Umbilical Cord Blood Transplantation In Patients Research Articles

Letermovir prophylaxis reduced cytomegalovirus reactivation and resistance post umbilical cord blood transplantation.

To explore the impact of letermovir (LET) prophylaxis on cytomegalovirus (CMV) reactivation and resistance in both adult and paediatric umbilical cord blood transplantation (UCBT) patients, we retrospectively compared 43 UCBT patients who received LET as CMV prophylaxis with a historical cohort of 207 UCBT patients without LET usage. LET was administered from Day +1 to Day +100. The 180-day cumulative incidence of CMV reactivation (47.3% vs. 74.4%, p < 0.001) and the proportion of refractory CMV reactivation (15.0% vs. 42.9%, p = 0.016) were significantly lower than those in the control group. However, more frequent late CMV infection (31.0% vs. 4.3%, p = 0.002) and the 180-day cumulative incidence of Epstein-Barr virus (EBV) reactivation (9.3% vs. 3.4%, p = 0.087) were observed in UCBT patients with LET prophylaxis. Meanwhile, older age (>15 years old) and the occurrence of pre-engraftment syndrome were identified as the significant risk factors for CMV reactivation, and in patients at high risk, the incidence of CMV reactivation in the LET group was lower than that in the control group (46.7% vs. 86.5%, p < 0.001), while this decline was less pronounced among patients at low risk (47.8% vs. 62.1%, p = 0.120).

Updated comparable efficacy of cord blood transplantation for chronic myelomonocytic leukaemia: a nationwide study.

Chronic myelomonocytic leukaemia (CMML) is a haematological malignancy with a poor prognosis. Allogeneic haematopoietic stem cell transplantation remains the only curative approach. Without human leucocyte antigen-matched related sibling donors, the optimal alternative donor has yet to be established. Although unrelated bone marrow transplantation (UBMT) has been extensively studied, cord blood transplantation (CBT) for CMML remains largely unexplored. This nationwide retrospective study compared the outcomes of UBMT and single-unit umbilical CBT in patients with CMML. This study included 118 patients who underwent their first allo-HSCT during 2013-2021. Of these, 50 received BMT (UBMT group), while 68 underwent CBT (CBT group). The primary endpoint was the 3-year overall survival (OS). There were comparable 3-year OS rates between the UBMT (51.0%, 95% confidence interval [CI]: 34.1-65.5%) and CBT (46.2%, 95% CI: 33.2-58.1%; P = 0.60) groups. In the inverse probability of treatment weighting analysis, CBT did not show significantly improved outcomes compared with UBMT regarding the 3-year OS rate (hazard ratio 0.97 [95% CI: 0.57-1.66], P = 0.91). Thus, CBT may serve as an alternative to UBMT for patients with CMML. Further research is necessary to optimise transplantation strategies and enhance outcomes in patients with CMML undergoing CBT.

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.

Efficacy of Cord Blood Transplantation for the Management of Chronic Myelomonocytic Leukemia: A Registry-Based Study in Japan

Introduction Chronic myelomonocytic leukemia (CMML) is a challenging malignancy that shares characteristics with myelodysplastic syndromes and myeloproliferative neoplasms. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for CMML. Numerous studies have examined transplant outcomes and prognostic factors; however, the focus has primarily been on bone marrow transplantation (BMT) and peripheral blood stem cell transplantation, while cord blood transplantation (CBT) is understudied. To address this knowledge gap, we conducted a nationwide retrospective study to comprehensively compare the outcomes of unrelated BMT and single-unit umbilical CBT in patients with CMML. Methods Data were collected from the Transplant Registry Unified Management Program 2 of the Japanese Data Center for Hematopoietic Cell Transplantation. The inclusion criteria were as follows: age of 16 years or higher, a diagnosis of CMML, and receipt of the first allo-HSCT between 2013 and 2019 through unrelated BMT from a human leukocyte antigen (HLA) 8/8-matched donor (UBMT group) or single-unit umbilical CBT (CBT group). The primary endpoint was overall survival (OS) after allo-HSCT, and the secondary endpoints included progression-free survival (PFS), cumulative incidences of relapse and non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host (GVHD)-free, relapse-free survival (GRFS). The impact of CBT versus unrelated BMT on outcomes was evaluated using inverse probability of treatment weighting (IPTW) analysis. In this analysis, the Cox proportional hazards regression model for OS, PFS, and GRFS and the Fine-Gray proportional hazards regression model for relapse, NRM, engraftment, and GVHD were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for all outcomes. The propensity score (PS) was calculated via logistic regression by using the following factors: age at allo-HSCT, sex, cytogenetic risk, disease status, days from diagnosis to allo-HSCT, and year of allo-HSCT. For the CBT group, the stabilized weights were calculated by dividing CBT prevalence by each individual's PS. Conversely, for the UBMT group, the weights were calculated by dividing the 1 minus prevalence of CBT by 1 minus each individual's PS. Results Between 2013 and 2021, 238 patients with CMML underwent their first allo-HSCT. Among them, 50 underwent HLA 8/8 allele-matched unrelated BMT (UBMT group) and 68 underwent single-unit umbilical CBT (CBT group). The median age at allo-HSCT was 58.5 (range: 26-75) years; the median follow-up period for survivors was 1,329.5 (range: 100-1,967) days. Intergroup differences in age at allo-HSCT, recipient sex, hematopoietic cell transplantation-specific comorbidity index, Eastern Cooperative Oncology Group performance status, cytogenetic risk, pre-transplant treatment, disease status at allo-HSCT, conditioning intensity, GVHD prophylaxis, and year of allo-HSCT were not significant. The transplantation outcomes are shown in Figure 1. There were no significant differences in the 3-year OS rate (UBMT: 51.0% [95% CI: 34.1-65.5%] vs CBT: 46.2% [95% CI: 33.2-58.1%]; P = 0.60; Figure 1A). IPTW analysis revealed no significant differences between the CBT and UBMT groups (HR: 1.21, 95% CI: 0.69-2.10, P = 0.51). PFS, relapse, NRM, and GRFS were not significantly different between the groups (Figure 1B-E). The neutrophil engraftment rate at 30 days was significantly higher in the UBMT group than in the CBT group (UBMT: 92.0% [95% CI: 78.9-97.1%] vs CBT: 79.4% [95% CI: 67.5-87.4%]; P &amp;lt; 0.01; Figure 1F). These observations associated with the secondary endpoints were concurrently corroborated by the IPTW analysis. Conclusion Our study suggests that CBT can serve as a viable treatment option, demonstrating efficacy comparable to that of unrelated BMT for patients with CMML. These findings underscore the improved outcomes over time after CBT in patients with CMML, which is a treatment previously perceived as inferior to other donor sources (Itonaga et al., Biol Blood Marrow Transplant. 2018;24:840-48). Further investigations are warranted to optimize transplantation strategies and improve outcomes in patients with CMML.

