Allogeneic Hematopoietic Stem Cell Transplantation Recipients Research Articles

Adenovirus infection and disease in paediatric haematopoietic stem cell transplant patients: clues for antiviral pre-emptive treatment

Human adenovirus (HAdV) infections constitute a major cause of morbidity in paediatric haematopoietic stem cell transplant (HSCT) patients. New antiviral treatments offer promising perspectives. However, it remains challenging to identify patients at risk for disseminated infection, and who should receive early antiviral intervention. We conducted a longitudinal study of allogeneic HSCT recipients, including weekly HAdV monitoring, to determine the risks factors associated with HAdV infection and dissemination, and to assess whether HAdV loads in stools may be used as surrogate markers for HAdV dissemination. Between September 2010 and December 2011, out of 72 patients, the cumulative incidence rates at day 100 of HAdV digestive infection, systemic infection and related disease were 35.9%, 24.0%, and 18.3%, respectively. In multivariate analysis, the risk factors for HAdV digestive and systemic infection were cord blood and in vitro T-cell depletion. Graft-versus-host disease (GVHD) grade >2 was also associated with systemic infection. In patients with HAdV digestive shedding, GVHD grade >2 and HAdV load in stools were the only risk factors for systemic infection. The median peak levels of HAdV in stool were 7.9 and 4.0 log10 copies/mL, respectively, in patients with HAdV systemic infection and in those without. HAdV monitoring in stools of paediatric HSCT recipients receiving cord blood or in vitro T-cell depleted transplants helps to predict patients at risk for HAdV systemic infection. Our results provide a rationale for randomized controlled trials to evaluate the benefit of anti-HAdV pre-emptive treatments based on HAdV DNA levels in stools.

Epidemiology, Management, and Outcome of Invasive Fungal Disease in Patients Undergoing Hematopoietic Stem Cell Transplantation in China: A Multicenter Prospective Observational Study

The China Assessment of Antifungal Therapy in Hematological Disease study, the first large-scale observational study of invasive fungal disease (IFD) in China, enrolled 1401 patients undergoing hematopoietic stem cell transplantation (HSCT) (75.2% allogeneic and 24.8% autologous) at 31 hospitals across China. The overall incidence of proven or probable IFD was 7.7% (108 of 1401); another 266 cases (19.0%) were possible IFD. After allogeneic or autologous HSCT, the incidence of proven/probable IFD was 8.9% (94 of 1053) and 4.0% (14 of 348), respectively. Some cases (14 of 108) developed during conditioning before transplantation. The cumulative incidence of proven/probable IFD increased steeply in the first month after transplantation and after 6 months, the incidence was significantly higher in allogeneic than it was in autologous transplant recipients (9.2% versus 3.5%; P = .001) and when stem cells were derived from cord blood or bone marrow and peripheral blood (P = .02 versus other sources). Independent risk factors for proven/probable IFD in allogeneic HSCT were diabetes, HLA-matched unrelated donor, prolonged severe neutropenia (absolute neutrophil count > 500/mm3 for >14 days), and immunosuppressants (odds ratio, 2.0 to 3.4 for all). Antifungal prophylaxis was independently protective (P = .01). Previous IFD and prolonged severe neutropenia were significant independent risk factors among autologous transplantation patients (P < .01, P = .04, respectively). In total, 1175 (83.9%) patients received antifungal prophylaxis (91.6% triazoles) and 514 (36.7%) were treated in the hospital with therapeutic antifungals (89.1% triazoles; median 27 days). Empirical, pre-emptive, and targeted antifungals were used in 82.3%, 13.6%, and 4.1% of cases, respectively. Overall mortality (13.4%; 188 deaths) was markedly higher in patients with proven (5 of 16; 31.3%), probable (20 of 92; 21.7%), or possible (61 of 266; 22.9%) IFD; allogeneic (171 of 1053; 16.2%) rather than autologous (17 of 348; 4.9%) HSCT and was significantly higher in patients receiving pre-emptive (18.6%) rather than empirical (6.1%) or targeted (9.5%) antifungal therapy (P = .002). Improvements in the selection and timing of prophylactic antifungals would be welcome. Health care providers should remain alert to the increased risk of IFD and associated mortality in allogeneic HSCT recipients and the ongoing risk of IFD even after discharge from the hospital.

Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P<0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

Epidemiology and outcomes of invasive fungal infections in allogeneic haematopoietic stem cell transplant recipients in the era of antifungal prophylaxis: a single-centre study with focus on emerging pathogens.

