Cord Blood Hematopoietic Cell Transplantation Research Articles

Real-World Data Showing Trends and Outcomes by Race and Ethnicity in Allogeneic Hematopoietic Cell Transplantation: A Report from the Center for International Blood and Marrow Transplant Research

The use of HLA-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined. We conducted this study to determine whether the use of mismatched donor platforms have increased the access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GVHD) prophylaxis regimens, and whether outcomes for diverse patients are comparable to those of non-Hispanic White patients. This observational cross-sectional study used real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the United States between 2009 and 2020 were included, with a focus on transplantations performed in 2020. Data from patients undergoing allogeneic HCT using bone marrow, peripheral blood, or cord blood from HLA-matched or mismatched related and unrelated donors were analyzed. Specifically, relative proportion of allogeneic HCT was generated as percentage of total for donor type and for patient age, disease indication, GVHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival. Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Although matched unrelated donor remains the most common donor type, the use of haploidentical donors has increased significantly over the last 5 years. Paralleling this increase in haploidentical HCT is the increased use of post-transplantation cyclophosphamide (PTCy) as GVHD prophylaxis. Relative to previous transplantation eras, the most contemporary era is associated with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. Nonetheless, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient racial/ethnic groups. Ethnically diverse patients are undergoing allogeneic HCT at higher rates, largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GVHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, remain urgent clinical needs.

2122. The Impact of HHV-6 DNAemia on hematopoietic cell transplant (HCT) recipients at high risk for CMV reactivation in the era of Letermovir

Abstract Background Letermovir (LTV) has reduced non-relapse mortality (NRM) in allogeneic hematopoietic cell transplant (allo-HCT) recipients by reducing the rate of clinically significant cytomegalovirus infections (CS-CMVi). The impact of LTV prophylaxis (PP) on other infections is unclear. We investigated the effects of LTV on human herpes virus 6 (HHV6) DNAemia in HCT recipients with or without CS-CMVi and studied the interaction of HHV6 DNAemia with CS-CMVi and its impact on NRM. Methods We performed a single center, retrospective cohort study from March 2016 to December 2018 of consecutive allo-HCT recipients who are CMV recipient seropositive (R+) with or without LTV prophylaxis. Baseline characteristics and infectious complications data were collected. Outcomes of interest was NRM at 100 days, 24 weeks and 48 weeks post allo-HCT. Univariate analysis was performed to identify risk factors for HHV6 reactivation within the first year including CS-CMVi and risk factors for NRM at 48 weeks post transplant. A logistic regression was performed to identify independent risk factors for HHV6 DNAemia and NRM at 48 weeks. Patients with relapse were excluded from NRM analysis. Results A total of 539 allo-HCT recipients were included in our analysis; 124 (23%) with and 415 (77%) without LTV PP. HHV6 DNAemia was identified in 111 (21%) allo-HCT recipients within the first year of transplant, where CS-CMVi occurred in 241 (45%) (table 1). Risk factors for HHV6 DNAemia included African American race, underlying ALL, Haploidentical or cord HCT, marrow or cord source of stem cells, use of Post-cyclophosphamide, and CS-CMVi. On multivariate analysis, CS-CMVi was the only independent predictor of HHV6 reactivation (Adjusted OR: 1.69) (table 1). Independent predictors of NRM on logistic regression included CS-CMVi (OR: 1.67, CI 95% 1.03-2.62), and age > 40 years (OR: 2.21, CI 95% 1.24-3.95), and matched related donor allo-HCT (OR: 0.36, CI 95% 0.18-0.70) as a protective factor (table 2). Conclusion HHV6 DNAemia is strongly associated with CS-CMVi, which is probably a reflection of poor T cell recovery post HCT such as Haploidentical or Cord blood HCT. Furthermore, CS-CMVi was associated with NRM whereas HHV6 DNAemia was not. Larger studies are needed to better elucidate this interaction. Disclosures Gabriella Rondon, MD, Omeros: Advisor/Consultant Elizabeth Shpall, MD, Adaptimmune: Advisor/Consultant|Affimed: License agreement|Axio: Advisor/Consultant|Bayer Helathcare Pharmaceuticals: Honoraria|Fibroblasts and FibrioBiologics: Advisor/Consultant|Navan: Advisor/Consultant|NY Blood Center: Advisor/Consultant|Takeda: License agreement Ella Ariza-Heredia, MD, MERCK: Grant/Research Support Roy F. Chemaly, MD/MPH, Karius: Advisor/Consultant|Karius: Grant/Research Support.

