Umbilical Cord Blood Transplantation Recipients Research Articles

Implementation and Evaluation of Discharge Planning for Patients Undergoing Umbilical Cord Blood Transplantation.

BACKGROUND Umbilical cord blood transplantation (UCBT) patients have high rates of unplanned readmissions and poor quality of life (QoL). The aim of this study was to evaluate the effects of discharge planning on unplanned readmissions, self-efficacy, QoL, and clinical outcomes. MATERIAL AND METHODS Patients who received their first UCBT from April 2022 to March 2023 were included. Participants (n=72) were assigned to a control group (CG: received usual care) or an intervention group (IG: received discharge planning from admission to 100 days after UCBT). The cumulative readmission rates 30 days after discharge and 100 days after UCBT were analyzed using the log-rank test. Self-efficacy and QoL were assessed at admission and 100 days after UCBT using the General Self-Efficacy Scale and FACT-BMT version 4, clinical outcomes derived from medical records. RESULTS Sixty-six patients completed the study. Discharge planning did not reduce readmission rates 30 days after discharge (20.59% vs 31.25%, P=0.376) or 100 days after UCBT (29.41% vs 34.38%, P=0.629). However, the IG showed significantly better self-efficacy (P<0.001), and except for social and emotional well-being, all the other dimensions and 3 total scores of FACT-BMT in the IG were higher than for the controls at 100 days after UCBT (P<0.05). CONCLUSIONS The discharge planning program can improve self-efficacy and QoL of UCBT recipients. The implementation of discharge planning for patients undergoing UCBT was necessary for successful hospital-to-home transitions.

Immune reconstitution after single-unit umbilical cord blood transplantation using anti-thymoglobulin and myeloablative conditioning in adults with hematological malignancies.

This study aimed to investigate the kinetics of immune recovery following umbilical cord blood transplantation (UCBT) in adults who received a myeloablative conditioning (MAC) regimen and antithymocyte globulin (ATG). While the immune recovery kinetics has been extensively studied in pediatric UCBT recipients, limited data exist for adults. We conducted a comprehensive analysis of 221 consecutive adult patients who underwent UCBT with MAC and ATG at a single institution. Our objective was to evaluate the influence of patient, disease, and transplant factors, along with acute graft-versus-host disease (aGVHD), on immune reconstitution and overall survival. Our findings confirm a delayed recovery of T cells, while B and NK cell reconstitution exhibited rapid progress, with NK cell counts reaching normal levels within 3 months post-transplantation and B cells within 6 months. Within CD3+ T cells, CD8+ T cells also experienced a delayed recovery (12 months), but to a lesser extent compared to CD4+ T cells (18 months). Delayed immune recovery of T-cell subsets was associated with the development of aGVHD grade II-IV, older age, CMV negativity, and a female donor. Patients with lymphoproliferative diseases showed slower NK cell recovery. Our study demonstrates that adult patients undergoing MAC with ATG and receiving a single unit UCBT for hematologic malignancies experienced rapid reconstitution of NK and B cells. However, T cell recovery, particularly CD4+ T cells, was significantly delayed. To enhance T cell recovery, it may be crucial to consider UCB units with higher cellularity and optimize ATG doses in conditioning.

Long-term lymphocyte subset number reconstitution is unique but comparable between umbilical cord blood and unrelated bone marrow transplantation.

The number of umbilical cord blood transplantation (U-CBT) procedures has been growing annually, but little research has been done on long-term immune recovery after U-CBT. Infection risk is high in U-CBT recipients, and this can be partially attributed to immature immunocompetent cells in umbilical cord blood. In this study, we analyzed lymphocyte subset (LST) number to determine the long-term recovery timeline. We included 36 U-CBT and 10 unrelated bone marrow transplantation (U-BMT) recipients who survived more than 2years after transplantation, and followed them for up to 10years post-transplant. Recovery kinetics in the early phase post-transplant was different for each LST. Recovery of CD19+ B cells was faster after U-CBT than after U-BMT in the first 5years after transplantation. Although CD4+ T cells increased in the first several months after U-CBT, long-term cell count recovery was impaired in approximately 20% of patients. Thus, although the LST recovery pattern after U-CBT was unique, LST number recovery was statistically comparable between U-CBT and U-BMT past 5years post-transplantation.