With increased use of expanded-spectrum triazoles for antifungal prophylaxis, the epidemiology of invasive fungal infections (IFIs) after allogeneic haematopoietic stem cell transplantation (HSCT) continues to evolve. To define the contemporary epidemiology of IFIs in this population, we reviewed all European Organization for Research and Treatment of Cancer-Mycoses Study Group proven and probable IFIs in adults transplanted from 2002 to 2011 and determined the incidence and risk factors for IFI and post-IFI mortality. All patients received antifungal prophylaxis. Fifty-three (14%) of 378 allogeneic HSCT recipients developed an IFI. There were 62 IFI episodes, of which aspergillosis (n=31; 50%) and candidaemia (n=15; 24%) were most common. Sixteen episodes (26%) were caused by other fungi, including Mucorales (n=6; 10%) and the following uncommon pathogens: Trichosporon asahii, Arthrographis sp., Cladosporium sp., Geosmithia argillacea and Hormographiella aspergillata. Independent IFI risk factors were hospitalisation in an intensive care unit [ICU; odds ratio (OR)=6.0], graft-versus-host disease (OR=5.3), central venous catheter use (OR=5.2) and hypoalbuminaemia (OR=0.3g(-1) dl(-1) increase in albumin). The 90-day mortality rate after IFI was 57%. Non-cytomegalovirus systemic viral co-infection (OR=3.5) and stay in an ICU (OR=2.9) were independent risk factors for death. Despite antifungal prophylaxis, IFIs remain common after allogeneic HSCT and previously uncommon pathogens are emerging.

Changes in intensive care for allogeneic hematopoietic stem cell transplant recipients.

Intensive care unit (ICU) admission is associated with high mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Whether mortality has decreased recently is unknown. The 497 adult allogeneic HSCT recipients admitted to three ICUs between 1997 and 2011 were evaluated retrospectively. Two hundred and nine patients admitted between 1997 and 2003 were compared with the 288 patients admitted from 2004 to 2011. Factors associated with 90-day mortality were identified. The recent cohort was characterized by older age, lower conditioning intensity, and greater use of peripheral blood or unrelated-donor graft. In the recent cohort, ICU was used more often for patients in hematological remission (67% vs 44%; P<0.0001) and without GVHD (73% vs 48%; P<0.0001) or invasive fungal infection (85% vs 73%; P=0.0003) despite a stable admission rate (21.7%). These changes were associated with significantly better 90-day survival (49% vs 31%). Independent predictors of hospital mortality were GVHD, mechanical ventilation (MV) and renal replacement therapy (RRT). Among patients who required MV or RRT, survival was 29% and 18%, respectively, but dropped to 18% and 6% in those with GVHD. The use of ICU admission has changed and translated into improved survival, but advanced life support in patients with GVHD usually provides no benefits.

Sca1(+) mesenchymal stromal cells inhibit graft-versus-host disease in mice after bone marrow transplantation.

Mesenchymal stromal cells (MSCs) have therapeutic potential for the prevention and treatment of graft-versus-host disease (GVHD). However, MSCs comprise several subpopulations, which have not been individually assessed for their role in GVHD suppression. In this study, we assessed the immunosuppressive effect of bone-related Sca1(+) MSCs on acute GVHD in a MHC-mismatched mouse model of allogeneic hematopoietic stem cell transplantation (HCT). Our results showed that Sca1(+) MSCs decreased the severity of acute GVHD (aGVHD) and prolonged the survival period of allogeneic HCT recipients. This effect was exerted through lowered T lymphocyte infiltration in target organs and by inhibition of CD80/86 expression on host dendritic cells. Furthermore, the expression of cytotoxic T-lymphocyte antigen-4 (CTLA-4), a negative regulator of T cells, was elevated in the recipient splenocytes. In conclusion, bone-related Sca1(+) MSCs subpopulation suppressed GVHD and could be a novel treatment for acute GVHD.

Association between Plasma Endothelin-1, Transforming Growth Factor-β, Fibroblast Growth Factor, and Nitric Oxide Levels and Liver Injury in Hematopoietic Stem Cell Transplantation Recipients with Persistent Iron Overload after Transplantation

