Umbilical Cord Blood Recipients Research Articles

Immune Reconstitution Profiling Suggests Antiviral Protection after Transplantation with Omidubicel: A Phase 3 Substudy

Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for hematological malignancies and non-malignant disorders. Rapid immune reconstitution (IR) following allogeneic HCT has been shown to be associated with improved clinical outcomes and lower infection rates. A global phase 3 trial (NCT02730299) of omidubicel, an advanced cell therapy manufactured from an appropriately human leukocyte antigen-matched single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients randomized to omidubicel compared with those randomized to standard UCB. This optional, prospective substudy of the phase 3 trial characterized the IR kinetics following HCT with omidubicel compared with UCB in a systematic and detailed manner. In this substudy, 37 patients from 14 global sites were included (omidubicel: n=17, UCB: n=20). Peripheral blood samples were collected over 10 predefined time points from 7 to 365 days post-HCT. Flow cytometry immunophenotyping, T cell receptor excision circle quantification, and T cell receptor sequencing were employed to evaluate the longitudinal IR kinetics post-transplant and their association with clinical outcomes. Patient characteristics in the two comparator cohorts were overall statistically similar, except for age and total body irradiation (TBI) based conditioning regimens. The median age (range) for patients who received omidubicel or UCB was 30 (13-62) years and 43 (19-55) years, respectively. The percentages of patients receiving TBI based conditioning regimens were 47% and 70% for omidubicel and UCB recipients, respectively. Graft characteristics differed in their cellular composition. Omidubicel recipients received a 33-fold higher median dose of CD34+ stem cells, while receiving one third of the median CD3+ lymphocyte dose infused to UCB transplanted patients. Compared with UCB, omidubicel recipients exhibited faster IR of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplant. This effect involved circulating natural killer (NK) cells, helper T cells, monocytes, and dendritic cells, with superior long-term B cell recovery from Day 28. One-week post-HCT, omidubicel recipients exhibited 4.1 and 7.7 -fold increases in the median helper T and NK cell counts respectively, compared to their UCB transplanted counterparts. By three weeks post-HCT, omidubicel transplanted patients were 3-fold more likely to achieve clinically relevant helper T and NK cell counts of 100 cells/ µL or above. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in the short to long term. Omidubicel's CD34+ cell content correlated with faster IR by Day 7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Lastly, early NK and helper T cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study. Our findings suggest that omidubicel efficiently promotes IR across multiple immune cells, including CD4+ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplant, potentially endowing recipients of omidubicel with early protective immunity.

Cytomegalovirus breakthrough and resistance during letermovir prophylaxis.

Letermovir is a relatively new antiviral for prophylaxis against cytomegalovirus (CMV) after allogeneic hematopoietic cell transplantation (HCT). CMV-seropositive HCT recipients who received letermovir prophylaxis from 2018 to 2020 at our center were evaluated for letermovir resistance and breakthrough CMV reactivation. Two-hundred twenty-six letermovir recipients were identified and 7/15 (47%) with CMV DNAemia ≥200 IU/mL were successfully genotyped for UL56 resistance. A single C325Y resistance mutation was identified in an umbilical cord blood recipient. Ninety-five (42%), 43 (19%), and 15 (7%) patients had breakthrough CMV at any level, ≥150 IU/mL, and ≥500 IU/mL, respectively. Risk factors for breakthrough CMV reactivation at each viral threshold were examined. Cumulative steroid exposure was the strongest risk factor for CMV at all evaluated viral thresholds. Graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide (aHR 2.34, 95% CI 1.28-4.28, p = 0.001) or calcineurin inhibitors plus mycophenolate (aHR 2.24, 95% CI 1.30-3.86, p = 0.004) were also associated with an increased risk of CMV reactivation at any level. De novo letermovir resistance is rare and can be successfully treated using other antivirals. Letermovir effectively prevents clinically significant CMV, however, subclinical CMV reactivation occurs frequently at our center.

Abstract 13 A Randomized, Placebo-Controlled, Phase II Trial of Intravenous Allogeneic Umbilical Cord Blood Infusion for Adults with Ischemic Stroke

IntroductionStroke is the fifth leading cause of death in the United States. Tissue plasminogen activator and mechanical thrombectomy are the only effective treatments, but many patients are ineligible for these treatments.ObjectiveThe objective of this study was to determine whether an intravenous infusion of a non-HLA matched, unrelated donor umbilical cord blood (UCB) would improve functional outcomes.MethodsWe conducted a phase II multicenter, randomized (2:1), placebo controlled, double-blinded trial of UCB in adults with acute ischemic stroke. Patients had to have adequate immune function. Cord blood units were selected from U.S. public cord banks based on blood type, race, and cell dose. Study product was infused 3-10 days post stroke. Participants were randomized within strata of National Institutes of Health Stroke Scale Score (NIHSS) (<12 vs ≥12), and study center. The primary endpoint was change in Modified Rankin Scale (mRS) (baseline minus day 90). The study was powered at 80% (odds ratio of 2). Key secondary outcomes included functional independence at day 90 (mRS <2), NIHSS, the Barthel Index, infusion reactions, and adverse events.ResultsSeventy-nine participants were enrolled at 6 centers when the trial was closed early due to slow accrual related to COVID19; 73 participants (47 randomized to UCB) were included in the safety and efficacy analyses. The median (range) of the change in mRS was 1 (–2, 3) in UCB and 1 (–1, 4) in placebo. A shift analysis based on the proportional odds model showed an odds ratio of 0.9 (95% CI: 0.4, 2.3) after adjustment for baseline mRS and randomization strata. No differences were observed on the key secondary outcomes. There were 17 mild infusion reactions (27.6% UCB; 15.4% placebo). The distribution of serious and non-serious adverse events was similar between arms.DiscussionThis study demonstrated the safety of infusing non-HLA matched UCB to adults with acute ischemic stroke. Feasibility and logistics were challenging. The primary efficacy endpoint did not demonstrate benefit in this underpowered sample size. In a secondary ad hoc analysis, a trend of improved functional outcomes at day 90 in recipients of UCB more than 5 days post stroke (Figure 1) could be explored in future trials.Figure 1.Cord blood versus placebo odds ratio by treatment latency (days).

The Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Different Donors in Recipients With Mucopolysaccharidosis.

There is limited information regarding hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis (MPS) IV and VI. This study examined the full donor chimerism, specific lysosomal enzyme levels, and the survival of different MPS children after HSCT from various donor sources and compared the prognosis. A total of 42 children with MPS underwent HSCT, 9 cases were type I, 14 were type II, 15 were type IV, and 4 were type VI. A total of 24 patients received peripheral blood stem cells (PBSC) and 18 patients received umbilical cord blood (UCB). Patients who received PBSC were conditioned with intravenous (IV) busulfan every 6 h for a total of 16 doses, IV cyclophosphamide (CY, 200 mg/kg), and antihuman thymocyte globulin (ATG, 10 mg/kg). While conditioning regimen of patients who received UCB was adjusted to ATG (preposed, pre-) + busulfan + fludarabine + Cy, which includes IV ATG (pre-, 6 mg/kg), IV busulfan every 6 h for a total of 16 doses, IV fludarabine (200 mg/m2) and CY (200 mg/kg). Also, 95.2% (40 of 42) of patients achieved full donor chimerism, and all patients’ specific lysosomal enzyme levels reached normal. The estimated overall survival (OS) at 1 year was 92.9%. There was no significant difference in 1-year OS between patients who received PBSC transplantation and those who received UCB grafts (87.5% vs. 100%, p = 0.0247). The incidence of acute and chronic GVHD did not differ between them. The incidences of pneumonia in PBSC recipients and UCB recipients were 45.8 and 33.3%, respectively, but there few patients suffering from respiratory failure (4.2 and 5.6%, respectively) due to pneumonia. The incidence of cytomegaloviremia was also high in both groups, 58.3 and 44.4% respectively, However, no patient developed CMV disease. All deaths (3 of 42) occurred in patients receiving PBSC grafts, and there was no death in patients receiving UCB grafts. There was no death after transplantation in patients with MPS IV and VI. In addition, respiratory and nervous system functions were improved, whereas valvular heart disease was improved in some patients but progressed in more patients after transplantation. In summary, HSCT is a good therapeutic option for MPS, not only for patients with MPS I or II but also for those with MPS IV or VI. The specific lysosomal enzyme levels can be completely restored to normal, which is the basis for patients to resolve a broad range of clinical outcomes. Moreover, UCB with suitable HLA (HLA-match above 7/10 and 4/6) is a suitable donor source for MPS. Patients who underwent UCB transplantation using the conditioning regimen ATG (pre-) + busulfan + fludarabine + Cy can achieve a higher proportion of full donor chimerism and survival with less severe complications. HSCT can improve organs function in patients with MPS, but it is still worth exploring.

Decreased Mortality in 1-Year Survivors of Umbilical Cord Blood Transplant vs. Matched Related or Matched Unrelated Donor Transplant in Patients with Hematologic Malignancies

Allogeneic hematopoietic stem cell transplantation (HCT) has the potential to cure hematologic malignancies but is associated with significant morbidity and mortality. Although deaths during the first year after transplantation are often attributable to treatment toxicities and complications, death after the first year may be due to sequelae of accelerated aging caused by cellular senescence. Cytotoxic therapies and radiation used in cancer treatments and conditioning regimens for HCT can induce aging at the molecular level; HCT patients experience time-dependent effects, such as frailty and aging-associated diseases, more rapidly than people who have not been exposed to these treatments. Consistent with this, recipients of younger cells tend to have decreased markers of aging and improved survival, decreased graft-versus-host disease, and lower relapse rates. Given that umbilical cord blood (UCB) is the youngest donor source available, we studied the outcomes after the first year of UCB transplantation versus matched related donor (MRD) and matched unrelated donor (MUD) transplantation in patients with hematologic malignancies over a 20-year period. In this single-center, retrospective study, we examined the outcomes of all adult patients who underwent their first allogeneic HCT through the Duke Adult Bone Marrow Transplant program from January 1, 1996, to December 31, 2015, to allow for at least 3 years of follow-up. Patients were excluded if they died or were lost to follow-up before day 365 after HCT, received an allogeneic HCT for a disease other than a hematologic malignancy, or received cells from a haploidentical or mismatched adult donor. UCB recipients experienced a better unadjusted overall survival than MRD/MUD recipients (log rank P = .03, median overall survival: UCB not reached, MRD/MUD 7.4 years). After adjusting for selected covariates, UCB recipients who survived at least 1 year after HCT had a hazard of death that was 31% lower than that of MRD/MUD recipients (hazard ratio, 0.69; 95% confidence interval, 0.47-0.99; P = .049). This trend held true in a subset analysis of subjects with acute leukemia. UCB recipients also experienced lower rates of moderate or severe chronic graft-versus-host disease (GVHD) and nonrelapse mortality, and slower time to relapse. UCB and MRD/MUD recipients experienced similar rates of grade 2-4 acute GVHD, chronic GHVD, secondary malignancy, and subsequent allogeneic HCT. UCB is already widely used as a donor source in pediatric HCT; however, adult outcomes and adoption have historically lagged behind in comparison. Recent advancements in UCB transplantation such as the implementation of lower-intensity conditioning regimens, double unit transplants, and ex vivo expansion have improved early mortality, making UCB an increasingly attractive donor source for adults; furthermore, our findings suggest that UCB may actually be a preferred donor source for mitigating late effects of HCT.

