Reduced‐intensity allogeneic stem cell transplantation for children with neuroblastoma who failed tandem autologous stem cell transplantation

Abstract

INTRODUCTIONHigh-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) has improved the outcome of high-risk neuroblastoma (NB). However, the 3-year event-free survival rates in the randomized trials by the Children's Cancer Group and the German Society of Pediatric Oncology and Hematology were 34% and 47%, respectively, which is still unsatisfactory [1,2]. Recently, a few investigators have shown that tandem HDCT/autoSCT may be a feasible approach to further improve the outcome [3][4][5][6]. Unfortunately, however, about half of patients still die from treatment failure even after tandem HDCT/autoSCT. The major cause of treatment failure is tumor relapse. Conventional chemotherapy has been ineffective in these patients, and there has been no realistic chance for cure with conventional options alone [7][8][9].In this context, allogeneic SCT (alloSCT) is being investigated as a potential curative treatment option for patients who failed HDCT/autoSCT because it offers a graft-versus-tumor (GVT) effect not seen in HDCT/autoSCT. The graft-versus-leukemia (GVL) effect is a widely accepted major component of alloSCT in leukemia [10], and there is emerging evidence for a GVT effect in solid tumors [11]. A GVT effect has been also demonstrated in patients with advanced NB who received alloSCT [12][13][14][15]. However, regimen-related mortality following standard alloSCT with an intensive conditioning regimen may be extremely high in patients who have been already heavily treated [16][17][18].In recent years, several groups of investigators have developed reduced-intensity conditioning (RIC) regimens that lead to engraftment of donor lymphoid and hematopoietic stem cells without the extra-hematopoietic toxicities of standard myeloablative conditioning, while conserving the GVL or GVT effect. This reduced regimen-related toxicity may make reduced-intensity alloSCT (RI alloSCT) especially suitable for patients at high-risk of regimen-related mortality, particularly previous tandem HDCT/ autoSCT recipients. In adults, striking GVT effects after RI alloSCT have been described in refractory breast cancer and renal cell carcinoma [19,20]. However, reports concerning the possible GVT effect of RI alloSCT remain very limited in pediatric solid tumors, particularly in NB [21]. In this context, we evaluated the feasibility and efficacy of RI alloSCT in patients with NB who failed tandem HDCT/autoSCT. PATIENTS AND METHODS PatientsFrom March 2008 to March 2009, patients with NB who failed tandem HDCT/autoSCT were eligible. Patient with grade III/IV comorbid organ dysfunction prior to RI alloSCT was excluded from the study. This prospective study was approved by Samsung Medical Center Institutional Review Board, and informed consent was obtained from all parents/guardians. Treatment Prior to RI AlloSCTConventional chemotherapy was administered in order to reduce the tumor burden as much as possible prior to transplant. A salvage chemotherapy regimen was selected according to the regimen used prior to relapse, tol...

Allogeneic hematopoietic cell transplantation for neuroblastoma: the CIBMTR experience

“…However, limited comparisons of autologous vs. allogeneic HCT have not shown an advantage for allo-HCT 6, 7 , and a retrospective review by the EBMT suggested that successful outcomes after allo-HCT have been limited by unacceptably high rates of regimen- related mortality and disease recurrence 8 . More recently, with improvements in supportive care, improved HLA typing and the advent of reduced intensity conditioning regimens, physicians have been re-exploring allo-HCT 9-12 . We therefore performed a retrospective study to describe the use of allo-HCT for neuroblastoma and to evaluate the outcomes of recipients of allo-HCT for neuroblastoma among patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR).…”

Remission With Donor Lymphocyte Infusion in a Child With Marrow Relapse After Haploidentical Stem Cell Transplantation for Relapsed Stage 4 Neuroblastoma

“…Murine models of neuroblastoma relapse confirmed the superiority of allogeneic versus syngeneic HSCT in controlling tumor growth . Clinical reports on patients with refractory/relapsed neuroblastoma also demonstrated partial or complete response to HSCT using a matched‐sibling, matched‐unrelated individual and a haploidentical individual as a donor . In particular, reports show that residual neuroblastoma disease after allogeneic HSCT could be cleared up with persistent engraftment but no additional treatment, especially during flare up of GvHD .…”

Treatment of high-risk neuroblastoma

“…Lang et al27) evaluated the feasibility and toxicity of haploidentical T- and B-cell depleted RI alloSCT with high numbers of NK cells and showed the feasibility and low toxicity of this approach even in intensively pre-treated NB patients. Sung et al34) also reported the results of RI alloSCT for NB patients who failed previous tandem HDCT/autoSCT. Regimen-related short-term toxicity was manageable and a GVT effect was observed in 2 of 6 patients after induction of acute GVHD; however, it was not sufficiently strong to control tumor progression in patients who had a significant tumor burden at transplant.…”