Hematopoietic Stem Cell Transplantation Characteristics Research Articles

Infection-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplants at a Referral Center in Mexico

Abstract Background Infections constitute a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, infection-associated mortality rate ranging from 7% to 17% has been reported, depending on the type of HSCT, being lower in autologous transplants and higher in cases involving unrelated donors. Other factors related to HSCT that influence the clinical outcomes of these patients include the intensity of the conditioning regimen, the development of graft-versus-host disease (GVHD), cytotoxic and immunosuppressive effects of the medications used, the presence of disease activity prior to HSCT, length of hospital stay, and the use of intravascular devices, among many others. Methods All pediatric patients (under 16 years old) undergoing HSCT at the ‘Dr. José Eleuterio González’ University Hospital over a 55-month period (March 2019 – October 2023) were included. Clinical and epidemiological characteristics of the patients, mortality rate, and risk factors related to transplantation and infectious events (IEs) in these patients were recorded. Results A total of 75 patients who received HSCT were included, among them, 52 patients (69%) presented IEs. The mortality associated with IEs among these patients was 6% at day 30 and 12% at day 100, compared to 0% and 1.3% respectively in the non-IEs related deaths. The epidemiological characteristics, baseline diagnosis, donors and graft source are described in table 1. The average number of IEs in the associated mortality cases was 2.8 compared to 1.6 in the survival group. Among the mortality group (8 cases), 67% presented multiple infections and 33% single infections, with a 75% of them caused by viral infections. Regarding HSCT characteristics, in the group with IE-associated mortality, a higher proportion of haploidentical transplants, myeloablative conditioning regimens, lower use of total body irradiation, and a higher proportion of patients with detectable disease by flow cytometry prior to HSCT were observed compared to the survival group. Among non-infectious complications related to HSCT a lower frequency of acute GVHD grade I-II, a higher frequency of acute GVHD grade III-IV in the IE-associated mortality group was identified. Among the risk factors associated with hospital care, the IE-associated mortality group showed a higher use of central venous catheters, mucositis, systemic steroids, and pediatric intensive care unit stay compared to the survival group. Conclusion Pediatric patients undergoing HSCT present multiple risk factors that increase the incidence of infectious events and contribute to higher mortality rates. It is crucial to identify those factors related to adverse events and death to implement strategies that reduce exposure to these factors and improve the clinical outcomes.

Late-Onset Noninfectious Pulmonary Complications After Allogeneic Hematopoietic Stem Cell Transplantation: Single-Center Experience.

We aimed to reveal the incidence of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome and risk factors involved in development. In this cross-sectional study, we retrospectively investigated 745 patients who underwent allogeneic hematopoietic stem cell transplantation in our hospital between January 2000 and December 2020. We evaluated demographic characteristics, comorbidities, and hematopoietic stem cell transplantation characteristics to determine possible risk factors affecting development of lateonset noninfectious pulmonary complications and bronchiolitis obliterans syndrome. Of 745 patients, 8.9% (n = 66) had late-onset noninfectious pulmonary complications. Complications included 38 patients with bronchiolitis obliterans syndrome, 13 with venous thromboembolism, 8 with cryptogenic organizing pneumonia, 5 with pneumothorax, 4 with interstitial lung disease-restrictive graft-versus-host disease, 5 with bronchiectasis, 2 with pneumomediastinum, and 1 with pleural effusion. Patients with and without complications were not significantly differentin terms of smoking history, hematopoietic stem cell transplantation characteristics, and conditioning regimens. Patients with complications had higher busulfan and lower antithymocyte globulin use than those without complications (both P<.05). Patients with complications more commonly had hematopoietic stem cell transplantation from related donors and chronic graft-versus-host disease (P < .05). Patients with bronchiolitis obliterans syndrome had more frequent use of busulfan (P <.05) but less frequent use of total body irradiation (P <.05) and antithymocyte globulin (P <.05) than those without this syndrome. Rate of hematopoietic stem cell transplantation from a related donor (P < .05) and frequency of chronic graftversus-host disease (P < .001) were significantly higher in patients with bronchiolitis obliterans syndrome, presented with bronchiectasis (78.6%), air trapping (67.9%), bronchial wallthickening (53.6%), and mosaic attenuation (39.3%) in thorax computed tomography. Pretransplant spirometry did not predict bronchiolitis obliterans syndrome development. Determining risk factors for late-onset noninfectious pulmonary complications is needed to aid in prevention and follow-up.

Routine Computed Tomography before Pediatric Hematopoietic Stem Cell Transplantation and Association with Length of Stay and Early Non-Relapse Mortality