Graft-versus-host disease, iron overload, and infections are the major causes of liver dysfunction in allogeneic hematopoietic stem cell transplantation (AHSCT) recipients. We investigated the relationship between serum iron parameters and the levels of transforming growth factor-β (TGF-β), fibroblast growth factor (FGF), endothelin-1 (ET-1), and nitric oxide (NO) as predictors of chronic liver injury in 54 AHSCT recipients who survived at least a year after transplantation. Serum samples from patients were obtained for the evaluation of ET-1, TGF-β, FGF, NO, and nontransferrin bound iron at the first year follow-up visit using commercially available ELISA kits. Patients were categorized depending on serum ferritin and transferrin saturation levels. The parameters were compared between the groups, and survival analysis was also performed. Most of the AHSCT recipients (81.5%) were in complete remission during the study. After a median follow-up time of 73 months (range, 13 to 109 months), 72.2% of the patients were alive. Mean serum levels of ET-1, NO, TGF-β, and FGF were 81.54 ± 21.62 μmol/mL, 31.82 ± 26.42 μmol/mL, 2.56 ± 0.77 ng/mL, and 50.31 ± 32.69 pg/mL, respectively. Nineteen patients (35.2% of the cohort) had serum ferritin levels higher than 1000 ng/mL. Mean serum levels of ET-1, NO, TGF-β, and FGF were similar in patients with serum ferritin levels below or above 1000 ng/mL (P > .05). Serum ferritin levels were positively correlated with serum alanine aminotransferase (r = .284, P = .042) and γ-glutamyl transferase (r = .271, P = .05) levels and were negatively correlated with serum albumin levels (r = .295, P = .034). There was a significant positive correlation between serum transferrin saturation and alanine aminotransferase levels (r = .305, P = .03). Serum ET-1 level was positively correlated with alkaline phosphatase levels (r = .304, P = .026). In univariate Cox regression analysis serum levels of iron parameters, ET-1, NO, TGF-β, and FGF did not have an impact on overall survival (P > .05). The probability of progression-free survival was also similar in patients with ferritin levels above or below 1000 ng/mL (P = .275). The probability of survival was similar in patients with transferrin saturation ≥70% and <70% (P > .05). Serum iron parameters showed a positive correlation with liver injury. However, there was no correlation between fibrogenic cytokines and liver transaminases. Our results suggest that iron overload at least with the current levels of ferritin might have a relatively benign course. Prospective randomized trials will guide the actual role of iron chelation in the post-transplantation setting.

Use of the Japanese Live Attenuated High-Titer Varicella Vaccine in Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Background: Hematopoietic stem cell transplantation (HSCT) recipients carry a high risk of primary varicella and varicella-zoster virus (VZV) reactivation. VZV infections can be fatal, and VZV reactivation can be complicated by postherpetic neuralgia, which worsens the recipients’ post-HSCT quality of life. VZV vaccines may prevent such infections; however, international vaccination guidelines do not recommend VZV vaccination of HSCT recipients because few data regarding safety among HSCT recipients are available. In Japan, we use a high-titer Oka stain vaccine for varicella vaccination and zoster prevention in the elderly; the plaque forming unit (PFU) value of this vaccine is as high as the zoster vaccine used in the U.S. Data regarding the safety of zoster vaccine in HSCT recipients is limited; therefore, we report our experience with this high-titer zoster-equivalent varicella vaccine in pediatric allogeneic HSCT recipients.Patients and Methods: Forty-seven pediatric allogeneic HSCT recipients who underwent transplantation at the Saitama Children’s Medical Center from 2000-2011 were vaccinated with live vaccines and their antibody titers were evaluated after vaccination. Among the 47 recipients, the Japanese high-titer varicella vaccine was administered to 32 recipients. Since establishing the live vaccine initiation criteria in 2009, allogeneic HSCT recipients were considered as recipients for live vaccines, including the varicella vaccine, if 24 months had passed after HSCT without active chronic GVHD or required immunosuppression. In addition, recipients were required to have a lymphocyte count >1500/μl or CD4 cell count >700/μl if they were <6 years and a lymphocyte count >1000/μl or CD4 cell count >500/μl if they were >6 years, normal phytohemagglutinin response, and serum IgG level >500 mg/dL. Before 2009, time for vaccination depended on each doctor’s judgment. Patients were given a single dose of the Biken varicella vaccine containing a minimum of 23,000 PFUs. We use EIA to measure the antibody titer and defined seropositivity as a titer >6.0. The time to evaluate the antibody titer was not fixed. We retrospectively collected the clinical data of recipients and laboratory data by reviewing the medical records.Results: The 32 recipients, who received the Japanese varicella vaccine, underwent HSCT at a median age of 5.15 years (range: 0.5-16.4 years) and were vaccinated at a median of 20.65 months (range: 4.8-112.1 months) after HSCT. Twenty and 11 patients had received myeloablative and nonmyeloablative conditioning, respectively. Nine patients received related-donor transplant, of which eight were bone marrow and one was peripheral blood. Twenty-three patients received unrelated-donor transplant, of which 14 were bone marrow and nine were cord blood. Antithymocyte globulin was administered to four patients. Eighteen of the 32 patients (56.3%) were seropositive after vaccination. Of the 26 patients, whose vaccination histories and pre-transplantation histories were available, eight were affected by natural disease, six had been immunized, and 12 had not been immunized. At vaccination, the median lymphocyte count was 3201/μl (range: 817-6630/μl) and the median IgG value was 880 mg/dL (range: 233-1461 mg/dL). There was no significant risk factor associated with vaccine failure. We experienced one case of varicella because of wild type VZV and no cases of zoster after vaccination during a median follow-up period of 4.8 years (range: 0.4-11.3 years); the single patient developed varicella 13 days after vaccination, immediately after an influenza virus infection. Whereas, two cases of varicella and one case of zoster developed before vaccination. Of the other 15 recipients, who did not receive varicella vaccine, three varicella and two zoster developed in three recipients.Conclusion: We safely vaccinated pediatric allogeneic HSCT recipients with the Japanese high-titer varicella vaccine. This finding could encourage the use in the U.S. of zoster vaccines such as Zostavax@, which contains similarly high PFUs, and low-titer varicella vaccines such as Varivax@. However, the efficacy of high-titer varicella vaccines for preventing VZV reactivation in this population remains unclear. Further studies are warranted to elucidate the efficacy and difference between low-titer and high-titer varicella and zoster vaccines. DisclosuresNo relevant conflicts of interest to declare.