A Predictive Model Combining Clinical Characteristics and Nutritional Risk Factors for Overall Survival after Umbilical Cord Blood Transplantation

Background: Umbilical cord blood transplantation (UCBT) is a curable therapy for hematological disease; however, the impact of nutritional status on UCBT outcomes remains controversial. To evaluate the joint effect of clinical characteristics and nutritional status on the prognosis of patients who underwent UCBT, we screened various factors to establish a predictive model of overall survival (OS) after UCBT. Methods: We performed an integrated clinical characteristic and nutritional risk factor analysis and established a predictive model that could be used to identify UCBT recipients with poor OS. Results : Four factors, including disease status, conditioning regimen, calf skinfold thickness and albumin level, were identified and used to develop a risk score for OS, which showed a positive predictive value of 84.0%. A high-risk score (≥2.225) was associated with inferior 3-year OS post-UCBT [67.5% (95% CI, 51.1%-79.4%), P=0.001]. Then, we built a nomogram based on the four factors that showed good discrimination with a C-index of 0.833 (95% CI, 0.743-0.922). Internal validation was performed by using the bootstrap method (corrected C-index:0.804). Multivariate analysis suggested that a high calf skinfold thickness (≥20.5mm) and a low albumin level (&amp;lt;33.6g/L) conferred poor disease-free survival (DFS). Conclusion: The predictive model combining clinical and nutritional factors could be used to predict OS in UCBT recipients, which may promote preemptive treatment.

Letermovir Prophylaxis Reduced Cytomegalovirus Reactivation and Resistance Post Umbilical Cord Blood Transplantation

Objective: Umbilical cord blood transplantation (UCBT) has proved to be an effective treatment with its own unique advantages nowadays, while long-lasting immunosuppression and delayed immune recovery make the UCBT recipients susceptible to a range of infections. Human cytomegalovirus (HCMV) is the main cause of viral complications post transplantation, which is associated with poor prognosis. Although the implementation of pre-emptive therapy (PET) has significantly reduced the incidence of CMV disease, the long-time antigenemia and the toxicity of antiviral drug remains challenging and risky. Letermovir (LET), a kind of CMV DNA terminase complex inhibitor, is a relatively new antiviral drug for prophylaxis against CMV and has received positive opinion in adult CMV-seropositive recipients of allogeneic haematopoietic stem cell transplant (allo-HSCT). Nevertheless, the clinical efficacy of LET prophylaxis on CMV reactivation and resistance post UCBT remained unknown. Methods: We retrospectively analyzed 43 UCBT patients with hematological diseases at the First Affiliated Hospital of University of Science and Technology of China between August 2022 and May 2023, who received LET prophylaxis since the first day post transplantation until 100d or CMV reactivation occurred, whichever came first. A historical cohort of 208 UCBT patients also from our transplant center between 2021 and 2022 without LET prophylaxis was compared as control group. The CMV DNA testing was performed using the quantitative real-time PCR (RT-PCR) method and CMV monitoring was examined twice per week for at least 100 days and once a week for at least half a year after UCBT. The 180-day cumulative incidences of CMV reactivation (defined as DNA achieved 500 copies/ml or 1000 copies/ml) and refractory CMV infection (defined as CMV viral load remains the same level or increases after at least 2 weeks of appropriately dosed antiviral therapy) were compared between the two groups. To explore independent predictors of the development of CMV reactivation and resistance, univariate and multivariate analyses were performed by using Fine-Gray proportional hazard regression. Results: The two groups were similar in demographic and transplant characteristics, and in the LET group, patients received LET for a median of 100 days (range, 16-100). The 180-day cumulative incidence of CMV DNA achieved 500 copies/ml and 1000 copies/ml and refractory CMV infection in the LET group were significantly lower than that in the control group [500 copies/ml: 33.8% vs. 78.4%, P &amp;lt; 0.001; 1000 copies/ml: 30.2% vs. 74.0%, P &amp;lt; 0.001; refractory CMV: 4.7% vs. 31.7%, P &amp;lt; 0.001]. Furthermore, multivariate competing risk analysis identified LET prophylaxis as an independent protective factor for CMV reactivation (adjusted hazard ratio [HR] 0.27, 95% CI 0.15 to 0.48, P &amp;lt; 0.001) and refractory CMV infection ([HR] 0.16, 95% CI 0.04 to 0.62, P = 0.004). However no significantly lower incidences of CMV disease (4.7% vs. 8.8%, P = 0.542) and recurrent CMV infection (3.7% vs. 9.6%, P = 0.386) were found in LET group. Among the patients who developed CMV reactivation, there was no significant difference in the time from UCBT to CMV reactivation between two groups (39 days vs. 41 days, P = 0.367). LET prophylaxis was associated with a shorter duration of CMV DNAemia (median 27 days vs. 42 days, P = 0.014), and there was a trend towards lower peak CMV viral load in the LET group (median 2620 copies/ml vs. 5380 copies/ml, P = 0.165). Conclusion: We demonstrated that LET is highly effective at preventing CMV reactivation and resistance after UCBT, and its benefit for UCBT patients perhaps will be observed in a longer-time following time.

Acute kidney injury and chronic kidney disease in umbilical cord blood transplant recipients.

