Published online Feb 24, 2019. doi: 10.5306/wjco.v10.i2.86
Peer-review started: July 30, 2018
First decision: September 11, 2018
Revised: September 14, 2018
Accepted: December 4, 2018
Article in press: December 5, 2018
Published online: February 24, 2019
Peripheral blood hematopoietic cell transplant (PBHCT) is the most commonly used allogeneic hematopoietic cell source due to its quick rate of neutrophil engraftment. A higher total nucleated cell (TNC) dose has been reported to improve survival after PBHCT, but analyses of specific T-cell subsets have been inconsistent. Factors such as T-cell depletion, conditioning regimen intensity, use of total body irradiation (TBI), and donor age may be interacting with graft cell doses to generate different effects on PBHCT outcomes. In addition, flow cytometric enumeration of cell doses are not standardized and may also lead to differences in results between studies.
While the optimal CD34+ cell dose range to minimize time to neutrophil and platelet recovery without increasing risk of acute graft-versus-host disease has been found to be 4-10 × 106/kg, some studies have reported a higher CD34+ cell dose yields improved overall survival while others have found no significant association. Further understanding of the impact of graft composition on post-transplant outcomes, and their potential interactions with conditioning regimens, could allow physicians to better target certain cell doses in order to improve post-transplant survival outcomes.
The objectives of this study were to examine whether the collected and infused CD34+, CD3+, CD4+, CD8+ or TNC dose influenced engraftment, overall survival, progression free survival, and incidence of acute and chronic GvHD, and whether the results were affected by conditioning regimen intensity or use of TBI.
Four conditioning regimen groups were defined a priori as (1) myeloablative (MA) without TBI (MA-noTBI), (2) myeloablative with TBI (MA + TBI), (3) Reduced intensity conditioning (RIC) without TBI (RIC-noTBI) and (4) RIC with TBI (RIC + TBI). Correlations between TNC dose and CD3+ dose, CD4+ dose, CD8+ dose, CD34 dose were calculated using the Pearson product-moment correlation coefficient. The cumulative incidence of acute and chronic GvHD was analyzed adjusting for the competing risk of disease relapse. Univariable analysis of OS and progression free survival (PFS) were analyzed as time-to-event; survival curves were generated using the Kaplan-Meier method and were compared using the log-rank test. Multivariable analyses tested each cell dose while adjusting for significant factors in the univariate analysis, first in all patients and then stratified by the four conditioning regimen groups. These analyses allowed us to explore the interaction of conditioning regimen and allogeneic donor apheresis product composition in relation to outcomes after unmanipulated peripheral blood hematopoietic cell transplantation.
The cohort consisted of 135 sibling and 112 unrelated donor transplant recipients. Overall, patients who received a CD34+ cell dose > 4 × 106/kg experienced faster neutrophil engraftment and platelet engraftment as compared to patients who received a CD34+ cell dose < 4 × 106/kg. Analysis by conditioning regimen demonstrated significantly faster neutrophil engraftment for an infused CD34+ cell dose > 4 × 106/kg in the RIC + TBI group. Overall and progression-free survival was significantly better in patients with a RIC + TBI regimen and TNC dose > 8 × 108/kg. Our results indicated that overall CD34+ cell dose is not associated with OS or PFS in our patient population, similar to other studies. We did find an overall and progression-free survival benefit in patients with a RIC + TBI regimen and TNC dose > 8 × 108/kg, which could indicate there is another graft cell subset that may better predict these outcomes.
Our single center study is the first to analyze the relationship of conditioning regimen intensity and use of TBI with infused cell doses. Neutrophil engraftment was significantly faster after reduced intensity TBI based conditioning and > 4 × 106 CD34+ cells/kg infused. In addition, overall and progression-free survival were significantly better in patients with a RIC + TBI regimen and TNC dose > 8 × 108/kg. Our study suggested that TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Our results demonstrated that immune cell subsets may predict improved survival after unmanipulated PBHCT.
This study suggests that TBI and conditioning intensity may alter the relationship between infused cell doses and outcomes after PBHCT. Further confirmation of our results in a larger, multi-center registry study could be performed. In addition, analysis of other cell populations, such as NK cell dose, could explain our findings. Further understanding of the impact of graft composition on post-transplant outcomes, and their potential interactions with conditioning regimens could allow physicians to better target certain cell doses in order to improve post-transplant survival outcomes.