Introduction: Computerized tomography (CT) scans of the sinus, chest, abdomen, and pelvis are often performed in children prior to hematopoietic stem cell transplantation (HSCT) to evaluate for occult infections. Identification of infectious abnormalities could allow for pre- or post-HSCT infection prophylaxis to reduce morbidity or mortality. However, the association of abnormal pre-HSCT and adverse outcomes post-HSCT has not been previously examined. Additionally, routine imaging may identify incidental non-infectious findings, potentially necessitating additional diagnostic workup and unnecessary radiation exposure. In this study, we sought to investigate the prevalence of abnormal findings on CT scans in children undergoing HSCT and their association with post-HSCT length of stay (LOS) and early non-relapse mortality (NRM). Methods:We constructed a retrospective cohort of children, adolescents, and young adults (0-26y) who received a HSCT at Children's of Alabama between 2003 and 2019. Institutional Review Board approval was obtained prior to data collection. Eligibility included availability of pre-HSCT CT reports which were abstracted by the study team from medical records and were coded as either normal, infectious, or non-infectious abnormalities. Demographic (age at HSCT, sex, race/ethnicity) and HSCT characteristics (indication [primary diagnosis], type of HSCT [allogeneic, autologous], cell source, donor type) were abstracted from medical records. Vital status at day +100 was ascertained and causes of death were classified as relapse-related mortality and NRM. Post-HSCT outcomes of interest included length of stay (using day of HSCT as day 0) and day +100 NRM. Association between abnormal pre-HSCT CT and LOS was modelled using linear regression after adjusting for age at HSCT, sex, race/ethnicity, primary diagnosis, type of HSCT, cell source and donor type. Stratified analyses for patients with infectious abnormalities and those who received allogeneic HSCT were performed. Association between pre-HSCT abnormal CT and early (day +100) NRM was examined using logistic regression after adjusting for above covariates. Results: Overall, 236 patients met eligibility for inclusion. Cohort characteristics are included in Table. Median age at HSCT was 5.8y (range, 0.1-26), 54.7% were male and 57.6% were non-Hispanic white. Most patients received an allogeneic HSCT (66.1%); most common source of stem cells was bone marrow (60.3%), and most common donor was matched unrelated (40.7%). The most common anatomic location imaged using CT scan was chest (91%) followed by abdomen (89%), pelvis (87%), sinus (57%), head (46%) and neck (8.5%). An abnormal pre-HSCT CT scan was identified in 99 patients (41.9%). Infectious abnormalities were identified in 73 (31%) and a non-infectious abnormality was identified in 26 (11%). Sinus CT was most likely to demonstrate any abnormality. Compared to no abnormality, infectious abnormality was more commonly noted in patients with acute lymphoblastic leukemia (20.4% vs 27.4%, P=0.01) and acute myeloid leukemia (8.0% vs 23.3%, P=0.01). Abnormalities noted on CT scans are shown in Figure. The most commonly identified infectious abnormalities were sinusitis (58.9%), lung densities (20.5%), and enteritis (8.2%). The most common non-infectious abnormality noted was active primary disease (15.4%). No association between an abnormal pre-HSCT CT scan and LOS was noted after adjusting for covariates ( b=1.0, 95% confidence interval [CI]= -6.2-8.3, P=0.8). Similarly, there was no association between infectious abnormalities noted on pre-HSCT CT and LOS ( b= -0.4, 95% CI=-5.8-5.1, P=0.9) or among patients undergoing an allogenic HSCT ( b=1.0; 95% CI=-6.2-7.4, P=0.8). Five patients died by day +100 due to NRM (respiratory failure=2, graft-vs-host disease=1, intracranial bleed=1, multi-organ failure=1). However, this was not significantly associated with abnormal pre-HSCT CT scan (odds ratio=1.9, 95%CI=0.1-87.8, P=0.7) Discussion: We show that routine pre-HSCT CT scans identify abnormalities in over 40% of children, adolescent and young adults undergoing HSCT, however, these are not associated with greater length of stay post-HSCT or early mortality. Future research is needed to understand the utility of pre-HSCT CT scans in identifying patients at risk of post-HSCT adverse events.

Hospital survival following pediatric HSCT: changes in complications, ICU therapies and outcomes over 10 years.

Hematopoietic stem cell transplantation (HSCT) is an increasingly utilized therapy for malignant and non-malignant pediatric diseases. HSCT complications, including infection, organ dysfunction, and graft-versus-host-disease (GVHD) often require intensive care unit (ICU) therapies and are associated with mortality. Our aims were to identify the HSCT characteristics, complications and ICU therapies associated with (1) survival, and (2) survival changes over a ten-year period in a national dataset. A national sample from the Health Facts (Cerner Corporation, Kansas City, MO) database from 2009 to 2018 was utilized. Inclusion criteria were age 30 days to <22 years and HSCT procedure code. For patients with >1 HSCT, the first was analyzed. Data included demographics, hospital length of stay (LOS), hospital outcome, transplant type and indication. HSCT complications included GVHD and infections. ICU therapies were positive pressure ventilation (PPV), vasoactive infusion, and dialysis. Primary outcome was survival to discharge. Statistical methods included bivariate analyses and multivariate logistic regression. 473 patients underwent HSCT with 93% survival. 62% were allogeneic (89% survival) and 38% were autologous (98% survival). GVHD occurred in 33% of allogeneic HSCT. Infections occurred in 26% of all HSCT. ICU therapies included PPV (11% of patients), vasoactive (25%), and dialysis (3%). Decreased survival was associated with allogeneic HSCT (p < 0.01), GVHD (p = 0.02), infection (p < 0.01), and ICU therapies (p < 0.01). Survival improved from 89% (2009-2013) to 96% (2014-2018) (p < 0.01). Allogeneic survival improved (82%-94%, p < 0.01) while autologous survival was unchanged. Survival improvement over time was associated with decreasing infections (33%-21%, p < 0.01) and increasing vasoactive infusions (20%-28%, p = 0.05). On multivariate analysis, later time period was associated with improved survival (p < 0.01, adjusted OR 4.28). Hospital survival for HSCT improved from 89% to 96% from 2009 to 2018. Factors associated with mortality included allogeneic HSCT, GVHD, infections and ICU therapies. Improving survival coincided with decreasing infections and increasing vasoactive use.