Extracellular DEK Activates NRF2 Antioxidant Targets and Drives Expansion of Functional and ROS-Low Human Hematopoietic Stem Cells

Umbilical cord blood (CB) is a promising source of hematopoietic stem cells (HSCs) for hematopoietic cell transplantation (HCT), a life-saving treatment, due to lower incidence of graft versus host disease and its availability. CB HCT is limited by low numbers of HSCs, thus there is a strong need to increase numbers of engraftable HSCs, for instance by expanding functionally competent HSCs ex vivo. We have shown that extracellular DEK protein, an epigenetic regulator that is secreted in response to stress and inflammation, is a novel hematopoietic regulatory chemokine. Treatment with extracellular DEK in growth stimulating media significantly enhances the expansion of engraftable HSCs in mouse bone marrow (BM) and human CB (Capitano, et al. JCI 2019; 129(6):2555-2570). To examine mechanisms driving enhanced expansion of functional HSCs after DEK treatment, we performed RNA-sequencing on CB HSCs, multipotent progenitor cells (MPPs), common myeloid progenitors (CMPs), and granulocyte macrophage progenitors (GMPs) after overnight DEK treatment in expansion media. All cell populations upregulated gene programs related to antioxidant responses upon DEK treatment. Indeed, 7/10 genes upregulated by DEK in all HSC/HPC populations (NMRAL2P, PIR, NQO1, SELENOW, FTL, RIT1, and QPCT) promote antioxidant activity. Overnight DEK treatment significantly reduced mean fluorescence of the activated reactive oxygen species (ROS) indicator CM-H2DCFDA in HSCs, MPPs, CMPs, and GMPs. Thus, DEK may induce antioxidant activity. We next found that all 10 genes commonly upregulated in HSCs/HPCs are either direct transcriptional targets of NRF2 (NMRAL2P, LUCAT1,PIR, NQO1, FTL, and QPCT) or are directly affected by changes in NRF2 activation (SELENOW, EBI3, TNFRSF9, and RIT1). Further, several genes highly upregulated by DEK treatment in HSCs (i.e., CCL2, KYNU, and CXCL8) are NRF2 targets. To examine if DEK activates NRF2 transcriptional activity, we utilized a transgene reporter assay where expression of red fluorescent protein (RFP) is driven by activation of promoter antioxidant response elements (ARE), to which active NRF2 binds. DEK treatment of hematopoietic derived cell lines (mouse MLL-AF9 AML and human HL-60 APL) expressing the transgene significantly increased RFP signal, indicating that DEK could activate NRF2. We further examined whether DEK treatment affects mitochondrial metabolism, a source of ROS and tightly regulated process in hematopoiesis. Seahorse XFe analysis, which measures metabolic flux, showed DEK treatment of MLL-AF9 cells significantly reduced mitochondrial oxygen consumption rate, suggesting a reduced reliance on oxidative phosphorylation as an energy source in DEK treated cells. These data suggest that DEK treatment during expansion of primitive hematopoietic cells drives activation of NRF2 transcription, upregulation of antioxidant response genes, reduction of intracellular ROS levels, and may reduce the mitochondrial metabolic rate. These effects in a sense "mimic” the in vivo niche of HSCs, where they reside in low oxygen tensions, have low intracellular ROS, and exhibit low levels of oxidative phosphorylation. To test this hypothesis, we examined if DEK treatment has similar effects to maintaining HSCs in physiologic oxygen tensions (3%) compared to HSCs exposed to extraphysiologic ambient air (21%), which drives oxidative stress (Mantel, et al. Cell 2015; 161(7):1553-65). Isolating and maintaining mouse BM in physiologic oxygen tensions or treating mice in vivo with recombinant DEK preserved HSC numbers compared to exposing the BM cells to ambient air or treating with vehicle. However, combining in vivo DEK treatment with physiologic isolation of HSCs/HPCs had no additive or synergistic effect, suggesting that the overall effects of DEK treatment and maintaining low oxygen tensions may be similar. Thus, extracellular DEK treatment leads to expansion of functionally competent HSCs and reduction of oxidative stress. These data have important implications for the regulation of HSCs/HPCs in stress conditions, where DEK is most likely to be secreted. Further, DEK may present a novel way to mimic physiologic oxygen conditions for enhancement of functional HSC expansion, and the elucidated mechanisms may be exploited for more efficient targeting of molecular programs critical for functional HSC competency, potentially providing new ways to enhance HCT.

Natural Killer Cell Alloreactivity Predicted By Killer Cell Immunoglobulin-Like Receptor Ligand Mismatch Does Not Impact Engraftment in Umbilical Cord Blood and Haploidentical Stem Cell Transplantation

