Risk-Factor Analysis of Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

The objective of this study was to investigate the main risk factors for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), to allow the improvement of transplantation outcomes through preventive measures. Clinical data for 124 patients who received allo-HSCT were analyzed retrospectively. There were 83 males (66.9%) and 41 females (33.1%) with a median age of 28 years (4-60 years). The median follow-up time was 7 months (1-116 months). Factors analyzed included age, gender, disease diagnosis, source of hematopoietic stem cells, donor type, human leukocyte antigen (HLA) matching, conditioning regimen, numbers of infused mononuclear cells and CD34⁺ cells, donor-recipient sex and blood-type matching, prophylactic treatment of graft-versus-host disease (GVHD), grades of GVHD, Epstein-Barr virus or cytomegalovirus (CMV) infection, post-transplantation lymphoproliferative disorders and hepatic veno-occlusive disease. Data were analyzed by univariate and multivariate conditional logistic regression analyses. Among the 124 patients who underwent allo-HSCT, 15 developed PGF (12.1%). Univariate logistic regression analysis identified age, donor-recipient blood type and CMV infection (in 30 days) as potential risk factors for PGF. Multivariate analysis of factors with P<0.1 in univariate analysis showed that age, donor-recipient blood type and CMV infection (in 30 days) were significant risk factors for PGF. Patients were divided into subgroups based on age <20, 20-30, 30-40, and >40 years. The risk of PGF increased 2.747-fold (odds ratio (OR)=2.625, 95% confidence interval: 1.411-5.347) for each increment in age level. Patients with mismatched blood type (OR=4.051) or CMV infection (OR=9.146) had an increased risk of PGF. We conclude that age, donor-recipient blood-type matching and CMV infection are major risk factors for PGF after allo-HSCT.     

Autoimmune Hematological Diseases after Allogeneic Hematopoietic Stem Cell Transplantation in Children: An Italian Multicenter Experience

Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab.     

Cytomegalovirus Infection in Patients Who Underwent Allogeneic Hematopoietic Stem Cell Transplantation in Portugal: A Five-Year Retrospective Review

Cytomegalovirus (CMV) infection is 1 of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (aHSCT), mainly within the first 100 days after transplantation. We aimed to characterize CMV infection in a cohort of 305 patients with different malignancies undergoing aHSCT at the Portuguese Institute of Oncology of Porto between January 2008 and December 2012. In total, 184 patients (60.3%) developed CMV infection, mainly viral reactivations rather than primary infections (96.2% versus 3.8%, respectively). The majority of patients (166 of 184) developed CMV infection ≤100 days after transplantation, with median time to infection of 29 days (range, 0 to 1285) and median duration of infection of 10 days (range, 2 to 372). Multivariate analysis revealed that CMV infection was increased in donor (D)-/recipient (R)+ and D+/R+ (odds ratio [OR], 10.5; 95% confidence interval [CI], 4.35 to 25.4; P < .001) and in patients with mismatched or unrelated donors (OR, 2.54; 95% CI, 1.34 to 4.80; P = .004). Cox regression model showed that the risk of death was significantly increased in patients >38 years old (OR, 1.89; 95% CI, 1.14 to 3.12; P = .0137), who underwent transplantation with peripheral blood (OR, 3.02; 95% CI, 1.33 to 6.86; P = .008), with mismatched or unrelated donor (OR, 2.16; 95% CI, 1.48 to 3.13; P < .001), and who developed CMV infection (OR, 1.76; 95% CI, 1.07 to 2.90; P = .025). Moreover, patients who developed CMV infection had a significantly reduced median post-transplantation survival (16 versus 36 months; P = .002).     

