Adult Hematopoietic Stem Cell Transplantation Recipients Research Articles

Enteral Vancomycin Is Effective Clostridium Difficile prophylaxis in Pediatric, Adolescent, and Young Adult Hematopoietic Stem Cell Transplant Recipients

Background Clostridium difficile infection (CDI) is a major source of morbidity for patients undergoing autologous and allogeneic hematopoietic stem cell transplantation (HSCT). CDI can complicate gastrointestinal mucositis, lead to mucosal barrier infections or sepsis, and compromise nutrition after HSCT. CDI may contribute to acute gastrointestinal graft-versus-host disease (GI aGVHD) and reduce overall survival in allogeneic HSCT patients. Use of enteral vancomycin as CDI prophylaxis may reduce morbidity and improve outcomes in HSCT recipients. Methods As a quality improvement initiative, enteral vancomycin was instituted as CDI prophylaxis in all autologous and allogeneic HSCT recipients at Methodist Children's Hospital beginning 02/13/19. Patients were prescribed vancomycin 125 mg oral/enteral twice daily (Ganetsky et al. Clin Infect Disease 2019; 68 (12):2003-2009) from HSCT admission to discharge home. Patients readmitted during the first 100 days after HSCT resumed enteral vancomycin while hospitalized. Physicians, advanced practice providers, and pharmacists monitored enteral vancomycin administration. The infectious disease and prevention team monitored CDI and weekly vancomycin resistant enterococcus (VRE) stool testing per institutional policy. Pre- and post-implementation data was retrospectively reviewed (number of HSCT patients, CDI, VRE, adverse events of enteral vancomycin, and GI aGVHD). Two-sided Fisher's exact test was used to compare CDI before and after institution of enteral vancomycin prophylaxis. Results Between 01/05/2018 and 02/12/2019, the rate of CDI was 29% (n=9/31). After implementation of CDI prophylaxis (02/13/19 to 09/16/19), the rate of CDI was 0% (n=0/23). Enteral vancomycin resulted in a significant reduction in the number of CDI cases (p=0.0068). Prior to implementation of CDI prophylaxis, 26% (n=7/27) of allogeneic HSCT recipients developed GI aGVHD. Of the 7 patients that developed GI aGVHD, 6 had a history of CDI. After implementation of CDI prophylaxis, 7% (n=1/14) of allogeneic HSCT recipients developed GI aGVHD. There were no VRE positive screens or infections. There were no adverse events related to enteral vancomycin. Conclusions Enteral vancomycin appears to be safe and effective CDI prophylaxis in pediatric, adolescent, and young adult HSCT recipients. Since institution of enteral vancomycin prophylaxis, there has been a significant reduction of CDI in our HSCT patients. This quality improvement project is ongoing and future analyses will compare GI aGVHD and overall survival with CDI pre- and post-implementation of enteral vancomycin prophylaxis.

Day 0 bone marrow pathology of allogeneic hematopoietic stem cell transplantation is a novel prognostic factor in myeloid malignancies.

Residual disease (RD) is one of the risk factors for relapse after hematopoietic stem cell transplantation (HSCT) in hematological malignancies. Although recent advances in the technology for detecting minimal/measurable RD, such as multiparameter flow cytometry and quantitative PCR, enable risk stratifications of disease relapse, these examinations still have limitations in routine clinical practice. In this study, we assessed RD in bone marrow (BM) specimens on day 0 of allogeneic HSCT by immunostaining of case-specific leukemic blast markers and analyzed the relationship between day 0 BM status and HSCT outcomes. We analyzed 82 adult HSCT recipients with myeloid malignancies. BM histology of day 0 revealed almost empty marrow with a small number of residual BM cells. However, residual blasts could be detected by immunostaining even for only a few cells. When patients were divided into two groups according to the existence of RD on day 0, those with positive RD showed significantly lower overall survival rate (27% vs. 73%, P<0.001) and higher cumulative incidence of relapse (46% vs. 9%, P=0.006) at one year compared to those with negative RD. Furthermore, even if they were not in remission at the point of the pre-conditioning evaluation, the patients who achieved negative RD on day 0 showed comparable prognosis with those who maintained remission before conditioning. This study shows the efficacy of day 0 BM pathology of allogeneic HSCT as a prognostic factor that can contribute to clinical decisions on post-transplant strategies.