Impact of Atorvastatin on Cellular Immunome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT)

Introduction: Donor T cells have been known to be the most powerful effectors for acute graft-versus-host-disease(aGVHD). The HMG-CoA reductase inhibitors, statins, have been shown to inhibit T-helper 1(Th-1) driven responses, reduce pro-inflammatory cytokines while increasing the migration of anti-inflammatory cytokines T-regs and T-helper-2 cells(Th-2), with a potential to reduce aGVHD. We analyzed the effect of atorvastatin on the immune reconstitution pattern on patients enrolled in a phase II study evaluating the efficacy of atorvastatin as GVHD prophylaxis in patients undergoing HLA-matched-related donor AHSCT in which donors and patients were exposed to atorvastatin. The results of this study were compared to historical matched controls at Ohio State where neither related donor nor patients were exposed to any cholesterol lowering medications. Methods: Forty patients (statin gp) were enrolled (NCT01491958) between March 2012 and January 2014. Atorvastatin at 40mg/day orally was administered to sibling donors, starting 14-28 days before the anticipated 1st day of stem cell collection. In AHSCT recipients, atorvastatin (40mg/day) was administered from day -14 to day +180 (or until stopping immunosuppression, toxicity, development of grade [Gr] II-IV aGVHD, or severe chronic GVHD (cGVHD). In addition all recipients received standard GVHD prophylaxis with tacrolimus and methotrexate. Historic matched controls were 25 patients (and related donors) not on any cholesterol lowering medications (non-statin gp) and had mobilized peripheral blood (PB) allograft samples (day 0) and PB samples on days 30 and 100 post AHSCT collected. We analyzed the absolute numbers of T, NK, NKT, B cells and immunophenotypic characterization of their activation status. Results: Median duration of atorvastatin prophylaxis in statin donors was 14 days (range 13-26) and in statin patients 132 days (32-400). Baseline patient’s characteristics were well matched between the groups with respect to age, sex, donor/recipient sex, intensity of regimen, disease and disease status at transplant and number of stem cells infused. The clinical results of this study are presented in a separate abstract in which we found no statistically significant difference in clinical outcomes including aGVHD and cGVHD between the two gps. While there were no differences in the B and total T cells reconstitution in all time points, the statin gp allografts contained less NK and T-regulatory cells (T-regs) than the non-statin gp (Table 1). This reduction of the NK and T-regs, appeared to affect the reconstitution of these subsets post-transplant as reflected by their continued decrease on days 30 and 100 post-transplant compared to the non-statin gp (Table 1). Conclusion: while we found no differences in clinical outcome with the addition of atorvastatin, it did result in a statistically significant decrease in NK and T-reg cells for the statin gp in the graft when administered to donors, and on days 30 and 100 post HSCT in the recipients. We are yet to determine the significance of this.TableStatin gp vs. non-statin gp allograft for % markersMedian (range)Statin N=40Median (range)Non-statin N=25Wilcoxon test p-valueCD3-/CD5616+8.00 (2.30-26.90)10.75 (4.7-20.0)0.0374CD3+/CD134+1.40 (0.30-8.70)3.1 (0.5-11.2)0.0367CD3+ / CD86+0.20 (0.05-0.56)0.3 (0.1-0.5)0.0148CD4+/CD25+/CD127-0.10 (0-1.60)1.0 (0-4.7)<0.0001CD4+/CD25+/CD127-ALT0.25 (0-1.20)0.6 (0.2-1.5)0.0072CD3-/CD5616+/CD158b+1.70 (0.30-5.40)2.7 (0.4-9.7)0.0225CD3-/CD5616+/CD159a+1.60 (0.20-5.30)3.4 (0.8-8.3)0.0003Statin gp D 30 vs. non-statin D 30CD19+1.20 (0-21.10)0.7 (0-5.8)0.0194CD3+/CD134+0.60 (0-9.60)3.4 (0.2-7.3)0.0010CD4+/CD25+/CD127-0.20 (0-2.30)0.9 (0-3.6)0.0010CD3-/CD5616+/CD69+0.30 (0-2.10)0.8 (0-18.9)0.0010CD3-/CD5616+/CD159a+13.80 (0.50-28.10)20.9 (1.3-48.3)0.0220CD3-/CD5616+/CD314+5.90 (0.60-28.60)15.1 (2.1-39.3)0.0021CD3-/CD5616+/CD63+/CD314+0.30 (0-3.40)2.7 (0.3-17.6)<0.0001CD16+/CD56+/CD3-/CD117-9.90 (0.70-38.20)21.6 (3.9-47.8)0.0009Statin gp D 100 vs. non-statin D 100CD3+ / CD86+0.2 (0-1.3)0.5 (0.1-1.3)0.0158CD4+/CD25+/CD127-0.1 (0-0.9)0.8 (0.1-1.8)0.0002CD3-/CD5616+/CD63+/CD314+0.3 (0-6.3)1.9 (0.2-14.8)0.0003CD16+/CD56+/CD3-/CD117-8.6 (0-28.8)11.5 (6.6-51.3)0.0660 DisclosuresBlum:Celgene: Consultancy.