Reconstitution of double-negative T cells after cord blood transplantation and its predictive value for acute graft-versus-host disease.

With an increasing number of patients with hematological malignancies being treated with umbilical cord blood transplantation (UCBT), the correlation between immune reconstitution (IR) after UCBT and graft-versus-host disease (GVHD) has been reported successively, but reports on double-negative T (DNT) cell reconstitution and its association with acute GVHD (aGVHD) after UCBT are lacking. A population-based observational study was conducted among 131 patients with hematological malignancies who underwent single-unit UCBT as their first transplant at the Department of Hematology, the First Affiliated Hospital of USTC, between August 2018 and June 2021. IR differences were compared between the patients with and without aGVHD. The absolute number of DNT cells in the healthy Chinese population was 109 (70-157)/μL, accounting for 5.82 (3.98-8.19)% of lymphocytes. DNT cells showed delayed recovery and could not reach their normal levels even one year after transplantation. Importantly, the absolute number and percentage of DNT cells were significantly higher in UCBT patients without aGVHD than in those with aGVHD within one year (F = 4.684, P = 0.039 and F = 5.583, P = 0.026, respectively). In addition, the number of DNT cells in the first month after transplantation decreased significantly with the degree of aGVHD increased, and faster DNT cell reconstitution in the first month after UCBT was an independent protective factor for aGVHD (HR = 0.46, 95% confidence interval [CI]: 0.23-0.93; P = 0.031). Compared to the number of DNT cells in Chinese healthy people, the reconstitution of DNT cells in adults with hematological malignancies after UCBT was slow. In addition, the faster reconstitution of DNT cells in the early stage after transplantation was associated with a lower incidence of aGVHD.

Health-Related Quality of Life Following Allogeneic Hematopoietic Cell Transplantation with Omidubicel versus Umbilical Cord Blood

Omidubicel is an advanced cell therapy derived from umbilical cord blood (UCB) for use in allogeneic hematopoietic cell transplantation (HCT). A recent randomized phase 3 clinical trial demonstrated faster engraftment, shorter length of hospital stays, and lower rates of infection with omidubicel compared with standard UCB transplantation in patients with high-risk hematologic malignancies. Despite the proven clinical benefits of omidubicel, its impact on health-related quality of life (HRQL) from the patient's perspective has not been described. This study analyzed patient-reported HRQL measures collected prospectively in the randomized phase 3 trial comparing omidubicel to standard UCB transplantation. A total of 108 patients at 33 international stem cell transplantation centers underwent myeloablative allogeneic HCT with either omidubicel or standard UCB. Patients completed serial HRQL questionnaires at screening and on days 42, 100, 180, and 365 post-transplantation. The HRQL surveys included the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT), a 50-item cancer-specific questionnaire assessing physical, functional, emotional, social/family, and HCT-specific well-being, and the EuroQol 5-Dimension 3-Level, a 5-item generic HRQL survey. A mixed model with repeated measures was used to compare changes in HRQL from baseline in the 2 treatment arms. The average change in HRQL scores over time was compared by estimating the difference in the area under the curve (AUC) in each treatment group. Seventy-five patients (omidubicel arm, n=37; standard UCB arm, n=38) who completed the FACT-BMT at baseline and on 1 or more follow-up visits were included in this study. Baseline characteristics were similar in the 2 treatment arms. Over the first year post-transplantation, the AUCs of mean changes in physical, functional, and total FACT-BMT scores indicated significantly better HRQL with omidubicel (P < .05), with mean differences across time points ranging from 1.4 to 3.1 points, 1.6 to 3.2 points, and 7.2 to 11.0 points, respectively. The minimal clinically important difference was exceeded at 1 or more time points for each of these measures. The HRQL improvements with omidubicel were observed as early as 42 days post-transplantation and persisted at 1 year, indicating the potential long-term benefits of omidubicel on HRQL. Across all patients, adverse clinical outcomes, such as grade 3 viral infections and lower rates of neutrophil engraftment, were associated with worse HRQL scores. The observed improvements in HRQL measures may reflect the known clinical benefits of omidubicel. Compared with standard UCB, allogeneic HCT with omidubicel resulted in significant and clinically meaningful improvements in patient-reported HRQL measures.