Allogeneic Blood and Marrow Transplantation for Pediatric Patients with Sickle Cell Anemia: An Institutional Experience

Introduction: Sickle cell anemia (SCA) is a genetic disease with potentially debilitating complications and shortened life-expectancy. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only cure for SCA, but is limited by the lack of available histocompatible sibling donors and transplant related morbidities. Alternative donor HSCT for SCA has been associated with variable outcomes. Methods: We conducted a retrospective review of all patients with SCA who underwent HSCT at our center between January 2014 and June 2017. Results: Table 1 shows the pre-HSCT characteristics of the study population (n=19). Candidates for HSCT were selected based on institutional and/or study eligibility criteria and were consented per the Declaration of Helsinki. The majority of patients were receiving chronic transfusions or hydroxyurea therapy. Two patients had concurrent autoimmune diseases and 79% had low 25-hydroxycholecalciferol levels (median 17.8 ng/ml). 9 patients (47.3%) received HLA-identical sibling transplants (MSD), 6 (31.5%) UD, and 4 (21%) α/β T cell depleted related haplo-identical (haplo) transplants. The median pre-HSCT comorbidity index (CI) was above 3 for patients receiving alternative donor transplants (>3 is associated with higher pre-HSCT acuity). HSCT characteristics are shown in Table 2. The majority of patients (68.4%) received bone marrow (BM), while 21% received mobilized peripheral blood stem cell (PBSC) grafts. All patients achieved initial high-level (>90%) donor chimerism. The median time to neutrophil engraftment (>500 cells/µL) was 14 days with significantly earlier engraftment seen among haplo recipients (median 10 days) compared to other graft sources (p < 0.02). The median time to platelet engraftment (>50,000 /µL) was 20 days. The median time to CD3+ T lymphocyte recovery (>200 cells/uL) was 195 days (range 20-384) (significantly earlier for the haplo group (figure 1a, p=0.01) and for CD19 (>66 cells/uL) was 104 (range 90-526) days post-HSCT (figure 1b). Secondary early graft rejection occurred in 2 patients who received haplo-identical HSCT, with sustained donor engraftment following a second transplant with the same donors in one of these patients. Overall incidence of > grade II (severe) acute graft versus host disease (GVHD) was 26%, with no significant difference observed among haplo recipients despite the absence of primary GVHD prophylaxis. Two UD recipients developed chronic GVHD (10.5% overall incidence). 11 (57%) patients (6 MSD, 3 UD, 2 haplo) developed CMV viremia, with one late onset disseminated CMV meningitis; 7 patients (36.8%) (3 MSD, 4 UD) developed adenoviremia; one patient developed HHV-6 viremia around the time of graft rejection. Both patients with concurrent autoimmune diseases did not experience significant post-HSCT complications. One patient with type I diabetes mellitus diagnosed 60 days prior to HSCT has had stable glycemic control. One patient with systemic lupus erythematous (SLE) remains in SLE remission post-HSCT. With a median follow-up of 568 (105-919) days, the overall 2-year survival was 84.2%. 88.8% for MSD, 83.3% for UD, and 75% (3 patients) survival for α/β T cell depleted haploidentical related HSCT (p=0.7) and a mean performance score of 90 among survivors. No adverse events were noted among donors with sickle cell trait, including 4 parent donors who received PBSC mobilization with either filgrastim and/or plerixafor. Conclusion: Alternative donor allogeneic HSCT should be considered for carefully selected patients with SCA. α/β T cell depleted related haplo-identical HSCT appears promising with low rates of severe acute GVHD in the absence of primary prophylaxis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary immunodeficiencies: HSCT experiences of a single center in Turkey.

Primary immunodeficiency diseases (PID) are characterized by the occurrence of frequent infections and are caused by many genetic defects. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for the majority of PID. As a Pediatric Hematology-Oncology-Immunology Transplantation Unit, we wanted to present our HSCT experience regarding treatment of primary immunodeficiency diseases. 58 patients were included in the study between January 2014 and June 2019. We searched 9/10 or 10/10 matched-related donor (MRD) firstly, in the absence of fully matched-related donor. We screened matched unrelated donor (MUD) from donor banks. MRD was used in 24 (41.3%) patients, MUD in 20 (34.4%) patients, and haploidentical donors in 14 (24.1%) patients. Demographic data, HSCT characteristics, and outcome were evaluated. While 16 patients had severe combined immunodeficiency (SCID), the remaining was non-SCID. Of the 58 patients, 38 were male and 20 were female. Median age at transplantation was 12months (range: 2.5-172months). Combined immunodeficiencies consisted 67.2% of patients. Mean follow-up time was 27months (6months-5years). Median neutrophil, lymphocyte, and thrombocyte engraftment days were similar in comparison of both donor type and stem cell source. The most common complication was acute GvHD in 15 (25.8%) patients. In total, five patients (31%) belonging to the SCID group and 10 patients (23.8%) belonging to the non-SCID group died. Our total mortality rate was 15 (25.8%) in all patients. We would like to present our HSCT experiences as a pediatric immunology transplantation center. Existing severe infections before transplantation period, BCGitis, and CMV are important issues of transplantation in Turkey. However, the follow-up time is shorter than some studies, our results regarding complications and survival are similar to previous reports.