Low 5-year health care burden after umbilical cord blood transplantation

AbstractRecipients of allogeneic hematopoietic cell transplantation (HCT) experience a substantial health care burden, with potentially differing patterns of long-term health care requirements using peripheral blood stem cells, bone marrow, and umbilical cord blood (UCB) grafts. We analyzed data from 1077 consecutive adult allogeneic HCT recipients who underwent transplant at the University of Minnesota between 2000 and 2016. To estimate health care burden over time, we compared the number of visits, laboratory studies, medications, and relative value units billed. Health care elements were analyzed both individually and together (ie, total health care elements used per patient days into a density composite score). UCB had the lowest density health care burden composite score from the time of transplant through year 5 (median score 64.0 vs 70.5 for peripheral blood stem cells and 88.0 for bone marrow; P < .01). In multivariate analysis of health care burden between years 1 and 5, recipients of either bone marrow (odds ratio [OR] 0.49 [95% confidence interval (CI) 0.29-0.84]) or peripheral blood stem cells (OR 0.49 [95% CI 0.36-0.67]) were half as likely to experience low health care burden compared with UCB. Adult recipients of UCB have a lower long-term health care burden compared with other graft sources, possibly reflecting a better quality of life.

The diagnostic and clinical significance of granulomas in gastrointestinal biopsies from haematopoietic transplant patients.

The diagnostic and clinical significance of granulomas in gastrointestinal (GI) biopsies from haematopoietic transplant patients remains disputed, especially following the proposal of cord colitis syndrome (CCS) as a new entity. The aim of the following study was to explore this controversy by identifying such biopsies with granulomas and detailing their clinicopathological associations. Twelve patients with granuloma-containing biopsies were identified from across three scenarios: prospectively during a GI pathologist's routine practice over a period of 5years; retrospectively from a cohort of transplant patients with clinically validated GI graft versus host disease (GVHD); and retrospectively from a cohort of patients who had received umbilical cord blood (UCB). Their clinicopathological assessments (which included unique long-term patient follow-up) showed that granulomas are only rarely seen across all GI biopsies from haematopoietic transplant patients, and may uncommonly constitute a histological feature of GI GVHD. Granulomas-and especially well-defined, non-cryptolytic ones-are more commonly present in GI biopsies from UCB recipients, but do not show any accompanying histological features that are different from those seen in granuloma-containing biopsies from other patient groups. Furthermore, the three UCB recipients with granuloma-containing biopsies were clinically diagnosed with GVHD rather than CCS. Finally, polymorphic post-transplant lymphoproliferative disorder (PTLD) can present histologically as GI granulomatous inflammation that mimics Crohn's disease. Granulomas in GI biopsies of haematopoietic transplant patients may often indicate a treatable aetiology such as GVHD or PTLD. Granulomas are more commonly seen in GI biopsies from UCB recipients, but do not necessarily indicate a diagnosis of CCS.

Cytomegalovirus-Specific Immunity Recovers More Slowly after Cord Blood Transplantation Compared with Matched Sibling Donor Allogeneic Transplantation

Rapid quantitative recovery of NK cells but slower recovery of T-cell subsets along with frequent viral infections are reported after umbilical cord blood (UCB) compared with matched sibling donor (MSD) hematopoietic cell transplantation (HCT). However, it remains unclear whether increased propensity for viral infections is also a result of slower recovery of virus-specific immunity after UCB as compared to MSD HCT. We examined the differences in the function of virus-specific peripheral blood mononuclear cells (PBMC) after UCB (N=17) vs. MSD (N=9) using previously collected patient blood samples at various time points after HCT. Interferon-gamma (IFN-γ) enzyme-linked immune absorbent spot (ELISpot) assay was used to quantify the PBMC frequencies that secrete IFN-γ in response to 11 immunopeptides from 5 common viruses. We included the patients who received the same reduced intensity conditioning regimen without ATG, no systemic glucocorticoids and had no relapse or acute/chronic graft-versus-host disease within 1 year after HCT. The CMV-reactive PBMC frequencies were higher in CMV seropositive vs. seronegative patients after HCT. Among CMV seropositive patients, the frequency of CMV-reactive PBMC was lower after UCB compared to MSD throughout one year of HCT. We observed no differences in virus-specific PBMC responses towards HHV6, EBV, BK, and adenovirus antigens between UCB and MSD. Our data demonstrate that the reconstitution of CMV-specific immunity is slower in CMV seropositive recipients of UCB vs. MSD HCT in contrast to other viruses which had similar recoveries. These study findings support implementation of more potent prophylactic strategies for preventing CMV reactivation in CMV seropositive patients receiving UCB HCT.