Natural killer cell alloreactivity is determined by killer cell immunoglobulin-like receptor (KIR) ligands in donor and recipient pairs. A small, single institution study suggested that the risk of primary graft failure after cord blood hematopoietic cell transplantation (CBT) can be predicted by host-versus-graft (HvG)–directed natural killer cell alloreactivity. In the haploidentical transplantation (Haplo HCT) cohort, graft failures were observed only in graft-versus-host (GvH) KIR ligand mismatched pairs. A subsequent study was designed to explore the association between HvG and GvH KIR ligand mismatching and engraftment in both CBT and Haplo HCT using the large, multicenter transplant population of the Center for International Blood and Transplant Research database. Nine hundred single CBT (sCBT), 954 double CBT (dCBT), and 671 Haplo HCT performed between 2008 and 2017 for acute leukemias and myelodysplastic syndrome were examined. Several models of KIR-L interactions were analyzed by multiple regression analyses for their association with engraftment, overall survival (OS), and transplant-related mortality (TRM). In sCBT, although HvG or bidirectional KIR ligand mismatch (KIR-L-MM) was initially associated with higher TRM in the first 6 months after transplantation, this effect was nullified after 6 months such that long-term survival was not different compared to GvH KIR-L-MM or KIR-L matched (KIR-L-M) pairs. There was no significant difference in neutrophil and platelet engraftment. In dCBT, no significant differences were seen in engraftment, OS and TRM. In the Haplo cohort there was faster platelet recovery in the GvH KIR-L-MM/KIR-L-M pairs versus HvG KIR-L-MM or bidirectional mismatch (HR 1.23, P= .0116). There was no significant association with OS, TRM, or neutrophil engraftment. In this large registry study, KIR-L mismatching did not significantly impact engraftment, TRM, or survival in CBT and Haplo HCT, although an association with platelet engraftment in Haplo HCT was demonstrated.

The Impact of Somatic Mutations on Allogeneic Hematopoietic Cell Transplantation in Chronic Myelomonocytic Leukemia: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

BackgroundSomatic mutations are an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted via the Center for International Blood and Marrow Transplant Research (CIBMTR) as well as its sample repository, we analyzed the landscape of somatic mutations in patients with CMML and their impact on post-HCT outcomes.MethodsUsing the CIBTMR database, adult patients with CMML who underwent HCT from 2001-2017 with an available specimen in the National Marrow Donor Program (NMDP) repository were identified; samples were collected prior to the start of conditioning. Patients who received umbilical cord blood, syngeneic, or haploidentical HCT or patients with disease transformation to acute myeloid leukemia prior to HCT were excluded. The primary endpoint was overall survival (OS); secondary endpoints included disease-free survival (DFS), relapse/progression, treatment-related mortality (TRM); survival outcomes were calculated from time of HCT. A mutation analysis for 131 genes recurrently mutated in myeloid disorders was performed.ResultsWe identified 313 patients across 78 centers who met inclusion criteria with available samples. The median age was 64, and 69% were male. By World Health Organization (WHO) criteria, 53%, 20%, and 9% of patients had CMML-0, -1, and -2, respectively. By French-American-British (FAB) criteria, 76% of patients had dysplastic (MD)-CMML and 24% had proliferative (MP)-CMML. The majority (61%) had received hypomethylating therapy prior to HCT, and 76% of HCT were from a matched unrelated donor. Distribution of patients by CMML-specific prognostic scoring system (CPSS) score was 29% low, 25% intermediate-1, 31% intermediate-2, and 4% high (11% missing). Distribution of patients by clinical/molecular CPSS (CPSS-Mol) score was 12% low, 17% intermediate-1, 38% intermediate-2, and 25% high (8% missing).Of the 313 patients studied, 290 (93%) had 1+ pathogenic mutation identified, and the median number of mutations was 3. The most frequently mutated genes were ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%); TP53 was mutated in 3% of patients (Figure 1). U2AF1 mutations were significantly correlated with MD-CMML, and ASXL1, EZH2, KIT, and SRSF2 mutations were significantly correlated with MP-CMML.The CPSS score was correlated with OS and DFS on univariate analysis, and the CPSS-Mol score was correlated with OS and TRM (Figure 2). Neither scoring system was predictive for progression/relapse.In multivariable analysis, as compared to a CPSS score of low, intermediate-2 (hazard ratio [HR]=1.46, p=0.049) or high (HR=3.22, p=0.0004) correlated significantly with overall survival (OS) (table 1a). When CPSS-Mol was applied, a high score (HR=2, p=0.0079) correlated significantly with OS (table 1b). In multivariable analysis, DNMT3A and TP53 mutations were associated with decreased OS (HR=1.70, p=0.0147; and HR=2.72, p=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased DFS (HR=1.66, p=0.0138; HR=1.79, p=0.0293; and HR=2.94, p=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR =2.94, p=0.0201). DNMT3A was associated with increased TRM(HR=1.89, p=0.0388) and PTPN11 was associated with decreased TRM (HR=0.205, p=0.0300). Goodness of fit was calculated by Harrell's C-index for CPSS and CPSS-Mol for OS, DFS, relapse, and TRM. For CPSS, the results were 0.56, 0.55, 0.52, and 0.56, respectively while for the CPSS-Mol they were 0.57, 0.55, 0.55, and 0.58, respectively.ConclusionOur study is the largest analysis of CMML patients who underwent HCT with paired mutation analysis. Via registry data we have provided the mutational landscape in patients with CMML who underwent HCT and demonstrated a strong association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond the CPSS. [Display omitted] DisclosuresMei: TG Therapeutics: Research Funding; EUSA: Honoraria; Epizyme: Research Funding; BMS: Research Funding; Morphosys: Research Funding; Janssen: Honoraria; Beigene: Research Funding. Sobecks: CareDX: Membership on an entity's Board of Directors or advisory committees. Scott: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding. Saber: Govt. COI: Other.