Factors Associated with CMV Disease in Pediatric Hematopoietic Stem Cell Transplantation

Cytomegalovirus (CMV) infection remains a significant source of morbidity in pediatric hematopoietic stem cell transplantation (HSCT). Current strategies for mitigating the effect of CMV on outcome include weekly measurement of CMV viral load in the blood through post-transplant day 100 and use of acyclovir prophylaxis in the peritransplant period in patients at risk for CMV infection (patients in which the HSCT donor or recipient had CMV IgG seropositivity indicative of latent infection). Risk factors predicting CMV infection in pediatric HSCT are not well understood, and factors affecting recurrence of CMV viremia following an initial episode have not been reported. We performed a retrospective review of consecutive cases at our institution between 2011 and 2014 where the recipient was at risk for CMV infection. We calculated odds ratios (OR) and 95% confidence intervals (CI) of CMV reactivation as a function of HSCT characteristics. This study was approved by the Institutional Review Board of the Dana-Farber Cancer Institute. Out of a total of 91 at risk patients, 26 (29%) patients had CMV infection (defined as CMV viremia without target organ involvement) occurring at a median of 46 days following HSCT (range: 9-127). One patient died from biopsy-proven CMV pneumonitis. There was a trend towards recipients with underlying malignant conditions having increased risk of CMV infection compared to others (OR=2.3; 95% CI=0.9-6.0; p=0.08). There was a significantly increased risk of CMV infection in recipients of an umbilical cord blood compared to other sources (OR=9.45; 95% CI=1.8-50.6; p=0.009). Patients with acute graft-versus-host disease (aGVHD) had a significantly increased risk of CMV infection (OR=3.6; 95% CI=1.1-12.1; p=0.04). All patients with viremia received a 14-day course of antiviral and immunoglobulin therapy. Patients who failed to clear the virus completely from the blood at the end of 14 days of therapy had no increased risk of CMV recurrence (p=0.2). A total of 6/26 (23%) HSCT recipients experienced CMV recurrence, at a median of 33 days (range 9-74) following initial CMV clearance. In the subset of recipients who experienced a recurrence of CMV infection, there was a trend toward increased treatment-related mortality (TRM; OR=9.5; 95% CI = 0.7-132; p=0.09). However, among all recipients at risk, CMV viremia was not associated with increased TRM (p=0.7). Pediatric patients seropositive for CMV who receive umbilical cord HSCTs have increased risk for CMV viremia in the post-HSCT period. CMV infection is associated with aGVHD. If treated with antivirals, recurrence of CMV can be prevented. Multiple episodes of CMV viremia may be associated with increased TRM. This study broadens understanding of CMV disease in pediatric HSCT, and is the first to analyze factors influencing recurrence of CMV infection.

A Risk Score to Predict CMV Viremia within the First 100 Days after Allogeneic Stem Cell Transplantation Based on Pre-Transplant Parameters

▪Introduction:Cytomegalovirus (CMV) is a major infectious complication following allogeneic hematopoietic stem cell transplantation (HSCT). Risk of CMV infection varies between patients and individualized strategies for monitoring and therapy for CMV are needed. In this study, we attempted to establish a clinical score based on patient and transplant characteristics in order to predict the probability for early CMV viremia (CMV-V) within the first 100 days after HSCT.Methods:A total of 548 patients were evaluated after receiving HSCT between 2005 and 2012 at Princess Margaret Cancer Centre. CMV sero-negative recipients with CMV sero-negative donors (R-D-) were excluded. CMV-V was diagnosed in peripheral blood samples obtained on two occasions either by PCR (>200 IU/ml) or antigenemia testing (>2 positive cells/100000). A total of 378 patients were included into the study. Uni- and multivariable analyses were performed to identify risk factors for CMV-V. A weighted score was assigned to each factor based on the odds ratios determined by the multivariable analysis. A total score was calculated for each patient and used for assignment into one of 4 risk categories, the low risk (score 0-1), the intermediate (score 2-3), the high (score 4-5) and the very high (score 6-8).Median age for all patients was 51 years (range 17-71) and 173 (46%) were female. Matched related donors were used for two hundred fifteen patients (57%). Two hundred forty-three patients (64%) were transplanted for myeloid and 108 (29%) for lymphoid malignancies. One hundred thirteen patients (30%) were CMV sero-positive with a negative donor (R+D-) while 191 (51%) were recipient and donor CMV sero-positivity (R+D+). Graft versus host disease (GVHD) prophylaxis included CSA/MMF (n=200, 52%), and CSA/MTX (n=178, 48%). Myeloablative conditioning regimens were administered to 220 patients (58%), 158 patients (42%) were treated with a reduced intensity regimen. Three hundred-thirty seven patients (89%) received peripheral blood stem cells as a stem cell source. In vivo T cell depletion (TCD) with alemtuzumab was used in 138 (37%).Results: CMV-V occurred in 246 (64%) patients by day 100 post HSCT. The impact of patient and HSCT characteristics on the risk of CMV-V was assessed by multivariable analysis. The significant factors were CMV sero-status R+D- and R+D+, TCD, GVHD prophylaxis with MMF administration of myeloablative preparative regimens (Table 1). [Display omitted] CMV-V rates on the 4 new risk categories amounted to 93% in the very high-risk, 78% in high-risk, 41% in intermediate-risk and 11% in low-risk group (Fig 1). The risk score was also predictive for the occurrence of multiple CMV-V reactivations with rates of 71%, 45%, 19% and 4% for the very high, high, intermediate and low-risk groups, respectively.The overall survival (OS) rate at 2 years was 33%(n=56) in the very high-risk group compared to 50% in other-risk groups (n=147) (P=0.01) (Fig 2). Non-relapse mortality (NRM) was 53% in the very high-risk versus 33% in other-risk groups (P<0.001). However, there was no difference on cumulative incidence of relapse between the groups (P=0.3).The cumulative incidence of grades 1-4 acute GVHD, grades 2-4, grades 3-4 at day 120 and overall chronic GVHD at 2 years was 68%, 47%, 25% and 39% in very high-risk group versus 65%, 52%, 21% and 52% in other-risk groups, suggesting slightly lower incidence of chronic GVHD in very high-risk vs other-risk groups.Conclusion: We present a new clinical scoring system to stratify the risk of early CMV viremia after allogeneic HSCT based on patients and HSCT characteristics. Identifying the risk for each patient would facilitate decision making with respect to strategies including CMV prophylaxis, pre-emptive treatment or inclusion into clinical trials, as well directing the CMV monitoring policy post-transplant. In addition, the risk score was associated with higher risk of overall mortality and NRM in the very high-risk versus other-risk groups. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Proinflammatory human 6-sulfo LacNAc-positive dendritic cells accumulate in intestinal acute graft-versus-host disease

