Search

The success of allogeneic hematopoietic stem cell transplantation (HSCT) from matched unrelated donors (UDs) for beta-thalassemia may be hampered by the occurrence of graft rejection. Here, we show that the rate of this complication can be reduced by selecting 5-loci HLA-matched donors without nonpermissive mismatches at HLA-DPB1, defined according to an algorithm previously described and based on principles of central T-cell tolerance. Seventy-two consecutive patients and their UDs, prospectively selected for matching at the allelic level for HILA-A, -B, -C, -DRB, and -DQB1 loci, were enrolled in the analysis. These pairs were either DPB1 matched/permissively mismatched (n = 45, control group) or had at least one nonpermissive DPB1 mismatch in the host-versus-graft (HvG; n 17) or in the graft-versus-host (GvH; n 10) direction. In multivariate analysis, the risk of rejection was significantly increased in the group with HvG disparity (FIR = 7.42; 95% CI = 1.29-42.68; P = .02) as compared to the control group. A lower, statistically significant, probability of thalassemia-free survival was found in patients belonging to the HvG group as compared to controls (FIR = 5.15; 95% CI = 1.58-16.82; P = .01). These data suggest that in patients with thalassemia, the incidence of graft failure after HSCT may be reduced by appropriate selection of UDs, with such selection taking into account the functional rules of immunogenetics.

Bone marrow transplantation (BMT) remains the only potentially curative treatment for patients with thalassemia major. However, most candidates for BMT do not have a suitable family donor. In order to evaluate whether BMT from an HLA-matched unrelated volunteer donor can offer a probability of cure comparable to that obtained when the donor is a compatible sibling, we carried out a study involving 68 thalassemia patients transplanted in six Italian BMT Centers. Thirty-three males and 35 females (age range, 237 years; median age, 15) were transplanted from unrelated volunteer donors, all selected using high-resolution molecular typing of both HLA class I and II loci. Fourteen patients were classified in risk class I; 16 in risk class 2; and 38 in risk class III of the Pesaro classification system. Nine patients (13 %) had either primary or secondary graft failure. Fourteen patients (20 %) died from transplant-related causes. Grade II-IV acute graft-versus-host disease (GVHD) developed in 24 cases (40 %), and chronic GVHD in 10 cases (18 %). Overall survival (OS) in the cohort of 68 patients was 79.3 % (CI 67-88 %), whereas the Kaplan-Meier estimates of disease-free survival (DFS) with transfusion independence was 65.8 % (CI 54-77 %). In the group of 30 thalassemic patients in risk classes 1 and 2, the probability of OS and DFS were 96.7 %.

Objective. Functional recovery of B lymphocytes after hematopoietic stem cell transplantation (HSCT) can take up to 2 years. HSCT recipients may obtain protective titers of pathogen-specific antibody through vaccination, but optimal timing of reimmunization remains to be defined.Patients and Methods. In this study, we evaluated the reconstitution of B-cell number and activity in 139 children given HSCT, by B-cell subset phenotyping and in vitro immunoglobulin (Ig) production.Results. Patients were longitudinally studied at 3, 6, 12, and 18 to 24 months after transplantation. At all time points, recipients displayed a significantly higher percentage of naive (IgD(+)CD27(-)) B cells and showed significantly lower production of stimulated in vitro Ig as compared to healthy controls. Moreover, during follow-up, we observed an increase in the proportion of patients who had CD27(+) B subsets and who were able to mount in vitro Ig production greater than the 5th percentile.Conclusion. Similar to what has been described in adults, most children lack memory B cells and produce low amounts of Ig. However, the number of B cells, as well as their function, gradually recovered over time and the spread of data we observed suggests that the reimmunization schedule should be individualized for each patient. It remains to be defined in a prospective clinical study the time point at which a patient should start reimmunization. A reasonable hypothesis to be explored is the time point at which a percentage of memory B cells greater than the 5th percentile of normal controls is reached. (c) 2005 International Society for Experimental Hematology. Published by Elsevier Inc.

Familial platelet disorder with propensity to acute myelogenous leukemia, or FPD/AML (OMIM #601399), is a rare autosomal dominant condition, with only 12 families reported. It is characterized by qualitative and quantitative platelet defects and predisposition to the development of myeloid malignancies. Causal mutations have been identified in the RUNX1 gene (also known as AML1, CBFA2) in the 11 families so far analyzed. RUNX1 is a gene frequently involved in the pathogenesis of sporadic leukemia and myelodysplastic syndromes, through acquired chromosome rearrangements and point mutations. We report an Italian family with three members affected with FPD/AML, two sibs and their father, who developed myelodysplastic syndromes (which in one subsequently evolved into AML). Direct sequencing and polymorphisms haplotype analysis of the region of chromosome 21 where RUNX1 is mapped demonstrated that FPD/AML in this family was not caused by any mutation of the RUNX1 gene, thus providing evidence for the genetic heterogeneity of this disorder. Cytogenetic studies showed monosomy 7 in the marrow of all the three affected subjects, as well as an independent clone with trisomy 8 in the father. The importance of mucator effects in the pathogenesis of familial myeloid malignancies characterized by relevant chromosome changes, in the presence or absence of an underlying Mendelian disorder, has already been suggested. Our results and a review of the cytogenetic literature led us to postulate that mutations also causing FPD/AML may have a mutator effect that could give origin to myelodysplastic syndromes and acute myeloid leukemias through acquired chromosome changes. (C) 2004 Wiley-Liss, Inc.

Dendritic cells (DCs) are fundamental for immunity. We investigated reconstitution of plasmacytoid DC (PDC) and myeloid DC (My-DC) precursors in the first 2 months after allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Circulating DCs were monitored from the earliest phase of hematopoietic reconstitution in 43 children given standard therapy to prevent graft-versus-host disease (GVHD) and either treated or untreated with granulocyte colony-stimulating factor (G-CSF) after HSCT. In patients without GVHD, both My-DCs and PDCs reached consistently high absolute values during the initial phase. Time of engraftment did not differ between My-DCs and PDCs, regardless of administration of G-CSF. Treatment with G-CSF (1) accelerated early recovery of My-DC absolute numbers; (2) was associated with lower numbers of both My-DCs and PDCs in the later phase; and (3) significantly reduced the proportion of interleukin-12 (IL-12)secreting cells. In some patients who developed acute GVHD, we found high numbers of circulating DC precursors during the early phase of this complication. However, treatment with steroids invariably induced rapid decrease of PDCs. Altogether, these data provide an evaluation of DC release after Allo-HSCT, indicate that postgrafting administration of G-CSIF impairs the appearance of IL-12-producing DCs, and suggest that DC homeostasis may be disrupted at onset of GVHD.

N/A