Acute kidney injury in hematopoietic stem cell transplantation.

Acute kidney injury (AKI) in the setting of hematopoietic stem cell transplantation (HSCT) is common in pediatric and adult patients. The incidence ranges from 12 to 66%, and development of AKI in the posttransplant course is independently associated with higher mortality. Patients who undergo HSCT have many risk factors for developing AKI, including sepsis, use of nephrotoxic medications, graft versus host disease (GVHD), and veno-occlusive disease (VOD). In addition, engraftment syndrome/cytokine storm, transplant-associated thrombotic microangiopathy (TA-TMA), and less common infections with specific renal manifestations, such as BK and adenovirus nephritis, may lead to kidney injury. There has been significant advancement in the understanding of TA-TMA in particular, especially the role of the complement system in its pathophysiology. The role of early dialysis has been explored in the pediatric population, but not well studied in adult HSCT recipients SUMMARY: This review provides an update on the risk factors, causes, and treatment approaches to HSCT-associated AKI.

A Single-Center Experience and Literature Review of Management Strategies for Clostridium difficile Infection in Hematopoietic Stem Cell Transplant Patients

The aim of our study is to evaluate risk factors associated with the development of C. difficile infection (CDI) in hematopoietic stem cell transplant (HSCT) patients, determine its incidence and report outcomes of CDI in our patient population. We performed a retrospective review of medical records of adult HSCT recipients diagnosed between 2013 and 2016 at our center. Logistic regression models were used to determine the relationship between risk factors and the odds of CDI. The overall incidence of CDI in HSCT patients was 9.4%. The incidence of CDI was higher in allogeneic HSCT (20%) versus autologous HSCT (4.8%). No statistically significant differences in age, gender, cancer type, transplant type were found between those who developed CDI and those who did not. However, patients with CDI had a longer length of stay (25 days) and used more antibiotics (30 days prior to and during admission for HSCT) than non-CDI patients (19 days). Only two of 17 patients (11.8%) with CDI experienced recurrence among 180 patients after HSCT. No patient suffered from toxic megacolon or ileus and no patient underwent colectomy. There was no mortality associated with CDI at our center. CDI has an incidence rate of 9.4% in HSCT recipients. Established risk factors including age, gender, cancer type, and transplant type were not identified as risk factors in our population. However, longer LOS and use of greater than four lines of antibiotics were observed among those with CDI compared to those without CDI.

Prevalence and Associated Factors for Arterial Hypertension in Adults Following Hematopoietic Stem Cell Transplantation

Background: Survivors of hematopoietic stem cell transplantation (HSCT) are 2 to 4 times more likely to develop cardiovascular diseases, accounting for 2-11% of mortality among long-term survivors. Early diagnosis and treatment of modifiable risk factors, such as arterial hypertension, are imperative in this group of patients. The aim of this study is to evaluate the prevalence and associated factors for arterial hypertension following HSCT in a Colombian population. Methods: A retrospective study was conducted in 220 consecutive adult HSCT recipients who underwent transplantation between 2009 and 2017 at a third level referral center in Colombia. Blood pressure data, from two different measures, were collected at 7 time points: day of mobilization for autologous HSCT (auto-HSCT) and day 0 before infusion for allogeneic HSCT (allo-HSCT), day 7, and months 1, 3, 6 and 12 post-HSCT. Arterial hypertension was defined as a systolic blood pressure 140mmHg and/or a diastolic blood pressure 90 mmHg. Patients with history of arterial hypertension were excluded. Descriptive statistics were used to analyze patient's demographic data. Bivariate and multivariate analyses were performed to assess the association between clinical characteristics and arterial hypertension. Results: One hundred and seventy-one patients were included, with a median age of 45 years (range 18-71). Eighty-nine patients (52.1%) were male. One hundred and fifteen patients (67.3%) underwent auto-HSCT and 56 (32.7%) allo-HSCT. The most common indication for HSCT were lymphomas (39.8%), followed by leukemia (28.6%) and multiple myeloma (23.4%). Thirty-six patients (21.1%) developed arterial hypertension by the end of the first year of follow-up. Prevalence of hypertension at each time point was 2.3% on day 7 post-HSCT, 4.7%, 5.3%, 5.5% and 8.1% at 1, 3, 6 and 12 months respectively. Allo-HSCT (P&lt;0.001), diagnosis of leukemia (P&lt;0.001) or lymphoma (P&lt;0.05), therapy with calcineurin inhibitors (P=0.004), prophylactic treatment for GvHD with mycophenolate (P&lt;0.05) and acute GvHD (P&lt;0.001) were significantly associated with the development of arterial hypertension. After performing multivariate regression analysis to identify arterial hypertension associated factors, patients with allo-HSCT were found to be 3 times more likely to develop arterial hypertension than patients with auto-HSCT (95% CI 1.85-8.60, P=0.000). Conclusions: Screening for arterial hypertension is warranted in HSCT survivors since it is a modifiable cardiovascular risk factor. Similar to previously reported findings, we found an association between post-HSCT arterial hypertension and allo-HSCT, use of calcineurin inhibitors and mycophenolate, and development of acute GvHD. Patients undergoing allo-HSCT are at increased risk of developing hypertension. Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