Vanishing Bile Ducts in the Long Term after Pediatric Hematopoietic Stem Cell Transplantation

There are no structured studies on liver histology after hematopoietic stem cell transplantation (HSCT). We aimed to prospectively describe the clinicopathologic features of liver disease in the long term after HSCT in an observational, longitudinal study of liver histology in a consecutive cohort of children undergoing allogeneic HSCT. First liver biopsy was performed in presence of abnormal liver function tests and repeated per protocol thereafter. A previously reported semiquantitative score evaluating inflammation, cholestasis, and ductopenia (bile ducts-to-portal tracts ratio ≤ .5) was adopted. Graft-versus-host disease (GVHD) was diagnosed according to standard criteria. We evaluated 131 biopsies taken in 50 HSCTs performed in 47 children (mean age, 9.7 ± 5.2 years). Pre-HSCT chemotherapy was administered in 36 of 50 (72%). GVHD was diagnosed in 17 of 50 (34%). Over time the overall score decreased from a mean of 6 ± 2.7 to 3.25 ± .96 (P < .01), inflammation from 1.22 ± 1.19 to 1 ± 0 (not significant), and cholestasis from 3.9 ± 2.08 to 1.5 ± .58 (P < .01). Ductopenia, found in 113 of 131 biopsies (93%), worsened from .63 ± .35 to .16 ± .14 (P < .01). On multivariate analysis severe ductopenia (ratio ≤ .2) was associated with previous chemotherapy (P?=?.04), in particular with thiotepa, but not with history of GVHD.Vanishing bile duct syndrome after HSCT may be due to drug-induced liver disease. Longer follow-up will reveal whether these patients are prone to late liver-related morbidity and mortality.     

Gene-Marked Autologous Hematopoietic Stem Cell Transplantation of Autoimmune Disease

In phase I (safety) trials, we have demonstrated the feasibility of autologous hematopoietic stem cell transplantation (HSCT) for patients with autoimmune diseases. Although this review comments on results of our phase I trials, the focus is on phase II (efficacy) trials using gene-marked autologous stem cells.     

Long-Term Immune Reconstitution and Infection Burden after Mismatched Hematopoietic Stem Cell Transplantation

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long-lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB (n = 30) or 9/10 MMUD (n = 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4⁺, and CD8⁺ T cells and their naïve and memory subsets, as well as regulatory T cells (Treg), were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8% and 3%, and of infections were 72% and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, .9 for viral, and .3 for fungal infections). Memory, naïve CD4⁺ and CD8⁺T cells, naïve B cells, and Treg cells reconstitution between the 2 sources were roughly similar. Absolute CD4⁺T cells hardly reached 500 per μL by 1 year after transplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4⁺ and high CD8⁺T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4⁺ T cell compartment, higher percentages of memory subsets were protective against late infections. Central memory CD4⁺T cells protected against overall and bacterial infections; late effector memory CD4⁺T cells protected against overall, bacterial, and viral infections. To the contrary, high percentage of effector- and late effector-memory subsets at 3 months among the CD8⁺ T cell compartment predicted higher risks for viral infections. Patients who underwent transplantation from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis.     

High Incidence of Severe Acute Graft-Versus-Host Disease with Tacrolimus and Mycophenolate Mofetil in a Large Cohort of Related and Unrelated Allogeneic Transplantation Patients

Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.     

Effect of Antithymocyte Globulin Source on Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia

We wanted to evaluate efficacy of porcine antithymocyte globulin (ATG) in HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for patients with severe aplastic anemia (SAA). The clinical data of 113 SAA patients who received MSD-HSCT from January 2005 to November 2016 were analyzed retrospectively. Of these, 58 patients received rabbit ATG as a part of conditioning regimen (R-ATG group), whereas the other 55 patients received porcine ATG (P-ATG group). Patient baseline characteristics and donor conditions of the 2 groups were similar, except patients were older and more received peripheral blood stem cell transplantation in the P-ATG group. All patients engrafted in 2 groups. There were significant differences in the incidence of acute (20.7%?±?5.3% versus 43.4%?±?7.0%, P?=?.015) and chronic graft-versus- host disease (GVHD; 20.1%?±?5.8% versus 46.0%?±?7.9%, P?=?.003) between the R-ATG and P-ATG groups. However, there were no significant differences in terms of 3-year overall survival (93.1%?±?3.3% versus 84.4%?±?5.7%, P?=?.235), grades III to IV acute GVHD (3.4%?±?2.4% versus 12.3%?±?4.7%, P?=?.098), moderate to severe chronic GVHD (12.6%?±?4.9% versus 11.5%?±?4.9%, P?=?.905), or graft rejection (7.4%?±?3.6% versus 5.5%?±?3.1%, P?=?.852). There was also no significant difference with regard to the incidence of severe bacterial infection (P?=?.075), invasive fungal disease (P?=?.701), or cytomeglovirus viremia (P?=?.770). P-ATG showed satisfactory efficacy and safety compared with R-ATG in the setting of MSD-HSCT for SAA patients. P-ATG could be a potential alternative preparation for R-ATG, further offering the advantage of lower costs.     