Poor survival and prediction of prolonged isolated thrombocytopenia post umbilical cord blood transplantationin patients with hematological malignancies.

Prolonged isolated thrombocytopenia (PIT) is a common complication after umbilical cord blood transplantation (UCBT). However, data on PIT prediction and impacts on transplantation outcomes for UCBT patients are rare. We retrospectively analyzed 244 patients with hematological malignancies who received single-unit UCBT at the First Affiliated Hospital of USTC between August 2018 and December 2019. Among them, PIT occurred in 49 recipients, with a crude incidence of 20.1%. In the PIT patients, the 2-year cumulative incidence of transplant-related mortality (TRM) was significantly higher, and the probabilities of 2-year overall survival, leukemia-free survival and graft-versus-host disease (GVHD)-free relapse-free survival were significantly poorer (57.1% vs. 88.6%; 53.1% vs. 81.9%; 22.4% vs. 59.8%; p<0.001), without remarkable increases in the cumulative incidence of relapse or chronic GVHD. Importantly, the multivariate analysis revealed that lower high-resolution HLA compatibility (≤6/10), lower infused CD34+ cell count (≤1.78×105 /kg), grade II-IV acute GVHD preplatelet engraftment, a lower pretransplantation platelet count (≤100×109 /L), and a longer neutrophil engraftment time (≥17 days) were independent risk factors for PIT after UCBT. These results demonstrate that PIT is common after UCBT, predicting inferior survival and the need for more monitoring during the early phase.

In-Hospital Mortality and Cost of Allogeneic Hematopoietic Cell Transplant (HCT) in Adult Acute Myeloid Leukemia: National Inpatient Sample (NIS) Years 2002-2013

Background: Allogeneic HCT can be curative for certain subgroups of patients with AML. However, the financial burden of HCT is significant, and no studies have examined trends in cost over the last decade. We use the NIS, a nationally representative sample of hospital discharges in the US, to describe morbidity, mortality and cost of HCT in adults with AML.Methods: Years 2002-2013 of the NIS were queried for patients aged 18 and older with a primary procedure code of allogeneic hematopoietic stem cell transplant (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 41.00, 41.02, 41.03, 41.05, 41.06, 41.08) and a primary diagnosis of acute myeloid leukemia (ICD-9-CM codes 205.0, 205.2, 205.3). Mortality, length of stay, hospital costs, and complications were analyzed over the 12-year period. Subgroups based on type of transplant (Peripheral blood stem cell transplant (PBSCT), bone marrow transplant (BMT), and umbilical cord blood transplant (UCBT)). Predictors of mortality and cost were identified using multivariable regression models. Cost was derived from total hospital charges which were converted to cost using the provided NIS cost-to-charge ratios and adjusted for inflation using the 2013 Consumer Price Index.Results: From 2002-2013, an estimated 19,965 adults with AML were admitted for HCT. Most (79%) had peripheral blood stem cell transplants (PBSCT); 15% had bone marrow transplants (BMT); 6% had umbilical cord blood transplants (UCBT). Twenty-seven percent of patients were aged 18-40, 49% aged 41-60, and 24% aged 61 and older. Most patients (81%) identified as non-Hispanic white; 5% identified as black, 7% as Hispanic; and 7% as Asian/other. Private insurance was the most common primary payer (68%), followed by Medicare (15%), Medicaid (11%), and Self-pay/Other (6%). The vast majority (97%) of hospitalizations took place at an urban teaching facility. Donor type (related versus unrelated) was not reported in 35% of PBSCT and 47% of HCT patients. Incidence of BMT (per 100,000 admissions) increased from 2.9 in 2002 to 5.1 in 2013 (Figure). Median length of stay was 26 days (Inter-quartile range (IQR), 22-33) for PBSCT, 28 days (IQR, 24-36) for BMT, and 35 days (IQR, 26-48) for UCBT. In hospital mortality was 8%, and did not differ significantly by age group (9% in patients 18-40, 7% in patients 41-60, and 8% in patients 61 and older). Mortality did significantly improve over the 12 year period (P<0.01 for linear trend). In-hospital mortality was significantly higher in the UCBT cohort (15%) compared to PBSCT (7%) (P<0.01) and BMT (10%) (P=0.03). Major complications included: stomatitis (36%), total parenteral nutrition (17%), neutropenic fever (14%), bacteremia (12%), mechanical ventilation (6%), and dialysis (3%). Upon univariate regression analysis, compared to PBSCT, UCBT patients were less likely to experience stomatitis (OR=0.60, P<0.01), but more likely to experience sepsis (OR=2.06, P<0.01), bacteremia (OR=2.08, P<0.01), disseminated Candida infection (OR=4.47,P<0.01), and mechanical ventilation (OR=2.15,P<0.01). Median hospital costs for the entire cohort were $96,478 (IQR, $66,460-$143,495). Average daily cost increased significantly over time (Coefficient=$68, P<0.01 for linear trend). UCBT incurred a median cost of $161,855 (IQR, $113,613-221,944), while PBSCT and BMT incurred median costs of $92,923 (IQR, $64,074-137,421) and $98,601 (IQR, $67,697-$142,220), respectively. After adjustment for socio-demographic factors and comorbidities, UCBT was associated with increased mortality (OR 2.25, P<0.01) and cost (coefficient $1,215, P<0.01) relative to PBSCT (Table). BMT did not significantly increase mortality or cost compared to PBSCT.Conclusions: This study demonstrates that initial costs for inpatient allogeneic HCT have increased significantly since 2002, while mortality has improved. It also demonstrates increased cost and mortality with umbilical cord transplants compared to PBSCT even after adjustments for socio-demographic factors and comorbidities. This is likely secondary to an increased risk of severe in-hospital complications in patients undergoing UCBT. Further research is needed to explain the increased morbidity, mortality and cost associated with this particular group. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Population pharmacokinetics of tacrolimus in umbilical cord blood transplant patients focusing on the variation in red blood cell counts.