One and a half million hematopoietic stem cell transplants: continuous and differential improvement in worldwide access with the use of non-identical family donors.

The Worldwide Network of Blood and Marrow Transplantation (WBMT) pursues the mission of promoting hematopoietic cell transplantation (HCT) for instance by evaluating activities through member societies, national registries and individual centers. In 2016, 82,718 first HCT were reported by 1,662 HCT teams in 86 of the 195 World Health Organization member states representing a global increase of 6.2% in autologous HCT and 7.0% in allogeneic HCT and bringing the total to 1,298,897 procedures. Assuming a frequency of 84,000/year, 1.5 million HCT were performed by 2019 since 1957. Slightly more autologous (53.5%) than allogeneic and more related (53.6%) than unrelated HCT were reported. A remarkable increase was noted in haploidentical related HCT for leukemias and lymphoproliferative diseases, but even more in non-malignant diseases. Transplant rates (TR; HCT/10 million population) varied according to region reaching 560.8 in North America, 438.5 in Europe, 76.7 in Latin America, 53.6 in South East Asia/Western Pacific (SEA/WPR) and 27.8 in African/East Mediterranean (AFR/EMR). Interestingly, haploidentical TR amounted to 32% in SEA/WPR and 26% in Latin America, but only 14% in Europe and EMR and 4.9% in North America of all allogeneic HCT. HCT team density (teams/10 million population) was highest in Europe (7.7) followed by North America (6.0), SEA/WPR (1.9), Latin America (1.6) and AFR/EMR (0.4). HCT are increasing steadily worldwide with narrowing gaps between regions and greater increase in allogeneic compared to autologous activity. While related HCT is rising, largely due to increase in haploidentical HCT, unrelated HCT is plateauing and cord blood HCT is in decline.

Frequent Eczematous Dermatitis in Unrelated Cord Blood Hematopoietic Cell Transplant Recipients Compared With Other Donor Types

We have consistently noticed in our clinical practice eczematous dermatitis (EcD) without other pathologic findings of graft-versus-host disease (GVHD) in recipients of unrelated cord blood transplantation (CBT). We hypothesized that the incidence of EcD was higher in CBT compared with other donor types, and our objective in this study was to compare the frequency, clinical course, and response to therapy of EcD between CBT and non-CBT recipients. We conducted a retrospective study of 720 consecutive adult recipients of allogeneic hematopoietic cell transplants from 2010 to 2016 from any donor type and with follow-up for at least 1 year after transplantation. After using keyword-based automated scanning to identify "eczema," "dermatitis," or "spongiosis" terms in medical records, we retrieved 217 cases for manual record review. We identified 23 EcD cases (12 in CBT recipients and 11 in patients with other types of donors) with a median onset at 8 months after transplantation. The 2-year cumulative incidence of EcD was 20% (95% confidence interval [CI], 11.2% to 31.5%) after CBT and 1.7% (95% CI, .90% to 2.90%) with other types of donors (P < .0001). Fifteen cases had a skin biopsy without distinctive pathologic features of GVHD. The most common EcD-involved sites in CBT recipients were face (75%), neck (50%), and antecubital fossae (50%). Compared with patients with other types of donors, EcD after CBT was more likely to involve three or more sites (10 of 12 vs. 2 of 10; P=.008) and had a more protracted course (lasting >6 months in 6 of 58 vs. 1 of 661; P < .0001). In both groups, EcD responded to topical therapy, and only a few cases required systemic therapy. EcD is a relatively frequent skin condition among recipients of unrelated CBT. Irrespective of donor type, most cases of EcD can be successfully managed with only topical therapy. These findings will help providers recognize EcD, avoid potentially harmful systemic therapy, and better counsel transplant recipients.

Immune Reconstitution after Haploidentical Donor and Umbilical Cord Blood Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for a variety of hematologic diseases. However, this therapeutic platform is limited by an initial period when patients are profoundly immunocompromised. There is gradual immune recovery over time, that varies by transplant platform. Here, we review immune reconstitution after allogeneic HCT with a specific focus on two alternative donor platforms that have dramatically improved access to allogeneic HCT for patients who lack an HLA-matched related or unrelated donor: haploidentical and umbilical cord blood HCT. Despite challenges, interventions are available to mitigate the risks during the immunocompromised period including antimicrobial prophylaxis, modified immune suppression strategies, graft manipulation, and emerging adoptive cell therapies. Such interventions can improve the potential for long-term overall survival after allogeneic HCT.

Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization

Healthcare Resource Utilization in Transplant Patients Who Are at a Higher-Risk to Develop Cytomegalovirus Infection during Their Primary Transplant-Related Hospitalization

Chains of Iron in Umbilical Cord Blood Hematopoietic Stem Cell Transplantation: Comment on "Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation" by Al Malki et al, 2020.