BK Virus Disease after Allogeneic Stem Cell Transplantation: A Cohort Analysis

The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.     

Novel Ultrasonographic Scoring System of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Sinusoidal obstruction syndrome (SOS)/hepatic veno-occlusive disease (VOD) is a well-documented complication after hematopoietic stem cell transplantation (HSCT). Transabdominal ultrasonography (US) enables the visualization of blood flow abnormalities and is therefore useful for the diagnosis of SOS/VOD. We herein prospectively evaluated accuracy of a novel US diagnostic scoring system of SOS/VOD based on US findings. We carried out US in 106 patients on day 14 and when SOS/VOD was suspected after allogeneic HSCT. Among 106 patients, 10 patients (9.4%) were diagnosed as SOS/VOD by Baltimore or Seattle criteria. According to univariate analysis of 17 US findings (US-17 screening), we established a novel scoring system (HokUS-10) consisting of 10 parameters, such as gallbladder wall thickening, ascites, and blood flow signal in the paraumbilical vein. The sensitivity and specificity were 100% and 95.8%, respectively. Diagnostic performance of the HokUS-10 was significantly better than US-17 screening. In 4 of 10 patients US detection of SOS/VOD preceded to clinical diagnosis. The HokUS-10 scoring system is useful in the diagnosis of SOS/VOD; however, our results should be validated in other cohorts.     

Impact of Thrombotic Microangiopathy on Renal Outcomes and Survival after Hematopoietic Stem Cell Transplantation

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of hematopoietic stem cell transplantation (HSCT). We characterized the incidence, risk factors, and long-term outcomes associated with TA-TMA by performing a comprehensive review of all adult patients (n?=?1990) undergoing allogeneic HSCT at the Dana Farber Cancer Institute/Brigham and Women's Hospital between 2005 and 2013. Using the City of Hope criteria, we identified 258 patients (13%) with “definite” TMA and 508 patients (26%) with “probable” TMA. Mismatched donor transplantation (subdistribution hazard ratio [sHR], 1.79; 95% confidence interval [CI], 1.17 to 2.75; P?=?.007), sirolimus-containing graft-versus-host disease prophylaxis (sHR, 1.73; 95% CI, 1.29 to 2.34; P?<?.001), myeloablative conditioning (sHR, 1.93, 95% CI, 1.38 to 2.68; P?<?.001), and high baseline lactate dehydrogenase (LDH) level (sHR, 1.64; 95% CI, 1.26 to 2.13; P?<?.001) were associated with definite TMA. Moreover, positive cytomegalovirus serostatus (sHR, 1.41; 95% CI, 1.16 to 1.71; P?<?.001), high and very high disease risk index (sHR, 1.48; 95% CI, 1.12 to 1.96, P?=?.007), and high baseline LDH level (sHR, 1.25; 95% CI, 1.05 to 1.49; P?=?.011) were associated with probable TMA. In multivariable analyses, definite and probable TMA were each independently associated with higher mortality (HR, 5.24; 95% CI, 4.43 to 6.20 and HR, 2.12; 95% CI, 1.84 to 2.44, respectively), and long-term kidney dysfunction (HR, 5.43; 95% CI, 4.61 to 6.40 and HR, 2.20; 95% CI, 1.92 to 2.51, respectively). Definite and probable TMA were also independently associated with an increased risk of nonrelapse mortality and shorter progression-free survival. Our findings indicate that TA-TMA is common following HSCT and is independently associated with increased risk of death and kidney dysfunction.     