Acute kidney injury (AKI) is a frequent early complication post hematopoietic stem cell transplant (HSCT), associated with high morbidity and mortality. Cord blood transplant (CBT) recipients are potentially exposed to more nephrotoxic insults, compared to patients undergoing HSCT from other donor sources. We aimed to identify risk factors for AKI in patients undergoing CBT. We also aimed to identify the impact of AKI on chronic kidney disease (CKD) and survival outcomes by one-year post-CBT. Adults and children who underwent a first CBT at our Institution were retrospectively evaluated. AKI was staged according to Kidney Disease Improving Global Outcomes (KDIGO) definitions. Cox regression models were used to estimate the association of demographic factors and post-CBT parameters with the cause-specific hazard of AKI. We identified 276 patients. Median age was 32 years, 28% (77/276) were children (<18 years) and 129 (47%) were white. A myeloablative conditioning regimen was administered to 243 patients (88%) and 248 (90%) received cyclosporine for GVHD prophylaxis. One-hundred and eighty-six patients (67%) developed AKI by day 60 post-transplant, with 72 (26%) developing severe AKI (stage 2 and 3). In a multivariable analysis, each increase in bilirubin level of 1 mg/dL was associated with a 23% increase in the risk of severe AKI (adjusted HR 1.23, 95% CI 1.13 - 1.34, p<.0001). Conversely, systemic steroid administration appeared to be protective of severe AKI (unadjusted HR 0.36, 95% CI 0.18 - 0.72, p=.004) in a univariate model . Two-hundred-forty-seven patients were evaluable at the one-year time point. Among those, 100 patients (40%) developed CKD one-year post-CBT. Severe AKI was associated with a higher hazard of non-relapse mortality (adjusted HR=3.26, 95% CI 1.65-6.45, p=.001) and overall mortality (adjusted HR=2.28, 95% CI 1.22-4.27, p=.01). AKI is a frequent complication after CBT and is associated with worse outcomes. Questions remain as to the mechanism of the protective role of steroids on kidney function in the setting of CBT.

Comparable survival outcomes with haploidentical stem cell transplantation and cord blood transplantation.

HLA-haploidentical stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) and umbilical cord blood transplantation (UCBT) are alternative to HLA-matched stem cell transplantation. We conducted a matched-pair analysis of PTCy-haplo and UCBT using the Japanese registry data. We identified 136 patients aged between 16 and 69 years who received PTCy-haplo as their first transplantation for acute leukemia or myelodysplastic syndromes. Control group included 408 UCBT recipients selected to match the PTCy-haplo group. Overall and relapse-free survival probabilities at 2 years were comparable between the PTCy-haplo and UCBT groups: 55% vs. 53% for overall survival (p = 0.46), and 47% vs. 48% for relapse-free survival (p = 0.79), respectively. The cumulative incidence of relapse was significantly higher (43% vs. 29%, respectively, p = 0.006), while the cumulative incidence of non-relapse mortality (NRM) was significantly lower (9% vs. 23%, respectively, p < 0.001) in the PTCy-haplo group. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the PTCy-haplo group compared to the UCBT group (29% vs. 41%, respectively, p = 0.016), while those of grade III-IV acute GVHD and chronic GVHD were not statistically different between the two groups. Our results suggest that both PTCy-haplo and UCBT are viable alternatives to HLA-matched stem cell transplantation.

Comparison of clinical outcomes between unrelated single umbilical cord blood and "ex-vivo" T-cell depleted haploidentical transplantation in children with hematological malignancies.

Over the last two decades, umbilical cord blood (UCB) and haploidentical transplantation (HaploHSCT) have emerged as alternative sources of hematopoietic stem cell for allogeneic transplantation. There are few retrospective studies and no prospective studies comparing both types of alternative transplantation in pediatric patients. We analyzed the data of 134 children with hematological malignancies who received a hematopoietic stem cell transplantation from a single umbilical cord blood (UCB) (n = 42) or an "ex-vivo" T-cell depleted transplant from a haploidentical-related donor (HaploHSCT) (n = 92) between 1996 and 2014. Hematological recovery was faster after HaploHSCT than the UCB transplant group (median times to neutrophil and platelet recovery: 13 vs. 16days, 10 vs. 57days, respectively) (P < 0.001). The HaploHSCT group had a significantly early immune reconstitution based on NK and CD8 + T cells compared with the UCB group. However, after thefirst year post-transplantation, HaploHSCT had a lower number of CD4 + T and B lymphocytes compared with the UCB transplant recipients. The cumulative incidence of TRM was 29±8% in the HaploHSCT group versus 40±5% in the UCB group. Relapse incidence was 21±7% in the HaploHSCT group and 19±8% in the UCB group. Probability of DFS was 58±8% in the HaploHSCT group versus 40±9% in the UCB group (P = 0.051). TCD haploidentical transplant is associated with advantages in terms of engraftment and early immune reconstitution kinetics. TCD haploidentical transplant was associated with lower incidence of infectious and non-infectious complications, especially in the early phases of the transplant compared with UCB transplant recipients. However, there are no advantages in transplant outcomes compared with UCB transplant.