The distribution of tacrolimus (TAC), an immunosuppressant used during cord blood transplantation (CBT)-one of the haematopoietic stem cell transplantations, to red blood cell (RBC) is approximately 90% in whole blood. In CBT patients, the total RBC count shows dramatic fluctuation due to conditioning before transplantation, including anticancer agents and total body irradiation, as well as RBC transfusions during the treatment period. Therefore, the amount of TAC in whole blood may show wide variation. However, therapeutic drug monitoring (TDM) of TAC has been performed based on the whole blood concentration. In this study, to contribute to TDM of TAC in CBT, we performed the population pharmacokinetic (PPK) analysis of TAC in 56 CBT patients and investigated the factors that affected the concentration of TAC, focusing the variation of RBC count. A one-compartment model was applied to the observed whole blood TAC concentrations, and a PPK analysis was conducted with a non-linear mixed effect model. Our final PPK model indicated good robustness and accuracy. In addition, haemoglobin (Hb) level was an influential covariate on Vd, which was expressed as Vd(L)=91.4×(Hb/8.2)(-1.07) . In this study, our results showed the necessity for the Hb level monitoring during TDM of TAC in CBT patients and provided useful information for improving TDM strategy of TAC.

Comparison of transfusion requirements in adult patients undergoing Haploidentical or single-unit umbilical cord blood stem cell transplantation.

Umbilical cord blood transplantation (UCBT) and haploidentical hematopoietic stem cell transplantation (haplo-HSCT) modalities have been developed to offset the lack of matched donors. In this study, we compare the transfusion requirements of patients undergoing UCBT and haplo-HSCT in a single institution with the aim of providing additional information for clinicians to choose the most adequate alternative graft for HSCT. The study reviewed 67 and 46 patients undergoing UCBT and haplo-HSCT, respectively. There were no significant differences for RBC and PLT requirements according to the transplantation modality. Median time to RBC transfusion independence was 35 and 25.5days in patients who received an UCBT and haplo-HSCT, respectively (P=0.38), while median time to platelet transfusion independence was 31days for UCBT patients and 23 for haplo-HSCT patients (P<0.001). Days until neutrophils>0.5×109 /L were the only variable that significantly influenced RBC and PLT requirements for both transplantation modalities. Cumulative incidence of RBC and PLT transfusion independence at 90days after transplantation was similar for both UCBT and haplo-HSCT. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy. Both transplantation platforms require prolonged and intensive supportive RBC and PLT transfusion therapy.

Viral Infection Rates and Associated Serious Complications in Pediatric Umbilical Cord Blood Transplant Patients over the Last Decade

Background Umbilical cord blood (UCB) transplantation has been demonstrated to be associated with higher risk of viral infections, but few studies have examined the rates of viral infections and morbidity in the pediatric population. Patients and methods Retrospective assessment of all pediatric patients who received an UCB transplant at UCLA from January 2007 to December 2017. Pre-transplant screening included serologies for CMV, HSV, EBV and hepatitis viruses. Prophylaxis was administered to patients seropositive for CMV and HSV, consisting of ganciclovir 6 mg/kg over days -7 to -2 and acyclovir 10-20 mg/kg/dose BID or TID from day 0 to +100, respectively. Results Sixty-two patients received 65 UCB transplants, 47 for malignancies and 18 for genetic disorders; the incidence of viral infections at thirty days and at one year after transplantation were 27.7% and 43.0%, respectively. Some patients were diagnosed with more than one viral infection in the first year after transplant (13.8%), and the adjusted incidence of viral infections was highest in the 16-21 age group (87.5%). Among patients who received prophylaxis, the incidences of CMV viremia and HSV infections were 45.5%% and 10.7%, similar to the literature. Of 33 CMV seropositive patients, viral reactivation progressing to CMV disease occurred in 30.3% of patients. HHV6 viral encephalitis was diagnosed in 5 patients, and 1 patient developed adenovirus encephalitis. Graft failure occurred in 12.3% of patients. Of 47 transplants for malignant disease, 14.9% patients died of relapse. Of 29 reported deaths, GvHD was the cause of death in 9.2% of these cases. Infections in the absence of relapsed disease or GvHD contributed to 41.3% of deaths. Respiratory viral infections contributed to the death of 3 patients. Conclusion Pre-transplant serological screening and viral prophylaxis were effective in preventing infections in patients with UCB transplants. Strategies for prevention and therapy of viral infections will improve transplantation outcomes.