1767. Incidence of Respiratory Syncytial Virus Infection among Adults Undergoing Hematopoietic Stem Cell Transplantation: A Prospective Study from India

Background Respiratory Syncytial Virus (RSV) is an important cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients; progression from Upper Respiratory Tract Infection (URI) to Lower Respiratory Tract Infection (LRTI) may occur in 30%–40% of transplant recipients with associated high fatality. Data on disease burden due to RSV among adult HSCT recipients is limited with no earlier reports from India.MethodsWe prospectively studied 50 HSCT recipients who underwent hematopoietic stem cell transplantation at our institute from January 2017 onwards. Patients were followed up for a period of 18 months post-transplant, initially during stay in transplant unit and subsequently on out-patient basis and telephonically for any episode of acute respiratory tract infection. Information on symptoms and signs at presentation as well as basic hematological and radiological investigations were collected. Nasal and throat swabs from symptomatic patients were taken in viral transport medium and tested for RSV by real-time RT–PCR. As per institute policy patients had received prophylaxis with acyclovir and itraconazole till day +30 post-transplant.ResultsA total of 68 episodes of acute respiratory tract infection were tested for RSV during the follow-up period (mean ± standard deviation = 12 ± 5 months; 11 patients expired during follow-up period). Of these 21 were URI episodes, 46 were acute bronchitis episodes and 1 was a pneumonia episode. Two episodes tested positive for RSV in two autologous HSCT recipients, both belonging to RSV-B subtype, one from a URI episode on day 163 of HSCT and the other from a pneumonia episode on day 8 after HSCT. Both recovered without specific targeted treatment against RSV. The incidence of RSV infection in post-HSCT adult patients calculated from this study is 4% per year.ConclusionThere is significant incidence of RSV infection among post-HSCT adults in India. Nevertheless, institution of targeted treatment options depends on weighing the cost and risk against benefit of using them. RSV-B subtype as seen in this study also is less virulent and less likely to lead to LRTI compared with RSV-A. Clinical predictors of poor outcomes can also help to decide upon prophylaxis. Larger studies focusing on preventing progression to LRTI need to be done. Disclosures All authors: No reported disclosures.