Delayed-onset cytomegalovirus infection is frequent after discontinuing letermovir in cord blood transplant recipients

AbstractCytomegalovirus (CMV)-seropositive umbilical cord blood transplantation (CBT) recipients have a high incidence of CMV-associated complications. There are limited data regarding the efficacy of letermovir for preventing clinically significant CMV infection (CS-CMVi), and the impact of letermovir prophylaxis on delayed-onset CMV reactivation after letermovir discontinuation, in CBT recipients. We compared the cumulative incidence of CS-CMVi and CMV detection in 21 CMV-seropositive CBT recipients receiving letermovir prophylaxis with a historical cohort of 40 CBT recipients receiving high-dose valacyclovir prophylaxis. Letermovir was administered on day +1 up to day +98. The cumulative incidence of CS-CMVi was significantly lower by day 98 in the letermovir cohort (19% vs 65%). This difference was lost by 1 year due to a higher incidence of delayed-onset CMV reactivation in the letermovir cohort. No patients developed CMV disease in the letermovir cohort within the first 98 days compared with 2 cases (2.4%) in the high-dose valacyclovir cohort; 2 patients developed CMV enteritis after discontinuing letermovir. Median viral loads were similar in both cohorts. Thus, letermovir is effective at preventing CS-CMVi after CBT, but frequent delayed-onset infections after letermovir discontinuation mandate close monitoring and consideration for extended prophylaxis.

Prospective Study of High Dose Foscarnet Prophylaxis for HHV-6 Related CNS Diseases in Cord Blood Transplantation for Adult Patients

Background: Umbilical cord blood transplant (UCBT) recipients showed higher incidence of HHV-6 related CNS diseases (HHV-6 RCD) than those of bone marrow (BM) or peripheral blood (PB). It causes short-term memory impairment or disorientation, which sometimes become irreversible, and convulsions in severe cases, resulted in high non-relapse mortality. We reported previously that in the group given higher doses of prophylactic Foscarnet (FCV) (≥60mg/kg), the incidence of HHV-6 RCD was reduced (Asano-Mori Y, et al. ASH 2013). We thus conducted a prospective study to assess efficacy of higher dose (120mg/kg) of prophylactic FCV to further reduce the incidence and to improve outcome of HHV-6 RCD.Patients and Methods: The study was started since May 2014 and was finished on September 2015. The protocol was approved by local IRB and UCBT recipients who gave written informed consent were included. FCV 120 mg/kg was administered prophylactically from day 7 to day 50 post UCBT.. FCV dose was adjusted according to renal function. The incidence of HHV-6 RCD, types of manifestation and severity of the symptoms, treatment response, and prognosis were evaluated.Results: Among 113 who were included in this study, 9 failed to start FCV from day 7 due to early death or renal impairment, 37 were switched to other drugs at some point before day 50 for reasons such as renal impairment or viral infections other than HHV-6 (23 changed to GCV, 10 to ACV, and 4 to CDV), and 67 received planned dose of FCV. Fifteen developed HHV-6 RCD (12 HHV-6 limbic encephalitis (LE) and 3 myelitis). The cumulative incidence of HHV-6 RCD was 11.5%. No significant risk factors before transplant associated with the development of HHV-6 RCD were identified. Six out of 22 who developed severe pre-engraftment immune reactions (PIR) developed HHV-6 RCD. PIR was shown to be a significant risk factor for HHV-6 RCD development when it was treated as a time-dependent covariate. The median onset day was day 40, and 4 out of 15 patients developed after the cessation of FCV. Only one of 12 encephalitis patients developed convulsions. The median number of copies of HHV-6 in the cerebrospinal fluid at onset was 40,400/µL. HHV-6 viral load in peripheral blood was examined on the same day of CSF examination in 13 and was not detected in 7. Six patients were treated with FCV and GCV in combination, 4 received increased dose of FCV, and 1 was switched from FCV to GCV. Two out of 4 patients who developed after the prophylactic administration of FCV resumed FCV, and the remaining 2 resumed GCV. The virus became undetectable in all 13 evaluable patients by follow-up CSF examination after treatment. The median day of viral disappearance from CSF was 19 days (8-34 days) after diagnosis. All but 2 who were unevaluable due to other complications, had their symptoms improved without sequalae. The median time from treatment intervention to symptomatic improvement was 28 days. The OS after 1 year from HHV6 encephalitis myelitis group was 46.2%, and there was no significant difference in the prognosis as 47.3% OS after 1 year from non-onset group when time-dependent co-analysis was performed (HR 1.88, 95%CI;0.49-2.84, p=0.69). Analysis of OS for 67 patients who were able to undergo preventative FCV administration and other group showed 53.2% and 38.3% respectively in 1 year, revealing a trend in which OS appeared to become higher as a result of continued prophylaxis.Conclusion: There was no difference in the incidence of HHV-6 RCD compared to the previous report even after prophylactic administration of high dose 120 mg/kg of FCV. However, there were few severely ill individuals, most of their symptoms improved due to antiviral treatment without significant sequalae. DisclosuresNo relevant conflicts of interest to declare.