Immune reconstitution following umbilical cord blood transplantation: IRES, a study of UK paediatric patients.

To obtain a qualitative as well as quantitative view immune reconstitution following umbilical cord blood (UCB) transplantation of paediatric patients, we utilised a broad panel of flow cytometry markers to monitor the phenotypes of lymphoid and myeloid cells at 1‐12 months post‐transplant. Samples were received from 46 patients with a median age of 3.3 years and survival was 76% at 1 year. Monocytes were at similar or higher median levels than in adult controls at all times tested, with a high CD16+ proportion in the first 3 months. NK cells were also within adult ranges, with a CD56++ high proportion in the first 6 months. B cell recovery was seen from 2 months in most patients and T cells from 3 months, both were delayed with anti‐thymocyte globulin (ATG) treatment. CD4:CD8 ratios were high in the first 6 months, and the proportion of T cells with recent thymic emigrant and naïve phenotypes rose from 3 months. NK and plasmacytoid dendritic cell numbers remained at reduced levels in patients not surviving to 1 year. Our results can serve as a useful reference for detailed monitoring of immune reconstitution in paediatric recipients of UCB.

Comparison of Haploidentical Related Donor with Post-Transplant Cyclophosphamide (PTCy) and Umbilical Cord Blood (UCB) Transplantation after Myeloablative Conditioning for Hematological Malignancy

<h3>Background</h3> In recent years, haploidentical related donor (haplo) transplantation has markedly increased, accounting for 17% of allogeneic transplantations in adults compared to 5% with UCB and 18% and 20% respectively, in children with hematological malignancy. As prior studies comparing these two hematopoietic stem cell (HSC) sources were largely limited to patients receiving reduced dose conditioning, the current analyses compared outcomes with these HSC sources after myeloablative conditioning. <h3>Patients</h3> Between 2012 and 2017, there were 375 transplants with haplo HSC (BM, n=126; PB, n=249), and 333 with UCB (188 matched at ≤5/8 HLA alleles and 145 matched at 6-8/8 HLA alleles). All haplo recipients had PTCy, calcineurin inhibitor (CNI) and mycophenylate mofetil (MMF) as GVHD prophylaxis and all UCB recipients were conditioned with TBI 1320 cGy, fludarabine and Cy and received CNI/MMF. The median infused total nucleated dose for ≤5/8 and 6-8/8 UCB transplants were 4.7 and 4.4 × 10⁷/kg, respectively. Recipients of 6-8/8 UCB transplants were younger (14 years vs. 21 and 29 years) and more likely to have lower co-morbidity scores (81% vs. 69% and 63%) compared to recipients of ≤5/8 UCB and haplo transplants. UCB recipients were more likely to have ALL and transplanted in second CR and haploidentical related donor transplants were more likely to have AML and transplanted in first CR. Cytogenetic risk did not differ between HSC groups. <h3>Results</h3> Compared to haplo transplants, relapse was lower in recipients of ≤5/8 UCB and similar to that in recipients of 6/8 UCB. Non-relapse mortality (NRM), however, was higher after UCB regardless of HLA match group (Table 1). While overall survival was higher 1-year after haploidentical transplant (81% vs 68% and 72% after ≤5/8 [p<0.001] and 6-8/8 UCBT [p=0.038], respectively), survival was similar at 2 and 3 years for HSC sources (figure 1). Similarly, leukemia-free survival (LFS) was lower at 1-year (61% vs. 71%, p=0.031) but not at 3-years (55% vs. 54%, p=0.82) after ≤5/8 UCB compared to haplo (Figure 1). LFS was similar after 6-8/8 UCB and haplo at 1-year (64% vs. 71%, p=0.16) and 3-years (52% vs. 54%, p=0.82) (figure 1). <h3>Conclusion</h3> Three-year LFS and overall survival were comparable in recipients of Haplo with PTCy and UCB. While greater HLA mismatch is associated with less relapse after UCB transplant, NRM counters this beneficial effect. Strategies that address the early mortality risk after UCB transplant could further enhance success with this HSC source.

Unlicensed Umbilical Cord Blood Units Provide a Safe and Effective Graft Source for a Diverse Population: A Study of 2456 Umbilical Cord Blood Recipients.

