Low CD34 Cell Dose Is Associated With Higher Non-Relapse and Overall Mortality After Reduced Intensity Conditioning Hematopoietic Cell Transplantation For Acute Myeloid Leukemia and Myelodysplastic Syndrome

In allogeneic hematopoetic cell transplantation (HCT) using myeloablative conditioning, the nucleated and CD34 cell doses were found to be of importance for several outcome parameters including survival, relapse and graft- versus- host disease (GVHD). Reduced intensity conditioning (RIC) HCT is increasingly used for older patients and for younger patients with co-morbidities. Peripheral blood progenitor cells (PBPC) is the predominant graft for RIC HCT. There is no large study of the effect of CD34 cell dose in the setting of RIC transplantation. Therefore, we studied the effect of CD34 dose on 1057 patients aged 45 – 75 years with acute myeloid leukemia (AML) or myelodysplasic syndrome (MDS) who received RIC regimen HCT between 2000 and 2011. Patients received grafts from HLA-matched siblings (n = 370) or from volunteer adult unrelated donors matched at the allele-level at HLA-A, -B, -C and –DRB1 (8/8; n = 522) or mismatched at 1 HLA-locus (7/8; n = 178). All patients received peripheral blood progenitor cells (PBPC), low dose TBI regimens (200 cGy) or alkylating agent plus fludarabine containing regimens. Separate analyses were conducted for HLA-matched and unrelated donor transplants. For HLA-matched sibling transplants (AML n=301; MDS n=69), exploratory analysis identified differences in survival for CD34 dose less than 4 x 10⁶/kg. Multivariate modeling, adjusting for performance score, disease status, cytogenetic risk and transplant period, showed transplantation of PBPC with CD34 dose < 4 x 10⁶/kg was associated with higher risks of overall mortality (HR 1.48, p=0.008) and non-relapse mortality (HR 2.03, p=0.004) compared to transplantation of PBPC with CD34 dose ≥ 4 x 10⁶/kg. The effect of CD34 dose was independent of the other factors associated with mortality. The likelihood of neutrophil (HR 0.76, p=0.03) and platelet recovery (HR 0.76, p=0.03) was also lower with CD34 dose < 4 x 10⁶/kg containing PBPC grafts. CD34 dose was not associated with acute or chronic GVHD or disease recurrence. In contrast, after unrelated donor transplantation (AML n=557; MDS n=130), the effect of CD34 cell dose on mortality was marginal. Exploratory analysis identified differences in survival for CD34 dose less than 6 x 10⁶/kg. After adjusting for age, performance score, disease status, interval from diagnosis to HCT, and HLA-match, transplantation of PBPC with CD34 dose < 6 x 10⁶/kg was associated with marginally higher risks for overall mortality (HR 1.20, p=0.05) and non-relapse mortality (HR 1.38, p=0.02) compared to transplantation of PBPC with CD34 dose ≥ 6 x 10⁶/kg. There were no significant differences in hematopoietic recovery, acute or chronic GVHD and disease recurrence by CD34 dose. Further, we did not identify a CD34 dose for either donor source above which acute or chronic GVHD risks were higher. In conclusion, in the setting of RIC transplants for AML and MDS, the data support optimizing PBPC collections such that the CD34 dose delivered is in excess of 4 x 10⁶/kg for HLA-matched sibling and CD34 dose in excess of 6 x 10⁶/kg for unrelated donor transplants.