Abstract Comment on “Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation” by Al Malki et al. 2020

Enhanced collection of phenotypic and engrafting human cord blood hematopoietic stem cells at 4°C.

The number of hematopoietic stem cells (HSCs) collected in cord blood (CB) at the birth of a baby is a limiting factor for efficacious use of CB in hematopoietic cell transplantation (HCT). We now demonstrate that collecting and processing of human CB at 4°C within minutes of the baby's birth results in significantly enhanced numbers of rigorously defined phenotypic HSC and self-renewing NSG immune-deficient mouse engrafting and SCID-repopulating cells. This was associated with decreased numbers of hematopoietic progenitor cells (HPC), as noted previously for hypoxia collected/processed cells blocking ambient air induced differentiation of HSC to HPC. We have thus defined a simple, cost-effective, means to collect increased numbers of CB HSC, of potential use for clinical CB HCT.

Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation.

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR)=2.26 (95% CI, 1.28 to 4.00, P=.005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR=2.18 (95% CI, 1.10 to 4.31, P=.025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR=0.58 (95% CI, 0.35 to 0.96, P=.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR=0.48 (95% CI, 0.23 to 0.98, P=.044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

High Incidence of Herpes Zoster After Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis.

Cord blood transplant (CBT) recipients have a high incidence of herpes zoster (HZ) in the context of short-term peritransplant antiviral prophylaxis. In 2009, international guidelines recommended HZ prophylaxis for at least 1 year after hematopoietic cell transplant. The impact of longer-term antiviral prophylaxis on HZ incidence after CBT is unknown. We retrospectively analyzed varicella zoster virus (VZV)-seropositive CBT recipients who were transplanted between 2006 and 2016. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ and used Cox proportional hazards regression to identify variables associated with HZ. The study cohort consisted of 227 patients. Among 1-year survivors, 91% were still receiving prophylaxis, for a median duration of 20.6 months. HZ occurred in 44 patients (19%) at a median of 23.6 months. The cumulative incidence of HZ by 1 year after CBT was 1.8% (95% confidence interval [CI], .1%-4%), but increased to 26% (95% CI, 19%-33%) by 5 years. In a multivariable analysis, acute graft-vs-host disease was associated with increased risk, whereas antiviral prophylaxis was associated with reduced risk for HZ (adjusted hazard ratio, 0.19 [95% CI, .09-.4]). There was no association between CD4+ T-cell counts at 1 year post-CBT and subsequent risk for HZ. We found a high incidence of HZ after CBT despite antiviral prophylaxis for > 1 year. Based on these findings, we suggest longer duration of prophylaxis for HZ after CBT. Compliance with antiviral prophylaxis, VZV-specific immune monitoring, and vaccination to mitigate HZ after CBT also require further study.

High Incidence of Herpes Zoster after Cord Blood Hematopoietic Cell Transplant Despite Longer Duration of Antiviral Prophylaxis