Umbilical cord blood (UCB) transplantation (UCBT) is a curative procedure for patients with hematologic malignancies and genetic disorders and expands access to transplantation for non-Caucasian patients unable to find a fully matched unrelated donor. In 2011, the US Food and Drug Administration required that unrelated UCBT be performed using either licensed UCB or unlicensed UCB under the Investigational New Drug (IND) program. The National Marrow Donor Program manages an IND under which 2456 patients (1499 adults and 957 children, 564 with malignant diseases and 393 with nonmalignant diseases) underwent single or double UCBT between October 2011 and December 2016. The median patient age was 31 years (range, <1 to 81 years), and 50% of children and 36% of adults were non-Caucasian. The median time to neutrophil engraftment (ie, absolute neutrophil count ≥500/mm3) was 22 days for adults, 20 days for pediatric patients with malignant diseases, and 19 days for pediatric patients with nonmalignant diseases, with corresponding rates of engraftment at 42 days of 89%, 88%, and 90%. In these 3 groups of patients, the incidence of acute graft-versus-host disease (GVHD) grade II-IV was 35%, 32%, and 24%; the incidence of chronic GVHD was 24%, 26%, and 24%; and 1-year overall survival (OS) was 57%, 71%, and 79%, respectively. In multivariate analysis, younger age, lower Hematopoietic Cell Transplantation-Specific Comorbidity Index, early-stage chemotherapy-sensitive disease, and higher performance score were predictive of improved OS for adults. In a subset analysis of children with malignancies undergoing single UCBT, the use of either licensed UCB (n=48) or unlicensed UCB (n=382) was associated with similar engraftment and survival. The use of unlicensed UCB units is safe and effective and provides an important graft source for a diverse population.

Decreased Mortality after the First Year of Allogeneic Hematopoietic Stem Cell Transplant in Recipients of Umbilical Cord Blood Vs. Matched Related or Matched Unrelated Donors

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-HCT) provides a potential cure for a multitude of diseases but can result in high rates of morbidity and mortality. These outcomes have been associated with donor choice, with umbilical cord blood (UCB) perceived as an inferior option to matched related or matched unrelated donors (MRD/MUD) due to increased morbidity and mortality the first year after allo-HCT due to delayed engraftment and increased graft versus host disease (GvHD). At the same time, studies have shown that recipients of cells from younger donors do better, and UCB is the youngest donor cell source available. Given that UCB may have long-term benefits, we evaluated long-term survival in recipients of UCB vs. MRD/MUD in patients who had survived at least 1 year. Methods: This is a retrospective analysis of ≥1 year (≥365 days) survivors of first allo-HCT from the Duke Adult Bone Marrow Transplant (ABMT) program over a twenty year period from January 1, 1996 to December 31, 2015. Detailed clinical data was extracted from the Duke ABMT database and electronic medical record. Patients who either died or were lost to follow-up within 1 year of transplant were excluded. Also excluded were those who received an allo-HCT for a disease other than a hematologic malignancy and those who received haploidentical or mismatched adult cells, as these donor sources have been associated with worse outcomes and the goal was to compare UCB to MRD/MUD. Patient characteristics included gender, race, ethnicity, transplant diagnosis, transplant year, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), Karnofsky performance score (KPS) at transplant workup, age at transplant, donor cell characteristics, conditioning regimen, acute GvHD (aGvHD), date of relapse, and date of death. Chi-square tests or Fisher's exact tests were used to compare categorical variables, as appropriate, and Wilcoxon Rank Sum tests or t-tests were used to compare continuous variables, as appropriate. A Kaplan-Meier estimator was used to analyze overall survival. A Cox Proportional Hazard model with stepwise selection with significance of entry=0.1 and significance of stay=0.2 was used to evaluate the patient characteristics of age, gender, race, disease, KPS, conditioning type, history of aGvHD, and decade of transplant and adjusted for selected covariates to compare the two groups. Results: Over the 20-year study period, 848 patients received a first allo-HCT, of whom 456 (54%) survived at least 1 year post-HCT: 102 (22%) UCB and 354 (78%) MRD/MUD. UCB recipients were more likely to be younger (median 42 years vs. 50 years, p=&lt;0.001), African American (25% vs 6%, p&lt;0.001), and have acute leukemia (70% vs. 49%, p=0.001). There were no differences in conditioning regimen (myeloablative conditioning 61% vs. 51%, p=0.08), pre-HCT performance status (KPS 80-100 87% vs. 82%, p=0.08), or comorbidities (HCT-CI ≤3 61% vs. 74%, p=0.052). With regard to post-HCT outcomes, UCB recipients had a higher rate of any aGvHD (70% and 59%, p=&lt;0.001). Conditional on ≥1 year survival of allo-HCT, UCB recipients had a better unadjusted overall survival than adult cell recipients (Figure 1, log rank p=0.03). After adjusting for selected covariates (age, gender, conditioning type, decade of transplant), the hazard rate of UCB recipients was 37% lower than that of MRD/MUD recipients after the 1 year threshold, though this was no longer statistically significant (p=0.09). Discussion: Among patients who survived at least 1 year post-HCT, those who received UCB had a significantly lower risk of mortality on univariate analysis than those who received adult cells. Though this finding was no longer statistically significant on multivariate analysis, there was a strong trend and the lack of statistical significance could be an effect of the small sample size. Additional research across larger populations (e.g. CIBMTR) is warranted to further explore the clinical characteristics and long-term health outcomes between the two groups, especially given the potential for newer UCB approaches such as ex-vivo expansion to decrease the early post-HCT morbidity and mortality associated with UCB and delayed engraftment. If other studies support improved long-term outcomes with UCB, those findings coupled with advances in UCB transplants may promote UCB as a donor source. Disclosures Gasparetto: Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding. Horwitz:Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding.