Assessment of a Multi-Cytokine Profile By a Novel Biochip-Based Assay Reveals Unique Correlation Patterns with Immune Reconstitution after Cord Blood Transplantation in Adults

Umbilical cord blood transplantation (UCBT) is an alternative stem cell source for allogeneic hematopoietic stem cell transplantation. The frequency of acute graft-versus-host-disease (aGvHD) in UCBT recipients is less than expected in recipients of adult donor allografts but delayed aGvHD can develop. Moreover, UCBT results in delayed and insufficient immune reconstitution leading to infection-related morbidity and mortality. We reasoned that an approach that would allow risk assessment for development of GvHD and/or for impaired immune reconstitution would be highly beneficial in adult UCBT recipients because it would guide therapeutic decisions for the prevention of these complications. Because reconstitution of hematopoietic lineages is delayed in UCB recipients, we focused on cytokines that can be assessed in patients' plasma at any time point before or after UCBT. Increase of proinflammatory cytokines IL-1b and TNF-α after BMT has been associated previously with the pathogenesis of GvHD. We previously determined that levels of IL-7 were inversely correlated with reconstitution of T cell subsets but were also associated with non-relapse mortality, development of GvHD and worse overall survival. In the present study, we employed a novel approach, which allows simultaneous assessment of multiple cytokines in a very small volume of patient's serum or plasma, to assess the prognostic value of this multi-cytokine profile in adult UCBT recipients. 32 patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by two sequential UCB graft transplantation (dUCBT) and GvHD prophylaxis with tacrolimus and sirolimus. Results are based on 27 evaluable patients. Assessments were done prior to transplantation and at 1, 2, 3, 6, 12 and 24 months after dUCBT. Quantification of cytokines IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IFN-γ, TNF-α and GM-CSF in serum samples was conducted using the LUNARISTM Human 11-Plex Cytokine Biochip384 from AYOXXA Biosystems. Briefly, after diluting as 1:2 using the respective assay diluent, 5µl of samples or assay standards were loaded in duplicates on the AYOXXA Biochip and the assay was performed according to the manufacturers' instructions. Readout was performed using the AYOXXA Reader AR01 (Cat. No. LRS-001, AYOXXA Biosystems) and data were analyzed using the LUNARISTM Analysis Suite Software (Cat. No. LAS-001, AYOXXA Biosystems). Based on their median levels, cytokines could be categorized in four patterns of kinetics in comparison to pre-transplant baseline values: 1) Without significant changes (IL-2); 2) decrease over time (IL-1b, IL-17); 3) increase at 1-month after dUCBT and subsequent decline (IL-4, IL-5, IL-6, IL-8, IL-10, TNF-α, GM-CSF); 4) increase at 2 months after UCBT and subsequent decline (IFN-γ). At baseline, most cytokines correlated with total lymphocytes, CD4+, CD8+ subsets, CD4+CD25+ Treg, CD56+CD16+ NK cells, CD20+ B cells and CD14+ monocytes. At 1-month after dUCBT, the correlations with immune cell types disappeared for most cytokines and only CD14+ monocytes correlated with IFN-γ. At 2-months after dUCBT, most cytokines were positively correlated with T cell subsets. IL-8 displayed a unique pattern of correlation with CD14+ monocytes and B cells, both of which have potent antigen presenting function. Specifically, at 2-months after dUCBT IL-8 inversely correlated with CD14+ cells (r=-0.71, p=0.0007) and this pattern persisted until day 100, when CD20+ cells also showed a significant inverse correlation with IL-8 (r=-0.56, p=0.006). These inverse correlations declined by 6 months after dUCBT. IL-8 levels after BMT were previously associated with infectious complications, which subsequently drive elevation of IL-6 and development of GvHD. Our findings pose the intriguing possibility that multicytokine profile analysis might serve as a biomarker to guide patient management such as work-up for infectious complications that might prevent GVHD development in dUCBT recipients. Analysis of correlations between multicytokine profile and such clinical outcomes is currently ongoing. Our results provide evidence for the feasibility of a novel method for multicytokine assessment in patients' plasma, which might guide patient management, to diminish complications after dUCBT. [Display omitted] DisclosuresAntin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Stenotrophomonas maltophilia bloodstream infections in adult recipients of umbilical cord blood transplantation

