Influence of bone marrow nucleated red blood cell dose on outcome after allogeneic haematopoietic stem cell transplantation

Field: Medicine (Health Sciences)

In patients undergoing allogeneic bone marrow transplantation (BMT), the infused total nucleated cell (TNC) or CD34+ stem cells doses have been shown to impact engraftment and overall survival (Bittencourt et al, 2002; Dominietto et al, 2002; Rocha et al, 2002; Gorin et al, 2003; Heimfeld, 2003; Lee et al, 2005). The present study aimed at evaluating the influence of the bone marrow (BM) nucleated red blood cell (NRBC) infused dose on haematopoietic reconstitution and overall survival, which has never been reported to date. Myeloid reconstitution was analysed according to BM cell subset in 80 patients who underwent allogeneic BMT (HLA identical sibling, n = 45; unrelated donor, n = 35). Thirty-three patients were children ≤15 years. Primary diseases were malignant haematological diseases in 62 patients (acute leukaemia, n = 46, chronic myeloid leukaemia, n = 7, lymphoma, n = 5, myelodysplastic syndrome, n = 4) or aplastic anaemia in 18 cases. Seventy patients received standard conditioning regimen based on high-dose cyclophosphamide associated with busulfan or total body irradiation. Ten patients received a reduced-intensity conditioning regimen because of co-morbidity (fludarabine 90 mg/m2/melphalan 140 mg/m2) or Fanconi disease. All patients displayed aplasia after conditioning regimen. BM NRBC were quantified by flow cytometry as previously described (Larghero et al, 2006). The mean number of infused cells was 7·3 × 106/kg CD34+ cells, 2·7 × 108/kg TNC and 62 × 106/kg NRBC. Engraftment characteristics were consistent with those reported by others (Link et al, 1994; Table I). Cumulative incidence of complete erythroid recovery (CER), defined as haemoglobin level (Hb) >120 g/l without any transfusion for 30 days, was only 26% (95% confidence interval: 16·5–36) at 6 months (Fig. 1A). As already reported by others, patients receiving a higher number of TNC/kg had better neutrophil and platelet recovery and patients receiving a higher number of CD34+ cells/kg had better platelet recovery (Table I, Figs 1B,C; Morariu-Zamfir et al, 2001; Bittencourt et al, 2002; Heimfeld, 2003; Lee et al, 2005). Interestingly, patients transplanted with >35 × 106/kg NRBC also had better neutrophil and platelet recovery, which was independent of the CD34+-infused cell dose. An association between the speed of myeloid engraftment and NRBC cell dose has already been reported after placental cord blood transplantation (Stevens et al, 2002) but never, to our knowledge, after BMT. Moreover, a higher NRBC- and CD34+-infused cell doses were independently predictive for a better early erythroid recovery (transfusion independence on day 100), but not for late erythroid recovery (Hb > 120 g/l; Fig 1A,D). TNC dose had no significant impact on erythroid reconstitution. Finally, higher NRBC and CD34+ cell dose was associated with a decreased incidence of transplantation-related mortality (Fig. 1E, Table I). This study showed that time to neutrophil, platelet and early erythroid recovery was shortened when a higher number of NRBC was infused. The quantification of NRBC in the graft was determined by CD34+ cell enumeration for quality control. Furthermore, NRBC may become a marker for early erythroid reconstitution. Cumulative incidence of myeloid recovery and transplantation-related mortality according to bone marrow subsets. Curves represent cumulative incidences for complete erythroid (A), neutrophil (B), platelet (C) and partial erythroid (= transfusion independence, D) reconstitution and transplantation-related mortality (E) according to nucleated red blood cell (NRBC) and CD34+ cell dose infused.