1393. Tuberculosis (TB) After Solid-organ Transplant (SOT) and Hematopoietic Stem Cell Transplant (HSCT)

BackgroundTuberculosis is an important opportunistic infection that affects transplant recipients; the risk of active infection increases significantly when compared with the general population. Most disease results from reactivation of latent infection, being extrapulmonary and disseminated disease the most common presentations. Most cases occur during the first year post-transplantation when immunosuppression is higher. We describe the clinical characteristics of patients diagnosed with TB after transplant.MethodsSingle-center, retrospective study of adult SOT and HSCT recipients in Mexico City, who developed active TB after transplant. We reviewed medical records, and collected demographic data, clinical characteristics, and outcome.ResultsWe identified 16 patients with post-transplant TB; 13 SOT, and 3 HSCT recipients. The majority of SOT recipients were women (53.8%); median age was 43 years, 9 were kidney and 4 liver transplant recipients. At TB diagnosis, 84.6% of patients were on 3 immunosuppressors. Latent TB was assessed before transplant in 5 patients (38.4%), of these 3 (60%) were tuberculin skin test+, and 2 received isoniazid. Extrapulmonary disease was most common (7, 53.8%). Predominant symptoms were fever (53.8%), chills (30.8%), and diaphoresis (38.5%); six were diagnosed during the 1st year (46.2%) post-transplant; the median of time to diagnosis was 24 months after transplant. The diagnosis was made by histopathology in most cases. Twelve patients received first-line anti-TB treatment. Overall mortality was 30.8%, directly attributable to TB in 2. In the HSCT group, 2 were women; median age was 22 years, 2 allogeneic and 1 autologous transplant. One patient had been treated for latent TB before transplantation. Two developed disseminated disease. Two patients presented within 6 months after the transplant, and the other within a year. Mortality was 100%, attributable to the infection in two patients.ConclusionIn regions with intermediate to a high prevalence of TB; post-transplant TB could result from reactivation or post-transplant exposure. Most cases occur within the first year post-transplant; clinical symptoms are nonspecific, which lead to a delay in diagnosis. Morbidity and mortality remains high.Disclosures All authors: No reported disclosures.

Common oral diseases, hyposalivation and survival post-HSCT, a longitudinal study.

Haematopoietic stem cell transplantation (HSCT) recipients are at risk of side effects within the oral cavity. The purpose of this study was to examine progression of common oral diseases and hyposalivation and their associations with survival in allogeneic HSCT recipients. Two hundred and sixty nine adult HSCT recipients treated with HSCT between 2008 and 2016 were included in this study. The associations of caries, decayed, missing, filled teeth (DMFT) index, radiological attachment loss and stimulated salivary flow rate with 6-month survival and the progression of the oral disorders within 2years were examined. Forty HSCT recipients (14.8%) deceased within 6months post-HSCT. Among the deceased recipients, hyposalivation and caries were more common pre-HSCT than in recipients who survived over 6months (P<0.05). HSCT recipients with hyposalivation pre-HSCT had higher risk of death (HR: 1.90, 95% CI:1.00-3.60; P=0.044) within 6months post-HSCT compared with recipients without hyposalivation. Hyposalivation pre-HSCT was associated with a higher DMFT index score (P<0.05) and a smaller number of teeth (P<0.005) 24months post-HSCT in comparison with those without hyposalivation. Hyposalivation and caries were associated with a lower rate of survival in HSCT recipients. Additionally, hyposalivation predisposed to deterioration of oral health post-HSCT.

Safety and Seropositivity after Live Attenuated Vaccine in Adult Patients Receiving Hematopoietic Stem Cell Transplantation

Vaccination against vaccine-preventable diseases (VPDs) is highly recommended for hematopoietic stem cell transplantation (HSCT) recipients by several guidelines; however, the safety and seropositivity after live attenuated vaccines remain unclear in adult HSCT recipients. We analyzed titers of antibodies against measles, rubella, mumps, and varicella zoster virus (VZV) from Japanese adult patients who underwent allogeneic HSCT (allo-HSCT) (n = 74), autologous HSCT (auto-HSCT) (n = 39), or chemotherapy (n = 93). The seropositive rates for measles, rubella, mumps, and VZV in allo-HSCT recipients were 20.2%, 36.4%, 5.4%, and 55.4%, respectively. These rates were equivalent to those in auto-HSCT recipients but were significantly lower than those in patients receiving chemotherapy. Antibody titers tended to gradually decrease with time. Twenty-nine allo-HSCT recipients and 8 auto-HSCT recipients received live attenuated vaccines against VPDs for which they tested seronegative. The titers of antibodies against measles, rubella, and mumps significantly increased after 2 shots of vaccine, and the seropositive rate increased up to 19%, 30%, and 27%, respectively. Three patients (8.1%) experienced mild adverse events, which resolved promptly, indicating safe administration of the live attenuated vaccines. In multivariate analysis, history of chronic graft-versus-host disease was significantly associated with high seropositivity for measles as well as high seroconversion rate for measles after vaccination. Live attenuated vaccines against VPDs were safely administered in seronegative adult HSCT recipients. A further observational study is crucial to evaluate the efficacy of vaccination in seronegative HSCT patients.