Significance of Ethnicity in the Risk of Acute Graft-versus-Host Disease and Leukemia Relapse after Unrelated Donor Hematopoietic Stem Cell Transplantation

The significance of patient and donor ethnicity on risk of acute graft-versus-host disease (GVHD) and disease relapse after unrelated donor hematopoietic cell transplantation (HCT) is not known. A total of 4335 patient–donor pairs from the International Histocompatibility Working Group in HCT met the following 3 criteria: (1) HLA-A, -B, -C, -DRB1, and -DQB1 allele matched donor, (2) diagnosis of leukemia, and (3) non–T cell depleted GVHD prophylaxis. Posttransplantation risks of acute GVHD and leukemia relapse were defined in Asian/Pacific Islander, white, African American, Hispanic, and Native American patients that underwent transplantation from donors with the same self-described background. Asian patients had a significantly lower incidence of acute GVHD (Japanese patients: 40.0% grades II to IV and 15.3% grades III to IV; non-Japanese Asian patients: 42.1% grades II to IV and 15.7% grades III to IV) compared with white patients (56.5% grades II to IV and 22.6% grades III to IV) (P < .001). The hazard ratio of acute GVHD for white patients was significantly higher than for Japanese patients. Unexpectedly, the hazard ratio of leukemia relapse in white patients with early disease status was also significantly higher than that in Japanese patients. These results provide a platform for future investigation into the genetic factors for unrelated donor HCT and clinical implications of diverse ethnic background.     

Etanercept plus Topical Corticosteroids as Initial Therapy for Grade One Acute Graft-Versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation

Clinical diagnosis of grade 1 acute graft-versus-host disease (GVHD) marks the beginning of a potentially progressive and fatal course of GVHD after hematopoietic stem cell transplantation (HSCT). However, interventional studies to treat early GVHD are lacking. We conducted a single-arm prospective phase II trial to test the hypothesis that treatment of newly diagnosed grade 1 acute GVHD with etanercept and topical corticosteroids would reduce progression to grade 2 to 4 within 28 days. Study patients (n = 34) had a median age of 51 years (range, 10 to 67 years) and had undergone unrelated (n = 22) or related (n = 12) donor HSCT. Study patients were treated with etanercept (.4 mg/kg, maximum 25 mg/dose) twice weekly for 4 to 8 weeks. Ten of 34 patients (29%) progressed to grade 2 to 4 acute GVHD within 28 days. The cumulative incidence of grade 2 to 4 and grade 3 to 4 acute GVHD at 1 year was 41% and 3%, respectively. Nonrelapse mortality was 19% and overall survival was 63% at 2 years. Among a contemporaneous control cohort of patients who were diagnosed with grade 1 acute GVHD and treated with topical corticosteroids but not etanercept during the study period, 12 of 28 patients (43%) progressed to grade 2 to 4 GVHD within 28 days, with a 1-year incidence of grade 2 to 4 GVHD and grade 3 to 4 GVHD of 61% (41% versus 61%, P = .08) and 18% (3% versus 18%, P = .05), respectively. Patients treated with etanercept also experienced less increase in GVHD plasma biomarkers suppression of tumorigenicity 2 (P = .06) and regenerating islet-derived 3-alpha (P = .01) 28 days after grade 1 acute GVHD diagnosis compared with contemporaneous control patients. This study was terminated early because of poor accrual. Future prospective studies are needed to identify patients with grade 1 acute GVHD at risk of swift progression to more severe GVHD and to establish consensus for the treatment of grade 1 acute GVHD. This trial is registered with ClinicalTrials.gov, number NCT00726375.     