Outcomes of Graft Failures after Umbilical Cord Blood Transplantation in Acute Leukemia: A Study from Eurocord and the Acute Leukemia Working Party of the EBMT

▪Backround & Methods. Approximately 12% of adult patients (pts) receiving umbilical cord blood transplantation (UCBT) as treatment for acute myeloid (AML) or lymphoblastic (ALL) leukemia are reported to experience graft failure (Baron et al., J Hematol Oncol 2015 ; 8 :107). No systematic large study has assessed their outcome thus far. Therefore the acute leukemia working party of the EBMT and EUROCORD performed a multicenter retrospective registry study on adult patients with AML or ALL receiving a first single or double UCBT between 2005 and 2016.Results. The study included 1836 pts. 215 of them (11.7%) had graft failure; 160 with AML and 55 with ALL. Their median age was 43 (range, 18-68) years. 115 pts were male and 100 female. Median year of transplantation was 2010. 67% of the patients were in complete remission (CR) at transplantation, while 33% had advanced disease. Conditioning regimen was myeloablative in 128 pts (60%) and RIC in 87(40%) pts, respectively. ATG was administered in 101 pts. 126 pts received a single UCBT and 49 a double UCBT. Among the 215 pts with graft failure 54 underwent a second allogeneic (n=53) or autologous (n=1) transplantation 16 to 700 (median 62) days after the first UCBT (the 1-year cumulative incidence of second transplantation was 24%). 100-day and 1 year OS in pts not undergoing a second transplantation were 21.9 % (95% CI: 16.3-29.3) and 10.6 % (95% CI: 6.7-16.8), respectively. Among the 53 pts who underwent a second allogeneic transplantation, the second donor was either an unrelated donor (n=34), an HLA-haploidentical (n=17), or an HLA-identical sibling (n=2). Stem cell source consisted of single (n=13) or double (n=13) UCB, PBSC (n=17), BM (n=7), PBSC + UCB (n=3) or PBSC + BM (n=1). Conditioning regimen for the second transplantation was a RIC in 87% of pts. Sustained engraftment was achieved by 33 pts (61%) after the second transplantation. One- and 3-year incidences of relapse, nonrelapse mortality, OS and LFS from second transplantation were 21% and 28%, 47% and 52%, 40% and 23%, and 33% and 21%, respectively. Main causes of death following second transplantation (n=39) included infection (n=14) and leukemia relapse/progression (n=12). In the 17 patients receiving an haploidentical transplantation as second graft 1- and 3-year OS were 51.8 % (95% CI: 32.4-82.7) and 41.4 % (95% CI: 21.8-78.6), respectively. In a multivariate Cox model assessing factors predicting OS in UCBT patients with graft failure, transplantation for advanced disease (HR=2.3; 95% CI : 1.6-3.3, P<0.0001) as well as graft failure after the salvage transplantation (HR=2.8; 95% CI : 1.6-5.0, P=0.0005) were predictive of poor OS while use of RIC conditioning for the first transplantation was associated with a better OS.Conclusions. In this large cohort of adult pts given UCBT as treatment for AML or ALL the incidence graft failure was 12%. A second transplantation could be performed only to a minority (24%) of patients with high, about 50%, TRM but led to a 3-year OS of 23%, rescuing about quater of the pts with graft failure post UCBT. Results were more encouraging in the 17 patients who received a salvage HLA-haploidentical transplantation (3-year OS of 41%). Future attempts should be focused on reducing the high TRM associated with the second transplant while recent progresses in cord blood engineering will likely dramatically decrease the incidence of graft rejction after UCBT. DisclosuresMohty:Sanofi: Honoraria, Speakers Bureau.

An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia.

Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89-70.71, 95% confidence interval (CI)] and 64.76% (64.33-65.86, 95% CI) to 14.78% (10.91-17.41) and 18.11% (14.40-22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19-69.04, range) and 65.78 (65.20-66.28) for 2 years OS and LFS, respectively.Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478-86. ©2017 AACR.

Coinfusion of Mobilized Hematopoietic Stem Cells From an HLA-mismatched Third-party Donor With Umbilical Cord Blood Graft to Support Engraftment

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Late Onset Colitis after Cord Blood Transplantation Is Consistent with Graft Versus Host Disease: Results of a Blinded Histopathological Review