New Interleukin-15 Superagonist (IL-15 SA) Combined with Donor Lymphocyte Infusion (DLI) Significantly Enhances Graft-Versus-Tumor Activity after Allogeneic Hematopoietic Stem Cell Transplantation

Donor lymphocyte infusion (DLI) has been successfully used clinically to augment the graft-versus-tumor (GVT) effect following hematopoietic stem cell transplantation (HSCT) in relapsed patients. However, improvements can still be made in enhancing anti-tumor activity, reducing graft-versus-host disease (GVHD) and decreasing complications from opportunistic infections. Our studies present clear evidence of increased tumor clearance via cytokine therapy in combination with DLI as a way to “boost” the infused cells function. Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cells number and function in normal mice and recipients of stem cell transplantation. Despite this, obstacles remain for use of IL-15 therapeutically, specifically its low potency and short in vivo half-life. To overcome this, a new IL-15 superagonist (IL-15 SA-(ALT-803)) has been developed with a longer half-life and increased potency.Administration of IL-15 SA to recipients of CFSE labeled T cells increases proliferation of CD8+T cells and IFN-γ and TNF-α secretion from CD8+T cells. We developed a murine DLI model by titrating the dose of infused T cells in a parent-F1 model, and then combined IL-15 SA administration with DLI in murine recipients of allogeneic HSCT. In this model, lethally irradiated CB6F1 (H2Kb/d) mice were transplanted with T- cell depleted bone marrow cells from C57BL6 mice (H2Kb). All recipients of HSCT were also co-injected A20 B-cell lymphoma cells transfected with a luciferase-producing gene, which allows bioluminescent imaging and tracking of tumor progress in vivo. Mice receiving DLI (2.5 X 105 T cells) with IL-15 SA injections given at 1μg/mouse on days 17 and 24 post-BMT show less tumor burden and increased overall survival (p = 0.04) and decreased tumor growth (p = 0.02) (Figure 1). The IL-15 SA treated group had a significantly less weight loss than the control group (p = 0.007). No GVHD symptoms were noted via weekly clinical scoring, highlighting both the efficacy and overall safety of the IL-15 SA therapy. Furthermore, we evaluated T- cell exhaustion markers on CD8+ T cells in surviving mice. We found increased programmed death-1 (PD-1) expression on T cells even when the tumor burden is cleared. Treatment with IL-15 SA reduced PD-1 expression on donor CD8+ T-cells in mice surviving more than 120 days post-transplant.We conclude that IL-15 SA enhances CD8+ T cell function by increasing cytokine secretion and proliferation of T cells whereas could also prevent T cell exhaustion. We suggest that IL-15 SA is a long-waited lymphoid growth factor and has the potential to use in combination with DLI for the treatment of recurrent disease after HSCT. DisclosuresNo relevant conflicts of interest to declare.

