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BACKGROUND: Unrelated cord blood transplantation (UCBT) is associated with delayed hematopoietic recovery. Intrabone injection of cord blood cells (IB-UCBT) and double-UCBT (dUCBT) are designed to circumvent this problem. METHODS: In a retrospective registry-based analysis, we compared outcomes of 87 IB-UCBT with 149 dUCBT recipients, after myeloablative conditioning regimen adjusting for the differences between the two groups. Median-infused total nucleated cells were 2.5×10/kg for IB-UCBT and 3.9×10/kg for dUCBT (P

Six cases of cytomegalovirus retinitis (CMVR) after allogeneic hematopoietic stem cell transplantation were diagnosed between 2002 and 2005 in our center, whereas only one case was diagnosed between 1985 and 2001. Cumulative incidence reaches 2.2%, whereas this complication has been rarely described after hematopoietic stem cell transplantation. We aimed to describe clinical and biologic features of CMVR and search for risk factors associated with CMVR. CMVR was diagnosed on specific funduscopic examination in all patients either on visual symptoms (n=3) or on systematic ophthalmologic examination (n=3). CMVR occurred in the context of unrelated transplantation in patients with profound immune defect and multiple episodes of cytomegalovirus (CMV) reactivation. The combination of a CMV-seropositive recipient and CMV-seronegative donor was the leading risk factor.

Human herpesviruses may cause severe complications after allogeneic hematopoietic stem cell transplantation (HSCT). However, the impact of some of these infections on transplant outcomes is still unclear. A prospective survey on the incidence and clinical features of herpesviruses infections after HSCT has not yet been conducted in Brazilian patients, and the impact of these infections on HSCT outcome remains unclear.We prospectively analyzed the incidence of infection of the eight human herpesviruses simultaneously in 1 045 peripheral blood samples from 98 allogeneic HSCT recipients. Samples were collected weekly starting at the time of transplant until day +100. All herpesviruses were screened and quantified in plasma by quantitative real-time polymerase chain reaction. Median follow up time was 24 months.The incidences of infection for each herpesvirus were as follows: cytomegalovirus (CMV), 44%; human herpesvirus [HHV] 6, 18%; HHV8, 6%; Epstein-Barr virus, 3%; herpes simplex virus 1, 3%; varicella zoster virus, 3%; HHV7, 2%; and herpes simplex virus 2, 1%. The CMV infection was significantly more frequent among adults and was associated with a higher risk of developing acute graft-versus-host disease. The HHV6 infection was significantly more frequent after umbilical cord blood transplant and was associated with an increased risk of platelet engraftment failure. There was no significant impact of these infections on the other transplant outcomes.Herpesviruses infections were uncommon after HSCT, except for CMV and HHV6, which, although relatively frequent, had no clinically relevant impact on the outcomes.

Background. Half of the patients with chronic graft-versus-host disease (GvHD) do not achieve a complete remission with first-line therapy. No clear recommendations are available regarding second-line treatments. Methods. We retrospectively report our single-center experience of low-dose thoracoabdominal irradiation (1-Gy TAI) in 41 patients with refractory extensive chronic GvHD from 1983 to 2000. Median time from extensive chronic GvHD to TAI was one year (median GvHD episodes before TAI, n=4). Results. Eighty-two percent of the patients achieved a clinical response at a median of 34 days after TAI (range, 15-180). Best response rates were observed in fasciitis (79%), and oral GvHD lesions (73%). A complete clinical response was achieved in 11 patients by 2 years postTAI. Fifty-seven percent of the patients had at least a 50% reduction of their corticosteroid daily dose by 6 months postTAI. Probability of corticosteroid discontinuation was 38% by 2 years postTAI (95% CI, 23-56%). Two-year chronic GvHD relapse incidence was 34%. Ten-year survival from irradiation was 57% (95% CI, 42-78%); patients with fasciitis, lymphocytes >1.0 × 109/L, and platelets >200 × 109/L had a better outcome. Conclusions. TAI is a safe and efficient option in patients with refractory chronic GvHD, leading to a significant tapering of systemic corticosteroid dose in most cases.

Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context.We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested.C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT.The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

Background. Current grading systems in acute graft-versus-host disease (GVHD) are not able to identify patients with poor prognosis at time of onset, because they take into account maximal grade. The aim of this study was to evaluate potential predictors for overall survival at disease onset. Methods. The study sample was composed of 142 allogeneic hematopoietic stem-cell transplant recipients who developed acute GVHD after a myeloablative conditioning regimen. Factors associated with the risk of nonrelapse mortality (NRM) were analyzed with proportional hazard models. Results. At time of diagnosis, GVHD involved a single organ in the majority of the patients (78%). Initial grade was I in 24%, II or III in 56% of patients. Significant risk factors for NRM were non-HLA matched sibling donor (68% vs. 55%, P=0.05), absence of methotrexate in GVHD prophylaxis (75% vs. 56%, P=0.02), initial liver involvement (80% vs. 56%, P

PTPN22 is a negative regulator of T-cell activation. The C1858T PTPN22 polymorphism has been associated with autoimmune diseases. The role of PTPN22 in immune response and autoimmune diseases suggested that PTPN22 polymorphism could impact outcome of allogeneic hematopoietic stem-cell transplantations that is impaired by immunological and infectious complications. One hundred ninety-two patients who received a non-T-depleted bone marrow transplant from a human leukocyte antigen-identical sibling donor were included in this study. Donor PTPN22 C1858T polymorphism was not associated with severe acute graft-versus-host disease, relapse, survival, cytomegalovirus, and fungal infections, but significant with severe bacterial infections (24% for donor CC vs. 0% for donor CT+TT genotypes, P=0.003). The association was confirmed by a multivariate analysis (P=0.036, hazard ratio=2.28, 95% confidence interval= 1.06-4.90). This could improve the genetic risk assessment of severe bacterial infections in allogeneic hematopoietic stem-cell transplantations.

Background The posttransplant period following hematopoietic stem cell transplantation (HSCT) is potentially high risk for developing survival-compromising complications, many of which are known to be under the control of immunogenetic factors. Given the dual role of human leukocyte antigen (HLA)-E molecules in innate and adaptive immune processes, we analyzed the impact of HLA-E polymorphism in genoidentical HSCT setting. Methods We analyzed 187 HLA-genoidentical sibling pairs for HLA-E polymorphism. To explore its potential association with the incidence of acute and chronic graft versus host disease (aGVHD, cGVHD), severe infections, risk for transplant-related mortality (TRM), and overall survival, HLA-E locus was genotyped by a polymerase chain-reaction-sequence-specific primer (PCR-SSP) strategy. Results Multivariate analysis, taking into account the patient-, donor- and transplant-related factors, showed that the incidence of aGVHD and TRM at day 180 were low when the genotype was HLA-E*0103/E*0103, either in the donor or in the recipient, the pairs being identical for HLA-E alleles (hazard ratio [HR]=0.71, P=0.009; and HR=0.42, P=0.04, respectively). We also found a trend towards association between E*0103 homozygosity and improved survival (P=0.05). There was no association between HLA-E polymorphism and incidence of severe infections. Conclusions These data suggest that the homozygous state for HLA-E*0103 allele behaves as a protective genetic factor against aGVHD and TRM and likely contributes to improved survival in HLA-genoidentical bone marrow transplantation.

In HLA-identical sibling bone marrow transplantation, certain recipient cytokine gene polymorphism genotypes and minor histocompatibility differences influence the occurrence and severity of acute graft-versus-host disease (aGvHD). The present study investigated the role of cytokine tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 gene polymorphisms HY, HA-1, and CD31 minor histocompatibility antigen (mHag) mismatch in the development of aGvHD after unrelated cord blood (CB) transplant (CBT).DNA samples of 115 CB recipients and their unrelated CB grafts were analyzed for genotype associated with TNF-alpha (TNFd3/d3) and IL-10 (IL-10(-1064), 11-16) and for disparities in major and three minor histocompatibility antigens, HY, HA-1, and CD31 codon 125. Results were correlated with the incidence of aGvHD grades II to IV.Neither the donor nor the recipient GvHD risk alleles TNFd3/d3 and IL-10(-1064) (11-16) were associated with the development of aGvHD grades II to IV and I to IV. Because of the heterogeneity of CBTs, the data were reanalyzed separately for patients with malignancies (n=83) or with inborn errors (n=24). No significant association was observed between the severity of aGvHD and the possession of either TNFd3/d3 or IL-10 (11-16) genotypes. Mismatches for the mHags HY, HA-1, and CD31 exon 125 between donor and recipient did not associate with aGvHD grades II to IV.In contrast to HLA-identical sibling bone marrow transplantation, in mismatched unrelated CBT, neither the cytokine genotypes TNFd3/d3 alone or in combination with IL-10(-1064) alleles nor the minor histocompatibility antigens HY, HA-1, and CD31 exon 125 were associated with aGvHD grades II to IV. Further determination of the cytokine gene polymorphism genotypes in CBTs compared with bone marrow transplants may identify those polymorphisms that could be potential predictive markers for the occurrence of aGvHD.