Cord colitis syndrome is a new proposed clinical entity characterized by late onset of watery diarrhea after umbilical cord blood transplantation (UCBT), with granulomatous inflammation and Paneth cell metaplasia, and response to antibiotics. We tested the hypothesis that recipients of UCBT at our institution had late occurring colitis distinct from colitis in other allograft recipients. We reviewed patients who had colon biopsies between days 70-365 after UCBT and marrow or peripheral blood allograft controls over a 5 years period. Archival histological material was reviewed by the pathologist who was blinded to any type of clinical information. For each patient, a minimum of 32 serial sections of colonic tissue were examined from different anatomical areas. For all patients included in the analysis, we reviewed immunosuppressive therapy treatments, anti-viral, antibacterial, anti-fungal and anti-parasite medications at the time of the colon biopsy. Forty-five UCBT patients were matched with 45 allograft controls (Figure 1). The two groups were similar with respect to age, intensity of conditioning regimen, sex, and diagnosis. No differences were seen in use of anti-bacterial and anti-fungal treatments, however patients receiving UCBT were more likely to be receiving valacyclovir than the control group (p=0.003).There was a significantly higher incidence of aGVHD grade 3-4 in the UCBT cohort compared to the controls (p=0.01). Forty-three patients in the UCBT group and 42 in the control group had evaluable biopsy specimens. Watery diarrhea was the indication for endoscopic biopsy in 10 UCBT and 11 controls while in the remaining patients the indication to colon biopsy was either abdominal pain, or nausea or anorexia. Among the UCBT group, the median time of onset and duration of diarrhea was 96 days (IQR 85-105) and 10 days (IQR 7-15), respectively. In the control group the median time of onset of diarrhea was 88 days (IQR 84-105 days) while the median duration was 10 days (IQR 7-15). Similar to the control group, no UCBT recipient with watery diarrhea was treated with antibiotics and all responded to systemic corticosteroids. No histological differences were seen between UCBT and controls except for increased eosinophils in the UCBT group (p=0.04). Distorted mucosal architecture and apoptotic crypt cells were the most common histological features in both groups, while Paneth cell metaplasia and epithelioid granulomas were rare findings (Figure 2). In this study population, colitis developing after day 70 post transplant was diagnosed as acute GVHD based on histopathology independent of the source of donor hematopoietic cells. We could not identify the presence of a cord colitis syndrome in our UCBT patients.Figure 2Histopathological resultsAll patients undergoing endoscopic procedure n=85Patients with diarrhea n=21UCBT n=43 n (%)Control Group n=42 n (%)p-valueUCBT n=10 n (%)Control Group n=11 n (%)p-valueIndividual featuresGranulomas1 (2)1 (2)0.9901 (9)0.99Paneth cells28 (65)28 (67)0.766 (60)7 (64)0.99Mucosal distortion28 (65)28 (67)0.766 (60)8 (73)0.66Apoptosis0.240.15None7 (16)11 (26)1 (10)6 (55)116 (37)9 (21)4 (40)3 (27)≥220 (47)21 (50)5 (50)2 (18)Increased eosinophils10 (23)3 (7)0.0401 (9)0.99Histologic GradeUpper gut acute GVHD33 (77)28 (67)0.489 (90)8 (73)0.99Lower gut acute GVHD0.860.86None14 (33)14 (33)4 (40)6 (55)Grade 113 (30)14 (33)3 (30)3 (27)Grade 2-316 (37)13 (31)3 (30)2 (18)Composite PatternChronic Active Colitis25 (58)26 (62)0.905 (50)6 (55)0.99Chronic Inactive Colitis6 (14)4 (10)1 (10)2 (18)Active Colitis10 (23)10 (24)3 (30)3 (27)Unclassified2 (5)2 (4)1 (10)0 Open table in a new tab

Umbilical Cord Blood Transplant Patients At High Risk Of Graft Rejection Achieve Early Full Donor Chimerism When 300cGy Is Used In The Reduced Intensity Conditioning Regimen

BackgroundWhile delayed or failed engraftment following reduced intensity conditioning (RIC) umbilical cord blood transplant (UCBT) now occurs less frequently than initially reported, it continues to be higher than in the conventional donor setting. It has been shown that patients who have had a prior autologous transplant or who have received chemotherapy within 4 months of UCBT have an increased incidence of sustained donor engraftment compared with those without this prior therapy (98% vs 64%) (Barker et al ASH abstract 2003). The standard measure of engraftment following UCBT is neutrophil recovery to > 500 x 3 days. However, there has recently been established a possible correlation between time to neutrophil engraftment and early full donor chimerism after UCBT (Avery S et al BMT 2012). Herein, we conducted an RIC UCBT trial in which patients were assigned to one of two treatment regimens based on their risk of graft failure. In addition to evaluating sustained donor engraftment characterized by time to neutrophil recovery, we also sought to assess the achievement of full donor chimerism at Day +28 post-transplant in patients pre-determined to be high versus low risk of graft failure. MethodsForty-eight patients median age 59 years (range 25 - 73) and comorbidity index = 3 (range 0 - 8) with high risk hematologic malignancies received an RIC regimen containing cyclophosphamide 50mg/kg on Day -6, fludarabine 40mg/m2 Day -6 to -2 (dose reduced to 35mg/m2 for creatinine clearance < 70), and either 200 cGy TBI (Arm 1 = low risk of graft failure) or 300 cGy TBI (Arm 2 = high risk of graft failure) on Day -1. High risk for graft failure was defined as “receiving < 2 cycles of multiagent chemotherapy or no multiagent chemotherapy within the 3 months prior to UCBT.” Low risk for graft failure was defined as “having received a prior autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months prior to UCBT.” Patients on both arms received GVHD prophylaxis with cyclosporine from Day -1 to Day +180 and mycopheolate mofeteil 1 gram every 8 hours until Day +40. Forty-seven of 48 patients received 2 UCB units (one patient received a single UCB) with a median TNC/kg of 4.05 x 107 and a post-thaw median CD34+cells/kg of 1.75 x 105. UCB grafts (98%) were 1-2 HLA antigen mismatched with the recipient. Twenty-six patients were assigned to Arm 1 and 22 patients were assigned to Arm 2. Bone marrow and peripheral blood chimerism assessment were performed at approximately Day +28 and Day +80. The blood was flow sorted in the clinical hematopathology lab into defined lineage subsets. Wilcoxon rank-sum test was used to compare the 2 groups. ResultsAll evaluable patients engrafted (n = 46). Patients on Arm 1 achieved neutrophil recovery (ANC > 500 x 3 days) at a median of 12 days (range 6 - 38) versus 23 days (range 7- 46) in patients on Arm 2 (p = 0.01). Day +28 chimerism values were evaluable for 23 patients on Arm 1 and 20 patients on Arm 2. Median chimerism in the CD3+ compartment was 100% (57 - 100) and 100% (0 - 100) on Arm 1 and Arm 2 respectively (p = 0.58). Median chimerism in the CD33+compartment was 98% (15 - 100) and 100% (44-100) on Arm 1 and Arm 2 respectively (p =0.26). Median chimerism in the bone marrow was 98% (15 - 100) and 100% (4 - 100) on Arm 1 and Arm 2 respectively (p = 0.84). This was maintained at Day +80. Acute graft versus host disease (GVHD) grades II - IV was seen in 84% (n = 21) and 68% (n = 15) of patients on Arm 1 and 2 respectively with 5% and 12% grade III-IV GVHD in the respective arms. Chronic GVHD was seen in 40% of patients on Arm 1 (8 mild, 2 moderate) and 23% on Arm 2 (3 mild, 1 moderate, 1 severe). Overall survival at 1 year in Arm 1 was 43% (95% CI: 22-62%) and Arm 2 was 46% (95% CI: 20-69%). ConclusionsThe goal of this RIC UCBT study was to assess engraftment rates by neutrophil recovery and Day +28 chimerism in patients at low versus high risk of graft rejection. Although time to neutrophil recovery was significantly faster in patients with low risk of graft failure, patients at high risk of rejection achieved a similar incidence of full donor chimerism at Day +28 as those with low risk of graft rejection. Using Day +28 chimerism as a measure of engraftment, patients deemed high risk of graft failure achieved early engraftment with UCBT following an RIC conditioning regimen containing 300cGy TBI. Disclosures:No relevant conflicts of interest to declare.