The Effect of Cidofovir on Adenovirus Plasma DNA Levels in Stem Cell Transplantation Recipients without T Cell Reconstitution

Cidofovir is frequently used to treat life-threatening human adenovirus (HAdV) infections in immunocompromised children after hematopoietic stem cell transplantation (HSCT). However, the antiviral effect irrespective of T cell reconstitution remains unresolved. Plasma HAdV DNA levels were monitored by real-time quantitative PCR during 42 cidofovir treatment episodes for HAdV viremia in 36 pediatric allogeneic HSCT recipients. HAdV load dynamics were related to T and natural killer (NK) cell reconstitution measured by flow cytometry. To evaluate the in vivo antiadenoviral effect of cidofovir, we focused on 20 cidofovir treatment episodes lacking concurrent T cell reconstitution. During 2 to 10 weeks of follow-up in the absence of T cells, HAdV load reduction (n = 7) or stabilization (n = 8) was observed in 15 of 20 treatments. Although HAdV load reduction was always accompanied by NK cell expansion, HAdV load stabilization was measured in 2 children lacking both T and NK cell reconstitution. In cases with T cell reconstitution, rapid HAdV load reduction (n = 14) or stabilization (n = 6) was observed in 20 of 22 treatments. In the absence of T cells, cidofovir treatment was associated with HAdV viremia control in the majority of cases. Although the contribution of NK cells cannot be excluded, cidofovir has the potential to mediate HAdV load stabilization in the time pending T cell reconstitution.

Immunotherapeutic strategies against mucormycosis in haematopoietic stem cell transplantation.

Mucormycoses remain a serious complication in patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT). In these patients, mortality rates of mucormycosis reach up to 90%, which is due, at least in part, to the severe and prolonged immunosuppression after transplantation. Although prolonged neutropaenia is one of the most important risk factors for mucormycosis, other cell populations, such as CD4(+) T cells may also provide critical defence mechanisms against this infection. The management of mucormycosis includes antifungal therapy, surgery and, most importantly, the control of the underlying predisposing conditions, such as the correction of an impaired immune system. Here, we review the current data of granulocytes, antifungal T cells and natural killer cells regarding their activity against mucormycetes and regarding a potential immunotherapeutic approach. It is hoped that further animal studies and clinical trials assessing immunotherapeutic strategies will ultimately improve the poor prognosis of allogeneic HSCT recipients suffering from mucormycosis.

Late-onset noninfectious interstitial lung disease after allogeneic hematopoietic stem cell transplantation

Various late-onset noninfectious pulmonary complications may occur after allogeneic hematopoietic stem cell transplantation (HSCT). Interstitial lung diseases (ILD) are often overlooked, and few data are available. We retrospectively analyzed the clinical features, pulmonary function tests, radiological features and outcomes of allogeneic HSCT recipients who were diagnosed with a noninfectious ILD and were managed in our center between 2001 and 2010. Forty patients were analyzed. The median time from transplant to ILD was 11.3 months. The donor hematopoietic stem cell source was peripheral blood stem cells in 75% of the cases. Seventy percent of the patients had extra-thoracic chronic graft versus host disease at ILD diagnosis. We identified two lung computed tomography (CT) scan patterns according to the predominance of ground glass opacities or alveolar consolidations. Restrictive ventilatory defect was the main pulmonary function pattern. Lung histology was available for seven patients and showed diffuse alveolar damage, non-specific interstitial pneumonia, organizing pneumonia or lymphoid interstitial pneumonia. Thirty-five patients (87.5%) were treated with systemic steroids. Thirteen patients died (32.5%), 10 of respiratory failure. The median survival rate at 24 months was 61%. This study highlights the existence of noninfectious post-allogeneic HSCT ILD and provides new insights into the characteristics of these illnesses.

Factors associated with cytomegalovirus reactivation following allogeneic hematopoietic stem cell transplantation: human leukocyte antigens might be among the risk factors.

Objective: Cytomegalovirus (CMV) is a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (AHSCT) recipients. Current practice includes prophylactic and preemptive treatment modalities, which have risks, side effects, and costs of their own. There is no established risk scoring system that applies to all patients. We aimed to investigate the risk factors for CMV reactivation in AHSCT recipients.Materials and Methods: We retrospectively analyzed the risk factors for CMV reactivation in 185 consequent AHSCT recipients transplanted between September 2003 and December 2009 at the Stem Cell Transplantation Unit of Gazi University. Besides the standard transplant-related parameters, HLA antigens were also included among the variables analyzed. Results: Despite the very high rate of donor (94.6%) and recipient (100%) seropositivity, which are the so-called major risk factors in previous reports, our reactivation rate was much lower, with a frequency of 24.9%. The underlying disease, sex, conditioning regimen, and presence of antithymocyte globulin or fludarabine in the conditioning regimen had no impact on reactivation rate. CMV reactivation was significantly more frequent in recipients with graft-versus-host disease (GVHD) compared to those without GVHD (p<0.0001). CMV reactivation was significantly more frequent (p<0.05) in patients with HLA-B14, HLA-DRB1*01, and HLA-DRB1*13 antigens and less frequent in recipients with HLA-A11 and HLA-DRB1*04 antigens (p<0.05). Conclusion: Universal risk factors/scores that apply to all transplant recipients are required for tailored prophylaxis and/or treatment strategies for CMV reactivation. Uncovering the role of genetic factors, including HLA antigens, as possible risk factors might lead the way to risk-adaptive strategies for adoptive cellular therapy and/or vaccination.