Introduction Herpes zoster (HZ) after hematopoietic cell transplant (HCT) is a well-known complication with a peak incidence during the first year post-HCT. Cord blood transplant (CBT) recipients are at increased risk for viral infections and historically have a cumulative incidence of HZ approaching 80% by 2.5 years in the context of short-term peri-HCT antiviral prophylaxis. In 2009, international guidelines for prevention of infections after HCT recommended maintaining HZ prophylaxis for at least 1 year after HCT. We retrospectively studied the impact of longer-term antiviral prophylaxis on the incidence of HZ after CBT. Methods Between 2006 and 2016, we performed 360 CBT at our Institution. Patients who were seronegative for varicella zoster virus (VZV) or received the live varicella vaccine (i.e. Varivax®) pre-CBT without a history of chickenpox or HZ were excluded. From 2006-2008, CBT recipients received acyclovir (ACV) 800 mg BID or valacyclovir (VACV) 500 mg BID for HSV and VZV prophylaxis. From 2008-2016, patients who were CMV seropositive received higher-dose prophylaxis with VACV 2g TID through day +100. Before 2009, institutional guidelines recommended to continue prophylaxis until the end of immunosuppression; after 2009, prophylaxis was recommended for at least 1 year and until 8 months after immunosuppression ends. For patients discharged from our center, data were collected through standardized questionnaires and medical records. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ after CBT, treating death and second HCT as competing risk events. Variables were evaluated for an association with development of HZ using Cox proportional hazards regression; those of biological interest and with a P value ≤ 0.3 in univariable analyses were considerate for multivariable model. Results The study cohort consisted of 227 CBT recipients with a median follow up of 25.4 months (interquartile range [IQR], 6.8 - 49). Follow up time was truncated at the time of death (n=113), second HCT (n=13) or last available records (n=32). Cohort characteristics are shown in Table 1. Among 1-year survivors, 91% were still receiving prophylaxis for a median duration of 20.6 months post-CBT (IQR, 14.1 - 29.4). HZ occurred in 44 patients (19%) at a median of 23.6 months (IQR, 16.1 - 30.3). Most patients (n=31/44, 70%) were not taking antiviral prophylaxis when HZ developed. The cumulative incidence of HZ by 1-year post-CBT was low (1.8%; 95% CI, 0.1%-4%) but increased starting from the second year and reached 26% (95% CI, 19%-33%) by 5 years (Figure 1). Disseminated HZ occurred in 5 cases (11%), and post-herpetic neuralgia occurred in 14 cases (31.8%). Of the 13 HZ episodes that occurred in patients reportedly taking antiviral prophylaxis, 6/13 had clear documentation of ongoing antiviral prophylaxis and 5/13 were still receiving immunosuppressive treatment for graft-versus-host disease (GvHD). All patients responded to antiviral treatment, which consisted of ACV (n=18), VACV (n=16), and famciclovir (n=1). In a multivariable analysis, patients who received myeloablative conditioning or had acute GvHD grades 2-4 had a higher risk of HZ, whereas the use of antiviral prophylaxis was associated with a lower risk of HZ (Table 2). Among 35 patients who discontinued prophylaxis before completing immunosuppressive therapy, 28.5% developed HZ. We found no association between CD4+ T cell counts at 1-year after-CBT and HZ risk. Conclusions In this cohort of 227 CBT recipients with up to 5 years of follow up, the cumulative incidence of HZ was 26% at 5 years, despite antiviral prophylaxis for &amp;gt;1 year in the majority of patients. Furthermore, these patients had high rates of post-herpetic neuralgia and disseminated VZV. Antiviral prophylaxis protected against HZ but there were breakthrough cases. Given that a high number of patients interrupted prophylaxis while still receiving immunosuppressants, adherence to antiviral prophylaxis should be emphasized by health care providers. Based on our findings, the lack of alternative prophylactic strategies at this time, and the safety of ACV/VACV, longer duration of prophylaxis should be considered, especially in patients with ongoing immunosuppression. Recent data demonstrating the safety and efficacy of the HZ subunit vaccine after autologous HCT support future study of HZ vaccination after allogeneic HCT. Disclosures Delaney: Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Boeckh:Chimerix: Research Funding; GSK: Other: Personal fees; GSK: Research Funding; Merck: Research Funding; Merck: Other: Personal fees; Clinigen: Other: Personal fees. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Hill:Takeda: Other: research support; Karius: Other: research support; Amplyx: Consultancy; Nohla Therapeutics: Consultancy, Other: research support.

Past, present, and future efforts to enhance the efficacy of cord blood hematopoietic cell transplantation.

Cord blood (CB) has been used as a viable source of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in over 35,000 clinical hematopoietic cell transplantation (HCT) efforts to treat the same variety of malignant and non-malignant disorders treated by bone marrow (BM) and mobilized peripheral blood (mPB) using HLA-matched or partially HLA-disparate related or unrelated donor cells for adult and children recipients. This review documents the beginning of this clinical effort that started in the 1980’s, the pros and cons of CB HCT compared to BM and mPB HCT, and recent experimental and clinical efforts to enhance the efficacy of CB HCT. These efforts include means for increasing HSC numbers in single CB collections, expanding functional HSCs ex vivo, and improving CB HSC homing and engraftment, all with the goal of clinical translation. Concluding remarks highlight the need for phase I/II clinical trials to test the experimental procedures that are described, either alone or in combination.

An Approach to the Cure of HIV using Cord Blood Hematopoietic Cell Transplantation

An Approach to the Cure of HIV using Cord Blood Hematopoietic Cell Transplantation

Donor KIR3DL1/Receptor HLA-Bw4-80I Combination Reduce Acute Leukemia Relapse after Umbilical Cord Blood Transplantation without in Vitro T-Cell Depletion