Common oral diseases in allogeneic haematopoietic stem cell transplantation (HSCT) recipients pre‐HSCT

The purpose of this study was to compare the prevalence of common oral diseases between allogeneic haematopoietic stem cell transplantation (HSCT) recipients and healthy controls. A total of 143 adult allogeneic HSCT recipients who were treated for haematological malignancies between 2008 and 2016 were included in the study. The HSCT recipients were age and sex matched with healthy controls. A dental examination was performed on the HSCT recipients prior to HSCT. Differences in stimulated saliva flow rate (SSFR), decayed, missing and filled teeth (DMFT) index, number of teeth, number of caries lesions, and measures of current or previous periodontitis (radiological attachment loss >3mm or probing pocket depth ≥4mm) between HSCT recipients and controls were examined. Stimulated saliva flow rate, DMFT index and the number of caries lesions were poorer in the HSCT recipients pre-HSCT compared to controls (all P-values <0.05). No statistically significant differences in the measures of current or previous periodontitis were observed. Stimulated saliva flow rate was low and caries was common in HSCT recipients prior to HSCT. Efficient preventive strategies are important in order to maintain the oral health of these patients.

5 Year Health Care Burden after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): Impact of Graft Source

BACKGROUND: Recipients of allogeneic HSCT experience significant short- and long-term healthcare burdens with differing general patterns of late effects between graft sources. For example, recipients of peripheral blood stem cell (PBSC) grafts benefit from more rapid engraftment after transplant as compared to bone marrow (BM) or umbilical cord blood (UCB), but experience a greater risk of chronic graft-versus-host disease (cGVHD) at later time points after HSCT. Little data exist regarding healthcare burden beyond first year of allogeneic HSCT, limiting our understanding of the long-term impact for each graft source.METHODS: To estimate the healthcare burden in adult allogeneic HSCT recipients over time, we analyzed clinical data from 1077 consecutive allogeneic HSCT recipients at the University of Minnesota Medical Center (UMMC) transplanted between 2000-2016. In order to understand changes in healthcare burden over time, we assessed the raw number of visits (both face-to-face and non-face-to-face care coordination visits), procedures, laboratory studies, medications, and relative value units (RVUs) over 3 time periods: (1) Day 0 to day 100, (2) 101 - 365 days, and (3) >1 year - 5 years after HSCT. We analyzed the counts of these healthcare elements both individually and as a composite score of all these elements (visits, procedures, labs, medications, RVUs). We then compared the estimated healthcare burden by graft source over each time period. We included only patients undergoing their first allogeneic HSCT in this analysis, and we included all clinical data from transplant to death or 5 years, whichever came first. We retained data from patients experiencing post-HSCT relapse in this analysis.RESULTS: Of the 1077 HSCT recipients, 102 received BM, 458 received PBSC, and 517 received UCB (84.7% double). The majority of BM donors were matched but unrelated to the recipient (57%), and the majority of PBSC donors were matched siblings (88%). The median age was 52.2 years (range 18.1 - 75.1 years), and 41.4% of the patients were female. The median distance from the patients' address to the transplant center was <30 miles, with no significant difference between the graft sources at any of the 3 time periods (p=0.12, p=0.10, p=0.09, respectively). The majority of patients had acute myeloid leukemia (40.8%), acute lymphoblastic leukemia (13.7%), non-Hodgkin lymphoma (13%), and myelodysplastic syndrome (12.8%). There was no significant difference in the proportions of patients with death (p=0.50) or relapse/progression (p=0.22) between graft sources over these time periods. As expected from previous data, recipients of PBSC had the lowest median composite healthcare burden in the first 100 days (p<0.01, Figure). During this earliest time period, the median number of laboratory studies (2,213 vs 2,448.0 vs 2,960, p<0.01), medications (132 vs 232 vs 203, p<0.01), and RVUs billed (423.2 vs 480.7 vs 466.7, p<0.01) were significantly lower for recipients of PBSC vs BM vs UCB respectively, with no difference in number of visits (p=0.07). From day 101 - 365, UCB had the lowest composite score (p=0.02) due to the fewest labs and visits performed (p<0.01 for each). There was no difference between medications (p=0.16) or RVUs (p=0.06) between graft sources in this second time period. Beyond 1 year, UCB continued to have the lowest composite score (p=0.02), with the lowest number of visits (p<0.01), labs (p<0.01), procedures (p=0.03), medications (p<0.01), and RVUs (p=0.02) with this graft source compared to BM and PBSC.CONCLUSION: Adult recipients of UCBT appear to experience a lower long-term healthcare burden compared to other graft sources. After the first year post-HSCT, recipients of UCBT have fewer clinic visits, laboratory tests, procedures, and medications. This study is the first step in analysis of complex, long-term healthcare burden data in allogeneic HSCT recipients within a single healthcare system. Despite the absence of cost data and details of care outside of Fairview, these data support the hypothesis that healthcare burden varies by graft source with favorable outcomes in long-term survivors after UCBT compared recipients of BM and PBSC. [Display omitted] DisclosuresBrunstein:Gamidacell: Research Funding. MacMillan:Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Wagner:Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding. Weisdorf:SL Behring: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy; FATE: Consultancy; Equillium: Consultancy. Holtan:Incyte: Consultancy.