Impact of a Nutritional Risk Index on Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation

Nutritional status is an important component of cancer care, and malnutrition itself can cause death in 10% to 20% of cancer patients. A nutritional risk index (NRI) is a useful tool for nutritional assessment of cancer patients. This study aimed to evaluate the impact of pretransplant NRI values on outcomes of allogeneic hematopoietic cell transplantation (allo-HSCT). One hundred sixty patients who underwent allo-HSCT between January 2008 and July 2017 at Konan Kosei Hospital were included in this single-center, retrospective analysis. NRI was calculated at the beginning of the conditioning regimen. The patients were divided into high NRI (NRI ≥ 97.5) and low NRI (NRI < 97.5) groups, and overall survival (OS), nonrelapse mortality (NRM), and cumulative incidences of acute and chronic graft-versus-host disease (GVHD) were evaluated. Two-year OS rates were 76% (95% confidence interval [CI], 63% to 83%) and 50.4% (95% CI, 38% to 62%) in the high NRI and low NRI groups, respectively (P < .001). One-year cumulative incidences of NRM were 7.9% (95% CI, 3.5% to 15%) and 23% (95% CI, 14% to 33%; P = .014) and 2-year cumulative relapse rates were 17% (95% CI, 10% to 26%) and 32% (95% CI, 21% to 43%; P = .10) in the high NRI and low NRI groups, respectively. The multivariate analysis indicated low NRI was a significant risk factor for OS and NRM. Conversely, high NRI was associated with increased incidences of grades II to IV acute GVHD and chronic GVHD. Additionally, the subgroup analysis according to stem cell source revealed a significant benefit of higher NRI on survival only in umbilical cord blood recipients. Overall, these results suggest that pretransplant NRI might predict OS and NRM after allo-HSCT.

Results of Allogenic Hematopoietic Stem Cell Transplantation in Fanconi Anemia Caused by Bone Marrow Failure: Single-Regimen, Single-Center Experience of 14 Years.

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for bone marrow failure (BMF) in patients with Fanconi anemia (FA). We retrospectively analyzed the records of patients with FA who underwent HSCT with a radiation-free, reduced-intensity conditioning regimen (fludarabine, cyclophosphamide, and antithymocyte globulin) along with an unmanipulated graft infusion between 2004 and 2018. A total of 44 patients underwent HSCT during the study period. Median age at transplantation was 121 months. Regarding the donor source, 22 transplants (50%) were collected from matched related donors (MRDs), and 22 transplants (50%) were collected from alternative donors (ADs). The median infused CD34+ cell dose was 4.7 × 106/kg (range, 0.8 to 23) in bone marrow or peripheral blood stem cell recipients and 1.2 × 105/kg (range, 1.1 to 3.6) in umbilical cord blood recipients. All but 2 patients achieved primary neutrophil engraftment (95%). In a median follow-up of 36 months (range, 1 to 159), 3-year overall survival was 70.5% in the entire group and 91% in the MRD recipients. Primary causes of death were infections (n = 5), acute grade 3 to 4 graft-versus-host disease (n = 4), and hemorrhagic cystitis (n = 3). All surviving patients have full (n = 29) and acceptable mixed (n = 2) donor chimerism and good clinical status. Our results showed an excellent outcome with unmanipulated grafts using a fludarabine-based, radiation-free preparative regimen for MRD recipients. Even though primary neutrophil engraftment rates were good in AD recipients, intervening complications increased mortality in these patients. In clinics where T cell depletion is not feasible, more effort is warranted to improve outcomes for AD recipients.

The influence of stem cell source on transplant outcomes for pediatric patients with acute myeloid leukemia

AbstractWhen hematopoietic stem cell transplant (HSCT) is necessary for children with acute myeloid leukemia (AML), there remains debate about the best stem cell source. Post-HSCT relapse is a common cause of mortality, and complications such as chronic graft versus host disease (cGVHD) are debilitating and life-threatening. To compare post-HSCT outcomes of different donor sources, we retrospectively analyzed consecutive transplants performed in several international centers from 2005 to 2015. A total of 317 patients were studied: 19% matched sibling donor (MSD), 23% matched unrelated donor (MUD), 39% umbilical cord blood (UCB), and 19% double UCB (dUCB) recipients. The median age at transplant was 10 years (range, 0.42-21 years), and median follow-up was 4.74 years (range, 4.02-5.39 years). Comparisons were made while controlling for patient, transplant, and disease characteristics. There were no differences in relapse, leukemia-free survival, or nonrelapse mortality. dUCB recipients had inferior survival compared with matched sibling recipients, but all other comparisons showed similar overall survival. Despite the majority of UCB transplants being HLA mismatched, the rates of cGVHD were low, especially compared with the well-matched MUD recipients (hazard ratio, 0.3; 95% confidence interval, 0.14-0.67; P = .02). The composite measure of cGVHD and leukemia-free survival (cGVHD-LFS), which represents both the quality of life and risk for mortality, was significantly better in the UCB compared with the MUD recipients (HR, 0.56; 95% confidence interval, 0.34-1; P = .03). In summary, the use of UCB is an excellent donor choice for pediatric patients with AML when a matched sibling cannot be identified.

Umbilical Cord Blood As an Alternate Donor Source for High Risk Elderly Patients Undergoing Allogeneic Stem Cell Transplantation for Hematological Malignancies

Allogeneic stem cell transplantation (alloHCT) remains the only curative option for a variety of hematological malignancies. AlloHCT is being increasingly offered in elderly patients with acceptable transplant related mortality. Umbilical cord blood (UCB) is established as an alternate donor source however some are reluctant to consider its use in elderly patients due to anticipated morbidity. We evaluated outcomes in alternate donor sources, prior to the initiation of haploidentical transplantation at our institution, of matched unrelated donor (MUD) and UCB in elderly patients (median age 64, range 60-74) from 2005-2015. One hundred and eighty four patients were included (MRD: 57; MUD: 69; UCB: 58). Eighty seven underwent myeloablative conditioning (52.7%). There was no difference in acute (aGVHD) or chronic graft versus host disease (cGVHD) between donor sources. ATG was protective for grade III-IV aGVHD (p=0.0498) and high disease risk index per Armand et al predictive of cGVHD (p=0.0496). UCB engraftment was longer for both neutrophils (p=0.005) and platelets (p 2) comorbidity index (42%) per Sorror et al. There was a trend toward inferior progression free survival (PFS) amongst both UCB (5.50 months; 95% CI 2.83—9.36) and MUD (5.59 months; 95% CI 3.68-17.68) as compared to MRD (18.3 months; 95% CI 8.38-64.79)(Table 1). Compared to MRD, UCB experienced inferior median overall survival (OS) HR 1.877 (95% CI 1.160-3.037) but no difference was seen between UCB and MUD or MUD and MRD in multivariable analysis (Table 1 and 2). The leading cause of death in UCB recipients was infections (40%) followed by relapse (17%). Our experience shows that even in this very high risk elderly cohort, UCB continues to be a viable alternate donor source. Methods to reduce late infectious complications are needed such as new approaches to accelerate T cell engraftment which is currently being explored at our center.

Incidence of Epstein-Barr Virus (EBV) Detection in the Blood, Pre-Emptive Therapy, and EBV-Posttransplantation Lymphoproliferative Disorder (EBV-PTLD) after Allogeneic Hematopoietic Cell Transplantation (HCT) across a Broad Range of HCT Approaches and All Graft Sources

Latent EBV infection can lead to EBV-PTLD when proliferating, EBV+ B cells are insufficiently controlled by cellular immunity. At the National Institutes of Health (NIH), all HCT recipients are monitored weekly from day 0-100 with whole blood EBV qPCR. We evaluated the cumulative incidence (CI) of EBV-related events across 4 T-cell manipulation strategies (posttransplantation cyclophosphamide (PTCy), proximal serotherapy, ex vivo T cell depletion (TCD), and calcineurin/mTOR inhibitor (CNI/mTORi)-based), across all graft sources (marrow (BM), peripheral blood (PBSC), and umbilical cord blood (UCB)), and across regimens with and without mTORi drugs. The CI of EBV events (detection of any EBV in blood (Any-EBV), detection of EBV > 3 log10 IU/mL (>3-EBV), pre-emptive therapy for EBV (EBV-Tx), and EBV-PTLD) were determined, with death as a competing risk. EBV-tx included rituximab and/or EBV-specific T-cells. Any-EBV and >3-EBV events were captured through day +100 and EBV-Tx and EBV-PTLD events were captured through 1-year post-HCT. Included are 356 consecutive patients receiving 1st HCT at NIH from 2011-2017 with sufficient weekly day 0-100 EBV qPCRs (> 63% of specimens) and 1 year of follow-up of survivors. Fig 1 shows cohort characteristics. Among T-cell manipulation strategies, the CI of Any-EBV and >3-EBV was lowest for serotherapy, p=0.0007 and p=0.0006, with no difference among strategies in the CI of EBV-Tx or EBV-PTLD. By graft source, UCB had the highest CI of Any-EBV at day +100, p=0.001, with no difference in the CI of >3-EBV owing to higher CI of EBV-Tx among UCB recipients compared to BM and PBSC grafts, p 3-EBV, but no difference in the CI of EBV-Tx or EBV-PTLD. Within CNI/mTORi-based approaches, the CI of Any-EBV and >3-EBV was lower for CNI+mTORi vs CNI without mTORi, p=0.004 and p=0.002, and the CI of EBV-Tx was 3% for CNI+mTORi vs 14% for CNI without mTORi, p=0.009, with no difference in the CI of EBV-PTLD. Among PTCy-containing approaches, with or without serotherapy, there were no differences in the CI of Any-EBV, >3-EBV, EBV-Tx, or EBV-PTLD. The CI of EBV events are summarized in Fig 2. While EBV detection in blood was common post-HCT, the clinical significance of detection and the role of pre-emptive therapy seem to vary by T-cell manipulation strategy, graft source, and use of mTORi. The finding of less EBV detection with mTORi-containing regimens across approaches warrants further investigation into the clinical significance and underlying mechanisms.

Monocyte Subpopulation Recovery as Predictors of Hematopoietic Cell Transplantation Outcomes.

