeutic modality in children with neuroblastoma (NBL) refractory to treatment. In order to reduce the tumor burden, a single infusion of radionuclide (10000 MBq 131 I-Meta-Iodobenzylguanidine; MIBG) was administered as tumor-targeting therapy followed by reduced intensity conditioning (RIC) and haploidentical HSCT. T cell graft depletion with post-transplant donor T cell add-backs were used to improve immunological reconstitution and mediate potential GVT. Piloting this concept 5 children (4 boys, 1 girl) of a median age of 7 (range 5–11) years entered the study. High-risk NBL was diagnosed at median age of 2 (1–7) years. Four had recurrent refractory, 1 primary therapy resistant NBL. All were heavily pretreated and 3 underwent auto-HSCT. G-CSF primed PBSC were harvested from haploidentical paternal donors. The graft consisted of CD34+ cells selected from the 1 st apheresis and CD3-depleted cells from the 2 nd one. RIC preparative regimen (Fludarabin 5×25 mg/m 2 , Thiotepa 2×5 mg/kg, Melphalan 2×60 mg/m 2 ) was given 2 weeks after MIBG from day -8 to day -1 followed by a single dose Rituximab (Mabthera® 375 mg/m 2 ) on day +1. GVHD prophylaxis with OKT3, steroids and Mycophenolate Mofetil was administered from day -8 to day +28. The median given dose of CD34+ cells was 12.5×10 6 (9.6–22.6) combined with CD3+ cells 0.96×10 5 (0.4–1.0) per kg. In order to reduce the risk of GvHD and facilitate engraftment donor-derived BM cultured mesenchymal stem cells were co-administered on day 0 at median dose 0.75×10 6 /kg (0.3–1.0). Commencing immunosuppression cessation escalated donor T cells add-backs were initiated with a starting dose of 2.5×10 4 CD3+ cells/kg (up to 5.0×10 5 /kg). All children engrafted with neurophils >500/μL on day +11 (10–13) and 4 out of 5 pts with platelets >50000/μL on day +11 (11–14). One patient rejected the graft on day +18 and was hematologically reconstituted with autologous back up, but died of progressive NBL five months later. GVHD did not occur before DLI was given. All 4 evaluable children developed aGVHD post DLI (grade I skin - 1 pt, grade II skin - 1 pt, grade III skin/gut -2 pts), which resolved without treatment (1 pt) or after short course of steroids ± CsA (3 pts). Three out 4 patients who engrafted received (preemptive) treatment for viral reactivation (AdV, CMV, BK/JC). One child relapsed 7 months post grafting and after local irradiation, the second high-dose MIBG with Melphalan was given with subsequent haplo-HSCT. The patient went into remission but died because of pulmonary toxicity. In August 2006 three children are alive and well (11, 10 and 9 months after haplo-HSCT) without any signs of NBL, one with active CNS disease before grafting has ongoing liposomal Ara-C (Depocyte®) intrathecal prophylaxis. High-dose MIBG and RIC followed by haplo-HSCT for treatment of high risk relapsed/refractory NBL is feasible with no major transplant related toxicity, however, evaluation of immune reconstitution and antitumor efficacy needs longer follow up. Viral reactivation and post-DLI GvHD remain a continuing challenge.
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