Low T-Cell Responses to Mitogen Stimulation Predicts Poor Survival in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation.

Successful engraftment and reconstitution of the innate and adaptive immune system are associated with improved outcomes in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). A clinically meaningful and simple biomarker of immunosuppression could potentially assist clinicians in their decision-making. We aimed to determine the relationship between T-cell production of interferon gamma (IFN-γ) in response to phytohemagglutinin (PHA) to clinical outcomes in HSCT recipients. A prospective observational multicenter study of 73 adult allogeneic HSCT recipients was conducted in Melbourne, Australia. Eligible participants were >18 years and at risk of cytomegalovirus disease. T-cell responses to PHA were assessed at 3, 6, 9, and 12 months post-HSCT using the commercial quantiferon-cytomegalovirus assay, which quantifies IFN-γ production by ELISA following stimulation with PHA. A low response was defined as IFN-γ <0.5 IU/ml following stimulation with PHA. At 3 months post-HSCT, high responses to PHA (median IFN-γ 7.68 IU/ml) were seen in 63% of participants and low responses to PHA (median IFN-γ 0.06 IU/ml) in 37%. IFN-γ responses to PHA were significantly associated with the severity of acute graft versus host disease (AGVHD) (spearman r = -0.53, p < 0.001) and correlated with blood lymphocyte count (spearman r = 0.52, p < 0.001). Twelve month overall survival was greater in individuals with high compared to low IFN-γ response to PHA at 3 months [92 vs. 62%, respectively, Cox proportional hazard ratio (HR): 4.12 95% CI: 1.2-13.7, p = 0.02]. Non-relapse mortality (NRM) was higher in individuals with low IFN-γ response to PHA (competing risk regression HR 11.6 p = 0.02). In individuals with no AGVHD compared to AGVHD and high IFN-γ response to PHA compared to AGVHD and low IFN-γ response to PHA, 12-month survival was 100 vs. 80 vs. 52%, respectively (log rank test p < 0.0001). Low IFN-γ response to PHA at the 3-month time-point following allogeneic HSCT was predictive of reduced 12-month overall survival, increased NRM, and reduced survival in recipients with AGVHD. Assessing IFN-γ response to PHA post-HSCT may be a clinically useful immune biomarker.

Effective use of oral ribavirin for respiratory syncytial viral infections in allogeneic haematopoietic stem cell transplant recipients

Respiratory syncytial virus (RSV) is a frequent cause of respiratory viral infections, increasing the morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) recipients. Little is known about the best management strategy in this immunocompromised group and there are very few data on oral ribavirin treatment. To evaluate the effectiveness of oral ribavirin in allogeneic HSCT patients with RSV infection. Twenty-three RSV cases treated with oral ribavirin were analysed retrospectively. RSV diagnosis was established by polymerase chain reaction assay. Oral ribavirin was initiated at 15mg/kg/day in three divided doses for 10 days, with no subsequent dose escalation, as per centre policy. At diagnosis, seven patients presented with lower respiratory tract infection (RTI), whereas 16 had upper RTI. Oral ribavirin was well tolerated with minor adverse effects. The median treatment duration was 10 days (range: 5-47). After a median follow-up of 17 months (range: 4-48), 17 patients are alive. We recorded one RSV-related and five non-related deaths. To our knowledge, this is the largest single centre study yet performed on adult allogeneic HSCT recipients with RSV infection treated with oral ribavirin. Prompt initiation of treatment is essential and may avoid hospital admission. Our experience supports the use of oral ribavirin, but large prospective studies are needed to determine the optimal therapy in this patient group.