Objective: How to reduce relapse is still a puzzle in the treatment of acute leukemia patients with allogeneic umbilical cord blood hematopoietic cell transplantation (UCBT). Donor natural killer (NK) cell alloreactivity in UCBT can control leukemic relapse, However, NK cell function is calibrated through education, that is governed by human leukocyte antigens (HLAs), our study aim to investigate the Graft-resistant leukemia effect after transplantation of KIR3DL1 and its different ligand HLA-B subtypes(BW6, Bw4-80T, Bw4-80I).Design and method: we retrospectivly analysed single center of 232 acute leukemia patients who underwent UCBT(myeloablative conditioning without ATG). The killer immunoglobulin-like receptor (KIR) genotype of cord blood donors was detected by SSP method, they all contains KIR3DL1. There were 104 cases of acute lymphoblastic leukemia, 112 cases of acute myeloid leukemia, 16 cases of myelodysplastic syndrome. 168 cases of transplant patients in remission period, and 64 cases of non-remission. There were 122 males and 110 females with a median age of 13 years (2-45 years). The patients were divided into three groups according to HLA-B locus, 1.patients had BW6 in both two HLA-B locus(group 1, N=86) , which means uneducated; 2.patients had HLA-Bw4-80T in the HLA-B locus(group 2, N=68), which means educated; 3.patients had HLA- Bw4-80I in the HLA-B locus(group 3, N=77), which means highly educated. The receptors were followed-up from July 31, 2012 to December 30,2017, in graft failure, neutrophil engraftment, platelet engraftment, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), relapse, overall survival (OS), and leukemia free survival (LFS).Results: In group 3 patients, donor KIR3DL1 and receptor HLA-Bw4-80I combinations that were predictive of highly educated were associated with significantly lower relapse (hazard ratio [HR], HR = 0.49; P =0 .004) and better LFS (HR = 0.68, p = 0.014), compared with the educated(group2) and uneducated (group3) group, with no significant increase in aGVHD and cGVHD incidence. While no difference was observed in the other index in the three group.Conclusion : Alloreactivity of NK cells demonstrated reproducible patterns of strong or weak graft-versus-leukemia (GVL) effect against leukemia blast, which is depend on donor KIR3DL1/receptor HLA-B subtype combinations. Our data suggests that donor KIR3DL1/receptor HLA-Bw4-80I combination in UCBT may achieve superior graft versus leukemia effects, lower risk for relapse among patients with acute leukemia.Keywords: KIR, Umbilical Cord Blood Transplantation, UCBT, GVL DisclosuresNo relevant conflicts of interest to declare.

200 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Umbilical Cord Blood Hematopoietic Cell Transplantation

200 - Impact of MHC Class I Chain-Related Gene a (MICA) Mismatch on Umbilical Cord Blood Hematopoietic Cell Transplantation

546 - Cytomegalovirus (CMV) Infection and Disease Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation (HCT) Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation From a Single Institution

CMV remains a major complication of allogeneic HCT, with over 40% of at risk recipients (donor (D) and/or recipient (R) seropositive) experiencing infection in the first 100 days post-HCT. At the NIH, all HCT recipients are monitored weekly from day 0-100 with blood CMV quantitative PCR (qPCR) with a uniform approach to preemptive therapy across HCT protocols. This offers a unique opportunity to comprehensively evaluate the cumulative incidence (CI) of and risk factors for post-HCT CMV infection and disease across different T cell manipulation approaches (posttransplantation cyclophosphamide (PTCy), proximal serotherapy, ex vivo T cell depletion (TCD), and calcineurin/mTOR inhibitor (CNI/mTORi) based) and different graft sources (marrow (BM), peripheral blood (PBSC), and cord blood (CB)). This is a retrospective study of 364 consecutive patients transplanted between Aug 10, 2011 and Feb 10, 2017. CMV infection was defined as 2 qPCRs between 3.08-4.11 log10 IU/mL in 1 week, 1 qPCR value >4.11 log10 IU/mL, or sufficient clinical suspicion for CMV disease to prompt therapy. Competing risks (CR) included death, relapse, and graft failure, with analyses including and not including systemic steroids for GVHD or engraftment syndrome as an additional CR. Recipient/donor/HCT characteristics are shown in Figure 1. Among at risk recipients, the 100 day CI of CMV infection was 46% (34% when systemic steroid use was included as a CR). The CI of CMV infection varied mainly by recipient CMV serostatus (Figure 2, P < .0001), with 100 day estimates of 2% (D/R −/−), 6% (+/−), 38% (−/+), and 40% (+/+). With regard to graft T cell manipulation, the 100 day CI of CMV infection, with (Figure 3, P = .029) and without steroids (p = NS) as a CR, respectively, was 25% and 42% (CNI/mTORi), 37% and 42% (serotherapy), 40% and 54% (PTCy), and 50% and 60% (TCD). CB was associated with 100 day CI of CMV infection of 64%, higher than BM at 39% and PBSCs at 30%, P = .002. There was a tendency toward lower 100 day CI of CMV infection for recipients of higher T cell doses when systemic steroid use was included as a CR, P = .07. Among CMV seropositive recipients, CMV therapy duration was longer with CMV seronegative donors (median 28 days) compared to CMV seropositive (median 20 days), P = .03. The median duration of CMV therapy was longer at 36 days for CB HCT, compared to PBSC (21 days) and BM (29 days), P = .03. CMV disease developed in 12 patients in the 100 days post HCT at a median of 27 days: 75% in the setting of GVHD, 83% in seropositive recipients, 75% involving gut, and occurring in .5% of PTCy, .4% of CNI/mTORi, .3% of serotherapy, and 0% of CB and TCD HCTs. In conclusion, CMV infection incidence varies based on recipient CMV serostatus, T cell manipulation strategy, and graft source, with longer treatment duration with seronegative donors and/or CB recipients. CMV disease rates before day 100 are similar across platforms and occur predominantly in the setting of GVHD.Figure 2Cumulative incidence of CMV infection in the first 100 days after HCT, by donor (D) and recipient (R) CMV serostatus.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Cumulative incidence of CMV infection in the first 100 days after HCT, by T cell manipulation strategy, with comparison using Gray's method of post-transplantation cyclophosphamide (PTCy), serotherapy (proximal ATG or alemtuzumab), ex vivo T cell depletion (TCD), and calcineurin inhibitor/mTOR inhibitor (CNI/mTOR)-based approaches.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Antagonizing PPARγ Expands Human Hematopoietic Stem and Progenitor Cells By Switching on FBP1-Repressed Glycolysis and Preventing Differentiation