Proinflammatory human 6-sulfo LacNAc-positive dendritic cells accumulate in intestinal acute graft-versus-host disease

Intensive Care Management and Outcomes In Allogeneic Hematopoietic Stem Cell Transplantation Recipients

Aim Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used for the treatment of various hematological conditions with poor outcome. However, despite its effectiveness opportunistic infection, graft versus host disease (GVHD), drug toxicity and relapse frequently lead to life threatening complications and 15-20% of HSCT recipients ultimately require life sustaining therapies. Nowadays, a trend toward the use of less toxic conditioning regiments, different graft sources and better management of GVHD is observed. Also recent finding emphasize advances in the ICU management and triage policies of hematological patients. However, it is not known whether these changes altered the typology and outcomes of HSCT recipient admitted to ICU. We then performed a multicenter study to assess the impact of these changes. Methods All adults admitted in 3 ICU in Paris France from 1997 to 2011 were included if they previously received an HSCT. Data from medical charts were retrospectively retrieved and analyzed after the patients gave written informed consent. 497 patients were included, among whom 209 were admitted in the 1997-2003 period (this cohort was already published)1 and 288 in the 2004-2011 period. This corresponded to 2286 HSCT procedures over the same centers and period of time. Patients, HSCT characteristics and outcomes of the 2 cohorts were compared and prognostic factors analysis was performed in the recent period cohort. Results Over the time, HSCT recipients were more likely to be older (48 vs. 41 years old p&lt;0.001), transplanted with a reduced intensity conditioning (46% vs. 10% p&lt;0.001), peripheral blood mobilized stem cell (67% vs. 28% p&lt;0.001) and an unrelated donor (37% vs. 29% p&lt;0.001). ICU admission rate was 22% and remain stable over time (p=0,17). ICU admission triage was more frequent with less patients admitted with graft versus host disease (GVHD) stade over 2 (27% vs. 52% p&lt;0,0001) and absence of hematological remission (33% vs. 56% p&lt;0,0001). Admission occurred with a median time of 72 vs. 75 days after HSCT procedure with no difference over time p=0.68. Finally, organ dysfunction severity scores were not different between the 2 cohorts. We observed a significant survival improvement over the time as ICU, Day 90 and 1 year survival in the 2004-2011 cohort was respectively 71%, 49% and 37% vs. 48%, 31% and 21% previously. This was mainly due to improvements in the subset of patients requiring mechanical ventilation as shown in Figure 1. Also non-invasive ventilation use was similar between the 2 cohorts but more frequently successful (not followed by invasive ventilation) in the 2004-2011 cohort (51% vs. 33%). In the recent cohort, univariate analysis of Day 90 mortality showed that no demographic or HSCT parameter was associated with mortality. Only graft versus host disease (p&lt;0.001) and life sustaining therapies use (p&lt;0.001) CMV reactivation (p&lt;0.001) and invasive fungal infection (p=0.03) were found as mortality determinant. We then tested whether the strength of prognostic factors were changing with time using Gail and Simon interaction test and revealed that renal and respiratory failure and CMV reactivation were all three most strongly associated with mortality in the recent cohort. Logistic regression analysis revealed that, in the 2004-2011 cohort, the presence of acute GVHD stade &gt; 2, mechanical ventilation and renal replacement therapy were independently associated with day 90 mortality. Conclusion Despite improvement of ICU care in HSCT patients with no GVHD, this study show that life-sustaining therapy still remains mostly unsuccessful when used in patients with GVHD and deep immunosuppression. These data argue for a more rational policy of ICU admission triage in HSCT recipient 1Pene, Aubron, Azoulay et al. J. Clin. Oncol. February 1, 2006; 24(4): 643 - 649. Disclosures: No relevant conflicts of interest to declare.