Mild Hyperthermia Treatment Of CD34+ Human Cord Blood Cells Increases Lipid Raft Aggregation Resulting In An Earlier Engraftment In NSG Mice Following Transplantation

Umbilical cord blood (UCB) is a viable source of hematopoietic stem cells (HSC) for transplantation to treat patients with malignant and non-malignant disease. Although the limitation of low stem cell dose in single UCB transplantation has been improved upon by the use of double UCB units, this has not resulted in a shortened time to engraftment. Therefore efforts are needed to enhance the speed of engraftment of these cells. Mild heating (39.5°C) of mature hematopoietic cells increases membrane fluidity, resulting in increased lipid raft aggregation, and priming cells for increased sensitization of responsiveness to cytokine signaling. We hypothesized that exposing CD34+ UCB cells to 39.5°C would enhance their capacity to respond to SDF-1/CXCL12, a chemokine secreted in the bone marrow microenvironment that strongly attracts HSCs and progenitor cells, by increasing lipid raft aggregation and CXCR4 expression, thus leading to better engraftment following transplantation. To determine if this mild heating had any effect on engraftment in vivo, NSG mice received 4Gy TBI followed one day later with 20,000 or 80,000 CD34+ UCB cells incubated for 4 hours at 37°C or 39.5°C prior to i.v. injection. Percent chimerism in the blood was determined through the detection of human CD45 by flow cytometry at 1, 2, 4 and 6 months following transplantation. Mild heat treatment significantly increased the percent chimerism following transplantation by 1.7 fold at 1 month (when 80,000 cells were used) and by 1.8 fold at 2 months (when 20,000 cells were used), without significant increases in percent chimerism at 4 or 6 months. This suggests that the effects of heat treatment are most likely occurring early following transplantation, potentially due to an increase in homing of the heated CD34+ UCB cells to the bone marrow microenvironment. To begin to test this hypothesis, CD34+ UCB and Mo7e cells (a human megakaryoblastic leukemia cell line) were exposed to 39.5°C for 4 hours followed by a chemotaxis assay. Exposure of the CD34+ UCB cells to 39.5°C manifested in a significant increase in the percent of cells that migrated towards 12.5 (1.8 fold increase), 25 (1.9 fold increase), 50 (2.2 fold increase), 100 (2.3 fold increase) and 200 ng/mL SDF-1 (2.5 fold increase). Mild heating also significantly increased the percent of Mo7e cells that migrated towards 12.5 (1.8 fold increase), 25 (1.4 fold increase), 50 (1.5 fold increase), 100 (1.3 fold increase), and 200 ng/mL SDF-1 (1.5 fold increase). Increases in chemotaxis towards SDF-1 following mild heating was associated with a significant, but modest, increase (1.3 fold as determined by MFI) in expression of the SDF-1 receptor, CXCR4, on the surface of CD34+ UCB cells as detected by flow cytometry. In order to optimize SDF-1 signaling, CXCR4 must be incorporated into the cholesterol-enriched lipid rafts of the cellular membrane followed by lipid raft aggregation. Mild heating increased the percent of Mo7e cells with aggregated lipid rafts from 13 percent for cells incubated for 4 hours at 37°C to 52% for cells incubated for 4 hours at 39.5C. By using a dose of MbCD (1.25mM), an agent that can deplete cholesterol in the cellular membrane thus blocking lipid raft aggregation, it was determined that the enhancement in chemotaxis seen following mild heating was dependent upon lipid raft aggregation in both CD34+ UCB and Mo7e cells. Overall, mild heating may be a simple and inexpensive novel adjuvant therapy to enhance engraftment following UCB transplantation in patients. Disclosures: No relevant conflicts of interest to declare.

