Haploidentical hematopoietic stem cell transplantation using T-cell-depleted grafts is a valid option for pediatric patients with hematological malignancies in need of an allogeneic transplantation and lacking an HLA-identical donor. Seventy-five transplantations were performed in 70 patients. Thirty-eight patients had ALL, 32 had AML, 3 had advanced myelodysplastic syndromes and 2 juvenile myelomonocytic leukemia; 19 were in first CR, 30 in second CR, 12 in greater than second CR and 14 were considered to be in refractory disease at time of transplantation. Four patients developed graft failure. Among engrafted patients, the median time to neutrophil and platelet recovery was 13 (range 8-20) and 10 days (range 8-70), respectively. In 64 (85%) cases, ⩾ 1 infections were diagnosed after transplant. The probability of nonrelapse mortality by day +100 after transplantation was 10 ± 4%. With a median follow-up of 22 months, the probability of relapse was 32 ± 6% and disease-free survival was 52 ± 6%. Haploidentical transplantation using CD3/CD19 depletion is associated with encouraging results especially in patients in early phase of disease. Killer-cell Ig-like receptor B haplotype donors confer a rapid natural killer cells expansion early after transplantation, resulting in lower probability of relapse and suggesting a GvL effect apart from graft-versus-host reactions. Donor infusion of high numbers of CD34+ cells is recommended in order to improve T-cell reconstitution.
Transplant-related problems have been partially overcome by using reduced-intensity conditioning (RIC), graft engineering, and alternative donors. In all, 21 leukemia patients with no suitable donor received a hematopoietic stem cell transplantation from a mismatched/haploidentical related (n=16) or unrelated donor (n=5). Fludarabine-RIC and PBSC graft were used. Manipulation was done by CD34+ selection (n=9) or CD3/CD19 depletion (n=12). Results were compared with patients (n=26) conditioned with the same regimen and grafted with a CD34+-selected PBSC from identical related donors. Median time to neutrophil recovery was 12 days (range, 10-19 d). Platelet engraftment was faster with a CD3/CD19-depleted graft (median, 11 d; range, 9-21) than with a CD34+ graft (median, 14 d; range, 9-53; P=0.003). Full donor chimerism in bone marrow CD34+ cells was higher in CD3/CD19-depleted graft group compared with CD34+-selected group (P=0.02). CD3/CD19 depletion showed higher natural killer cell counts even after 1 year. Nonrelapse mortality (7% for matched CD34+-selected grafts and 11% for mismatched/haplo-CD3/CD19-depleted grafts), relapse probability (27% for related CD34+-selected patients and 33% for related CD3/CD19-depleted patients), and disease-free survival were similar for both the groups. In conclusion, using graft engineering procedures after RIC for hematopoietic stem cell transplantation offers a high probability of engraftment, fast immune recovery, and very low mortality even with mismatched donors.
Extracorporeal photopheresis (ECP) has been used for treatment of steroid-refractory graft-versus-host disease (GVHD) with encouraging results. However, only a few pediatric centers have experienced with ECP, mainly by technical difficulties of leukapheresis in children. We retrospectively analyzed 27 patients treated during 5 years with ECP for steroid-refractory acute and chronic GVHD. We performed an "off-line" approach using a continuous flow cell separator (Cobe Spectra) and a Ultraviolet A irradiator (UVAMATIC). Among acute GVHD patients, 11 of 21 obtained a complete remission (CR) and another 8 reached partial remission. In the chronic GVHD group, 3 patients obtained CR and another 2 were in partial remission. Disease-free survival probability was 43±9% in the whole group. The only variable that impacts on disease-free survival on multivariate analysis was achieving CR with ECP. We also found a better CD4/CD8 ratio after ECP. In detail, among CD4 lymphocyte population, an increase in the effector memory and T-regulatory population was found. We may conclude that ECP is a safe and effective steroid-refractory GVHD treatment using the ex-vivo collection method, even in small children. Clinical response favorably impacts on long-term survival and seems to be associated with peripheral blood lymphocyte subset changes generating peripheral tolerance.
We prospectively analyzed outcomes of haploidentical hematopoietic stem cell transplantation using αβ+ T-cell receptor/CD19+ depleted grafts. Sixty-three transplantations were performed in 60 patients. Twenty-eight patients were diagnosed with acute lymphoblastic leukemia (ALL), 27 patients were diagnosed with acute myelogenous leukemia, and in eight other hematological malignancies were diagnosed. Twenty-three were in first complete remission (CR), 20 in second CR, 20 beyond second CR. Four patients developed graft failure. Median time to neutrophil and platelet recovery was 14 (range 9–25) and 10 days (range 7–30), respectively. The probability of non-relapse mortality (NRM) by day +100 after transplantation was 10 ± 4%. With a median follow-up of 28 months, the probability of relapse was 32 ± 6% and disease-free survival was 52 ± 6%. Immune reconstitution was leaded by NK cells. As such, a high CD56dim/CD56bright NK cell ratio early after transplantation was associated with better disease-free survival (DFS) (≥3.5; 77 ± 8% vs. <3.5; 28 ± 5%; p = 0.001) due to lower relapse incidence (≥3.5; 15 ± 7% vs. <3.5; 37 ± 9%; p = 0.04). T-cell reconstitution was delayed and associated with severe infections after transplant. Viral reactivation/disease and presence of venooclusive disease of liver in the non-caucasian population had a significant impact on NRM. αβ+ T-cell receptor/CD19+ cell-depleted haploidentical transplant is associated with good outcomes especially in patients in early phase of disease. A rapid expansion of “mature” natural killer cells early after transplantation resulted on lower probability of relapse, suggesting a graft vs. leukemia effect independent from graft-vs.-host reactions.
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