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

Abstract 1927BK virus (BKV) reactivation after allogeneic hematopoietic stem cell transplantation (HSCT) affects the genitourinary (GU) tract with manifestations ranging from asymptomatic viruria to severe hemorrhagic cystitis. Knowledge about epidemiology, morbidity and clinical spectrum of BKV disease is limited. We studied a recent HSCT cohort at our institution to assess and quantify the incidence and severity of BKV disease.Between January 1, 2010 and December 31, 2011, 491 patients underwent first HSCT. BKV disease was defined as detection of BKV by PCR testing in association with GU symptoms. BKV disease was considered severe when patients had at least 1 of the following: hematuria with clot formation, GU tract inflammation on imaging, need for invasive GU interventions, or hospitalization for BKV disease management. Medical records were reviewed for patient and HSCT characteristics. For patients with BKV disease, reason for testing, clinical presentation and course, imaging results, and treatments were captured. Time at risk was censored at time of death, second HSCT or on July 1, 2012. Fisher's exact or Wilcoxon test were used to compare variables. Cox modeling was used to analyze potential risk factors for BKV disease.168 (34.2%) patients were tested for BKV at our institution during the study period. Median time to testing was 61 days (range, 2–663; IQR 19.5 – 114). 88 patients (17.9%) were diagnosed with BKV disease with an incidence rate of 0.54/1000 patient-days (95% CI, 0.43 – 0.66). Most common symptoms at presentation and during a first BKV disease episode are shown in the Table.TableCommon symptoms of BKV disease (n=88).SymptomAt presentationDuring first episodeDysuria45 (51.1%)59 (67.0%)Hematuria31 (35.2%)42 (47.7%)Urinary frequency16 (18.2%)40 (45.5%)Urgency10 (11.4%)21 (23.9%)Bladder spasms3 (3.4%)15 (17.0%)Flank pain3 (3.4%)11 (12.5%)31 patients had severe BK disease (35.2%, 6.3% of the cohort): 17 patients (19.3%) had hematuria with clot formation; 16 patients (18.2%) demonstrated GU tract inflammation on imaging studies, including bladder wall (14, 15.9%) or ureteral (5, 5.7%) thickening. 4 patients were hospitalized for management of BKV associated symptoms. Invasive GU interventions were performed in 16 (18.2%) patients including Foley catheter placement in 12, bladder irrigation in 7, intravesicular cidofovir in 3, cystoscopy in 2, and alum instillation in 1. Additional prescribed treatments during BKV disease episodes included quinolones (39, 44.3%), antispasmodics (29, 33.0%), IVIG (20, 22.7%) and pain medications (18, 20.5%). Cidofovir was used in 7 (8.0%) patients and leflunomide in 8 (9.1%). 3 patients had concomitant bacterial GU infections; 1 patient had GU adenovirus disease. Patients (n=71) were symptomatic for a median of 31 days (range 2–385, IQR 9–67). Additional BKV disease episodes were seen in 26/88 patients (29.5%).Median initial urine BKV load was 3.4×108 copies/mL (range; 600, >1×1010). Median peak urine BKV load during first BKV disease episode was 1.5×109 c/mL (range; 600, >1×1010). Blood BKV loads were obtained in 35 patients, with median initial BKV load of 800 c/mL (range, 0, 1.52×106) and median peak BKV load of 2000 c/mL (range, 0, 1.52×106). Detection of BKV viremia was 74% sensitive and 38% specific for severe BKV disease.Cohort characteristics associated with increased BKV disease risk included myeloablative conditioning (p=0.01), cyclophosphamide conditioning (p=0.0008), cord blood HSCT (p=0.03), GVHD prophylaxis with mycophenolate (MMF, p=0.0006) and acute GVHD (aGVHD) grades II-IV (p< 0.0001). On multivariate Cox modeling, time-dependent aGVHD (adjusted HR [aHR] 3.65, 95%CI 2.23 – 5.97), MMF use (aHR 3.11, 95%CI 1.76 – 5.48), and cyclophosphamide use (aHR 1.95, 95%CI 1.25 – 3.04) remained significant. Time-dependent aGVHD (aHR 5.02, 95%CI 2.20 – 11.5), cord blood HSCT (aHR 4.60, 95%CI 1.67 – 12.7) and cyclophosphamide use (aHR 2.17, 95%CI 1.04 – 4.56) were independent risk factors for severe BKV disease.BKV disease is a common complication of HSCT, associated with significant and prolonged morbidity, especially in the setting of aGVHD, cyclophosphamide and MMF use, and after cord blood HSCT. Prospective studies are needed to better define the morbidity of BKV disease and to properly inform the impact of future prophylaxis and treatment trials. Disclosures:Off Label Use: ciprofloxacin, levofloxacin, moxifloxacin, cidofovir, leflunomide use for treatment of BK virus infection. Marty:Chimerix: Consultancy, Research Funding.

High Impact of Matching Score On Different HSCT Outcomes After Single and Double Umbilical Cord Blood Transplantation for Hematological Malignancies

AbstractAbstract 1992Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological malignancies for which umbilical cord blood (UCB) represents an alternative source of HSC. In order to overcome the low cellularity of one UCB unit, double (d) UCBT has been developed. The impact of different matching variables between UCB units and recipient including HLA, sex and ABO on the different transplantation outcomes are still unclear and not very well defined yet. On the other hand, a major focus in previous studies has been on cellularity with different thresholds, despite the heterogeneous pre-freezing and post-thawing counting techniques especially without any link to matching variables. In this study, we evaluated the impact of the different matching variables in addition to cellularity and other disease and patient characteristics on single(s) and double UCBT outcomes in pediatric and adult patients between 1998 and 2011. There were 53 adults (37 dUCBT and 16 sUCBT) with a median age of 36 years (18–64) and 48 children (3 dUCBT and 45 sUCBT) with a median age of 2 years (0–14) and a median follow-up of surviving patients of 24 months (1–85). The different patient, UCB, disease and HSCT characteristics have been analyzed and taken into account. The median number of pre-freezing and post-thawing cells was for 1) TNC: 3.3×107/kg (1.9–5.1) and 2.6×107 (1.5–4.6) in adults; 1.6×107 (0.5–4) and 1.18×107 (0.5–3) in children; 2) CD34: 1.89×105 (0.57–4.2) and 1.55×105 (0.5–4.1) in adults; 4×105 (0.6–19.3) and 2.8×105 (0.26–19) in children with a respective cells viability of 54% and 58%. We built a scoring scale that took into account the matching variables (sex, ABO and HLA) between UCB units and recipient and between UCB units each other in case of dUCBT. The median score was 3.8 (1–7) in adults and 3 (1–6) in children; the detailed score calculation method will be communicated later. We evaluated in multivariate analysis separately in adults and children, the impact of the matching score, cellularity, single or double UCBT, type of disease, disease status and conditioning on different HSCT outcomes. We found a positive impact of infused CD34 ≥1.55×105 on neutrophiles recovery in adults [HR=2.1 (1.16–3.8), p=0.015] and infused CD34 ≥2.8×105 on neutrophiles and platelets recovery [HR=2.5 (1.2–5), p=0.007 and HR= 4.4 (1.6–11.6), p=0.002 respectively] in children; no significant factor was observed on the cumulative incidence of acute GVHD≥grade II. In addition, we showed a significant negative impact of matching score > 3.8 on adults overall survival (OS) with a 3 years probability of 19% (6–60) vs. 57% (38–84) for those with score ≤3.8 [HR=3.9 (1.5–9.8), p=0.003]. Similarly, score >3.8 had a significant negative impact also on progression-free survival (PFS) only in adults with a 3 years probability of 13% (3–65) vs. 21% (5–94) for patients with a score ≤3.8 [HR=2.8 (1.01–8), p=0.04]. No significant factor was found to influence transplant related mortality.In conclusion, cell dose remains a significant impacting factor on short term transplantation outcome while the matching score appears to have a strong impact on adult long term outcomes mainly OS and PFS. These very promising results lead us to evaluate this score in larger number of patients for its validation and in order to include it in the UCB unit choice either in simple or double UCBT. [Display omitted] Disclosures:Nicolini:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