Evaluation of the immune status against measles, mumps, and rubella in adult allogeneic hematopoietic stem cell transplantation recipients

BackgroundPrevious studies have shown that most patients lose immunity to measles, mumps, and rubella (MMR) during long-term follow-up after allogeneic hematopoietic stem cell transplantation (HSCT), and immunizations against them have been investigated. However, these previous studies mainly targeted pediatric patients and information in adult patients is still insufficient.MethodsWe evaluated the immunity to MMR in 45 adult allogeneic HSCT patients. None of these patients received vaccination after HSCT.ResultsThe seropositive rates at six years after allogeneic HSCT were estimated to be less than 44% for measles, less than 10% for mumps, and less than 36% for rubella. Thirteen of the 16 female patients who were 16–39 years old were negative or equivocal for rubella. Patients who developed grade II–IV acute graft-versus-host disease tended to become seronegative for measles and rubella at two years after HSCT, although the difference was not statistically significant.ConclusionsThis study showed that most adult patients lost immunity to MMR after allogeneic HSCT. Although we did not evaluate the safety and efficacy of vaccination in this study, most HSCT guidelines recommend vaccination for HSCT recipients without active chronic graft-versus-host disease or ongoing immunosuppressive therapy at 24 months after HSCT. Immunization against rubella is especially important for female patients of reproductive age. Further studies will be necessary to evaluate the effect of vaccination on the antibody response in adult allogeneic HSCT recipients.

Busulfan dosing (Q6 or Q24) with adjusted or actual body weight, does it matter?

In hematopoietic stem cell transplantation (HSCT), patients receive individualized treatment planning in conditioning regimens to prevent unwarranted toxicities while maximizing desired outcomes. The dose of a widely studied agent in this setting, busulfan, can be adjusted based on area under the curve (AUC); however, choice of actual body weight (ABW) versus adjusted body weight (DBW) weight to calculate the initial dose may be critical in attaining goal AUC. To determine which weight best correlates with achievement of goal AUC for patients receiving busulfan conditioning for HSCT. Secondary objectives include evaluation of AUC results with clinical outcomes such as toxicity and survival. An institutional review board-approved retrospective analysis was performed on 31 allogeneic HSCT recipients who received intravenous busulfan (Q6H with cyclophosphamide [Bu/Cy] or once daily with fludarabine [Flu/Bu]). Eighteen patients received Flu/Bu (50% ABW, 50% DBW) and 13 received Bu/Cy (23% ABW, 77% DBW). Overall, patients dosed by DBW were more likely to undershoot goal AUC (-12.8% vs. +19.5%, p = 0.018) and require dose increases (+20% vs. -19.9%, p = 0.012) versus those dosed by ABW. Subgroup analysis confirmed these results for Bu/Cy (-23.6% vs. +2.2%, p < 0.001 for goal AUC; +36.2% vs. -4.5%, p = 0.008 for busulfan dose increase), but not Flu/Bu (-0.8% vs. +25.3%, p = 0.123 for goal AUC; +3.4% vs. -25.1%, p = 0.174 for busulfan dose increase). Time to engraftment, progression-free survival, and overall survival were not different between dosing groups (p > 0.05). No patient experienced busulfan-related toxicity. Further prospective studies are warranted to elucidate which weight is most likely to achieve goal AUC and subsequent optimal patient outcomes.

Impact of peri-transplant vancomycin and fluoroquinolone administration on rates of bacteremia in allogeneic hematopoietic stem cell transplant (HSCT) recipients: A 12-year single institution study