Limited data are available on Stenotrophomonas maltophilia bloodstream infections (SM-BSIs) and the therapeutic efficacy of trimethoprim–sulfamethoxazole (SXT) against SM-BSI in umbilical cord blood transplant (uCBT) recipients. Medical and microbiological records of adult patients who received uCBTs between December 2008 and December 2015 at Toranomon Hospital (Tokyo, Japan) were reviewed. The efficacy and safety of SXT were evaluated only for recipients who were treated with ≥7 days of intravenous SXT for SM-BSI (evaluation cohort). Of 561 uCBT recipients, 34 developed SM-BSI. Diabetes mellitus (P = .005) and age ≥ 60 years (P = .013) were significant independent risk factors for SM-BSI. Moreover, SM-BSI was identified as an independent risk factor for all-cause mortality up to 100 days following uCBT (P = .025). Of the 34 recipients with SM-BSI, 24 were treated with an intravenous SXT-containing regimen (iSXT-CR). Septic shock (P = .0021), pneumonia (P = .011), neutropenia (P = .0015), and systemic steroid administration (P = .018) were identified as significant independent risk factors for 7-day crude mortality. The evaluation cohort included nine recipients. Doses of SXT were 2.4 to 6.9 mg/kg/day of the trimethoprim component. Of the nine recipients, five developed SM-BSI during the pre-engraftment phase. The 30-day crude-mortality rate and clinical cure rate of the cohort were 22% and 67%, respectively. Only one of the nine recipients experienced significant neutrophil toxicity. In this study, the epidemiology of SM-BSI in uCBT recipients was determined and its negative impact on survival was demonstrated. A low- to moderate-dose iSXT-CR appeared to be a tolerable and important therapeutic option for SM-BSI in the uCBT setting, including during the pre-engraftment phase.

Use of Potentially Inappropriate Medications in Older Allogeneic Hematopoietic Cell Transplantation Recipients

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n=114)and younger (40 to 64 years; n=240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P=.65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P=.03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P=.02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P=.02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P=.02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P=.01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P=.01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P=.05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P=.04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities.Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Community acquired respiratory virus infections in adult patients undergoing umbilical cord blood transplantation

Characteristics and risk factors (RFs) of community-acquired respiratory virus (CARV) infections after umbilical cord blood transplantation (UCBT) are lacking. We retrospectively analyzed CARV infections in 216 single-unit myeloablative UCBT recipients. One-hundred and fourteen episodes of CARV infections were diagnosed in 62 (29%) patients. Upper respiratory tract disease (URTD) occurred in 61 (54%) whereas lower respiratory tract disease (LRTD) in 53 (46%). The 5-year cumulative incidence of CARV infection was 29%. RFs for developing CARV infections were: prednisone-based graft-versus-host disease (GVHD) prophylaxis and grade II–IV acute GVHD. RFs analysis of CARV progression to LRTD identified 2007–2009 period and absolute lymphocyte count (ALC) < 0.5 × 109/L. ALC < 0.5 × 109/L had a negative impact on day 60 mortality in both overall CARV and those with LRTD, whereas proven LRTD was associated with higher day 60 mortality. CARV infections had a negative effect on non-relapse mortality. Overall survival at day 60 after CARV detection was significantly lower in recipients with LRTD compared with URTD (74% vs. 93%, respectively). In conclusion, CARV infections after UCBT are frequent and may have a negative effect in the outcomes, in particular in the context of lymphocytopenia.

Hemophagocytic Lymphohistiocytosis and Graft Failure Following Unrelated Umbilical Cord Blood Transplantation in Children.

Hemophagocytic lymphohistiocytosis (HLH) following hematopoietic stem cell transplantation is closely correlated with graft failure and poor prognosis. Because of its rarity, the incidence, risk factors, and optimal treatment strategy are unclear. We analyzed data from cases of HLH following umbilical cord blood transplantation (UCBT) performed for pediatric patients at our center. Among 66 UCBT recipients, 5 developed HLH and imminent graft failure. The median time of diagnosis of HLH was 22 (range, 19 to 30) days after UCBT, and the cumulative incidence of HLH was 7.6% (95% confidence interval, 2.8-15.7) at day 60. In univariate analysis, the cumulative incidence of HLH was significantly higher in patients with infused CD34 cells <1.0×10/kg than in patients with higher CD34 cells. Patients with preengraftment infection showed a trend toward higher incidence of HLH compared with patients without any infection. All 5 patients with HLH received corticosteroids and low-dose etoposide (VP-16), with or without high-dose intravenous immunoglobulin. Following these treatments, successful engraftment was observed in 2 patients. Corticosteroids and low-dose VP-16 may be worthy of a trial before attempting salvage hematopoietic stem cell transplantation. Further analyses are required to identify risk factors and to develop methods for prophylaxis, diagnosis, and treatment of HLH.