HHV-6-Associated Post-Transplantation Acute Limbic Encephalitis Following Cord Blood Stem Cell Transplantation: A Cohort Analysis

Abstract 649Human Herpesvirus-6 (HHV6) frequently reactivates after allogeneic hematopoietic stem cell transplantation (HSCT). One serious manifestation of HHV6 reactivation is the syndrome of post-transplantation acute limbic encephalitis (PALE) associated with HHV6 reactivation in the central nervous system. We previously described this disease after peripheral blood HSCT (PBSCT), but the epidemiology and characteristics of PALE in patients receiving unrelated cord blood transplantation (UCBT) is not well characterized.We analyzed all patients undergoing allogeneic HSCT at our center from 3/2003 through 3/2010. HHV-6-associated PALE (HHV6-PALE) was diagnosed in patients who had a positive CSF PCR test for HHV6 DNA in the context of a) acute-onset altered mental status, anterograde amnesia, or seizures and/or b) MRI or EEG abnormalities involving the limbic system with no other identifiable etiology. Medical records were reviewed for demographic and HSCT characteristics, as well as the clinical, laboratory and radiographic features of cases. Patient time-at-risk was censored at day of HHV6-PALE symptom onset, death or day +100 after HSCT, as all cases occurred within this period. Incidence rates were calculated for pertinent characteristics, and Cox modeling was used to analyze potential HHV6-PALE risk factors.A total of 1,344 patients underwent an initial HSCT during the study period: 725 from adult unrelated donors, 518 from adult related donors and 101 from UCB donors. Fifteen patients underwent a second HSCT procedure (8 UCB and 7 PBSC) during the 100-day follow up period. HHV6-PALE was diagnosed in 19 patients. Two of these cases occurred after a subsequent UCBT. The cumulative incidence of HHV6-PALE was 1.4% for an overall incidence rate of 0.15/1000 patient-days (95% confidence interval (CI), 0.09–0.24). HHV6-PALE incidence rate was higher among UCBT patients (10/101, IR 1.2/1000 patient-days) compared with the rest of the cohort (9/1243, IR 0.08/1000 patient-days, p<0.001). Other relevant characteristics associated with HHV6-PALE included acute graft-versus-host disease (GVHD) grade II-IV (p=0.05), adult mismatched donor (p=0.03) and conditioning with thymoglobulin (p=0.003). On multivariable Cox modeling, UCBT (adjusted HR 20.0, 95% CI, 7.3–55.0), adult mismatched donor (adjusted HR 4.3, 95% CI, 1.1–17.3) and time-dependent acute GVHD (adjusted HR 7.5, 95% CI, 2.8–19.8) remained significant.Interesting clinical features were noted when comparing the 10 UCBT HHV6-PALE cases to the 9 PBSCT cases. Encephalitis developed prior to engraftment in 7 recipients of UCB compared with 1 recipient of PBSC. HHV6-PALE symptom onset occurred at a median of 20 days (range, 7–37) in PBSCT compared with 32 days (range, 16–67) in UCBT patients (p=0.07). Brain MRI abnormalities were limited to the limbic system in PBSCT recipients but extended beyond the temporal lobes in 2 UCBT patients. Intravenous foscarnet was used to treat 18/19 patients for a median of 21 days (range, 7–42); time to treatment after symptom onset was a median of 3 days (range, 1–13) in PBSCT and 6 days (range, 1–13) in UCBT patients. No PBSCT patients died from HHV6-PALE, although most patients had long-term neurocognitive deficits. Five UCBT patients died a median of 45 days after transplant and 18 days after symptom onset. Deaths occurred after similar courses punctuated by progressive encephalopathy and unresponsiveness requiring mechanical ventilation. Of 68 UCBT patients who underwent plasma HHV6 PCR testing, 49 (72.1%) had positive results. All patients with HHV6-PALE had detectable HHV6 DNA in their plasma. HHV6 PCR results were higher in patients with HHV-6 PALE (median 173,500 copies/mL, range, 7,100– >106) than in patients without HHV6-PALE (median 8,160 copies/mL, range, <1,000– >106, p=0.003). Plasma HHV6 PCR values greater than 250,000 copies/mL were 95% specific for a diagnosis of HHV6-PALE.Patients receiving UCBT are at increased risk for developing HHV6-PALE. This disease has different characteristics after UCBT with greater morbidity and mortality. Preventive strategies to minimize the impact of HHV6-PALE in this population need to be further evaluated. Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation Co-Morbidity Index (HCT-CI) to Predict Non Relapse Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Abstract 4561 Introduction:In recent decades, several advances were made in the management of patients (pts) who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Despite that, the transplant related mortality (TRM) is not negligible. Tools that could predict TRM, based on pre HSCT characteristics and co-morbidities were always sought. Some of these tools are the modified hematopoietic cell transplantation co-morbidity index (HCT-CI). Objectives:To apply the modified HCT-CI and correlate it with overall survival (OS) and non-relapse mortality (NRM). Pts and Methods: This analysis include patients who received allogeneic HSCT, for malignant and non malignant hematological diseases, after high or low dose conditioning regimens, from related and unrelated donor, at the HSCT unit of the University Hospital of Campinas between 1993 to 2010. The conditioning regimens and graft versus host disease (GVHD) prophylaxis were selected according to ongoing protocols at the University Hospital. Informed consent for transplant was obtained from all patients. We defined low dose conditioning regimen as follow: busulfan dose < 9 mg/kg, melphalan dose < 150mg/m2, and total body irradiation dose of 2Gy. All patients received cyclosporine-A (CsA) with methotrexate or CsA with mycophenolate mofetil as GVHD prophylaxis. Screening for cytomegalovirus with antigenemia and preemptive treatment with ganciclovir were made for all patients. Prophylaxis for Candida infections was made with fluconazole; for bacterial infections ciprofloxacin was used. Prophylaxis for Pneumocystis jirovecii was made with sulfamethoxazole and trimethoprim. For viral agents as herpes simplex virus and varicella zoster virus, acyclovir was used. The diagnosis and clinical grading of acute and chronic GVHD were performed using standard criteria. Information on co morbidities was extracted, retrospectively, from medical charts. Each co-morbidity was assigned an integer weight, based on derived scores from Sorror et al. The HCT-CI score was the sum of this integer weights, and the patients were then assigned to one of the risk groups: 0, 1, 2 and 3 or more. Kaplan-Meier was applied for estimation of overall survival. NRM was estimated by cumulative incidence considering primary relapse disease as competing risk. Results:457 pts were analyzed at the beginning. However, 331 (72.4%) were evaluable, 126 (27.6%) were excluded when at least one parameter was missing. 208 (63%) were male with a median age of 36.5 (5–65) years, 249 (75%) pts received high dose (HD) conditioning and 82 (25%) low dose (LD). Distribution of diseases in the HD was: 110 (44%) acute leukemias; 109 (43%) CML and 30 (13%) others; LD was: 42 (51%) severe aplastic anemia; 14 (17%) lymphomas; 12 (15%) myeloma and 14 (17%) others. HCT-CI in HD was: 127 (51%) score 0; 39 (16%) score 1; 19 (7%) 2 and 64 (26%) score ≥ 3; in LD 33 (40%) score 0; 14 (17%) score 1; 8 (10%) score 2 and 27 (33%) score ≥ 3. The median follow up in HD was 22 months (0–201) and 9 (0–203) in LD. The adjusted OS at 10 year for HD conditioning according to the HCT-CI was 55% for score 0, 34% for score 1–2 & 34% for score ≥ 3 and for LD conditioning was 58% for score 0, 53% for score 1–2 & 15% for score ≥ 3 (P< 0.0001). The NRM rate in the HD cohort was 32% in the pts with a score 0, 42% for score 1–2 and 53% in the score ≥ 3. In the LD cohort, the NRM was 23% in the pts with a score of 0; 35% for score 1–2 and 54% in the score ≥ 3 (P= 0.002). The adjusted OS for conditioning type in patients with cardiac valve disease was associated to a lower OS (29% and 33% P= 0.002) whereas mild hepatic involvement was just significant in the HD cohort. Conclusion:The OS and NRM were worse for score ≥ 3 either in HD and LD groups. The heart valve disease emerged as a worse outcome in both conditioning type and mild hepatic involvement only in HD group. The HCT-CI showed to be a valid tool to predict outcome after allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Complicaciones neurológicas después de un trasplante de progenitores hemopoyéticos. Estudio de 14 pacientes