We analyzed the effect of peri-transplant prophylaxis on the epidemiology of bacteremia in a 12-year contemporary cohort of allogeneic HSCT recipients at our center. This was an observational study of 1052 consecutive adult HSCT from 2000 to 2011. Formal prophylaxis with vancomycin only, fluoroquinolone (FQ) only, or vancomycin+FQ was implemented in 2006. The cumulative incidence of day 100 bacteremia was compared between the Early Period (2000-2005) and the Recent Period (2006-2011). Predictors for pre-engraftment bacteremia were analyzed with Cox-proportional hazard models in a subcohort of 821 HSCT who received myeloablative or reduced intensity conditioning (MA/RIC). The incidence of bacteremia decreased in the Recent Period (32% vs 27%; P=0.002), whereas the rates of resistance in gram-negative rods (GNR) and vancomycin-resistant enterococci (VRE) were similar between the two Periods (P values are not statistically significant.) In multivariate analyses, prophylaxis with vancomycin only or vancomycin+FQ was protective (HR=0.5; CI=0.30-0.72) and (HR=0.3; CI=0.12-0.52, P<0.01). Vancomycin or vancomycin+FQ eliminated viridans streptococcal bacteremia (VSB); vancomycin+FQ decreased GNR bacteremia (HR=0.35; CI=0.15-0.85). Vancomycin-based prophylaxis peri-transplant in MA/RIC HSCT was associated with elimination of VSB and may be considered at centers with high incidence of this infection.

Outcomes of Lung Transplantation after Allogeneic Hematopoietic Stem Cell Transplantation

Other than lung transplantation (LT), no specific therapies exist for end-stage lung disease resulting from hematopoietic stem cell transplantation (HCT)-related complications, such as bronchiolitis obliterans syndrome (BOS). We report the indications and outcomes in patients who underwent LT after HCT for hematologic disease from a retrospective case series at our institution and a review of the medical literature. We identified a total of 70 cases of LT after HCT, including 9 allogeneic HCT recipients from our institution who underwent LT between 1990 and 2010. In our cohort, the median age was 16 years (range, 10 to 35 years) at the time of HCT and 34 years (range, 17 to 44 years) at the time of LT, with a median interval between HCT and LT of 10 years (range, 2.9 to 27 years). Indications for LT-included pulmonary fibrosis (n = 4), BOS (n = 3), interstitial pneumonitis related to graft-versus-host disease (GVHD) (n = 1), and primary pulmonary hypertension (n = 1). Median survival was 49 months (range, 2 weeks to 87 months), and 1 patient remains alive at more than 3 years after LT. Survival at 1 year and 5 years after LT was 89% and 37%, respectively. In the medical literature between 1992 and July 2013, we identified 20 articles describing 61 cases of LT after HCT from various centers in the United States, Europe, and Asia. Twenty-six of the 61 cases (43%) involved patients age <18 years at the time of LT. BOS and GVHD of the lung were cited as the indication for LT in the majority of cases (80%; n = 49), followed by pulmonary fibrosis and interstitial lung disease (20%; n = 12). In publications reporting 3 or more cases with a follow-up interval ranging from the immediate postoperative period to 16 years, the survival rate was 71% (39 of 55). Most deaths were attributed to long-term complications of the lung allograft, including infections and BOS. Two deaths were related to recurrent or relapsed hematologic malignancy. LT can prolong survival in some patients who suffer from end-stage pulmonary complications after HCT. Patient factors that likely improve the chances of a good long-term outcome include young age, at least 2 years post-HCT free of relapse from the original hematologic malignancy, and lack of other end-organ dysfunction or manifestations of chronic GVHD that require treatment with immunosuppressive agents.

Immunosuppressive Compounds Exhibit Particular Effects on Functional Properties of Human Anti-Aspergillus T H 1 Cells

Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at high risk for invasive aspergillosis. Whereas adoptive immunotherapy transferring donor-derived anti-Aspergillus TH1 cells has been shown to be beneficial for HSCT recipients suffering from invasive aspergillosis, little is known about the impact of commonly used immunosuppressants on the functional properties of anti-Aspergillus TH1 cells. Anti-Aspergillus TH1 cells were coincubated with different concentrations of methylprednisolone, cyclosporine (CsA), mycophenolic acid (MPA), the active component of mycophenolate mofetil, and rapamycin. Immunosuppressants were tested in concentrations reflecting common target levels in serum and in significantly lower and higher concentrations. Apoptosis of anti-Aspergillus TH1 cells, as well as proliferation and production of gamma interferon (IFN-γ) and CD154 upon restimulation, was evaluated in the presence and absence of immunosuppressive compounds. All dosages of CsA, MPA, and methylprednisolone significantly decreased the number of viable anti-Aspergillus TH1 cells in the cell culture, which was due partly to an impaired proliferative capacity of the cells and partly to an increased rate of apoptosis. In addition, CsA significantly decreased the number of IFN-γ-producing cells and had the highest impact of all immunosuppressants on IFN-γ levels in the supernatant. CsA also significantly decreased the expression of CD154 by anti-Aspergillus TH1 cells. Variant dosages of immunosuppressants exhibit particular effects on essential functional properties of anti-Aspergillus TH1 cells. Our findings may have an important impact on the design of clinical trials evaluating the therapeutic benefit of anti-Aspergillus TH1 cells in allogeneic HSCT recipients suffering from invasive aspergillosis.

Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.