Double megatherapy and autologous bone marrow transplantation for advanced neuroblastoma: the LMCE2 study

In the LMCE1 study using a single course of megatherapy most of the relapses occurred during the first 2 years after autologous bone marrow transplantation. A second pilot study (LMCE2) was therefore set up using a double harvest/double graft approach with two different megatherapy regimens. Objectives were to test the role of increased dose intensity on response status, relapse pattern and overall survival. Thirty-three patients (20 boys, 13 girls) with a median age of 53 months at first megatherapy (range, 17-202 months) entered this study. They were cases either with refractory disease in partial response after second line treatment for stage 4 neuroblastoma (n = 25) or after relapse from stage 4 (n = 5) or stage 3 disease (n = 3). All patients received Etoposid and/or Cisplatinum (or Carboplatin) containing treatments before megatherapy. The first megatherapy regimen was a combination of Tenoposid, Carmustine and Cisplatinum (or Carboplatin), the second applied Vincristin, Melphalan and Total Body Irradiation. The first harvest was scheduled 4 weeks after the last chemotherapy, the second 60 to 90 days after megatherapy. All marrows were purged in vitro by an immunomagnetic technique. Median follow up time since first megatherapy is 56 months. Response rates for evaluable patients were 65% (complete response rate: 16%) for megatherapy 1 and 60% (complete response rate: 25%) for megatherapy 2. Considering that only patients with delayed response or relapse were eligible for this pilot study the overall survival was encouraging with 36% at 2 years and still 32% at 5 years. The costs for these survival rates were high in terms of morbidity (four early and four late toxic deaths; toxic death rate: 24%). Double harvesting may have the disadvantage of delayed engraftments related in part to a disturbance of marrow microenvironment by megatherapy 1. This double megatherapy approach achieved a prolonged relapse free interval (median 11 months, range 2-31 months) in patients reaching megatherapy 2 and justifies further evaluation of concepts with consecutive dose-escalation.