The frequency and cause of neurologic complications (NC) following hematopoietic stem cell transplantation (HSCT) have changed over time. We have analyzed the NC in 185 consecutive patients who underwent HSCT in a period of 5 years in a single HSCT Unit. 185 consecutive patients underwent HSCT (44 allogeneic) between February 2000 and March 2005 to treat hematologic malignancies. Most frequent diagnoses were multiple myeloma (41 patients) and acute myeloblastic leukemia (n = 35). Demographic and clinical data, HSCT characteristics and procedure-related events with special attention to neurological findings were recorded. Imaging studies (magnetic resonance imaging and/or computerized tomography scan), cerebro-spinal fluid analyses and microbiological studies were performed in all patients developing NC. After a median follow-up of 27 months, 14 patients (7.5%) developed NC, 6 of them after an allogeneic HSCT. The most common conditioning regimen in these patients was BEAM (5/14); 6 patients submitted to allogenic-HSCT received methotrexate and cyclosporin as graft-versus-host disease prophylaxis, and intrathecal prophylaxis of relapse was administered to 3 patients. The median time to the appearance of a NC was 13 days from HSCT (range: -4 to + 135 days). Seizures (8 cases) and encephalopathy (n = 2) were the most frequent clinical manifestations. In 12 cases the cause of the NC was related to drugs, there was one case of viral encephalitis and in the remaining case was caused by hemorrhage. Two patients died, one due to thrombotic thrombocytopenic purpura attributed to cyclosporin and the other due to viral encephalitis. In our series drug toxicity was the main cause of NC (particularly seizures) following HSCT. Our results contrast with previous studies in which infections, especially of fungal origin, were the main cause of NC. These changes over time should be taken into account during diagnostic procedures.