Severe myelosuppression has been dose-limiting for many intensified treatment regimens and led to the investigation of PBSC support as a means of mitigating hematologic toxicity 23-27
. We sought to assess the feasibility of utilizing sequential reinfusions of autologous PBSC to allow administration of dose intensive non-myeloablative induction cycles every 28 days. The primary aim was to determine an MTD of carboplatin, with fixed dose cyclophosphamide and etoposide in the treatment of children with advanced neuroblastoma. Within the context of this study, PBSC re-infusion at protocol specified dose was not sufficient to permit administration of induction cycles every 28 days due to prolonged thrombocytopenia.
This study provides important data regarding the technique, timing, and applicability of PBSC harvest and reinfusion in the treatment of young patients with advanced neuroblastoma. Prior to beginning this study, apheresis and reinfusion had been utilized effectively in patients as small as 20 kg, but very limited data existed regarding the use in smaller children28
. In this study, 21/22 patients weighed less than 17.5 kg. Apheresis was accomplished with acceptable toxicity. Another key finding of this study was that the PBSC apheresis schedule could be amended from three sequential collections to a single large-volume apheresis. It was possible to perform PBSC collection after 2 induction cycles to obtain the required CD34/kg yield. This could be done without immunocytochemical evidence of PBSC tumor contamination, regardless of BM disease status at the time of apheresis. Theoretically, future studies utilizing a single large volume apheresis series early in induction would reduce the number of apheresis procedures, minimize the impact of platelet depletion known to occur with apheresis29
, and potentially provide an extra aliquot of PBSC for use with novel therapy in the event of relapse30
As this was a phase I dose escalation study of induction chemotherapy, followed by transplant on other protocols after study completion, it was not designed to evaluate survival. Sixty-nine percent (11/16) of patients completing Induction II had either a CR/VGPR (4) or PR (7) following chemotherapy alone. Unlike most induction regimens, response was assessed prior to delayed surgical resection and radiation to the primary tumor. Given that response rates on prior CCG or POG studies have measured outcomes based on the combination of chemotherapy and local control, it is difficult to compare the response rates on this protocol to historically reported data. It is also difficult to compare EFS/OS to historical data as this protocol only included patients with Stage 4 disease > 365 days of age and patients did not receive uniform therapy following completion of the A3951 regimen.
There are two major implications of this study. First, sequential PBSC collection and reinfusion is possible in young patients weighing less then 20 kg. A single large-volume apheresis after 2 induction chemotherapy cycles provides an adequate tumor-free yield to support multiple reinfusions. Second, within the parameters defined by this study the carboplatin doses in combination with cyclophosphamide and etoposide were not tolerable using the administered PBSC doses. Perhaps an agent associated with less thrombocytopenia, such as topotecan, may be a more feasible candidate for dose escalation. In the immediate future, high dose chemotherapy remains a key element in the treatment of neuroblastoma, however this research did not address the urgent need for new approaches to treat high risk disease.
The results of this trial were integral in developing a standardized collection and re-infusion procedure for peripheral blood stem cells in small pediatric cancer patients. These results proved instrumental in the design and implementation of a large, multi-center, randomized Phase III trial in the Children’s Oncology Group, COG A3973, in which PBSC apheresis was performed following the second cycle of induction chemotherapy.