Allogeneic hematopoietic cell transplantation (HCT) is widely used as a life-saving treatment for malignant and non-malignant blood disorders. Hematopoietic stem cells (HSCs) are a major contributing cell population for a successful HCT. While cord blood (CB) is an acceptable source of HSCs for clinical HCTbecause of its many advantages including prompt availability, lower incidence of GvHD and virus infection, CB HCT is usually associated with slower time to engraftment especially in adult patients when compared with other cell sources; this is partly due to limiting numbers of HSCs in single cord units. In order to overcome this limitation, ex vivo expansion of CB HSCs has been evaluated in preclinical and clinical studies for improvement of the clinical efficacy of CB HCT. While a number of different ways have been evaluated to ex-vivo expand human HSCs, little is known about the mechanisms involved, and whether efficient expansion of CB HSCs could be achieved by metabolic reprogramming.In a compound screen for potential candidates which could promote ex vivo expansion of CB HSCs, we found that PPARγ antagonist GW9662 treatment significantly enhanced ex vivo expansion of CB phenotypic HSCs (~5 fold) and progenitor cells (HPCs) (~6.8 fold) in RPMI-1640 medium containing 10% fetal bovine serum (FBS) and cytokines (SCF, FL, TPO) when compared with vehicle control. GW9662 significantly increased numbers of CB colony-forming unit (CFU) granulocyte/macrophage (GM) (~1.8 fold) and granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM) (~3.2 fold) progenitors after 4 days ex vivo culture. To assess whether the ex vivo expanded CB HSCs enhanced by the PPARγ antagonist were functional in vivo, we performed both primary and secondary transplantation in immunocompromised NSG mice. Engraftment of CB CD34+ cells in primary recipients was significantly increased (~3 fold) both in bone marrow (BM) and peripheral blood (PB) by the cultured cells treated with GW9662. The percentages of both myeloid and lymphoid lineages were enhanced in BM of primary recipients transplanted with GW9662-treated CB CD34+ cells. We also transplanted CB CD34+ cells transfected with control shRNA or PPAR γ shRNA into NSG mice, and consistently found that both myeloid and lymphoid chimerism was enhanced in BM of recipients which were infused with PPAR γ shRNA transfected-CD34+ cells compared with control shRNA transfected-CD34+ cells. Long term reconstituting and self-renewing capability of GW9662-treated CB CD34+ cells with both enhanced myeloid and lymphoid chimerism, was confirmed in PB and BM in secondary recipients. Limiting dilution analysis was performed to calculate SCID-repopulating cells (SRC), a measure of the number of functional human HSCs. The SRC frequency of GW9662-cultured CB CD34+ cells was 4 fold greater than that of day 0 uncultured CD34+ cells, and 5 fold increased above that of vehicle-treated CD34+ cells with cytokines alone.To gain mechanistic insight into how PPARγ antagonism enhances expansion of human CB HSCs and HPCs, we performed RNA-seq analysis. Antagonizing PPARγ in CB CD34+ cells resulted in downregulation of a number of differentiation associated genes, including CD38, CD1d, HIC1, FAM20C, DUSP4, DHRS3 and ALDH1A2, which suggests that PPARγ antagonist may maintain stemness of CB CD34+ cells partly by preventing differentiation. Of interest, we found that FBP1, encoding fructose 1, 6-bisphosphatase, a negative regulator of glycolysis, was significantly down-regulated by GW9662, which was further confirmed by RT-PCR, western blot and flow cytometry analysis. GW9662 significantly enhanced glucose metabolism in CB HSCs and HPCs without compromising mitochondrial respiration. Enhanced expansion of CB HSCs by antagonizing PPARγ was totally suppressed by removal of glucose or by inhibition of glycolysis. Importantly, suppression of FBP1 greatly promoted glycolysis and ex vivo expansion of long-term repopulating CB HSCs (~3.2 fold). Overexpression of FBP1 significantly suppressed enhancedexpansion and engraftment of CB HSCs by PPARγ antagonist. Our study demonstrates that PPARγ antagonism drives ex vivo expansion of human CB HSCs and HPCs by switching on FBP1 repressed glucose metabolism and by preventing differentiation. This provides new insight into human HSC self-renewal, and suggests a novel and simple means by which metabolic reprogramming may improve the efficacy of CB HCT. DisclosuresNo relevant conflicts of interest to declare.