Antibiotic Exposure and Reduced Short Chain Fatty Acid Production after Hematopoietic Stem Cell Transplant

Human studies have shown loss of diversity of the gut microbiome following hematopoietic stem cell transplantation (HSCT) in association with significant gut injury caused by the preparative regimen. Prolonged antibiotic use worsens loss of microbiome diversity and increases risk of complications such as graft-versus-host disease (GVHD). Our data support the hypothesis that loss of intestinal commensals that produce short-chain fatty acids (SCFAs) may increase dysbiosis. Here, we report an extensive longitudinal examination of changes in the luminal SCFAs in children undergoing allogeneic HSCT, and the relationship of those changes to the microbiota and antibiotic exposure. We found significant and progressive alterations in butyrate, and in additional SCFAs in stool in the first 14 days after transplant, a finding not observed in published mouse studies. SCFA levels were lower in children receiving antibiotics with activity against anaerobic organisms. Moreover, day 14 post-HSCT butyrate and propionate levels are lower in children who went on to develop GVHD, although our disease population was small. These data provide insight into the mechanism of prior observations that loss of diversity and increased antibiotic use are associated with GVHD following HSCT. Our findings offer potential modifiable targets to reduce risk of GVHD and improve survival after HSCT.     

Lung Function after Allogeneic Hematopoietic Stem Cell Transplantation in Children: A Longitudinal Study in a Population-Based Cohort

Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF during follow-up in a population-based pediatric HSCT cohort and to investigate factors in the transplantation process associated with PF decline. A retrospective, population-based, single-center study of HSCT patients spanning 2 decades was performed. Longitudinal changes in PF over time and associations to transplantation-related factors were investigated using a mixed linear model. One hundred thirty patients were included in the longitudinal analysis and observed for a median (range) of 3.3 (.2 to 16.8) years, during which 1084 PF tests were performed. Sixty-two percent of the patients experienced a decline in lung function of more than 10% during the first 3 to 9 months after HSCT. The decline in forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity and diffusion capacity of the lung for carbon monoxide were strongly associated with acute graft-versus-host disease (GvHD). Other factors associated with PF decline were malignant diagnosis, busulfan-based conditioning, patient and donor age, female donor to male recipient, as well as chronic GvHD. Mild to moderate decline in PF is frequent and appears associated with acute GvHD and other parameters that are risk factors for chronic GvHD in children. This indicates that alloreactivity is central in pathogenesis of the decrease in PF that follows HSCT in children.     

Impact of Hematopoietic Stem Cell Transplantation on Dental Development

To investigate dental development in patients treated with a hematopoietic stem cell transplantation (HSCT), 42 children and young adults who were under 12 years old at time of HSCT were examined for dental agenesis, microdontia, and root-to-crown ratio. Conditioning regimens were total body irradiation (TBI) based in 12 patients, busulfan based in 21 patients, and 9 patients had other chemotherapeutic agents. Sixteen patients were <3 years old, 9 patients were 3 to 6 years old, and 17 patients were 6 to 12 years old at HSCT. Prevalence of agenesis and microdontia of at least 1 permanent tooth were, respectively, 51.3% and 46.2% in the study population, and 76.3% had an aberrant root-to-crown ratio. All these results were highly different from the prevalence in the healthy population. Patients treated before the age of 3 years had more microdontia (76.9%) and agenesis (92.3%) compared with patients treated at an older age. In the subgroup of patients treated after 6 years, there was more microdontia when treated with busulfan (50%) compared with treatment with TBI (0%) (P?=?.044). Patients treated with HSCT had many disturbances in dental development. Age at HSCT and possibly also the conditioning regimen used had an effect on their type and prevalence. Dental follow-up should be incorporated in the multidisciplinary follow-up program of these patients.     

Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Hemoglobinopathies Using a Reduced-Intensity Conditioning Regimen and Third-Party Mesenchymal Stromal Cells

Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m²), melphalan (140 mg/m²), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated. Further investigations into understanding the mechanisms of graft resistance and development of strategies to overcome this barrier are needed to move this field forward.     

Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Adults

Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post-transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI-GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P?=?.015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P?=?.024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P?=?.42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition.