Stem cells support multiple cycles of high‐dose induction therapy: Lots from tots

P ediatric oncologists have found value in dose intensity. Sequential improvements in survival have been observed with increasing intensities of treatment for patients with diseases ranging from ALL to AML to Ewing Sarcoma [1]. High-risk neuroblastoma has been more of a challenge, but inclusion of high-dose therapy with stem cell rescue has somewhat improved the outcome of neuroblastoma as well. This has been most clearly demonstrated by the phase III randomized Children’s Cancer Group 3891 study, which showed an improvement in event-free survival (EFS) for patients undergoing autologous bone marrow transplantation compared to continuation chemotherapy [2]. This study used purged bone marrow [3] as an autologous stem cell source. More recently, bone marrow has been almost completely supplanted as a stem cell source by peripheral blood-stem cells (PBSC). PBSC are unequivocally superior for autologous transplantation. A far higher progenitor cell dose provides more rapid engraftment and recovery than marrow, and the risk and extent of tumor cell contamination is lower. Because of this latter fact, the Children’s OncologyGroup is currently testing whether PBSC purging improves outcome in children undergoing PBSC transplantation for neuroblastoma. The challenge for a disease like high-risk neuroblastoma, where the median age is 3, is collecting the PBSC by apheresis. There are special challenges in this small population, principal among which is the issue of access, which has improved with the availability of eight Fr. tunneled dialysis/apheresis catheters. These catheters have obviated the need for femoral catheter placement in the large majority of these young patients. Much dedicated work by the pediatric apheresis community has extended this modality to patients 10 kg or smaller [4]. What we have learned, and what Pradhan et al. demonstrate quite clearly in their paper is that these small patients mobilize stem and progenitor cells into their peripheral blood extremely well. Indeed, cell yields from young children are often better than their larger counterparts as measured by numbers of CD34þ cells collected per kg of patient weight [5]. This report shows us the feasibility of collecting PBSC at multiple times for multiple infusions to support high dose but submyeloablative chemotherapy cycle in induction. A low degree of tumor contamination, even among products collected after 1 cycle of chemotherapy from patients initially diagnosed with substantial marrow disease, confirms the lower risk of tumor cell contamination in the PBSC product compared to marrow. An innovative strategy was employed in this study, with PBSC collected after cycles 1, 2, and 3 of induction and reinfused sequentially to support dose-intensified chemotherapy. Toxicity was manageable and the PBSC clearly improved neutrophil recovery. Unfortunately, platelet recovery lagged behind somewhat, limiting the ability to compress the intervals and thus further increase dose intensity. Response rate to this induction regimen was similar to other dose-intensive induction regimens for high-risk neuroblastoma. The inability of PBSC to support rapid platelet recovery after high-dose carboplatin may have been partially due to the sequential nature of the PBSC collection. Yields clearly dropped with each cycle. One lesson from this study and the broad experience with PBSC in autologous transplant is that it may be best to collect sufficient cells early for all intended stem cell supported therapies. This issue is also addressed in a position paper from the Children’s Oncology Group Neuroblastoma Disease Committee and the Hematopoietic Stem Cell Discipline in this issue [6]. A day longer in the apheresis unit may suffice to supplymultiple PBSC aliquots for all planned high-dose chemotherapy with stem cell rescue episodes, as well as leaving an aliquot available for any possible later need for retrieval therapies. The additional resources expended for that extra day of collection are minimal compared to the challenges of setting up for a second episode later in treatment or after a recurrence, and the experience in the current report confirms that the quality will very likely be higher. With little evidence of clinical benefit from infusing more than 5 10 CD34þ cells/kg, collection of multiple such PBSC aliquots even in small children becomes quite feasible.