Balancing Acute Graft Versus Host Disease (aGVHD) and Survival after Peripheral Allogeneic Stem Cell Transplantation (SCT) in Hematological Malignancies: A Potential for Graft Engineering.

Purpose: Peripheral allogeneic SCT is used to treat different types of hematologic malignancies. The target CD34 stem cell dose is 2 -5 x 10⁶/Kg. The dose of CD3+ cells in the infusate is not taken into account except in T-depleted transplant. T-cell dose in peripheral blood stem cell collections is at least 10-fold more than that in a bone marrow harvest. Regulatory T cells (CD4+, CD25+), which comprises 5–10% of CD4 + T cells have been correlated with less incidence of aGVHD. In our study we are trying to determine the impact of T-cell dosing on the overall survival and incidence of aGVHD after peripheral allogeneic SCT in a group of patients with hematological malignancy.

Methods: A retrospective study of 66 consecutive patients who underwent peripheral allogeneic SCT for hematological malignancy in our institution between January 2003 and April 2006. The median duration of follow up after SCT was 12.6 months (range 0.2–53). Duration of follow up was compromised only in a subset of patients who had early mortality following SCT. Proportional hazard model was used to define the cutoff value of CD3, CD4, and CD8 cell dose that separate 2 groups of patients with highest statistically significant difference in terms of incidence of aGVHD. Kaplan-Meier Survival Analysis was used for correlate the overall survival (calculated from date of transplant) among these groups subdivided in terms of CD3, CD4, and CD8 cell doses.

Results: The 66 patients (6 females, and 60 males) with median age of 48 years (range: 19–63 years) had different malignancies; 6 ALL, 34 AML, 1 biphenotypic leukemia, 1 CLL, 11 CML, 5 Hodgkin lymphoma, 8 NHL. The SCT was from matched related donors in 39 patients, and from matched unrelated donors in 27 patients. The incidence of aGVHD (grade 2–4) was statistically significantly less among those who received CD3 dose < 33.5 × 10⁷/kg IBW (P value: 0.04), tended to be less among those who received CD4 dose < 32.6 × 10⁷/kg IBW (P value: 0.06), and was statistically significantly less among those who received CD8 dose < 6.2 × 10⁷/kg IBW (P value: 0.04). Survival analysis showed no statistically significantly difference in the overall survival (OS) among all patients groups. Median OS was 10.5 months for those who received CD3 dose ≤ 33.5 ×10⁷/kg IBW and 17 months for those who received > 33.5 ×10⁷/kg IBW (P value: 0.35). Median OS was 12 months for those who received CD4 dose ≤ 32.6 ×10⁷/kg IBW and 16.3 months for those who received > 32.6 ×10⁷/kg IBW (P value: 0.8). Median OS was 6 months for those who received CD8 dose ≤ 6.2 ×10⁷/kg IBW and 14.4 months for those who received > 6.2 ×10⁷/kg IBW (P value: 0.13).

Conclusions: In our series, CD3 dose less than 33.5 ×10⁷/kg IBW and CD8 dose less than 6.2 ×10⁷/kg IBW were associated with statistically significant reduced risk of grade 2–4 acute GVHD following peripheral allogeneic SCT. Overall survival was not statistically different among these groups of patients. These data suggest that, in addition to considering CD34 dose required for engraftment in allogeneic transplant, the CD3 dose and its subsets CD8 and CD4 may need to be considered to try to minimize the risk of acute GVHD without compromising survival after transplant.