Dynamics of Epstein-Barr viral load after hematopoietic stem cell transplantation and effect of preemptive rituximab therapy.

Epstein-Barr virus (EBV) displays oncogenic properties, particularly in the immunocompromised host. Notably, hematopoietic stem cell transplantation (HSCT) recipients with a detectable blood EBV viral load (BEBVL) are considered at higher risk of post-transplant lymphoproliferative diseases (PTLD). Therefore, BEBVL is monitored after HSCT, and preemptive rituximab may be used in patients with high values. However, little is known about post-HSCT BEBVL dynamics, and the threshold that should lead to anti-CD20 therapy is poorly defined. We retrospectively analyzed the post-HSCT BEBVL of 332 adult HSCT recipients in our center from 2005 to 2013, including the effect of rituximab. Detection of BEBVL >100, 1000, 5000, 10000, and 50000copies/mL occurred in, respectively, 77.7%, 69.6%, 37.0%, 27.1%, and 7.5% of the patients after a respective median time of 9, 14, 15, 16, and 14weeks. No BEBVL threshold was associated with an overall survival difference. Seventy-eight patients received rituximab, with a BEBVL decrease in most. Among patients with detectable BEBVL, long-term survival did not differ in rituximab treated and non-treated, except for patients with BEBVL ≥50000. Only one case of PTLD was observed. BEBVL is frequently detectable after HSCT, but suggests no strong association with survival. Preemptive rituximab therapy threshold remains to be defined.

Community Acquired Respiratory Viral Infections (CARV) in Patients with Acute Leukemia and Hematopoietic Stem Cell Transplant (HSCT) Recipients

CARV infections are significant causes of morbidity and mortality in adult HSCT recipients. In 2008, the FDA approved the use of multiplex PCR assay to detect respiratory viruses. CARV infections have been studied mostly in the HSCT population where lymphopenia has been identified as a risk factor for poor outcomes. These infections have been less well studied in the acute leukemia population. This report, however, encompasses both patient populations.

Randomized Double-Blind Study of the Safety and Immunogenicity of Standard-Dose Trivalent Inactivated Influenza Vaccine versus High-Dose Trivalent Inactivated Influenza Vaccine in Adult Hematopoietic Stem Cell Transplantation Patients

Hematopoietic stem cell transplantation (HCT) survivors are less likely than matched healthy controls to mount a strong immune response to trivalent inactivated influenza vaccine (TIV). High-dose (HD) or standard-dose (SD) TIV were given to adult HCT subjects 18 years or older at least 6 months after transplantation. Subjects were randomized 2:1 to receive either the HD (60 μg hemagglutinin [HA]/strain/dose) or the SD (15 μg HA/strain/dose) TIV. Injection-site and systemic reactions were documented after each vaccination and immune responses were measured before and after each vaccination. A total of 44 subjects were enrolled (25 in year 1 and 19 in year 2), with 15 in the SD group and 29 in the HD group. The median time to vaccination after transplantation was 7.9 months (range, 6 to 106 months), the median age was 50 years (range, 19.6 to 73 years), and 61% were male. No differences in demographic or lab data were noted between groups; however, the HD group had higher median baseline total IgG level (676 versus 469 mg/dL, P = .025). No differences in individual injection-site or systemic reactions were noted between groups; however, more events of any injection-site symptom combined were reported in the HD group. No serious adverse events were attributed to vaccination. After vaccination, the HD group had a higher percentage of individuals with titers ≥1:40 and a higher geometric mean titer (GMT) against the H3N2 strain compared with that of the SD group. HD and SD TIV were found to be safe and well tolerated in adult HCT recipients. However, the HD group had higher frequency of injection-site reactions but the majority of the reactions were mild and resolved. The HD group had a higher percentage of individuals with post-vaccination titer ≥ 1:40 and GMT for H3N2 antigen, indicating better immunogenicity. These data support the need for a phase II immunogenicity trial in HCT recipients.

