Non-T-Cell Depleted HLA Haploidentical Hematopoietc Stem Cell Transplantation for Refractory or Relapsed Pediatric Solid Tumor

Despite intensive multi-modal therapies, prognosis of refractory or relapsed pediatric solid tumor is dismal because majority of those tumors already get acquired chemo-resistance. Therefore new break through approaches are expected in order to improve their survival. The efficacy of allogeneic hematopoietic stem celltransplantation(SCT) is primarily attributed to a T/NK- cell-mediated response to HLA disparity between donor and tumor cell. Non–T-cell depleted (non TCD) haploidentical hematopoietc stem cell transplantation as immunothrapy is attractive challenge for refractory tumor, however, there are several reports describing graft-versus-tumor (GVT) effects in patients with solid tumors. The major problems of non-TCD haplo-SCT are lethal graft-versus-host disease (GVHD), graft failure (GF) and high-risk of early death. Previously we reported the safety profile from the retrospective study assessing GVHD prophylaxis that was conducted with anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone in non-TCD haplo-SCT (Mochizuki, Kikuta, Clin Transplant,2010 DOI:10.1111/j.1399-0012.2010.01352.x). We started clinical study of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor as cell-mediated immune therapy since July, 2007.

This study presents a series of transplant experiments aiming to evaluate the efficacy and feasibility of non-TCD HLA haploidentical hematopoietc stem cell transplantation for refractory or relapsed pediatric solid tumor. Seven cases (3males, 4females) with refractory or relapsed pediatric solid tumor were enrolled on this study between July 2007 to December 2010. One patient had second transplantation due to tumor progression 1year after transplantation. Among 7 patients, there are 3 cases of relapsed neuroblastoma, 1 case of relapsed Mesenchymal Chondrosarcoma, 1 case of relapsed Ewing sarcoma family tumor, 1 case of refractory alveolar soft part sarcoma with multiple lung metastasis, and 1 case of refractory primitive neuroectodermal tumor. Conditioning regimens consisted with fludarabine30mg/m² at day-9 to -5+Melphalan70mg/m² at day-4 to-3+rabbit ATG 1. 25mg/kg at day-2 to -1. The GVHD prophylaxis was conducted with tacrolimus (0.03mg/kg/day, start on day-1), methotrexate (10mg/m², 7mg/m², 7mg/m² on day+1, +3, +6) and predonisolone (1mg/kg/day, day 0–29, taper on day30 without GVHD). HLA disparities were 3/8 in 3, 4/8 in 5. Donors included father(1), mothers(5), siblings(1), mother’s younger brother(1). Four pts received peripheral blood stem cells and 4 pts received bone marrow.

All of seven patients achieved primary engraftment but secondary graft rejection was observed in one patients. Median follow up period after transplantation were 14 months (range 11–40 months). Incidence of acute GvHD was 3/7 cases (grade±:1, gradeII:1, grade III:1), chronic GvHD was observed in 5(83%) of 6 evaluable patients. Three cases were underwent DLI for tumor progression. Treatment-related mortality(TRM) was not observed and reactivation of VZV, interstitial pneumonia, and HHV6 related limbic system encephalitis were recognized as major complication within 100 days after transplantation. Five cases of patients had tumor progression after transplantation, and two children were dead by tumor progression, other 3 cases had additional treatment. Two cases are alive and well, with no evidence of disease 13 and 14 months after transplantation. Graft versus Tumor effect was clearly observed in three cases.

The survival rate of relapsed or refractory pediatric solid tumor is under 20%, however, the two-year probability of overall survival was 71.4% with no TRM in this study. These results indicated the feasibility and the possibility of efficacy of non-TCD HLA haploidentical hematopoietc stem cell transplantation for relapsed or refractory pediatric solid tumor.

No relevant conflicts of interest to declare.