Improved Insulin Secretion Following Intrapancreatic UCB Transplantation in Patients With T2DM

Transplantation with stem cells has been reported as a potential treatment for diabetes. However, there are few reports examining transplantation with umbilical cord blood (UCB) in type 2 diabetes (T2DM). The aim of the study was to evaluate the efficacy of intrapancreatic UCB transplantation in patients with T2DM. Three patients were enrolled in the study, which was performed in a hospital setting from 2010 to 2012, and the duration of follow-up was approximately 6 months. UCB cells were infused by microcatheter into the dorsal pancreatic artery in 3 T2DM patients with different diabetic histories. Blood glucose (including 72-h continuous blood glucose), C-peptide, hemoglobin A1c, the requirement for insulin, and transplant complications were monitored before and after transplantation. After the transplantation, C-peptide levels had increased in all of the patients. In addition, the 72-hour continuous blood glucose monitoring results obtained after transplantation revealed that levels were more stable than before transplantation for all of the patients (P < .05). In addition, the requirements of insulin were reduced in all patients after transplantation. UCB transplantation may be an approach that could somewhat improve C-peptide levels in patients with T2DM.

Umbilical Cord Blood Transplantation

The use of umbilical cord blood (UCB) as a stem cell donor source has dramatically increased over the last 2 decades. Patients undergoing UCB transplantation share medical management issues with patients receiving a hematopoietic stem cell transplantion using adult donor sources (peripheral blood stem cells or bone marrow stem cells) and may also have more complex medical issues that appear to be related to delayed immune recovery from UCB-derived stem cells. The interface with critical care providers is likely to occur in the transplant and posttransplant setting. Patients may experience UCB infusion reactions that range from mild to rarely severe. Following transplant, patients are transfusion dependent for long periods due to the prolonged engraftment of UCB cells. They are at high risk of infection, particularly viral. Once engrafted, UCB transplant patients have a lower rate of graft versus host disease compared to other donor sources. Some of the other complications that are seen in patients undergoing UCB transplant are posttransplant lymphoproliferative disease, diffuse alveolar hemorrhage, and posterior reversible encephalopathy will also be discussed.

Pre-Emptive Rituximab for the Prevention of EBV-Related PTLD in Umbilical Cord Blood Transplantion Patients

Abstract 3031 Objective:We observed a high rate of Epstein-Barr virus (EBV) associated post-transplant lymphoproliferative disease (PTLD) in our umbilical cord blood transplantation (UCBT) patients. We retrospectively analyzed all UBCTs performed at our institution in order to 1) define risk factors for the development of PTLD and 2) assess whether pre-emptive therapy with rituximab (RTX) altered the incidence and outcomes of PTLD in patients with EBV viremia. Patients and Methods:One hundred twenty-seven patients underwent UCBTs, with primarily double cord units, between March 2003 and April 2010. EBV viral loads were monitored by quantitative PCR. Viremia was defined as any detectable level of EBV DNA in peripheral blood. EBV events included all cases of isolated viremia, sustained viremia (≥ 2 positive viral loads on two separate dates), or biopsy/autopsy proven PTLD. One to four weekly doses of RTX (375mg/m2) were given pre-emptively to prevent PTLD in patients with sustained viremia. The frequency of monitoring, the decision to treat with RTX and the duration of treatment were at the clinician’s discretion. Fisher’s exact test and Cox modeling were used to evaluate the effect of clinical variables on the probability of developing PTLD. Results:Cohort Characteristics: Ninety-nine of 127 patients (77%) underwent reduced-intensity conditioning (RIC) transplantion. Eighty-five (86%) of those who received RIC transplants were conditioned with fludarabine, melphalan and anti-thymocyte globulin (ATG). Seventy-nine of the 99 patients (80%) who underwent RIC transplantation received ATG doses at 6mg/kg or greater.PTLD rate and risk factors: Thirty-three patients (26%) had an EBV event. 9 patients (7%) had isolated viremia. No patient with isolated viremia was treated with RTX and none developed PTLD. 11 patients developed sustained viremia but not PTLD. Thirteen patients (10%) had biopsy-proven PTLD, a one-year cumulative probability of 12% (95% CI, 0.08–0.15). All patients who developed PTLD underwent RIC transplant and received at least 6mg/kg of ATG. ATG use was found to be a statistically significant risk factor for PTLD (p = 0.02) yet ATG use was not associated with decreased survival. Age, primary disease, degree of HLA match, graft-versus-host disease (GVHD) and type of GVHD prophylaxis were not identified as PTLD risk factors.Effect of pre-emptive rituximab: 14 patients developed sustained viremia and did not have clinical evidence of PTLD at the time viremia was detected (12%). Twelve of these patients were treated pre-emptively with RTX. EBV DNA became undetectable in 9 of 12 (67%) of these patients, none of whom developed PTLD. EBV viremia resolved in 1 patient without RTX; this patient did not develop PTLD. One patient died of other causes before RTX could be given. Viremia initially cleared in one patient who later progressed to PTLD but achieved complete remission after treatment with virus-specific cytotoxic T-lymphocytes (CTL). Viremia did not resolve in 2 patients, both of whom developed PTLD. Despite treatment with virus-specific CTL both died of PTLD.The adjusted hazard ratio (HR) for the development of PTLD among patients with sustained viremia was 230 (95% CI, 29–1856); the adjusted HR of pre-emptive rituximab was 0.24 (95% CI, 0.07 – 0.9). Conclusions:ATG doses of 6mg/kg or greater were associated with PTLD in the UBCT population. Isolated EBV viremia was not a risk factor for the development of PTLD. Sustained EBV viremia conferred considerable risk. This risk of developing PTLD in patients with sustained viremia was reduced when RTX was given as pre-emptive therapy in this cohort. Further studies to better define the optimal duration of RTX therapy are needed. Prophylactic immune reconstitution with closely HLA-matched virus-specific CTL may also be an alternative option in this high-risk population. Disclosures:No relevant conflicts of interest to declare.