Prognosis of Allogeneic Haematopoietic Stem Cell Recipients Admitted to the Intensive Care Unit: A Retrospective, Single-Centre Study

Background: Allogeneic haematopoietic stem cell transplantation (HSCT) is a procedure with inherent complications and intensive care may be necessary. We evaluated the short- and long-term outcomes of the HSCT recipients requiring admission to the intensive care unit (ICU). Methods: We retrospectively examined the outcome of 54 adult haematological HSCT recipients admitted to the ICU at the University Hospital Rigshospitalet between January 2007 and March 2012. Results: The overall in-ICU, in-hospital, 6-month and 1-year mortality rates were 46.3, 75.9, 79.6 and 86.5%, respectively. Mechanical ventilation had a statistically significant effect on in-ICU (p = 0.02), 6-month (p = 0.049) and 1-year (p = 0.014) mortality. Renal replacement therapy also had a statistically significant effect on in-hospital (p = 0.038) and 6-month (p = 0.026) mortality. Short ICU admissions, i.e. <10 days, had a statistically significant positive effect on in-hospital, 6-month and 1-year mortality (all p < 0.001). The SAPS II, APACHE II and SOFA scoring systems grossly underestimated the actual in-hospital mortality observed for these patients. Conclusion: The poor prognosis of critically ill HSCT recipients admitted to the ICU was confirmed in our study. Mechanical ventilation, renal replacement therapy and an ICU admission of ≥10 days were each risk factors for mortality in the first year after ICU admission.

Variable Eculizumab Clearance Requires PharmacodynamicMonitoring to Optimize TherapyforThrombotic Microangiopathy after HematopoieticStem Cell Transplantation.

Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with eculizumab. We measured eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with eculizumab (n=18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n=11). In the PK analysis, we found significant interpatient variability in eculizumab clearance, ranging from 16 to 237mL/hr/70kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P=.003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first eculizumab dose (mg), accurately determined eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.

Reconstitution of Human Cytomegalovirus-Specific CD4+ T Cells is Critical for Control of Virus Reactivation in Hematopoietic Stem Cell Transplant Recipients but Does Not Prevent Organ Infection.

The relative contribution of human cytomegalovirus (HMCV)-specific CD4(+) and CD8(+) T cells to the control of HCMV infection in hematopoietic stem cell transplant (HSCT) recipients is still controversial. HCMV reactivation and HCMV-specific CD4(+) and CD8(+) T cell reconstitution were monitored for 1 year in 63 HCMV-seropositive patients receiving HSCT. HCMV reactivation was detected in all but 2 patients. In 20 of 63 (31.7%) patients (group 1) HCMV infection resolved spontaneously, whereas 32 of 63 (50.8%) patients (group 2) controlled the infection after a single short-course of pre-emptive therapy and the remaining 9 (14.3%) patients (group 3) suffered from relapsing episodes of HCMV infection, requiring multiple courses of antiviral therapy. The kinetics and magnitude of HCMV-specific CD8(+) T cell reconstitution were comparable among the 3 groups, but HCMV-specific CD4(+) T cells were lower in number in patients requiring antiviral treatment. HCMV-seronegative donors, as well as unrelated donors (receiving antithymocyte globulin) and acute graft-versus-host disease (GVHD) were associated with both delayed HCMV-specific CD4(+) T cell reconstitution and severity of infection. Conversely, these risk factors had no impact on HCMV-specific CD8(+) T cells. Eight patients with previous GVHD suffered from HCMV gastrointestinal disease, although in the presence of HCMV-specific CD4(+) and CD8(+) systemic immunity and undetectable HCMV DNA in blood. Reconstitution of systemic HCMV-specific CD4(+) T cell immunity is required for control of HCMV reactivation in adult HSCT recipients, but it may not be sufficient to prevent late-onset organ localization in patients with GVHD. HCMV-specific CD8(+) T cells contribute to control of HCMV infection, but only after HCMV-specific CD4(+) T cell reconstitution.

Prediction of Allogeneic Hematopoietic Stem-Cell Transplantation Mortality 100 Days After Transplantation Using a Machine Learning Algorithm: A European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. OM prevalence at day 100 was 13.9% (n=3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100-day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; P<.001). Calibration was excellent. Scores assigned were also predictive of secondary objectives. The alternating decision tree model provides a robust tool for risk evaluation of patients with AL before HSCT, and is available online (http://bioinfo.lnx.biu.ac.il/∼bondi/web1.html). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT.