Higher doses of CD34+ peripheral blood stem cells are associated with increased mortality from chronic graft-versus-host disease after allogeneic HLA-identical sibling transplantation

Abstract

Allogeneic peripheral blood stem cell transplantation (PBSCT) has emerged as an alternative to bone marrow transplantation. PBSCT can be associated with a higher incidence of chronic graft-versus-host disease (cGVHD). In this study, we investigated whether there was a correlation between the composition of PBSC grafts (CD34+ and CD3+ cells) and hematological recovery, GVHD, relapse, and relapse-free survival (RFS) after myeloablative HLA-identical sibling PBSCT. The evolution of 100 acute or chronic leukemia patients was analyzed. Neither hematological recovery, acute or cGVHD, nor relapse, was significantly associated with CD3+ cell dose. Increasing CD34+ stem cells was associated with faster neutrophil (P ¼ 0.03) and platelet (P ¼ 0.007) recovery. Moreover, 47 of the 78 patients evaluable for cGVHD (60%; 95% CI, 49-71%) developed extensive cGVHD. The probability of extensive cGVHD at 4 years was 34% (95% CI, 21-47%) in patients receiving a 'low' CD34+ cell dose (o8.3 Â 10 6 /kg), as compared to 62% (95% CI, 48-76%) in patients receiving a 'high' CD34+ cell dose (48.3 Â 10 6 /kg) (P ¼ 0.01). At a median follow-up of 59 months, this has not translated into a difference in relapse. In patients evaluable for cGVHD, RFS was significantly higher in patients receiving a 'low' CD34+ cell dose as compared to those receiving a 'high' CD34+ cell dose (P ¼ 0.04). This difference was mainly because of a significantly higher cGVHD-associated mortality (P ¼ 0.01). Efforts to accelerate engraftment by increasing CD34+ cell dose must be counterbalanced with the risk of detrimental cGVHD.

The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin

“…[17][18][19] Although no significant association between the number of infused CD3 þ cells and incidence of GVHD was found; paradoxically they showed that the more CD34 þ cells infused, the higher the incidence of cGVHD. 18,19 An explanation for this interesting finding remains a mystery. In elegant experiments, Reisner et al 20 showed that donor CD34 þ cells can act as 'veto' cells and may inactivate host T-cells, with donor alloreactivity.…”

Reduced risk of acute GVHD following mobilization of HLA-identical sibling donors with GM-CSF alone

“…While some studies have suggested that high doses of CD34 þ cells are associated with a greater likelihood of chronic GVHD, our data suggest that other factors may be more important since the risk of chronic GVHD was high within GM-CSF group despite the fact that they received a relatively modest median CD34 þ cell dose (3.1 Â 10 6 /kg). 10,38,39 Despite the fact that the cohort of donors receiving combination G/GM-CSF mobilized the greatest numbers of CD34 þ cells without significant additive toxicity, this did not translate into any clear clinical advantages to the recipients as the rate of hematopoietic engraftment, incidence of chronic GVHD, risk of relapse, and overall likelihood of survival did not differ significantly from the G-CSF alone group. In fact, the risk of acute GVHD was greatest in this combination group.…”

“…[1][2][3][4][5][6][7][8] Nevertheless, in only a minority of the randomized comparative trials did this translate into an overall survival advantage and some studies suggested the use of G-CSF mobilized PBPC was associated with a greater risk of either acute or chronic graft-versus-host disease (GVHD), or both. 6,[8][9][10] In two recent retrospective studies in patients with aplastic anemia or children with leukemia performed by the International Bone Marrow Transplant Registry, transplantation of G-CSF mobilized PBPC was associated with higher rates of GVHD. 11,12 Therefore, strategies to limit GVHD following PBPC transplantation are necessary.…”

Impact of CD34+ cell dose in children who receive unrelated PBSCT with in vivo T-cell depletion for hematologic malignancies

“…Previous studies found a greater incidence of extensive chronic GVHD in recipients of a higher CD34 + dose after PBSCT. 17,18 However, in our pediatric cohort a higher CD34 + dose resulted only in the salutary effect of decreasing relapse and improving survival without increasing the risk for either acute or chronic GVHD. One factor that we believe is key to the lack of association between cell dose and GVHD was the use of rabbit ATG (2.5 mg/kg per day for 3 days) during conditioning before transplant.…”