Outcomes of Chronic Graft-Versus-Host Disease (cGVHD) Following Matched Sibling Donor (MSD) Versus Umbilical Cord Blood Transplant (UCBT)

Outcomes of Chronic Graft-Versus-Host Disease (cGVHD) Following Matched Sibling Donor (MSD) Versus Umbilical Cord Blood Transplant (UCBT)

Development of HHV-6-Specific Immunity after Cord Blood Transplantation in Adults Depends on Reconstitution of Thymopoiesis and Regeneration of CD4+ T Cells

The treatment of hematological malignancies with umbilical cord blood transplantation (UCBT) is rapidly increasing for adult patients. Disadvantages of UCBT include insufficient cell numbers for adult patient reconstitution, a lack of antigen experienced cells, and deficits in T cell signal transduction mechanisms. Consequently, UCBT is frequently associated with impaired immune function and high infection-related mortality. To counter these difficulties, transplantation with two UCB units has been employed to improve immune reconstitution in adult patients. We evaluated both the quantitative and functional reconstitution of cellular immunity in a group of adult patients undergoing UCBT. Thirty-two patients with a median age of 50 years with hematopoietic malignancies were treated with reduced intensity conditioning (Flu/Mel/rATG) followed by infusion with two sequential UCB grafts and GvHD prophylaxis with tacrolimus and sirolimus. The grafts were at least a 4/6 match with each other and the recipient. Here we report the results of 27 patients who have completed at least one year of follow up. Assessments were done prior to transplant and at various time intervals until 12 months post UCBT. Neutrophil and platelet engraftment occurred at a median of 21 days and 42 days, respectively. CD3+ populations remained severely depressed until 8 wks post-transplant when they gradually began to re-emerge. However the CD4+ and CD8+ populations demonstrated distinctly different reconstitution kinetics. At 6 months the median value of absolute numbers of CD4+ lymphocytes was 35% of pre-transplant levels increasing to 42% at 1 yr post-transplant, a median value far below the normal range for adults. In contrast, at 6 months post-transplant CD8+ lymphocytes remained severely depressed to 12% of pre-transplant levels, but dramatically increased and reached normal levels by 1 yr after UCBT. Interestingly, both the CD14+ monocyte and the CD16+CD56+ NK cell populations expanded dramatically at 4 wks post-transplant and reached pre-transplant levels and were within the normal range by 6 months. CD20+ B cell repopulation began at 8 wks post-transplant, displayed a striking expansion leading to a 17-fold increase in the median value for B cell numbers over pre-transplant values at 1 year and resulting in a median value of absolute numbers near the top of the normal range. To evaluate functional T cell immune reconstitution in vivo, we performed IFN-γ ELISpot analysis on CMV stimulated PBLs and compared the results to a PCR-based assay for CMV viremia. Additionally, we assessed the reconstitution of thymopoiesis with the T cell receptor excision circle (TREC) assay and real-time PCR. 16/27 patients and 26/52 UCB products were CMV seropositive prior to transplant. In the post-UCB period, development of CMV-specific effectors as determined by ELISpot did not always correlate with clearance of CMV viremia. Specifically, prior to 8 weeks post-UCBT, 8 out of 12 (67%) patients with CMV-positive ELISpot displayed CMV viremia, between 8 weeks and 100 days post-UCBT 4 out of 11 (36%) patients with CMV-positive ELISpot displayed CMV viremia and after 100 days post-UCBT only 3 out of 10 patients (30%) who developed CMV-positive ELISpot remained positive for CMV viremia. Identification of functional CMV effectors was only associated with the numbers of CD8+CD45RA+ cells (p=0.01) and the development of high TREC concentrations (p=0.01) that were detected after 6 months of UCBT, and was independent of GvHD or mixed chimerism. Taken together these results indicate that reconstitution of T cell immunity after UCBT is characterized by delayed recovery of CD4+ and CD8+ T cells and correlates with reconstitution of thymopoiesis and increase of naive CD8+CD45RA+ T cells that can develop into efficient pathogen-specific effectors.

Prospective Randomized Study Comparing Myeloablative Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Stem Cell Transplantation for Adults with Hematologic Malignancies.

