Intra-BM injection to enhance engraftment after myeloablative umbilical cord blood transplantation with two partially HLA-matched units

Abstract

The time to neutrophil engraftment for adult patients after myeloablative double unit umbilical cord blood (UCB) transplantation is 23 days when the two units are given i.v. We hypothesized that the intra-BM injection (IBMI) of one of the two UCB units would reduce systemic loss of hematopoietic progenitors and shorten time to neutrophil recovery after myeloablation. Ten patients with a median age of 35 years were transplanted. The unit to be given by IBMI was randomly assigned; the other unit was given i.v. The median infused graft total nucleated cell dose was 3.7 × 107/kg with no difference between i.v. and IBMI units. All patients tolerated the procedure well, and there was no severe adverse event related to IBMI. The median time to neutrophil engraftment and plt recovery >50 000/μl was 21 and 69 days, respectively. In all, 9 of 10 patients engrafted, 5 with the i.v. unit and 4 with the IBMI unit; 7 of 8 evaluable patients developed acute GVHD and 5 of 10 patients died from treatment-related causes. Survival was 47% at 1 year. Despite safety of administration, IBMI of one of two UCB units did not shorten the time to neutrophil engraftment and offers no advantage over conventional double unit transplantation.

Negative selection by apoptosis enriches progenitors in naïve and expanded human umbilical cord blood grafts

“…[7][8][9][10] Proposed solutions include direct inoculation of UCB cells into the bone marrow to overcome ineffective UCB cell homing, 12,38,39 and increasing the effective number through the combination of several cord units 11,12 and ex vivo expansion of progenitors. [13][14][15] In addition to generation of a progenitor-enriched graft by functional-negative selection (as compared with phenotypic identification), pretransplant exposure to the death ligands enhanced progenitor activity.…”

“…[1][2][3][4][5][6] The use of UCB for transplantation is limited by the insufficient cell numbers required to attain the threshold of adult recipients and the slow tempo of engraftment. [7][8][9][10] Approaches to overcome the small cell numbers have been implemented with relative success, including transplantation of two or more UCB units 11,12 and ex vivo expansion of progenitors. [13][14][15] The second limitation of UCB transplants is a relatively slow tempo of reconstitution, which is likely an intrinsic characteristic of circulating primitive progenitors inexperienced in interaction with the bone-marrow stroma.…”

Future of cord blood for oncology uses

“…Frassoni et al 25 reported on the IBMI in the setting of UCB transplantation with one unit, whereas our group studied this technique in the setting of two UCB units. 24,25 Frassoni et al 25 observed consistent engraftment and a reduced incidence of acute GVHD, but all patients received anti-thymocyte globulin, which may have favorably influenced the risks of GVHD. Nevertheless, considering the cell doses infused, their results with this IBMI approach were encouraging.…”

“…Recently reported studies have investigated the intra-BM injection (IBMI) of UCB grafts. 24,25 The rationale for these studies was to enhance neutrophil recovery by delivering the HSCs directly into the BM space, thus reducing the systemic 'wasting' of an already limited number of progenitors. Frassoni et al 25 reported on the IBMI in the setting of UCB transplantation with one unit, whereas our group studied this technique in the setting of two UCB units.…”

“…Larger numbers of patients and more uniform management in the context of prospective clinical trial may be warranted to validate the findings in the single UCB setting. In our study, 24 we randomly assigned one of the UCB units to be delivered by IBMI, whereas the other was infused intravenously. We hypothesized that the procedure would be safe and that the IBMI unit would have a repopulating advantage.…”