In this prospective randomized study, we compared the outcomes of single-unit umbilical cord blood transplantation (UCBT) and unmanipulated haploidentical stem cell transplantation (haplo-SCT) with post-transplantation cyclophosphamide (PTCy) in adults with hematologic malignancies. All patients received a myeloablative conditioning (MAC) regimen consisting of thiotepa, busulfan, and fludarabine, with antithymocyte globulin (ATG) added for UCBT recipients. Nineteen patients were randomized to UCBT and the other 26 to haplo-HSCT. Four patients (15%) allocated to the haplo-HSCT arm lacked a suitable donor and were crossed over to the UCBT arm. Finally, 23 underwent UCBT and 22 underwent haplo-HSCT. The cumulative incidence of neutrophil recovery was 87% at a median of 19 days (range, 13 to 24 days) in the UCBT arm versus 100% at a median of 17 days (range, 13 to 25 days) in the haplo-SCT arm (P=.04). Platelet recovery was 70% at a median of 40 days (range, 18 to 129 days) in the UCBT arm versus 86% at a median of 24 days (range, 12 to 127 days) in the haplo-HCT arm (P=.02). Rates of acute graft-versus-host disease (GVHD) grade II-IV or grade III-IV, overall chronic GVHD, and extensive chronic GVHD in the UCBT and Haplo-SCT arms were 43% versus 36% (P=.8), 9% versus 9% (P=1), 66% versus 43% (P=.04), and 41% versus 23% (P=.2), respectively. Two-year nonrelapse mortality and relapse in the 2 arms were 52% versus 23% (P=.06) and 17% versus 23% (P=.5), respectively. Two-year disease-free survival, overall survival, and GVHD/relapse-free survival in the 2 arms were 30% versus 54% (P=.2), 35% versus 59% (P=.1), and 17% versus 40% (P=.04), respectively. Our data show that in the context of an MAC regimen, haplo-SCT with PTCy provides improved outcomes compared with ATG-containing single-unit UCBT.

Reactivation of BK virus after double umbilical cord blood transplantation in adults correlates with impaired reconstitution of CD4+ and CD8+ T effector memory cells and increase of T regulatory cells

BK virus (BKV), a human polyomavirus that remains latent in renal epithelial cells, can be reactivated after hematopoietic stem cell transplantation (HSCT) leading to hemorrhagic cystitis. The incidence of BK viremia is higher after Umbilical cord blood transplantation (UCBT) than HSCT from adult donors. Data regarding the role of immune recovery after UCBT in BKV reactivation is lacking. We examined the correlation between the development of BK viremia and immune reconstitution in 27 adult recipients of UCBT. The incidence of BK viremia was 52% and developed most frequently within the first 8 weeks after the transplantation, but persisted in seven patients at 6 months, and three patients at 1-year post UCBT. Detection of BK viremia 1 year after transplant was negatively associated with the number of CD8+ cells (p = 0.03) and CD8+CD45RO+ cells (p = 0.05) at 6 months, and the number of CD4+ (p = 0.03) and CD4+CD45RO+ cells (p = 0.03) at 12 months after UCBT. Conversely, BK viremia at 6 and 12 months was positively correlated with the number of T regulatory (Treg) cells at 1 month (p = 0.005 and p = 0.016, respectively). Because UCB Treg have highly potent immunosuppressive function, our findings indicate that sustained BK viremia in UCBT recipients might be associated with the increase of Treg cells early after transplantation, which mediate impaired and delayed reconstitution of CD4+ and CD8+ T effector cells.

Invasive fungal disease in patients undergoing umbilical cord blood transplantation after myeloablative conditioning regimen.

Characteristics and risk factors (RFs) of invasive fungal disease (IFD) have been little studied in the setting of umbilical cord blood transplantation (UCBT). We retrospectively included 205 single-unit myeloablative UCBT recipients with a median follow-up of 64months. Fifty-six episodes of IFD were observed in 48 patients (23%) at a median time of 123days after stem cell infusion. Invasive mold disease (IMD) occurred in 42 cases, 38 of them (90%) caused by invasive aspergillosis whereas invasive yeast disease (IYD) occurred in 14 cases, most of them due to candidemia (n=12, 86%). The 5-year cumulative incidence of IFD, IMDs, and IYDs was 24% 19%, and 7%, respectively. In multivariate analysis, three RFs for IMDs were identified: age >30years (HR 3.5, P=0.017), acute grade II-IV graft-versus-host disease (HR 2.3, P=0.011), and ≥1 previous transplant (HR 3.1, P=0.012). The probability of IMDs was 2.5%, 14%, and 33% for recipients with none, 1, or 2-3 RFs, respectively (P<0.001). Among IFD, IMDs had a negative effect on non-relapse mortality in multivariate analysis (HR 1.6, P=0.039). IMDs showed a negative impacton overallsurvival (HR 1.59, P=0.018). Invasive mold disease were very common and serious complication after UCBT.