Monocyte recovery after hematopoietic cell transplantation (HCT) has been correlated with overall survival (OS). However, monocytes are heterogeneous and consist of classic (CD14++CD16-), intermediate (CD14+CD16+), and nonclassic (CD14+CD16++) subpopulations, with unique functional properties. We hypothesized that monocyte subpopulation reconstitution would vary based on allogeneic stem cell source and would be associated with outcomes. We studied monocyte subpopulation recovery at days 28, 60, 100, 180, and 365 post-HCT among 202 patients with hematologic malignancy. Significant differences in absolute monocyte count (AMC) and monocyte subpopulation counts at days 60 and 100 were identified based on stem cell source (all P < .01), with more robust recovery in umbilical cord blood (UCB) recipients. Using 2-fold cross-validation, optimal cutpoints were calculated for day 28 AMC and monocyte subpopulations based on OS. These were used to calculate hazard ratios for OS, disease-free survival (DFS), relapse, transplant-related mortality (TRM), and acute and chronic graft-versus-host disease. OS and DFS were superior when AMC and classic monocyte recovery were above optimal cutpoints (all P < .03). Relapse was reduced for those with AMC (P < .01) and classic (P = .05) monocyte counts above optimal cutpoints. TRM was also reduced when classic (P = .02) monocyte count exceeded optimal cutpoints. Intermediate and nonclassic monocyte recovery were not associated with outcomes. In summary, hematopoietic cell source is associated with monocyte subpopulation recovery, with the early robust recovery in UCB recipients. Recovery of AMC and classic monocytes were prognostic for survival, relapse, and TRM. These indicators may identify patients at increased risk for post-HCT failure and guide therapeutic interventions.

Phase I/II Study of Stem-Cell Transplantation Using a Single Cord Blood Unit Expanded Ex Vivo With Nicotinamide

PurposeIncreasing the number of hematopoietic stem and progenitor cells within an umbilical cord blood (UCB) graft shortens the time to hematopoietic recovery after UCB transplantation. In this study, we assessed the safety and efficacy of a UCB graft that was expanded ex vivo in the presence of nicotinamide and transplanted after myeloablative conditioning as a stand-alone hematopoietic stem-cell graft.MethodsThirty-six patients with hematologic malignancies underwent transplantation at 11 sites.ResultsThe cumulative incidence of neutrophil engraftment at day 42 was 94%. Two patients experienced secondary graft failure attributable to viral infections. Hematopoietic recovery was compared with that observed in recipients of standard UCB transplantation as reported to the Center for International Blood and Marrow Transplant Research (n = 146). The median time to neutrophil recovery was 11.5 days (95% CI, 9 to 14 days) for recipients of nicotinamide-expanded UCB and 21 days (95% CI, 20 to 23 days) for the comparator (P < .001). The median time to platelet recovery was 34 days (95% CI, 32 to 42 days) and 46 days (95% CI, 42 to 50 days) for the expanded and the comparator cohorts, respectively (P < .001). The cumulative incidence of grade 2 to 4 acute graft-versus-host disease (GVHD) at day 100 was 44%, and grade 3 and 4 acute GVHD at day 100 was 11%. The cumulative incidence at 2 years of all chronic GVHD was 40%, and moderate/severe chronic GVHD was 10%. The 2-year cumulative incidences of nonrelapse mortality and relapse were 24% and 33%, respectively. The 2-year probabilities of overall and disease-free survival were 51% and 43%, respectively.ConclusionUCB expanded ex vivo with nicotinamide shortens median neutrophil recovery by 9.5 days (95% CI, 7 to 12 days) and median platelet recovery by 12 days (95% CI, 3 to 16.5 days). This trial establishes feasibility, safety, and efficacy of an ex vivo expanded UCB unit as a stand-alone graft.

Diffuse alveolar hemorrhage is most often fatal and is affected by graft source, conditioning regimen toxicity, and engraftment kinetics.

Diffuse alveolar hemorrhage after hematopoietic stem cell transplantation is a frequently fatal complication with no standard therapy. Although significant changes in supportive and intensive care measures for patients undergoing hematopoietic stem cell transplantation have been made over the past decades, the impact of these changes on the incidence and outcome of patients with diffuse alveolar hemorrhage has not been examined. We analyzed 1228 patients who underwent allogeneic hematopoietic stem cell transplantation between 2008-2015 at the University of Minnesota to study the incidence, risk factors, and outcomes of diffuse alveolar hemorrhage. Diffuse alveolar hemorrhage developed in 5% of allogeneic hematopoietic stem cell transplant recipients, at a median of 30 days (range +3 to +168 days) after transplantation. The incidence of diffuse alveolar hemorrhage was significantly greater in recipients of umbilical cord blood than peripheral blood or bone marrow grafts (HR: 2.08, 95% CI: 1.16-3.74; P=0.01). In multivariate analysis, delayed neutrophil engraftment or primary graft failure was a risk factor for diffuse alveolar hemorrhage following peripheral blood or bone marrow hematopoietic stem cell transplants (HR: 5.51, 95% CI: 1.26-24; P=0.02) and delayed platelet engraftment was associated with significantly increased diffuse alveolar hemorrhage in umbilical cord blood transplant recipients (HR: 6.96, 95% CI: 2.39-20.29; P<0.05). Myeloablative regimens including total body irradiation were also risk factors for diffuse alveolar hemorrhage (HR: 1.8, 95% CI: 1.03-3.13, P=0.05) in both peripheral blood or bone marrow and umbilical cord blood hematopoietic stem cell transplants (HR: 1.87, 95% CI: 0.95-3.71). Patients with diffuse alveolar hemorrhage had an inferior 6-month treatment-related mortality (HR: 6.09, 95% CI: 4.33-8.56, P<0.01) and 2-year overall survival (HR: 4.16, 95% CI: 3.06-5.64; P<0.01) using either graft source. The etiology of diffuse alveolar hemorrhage is multifactorial, involving lung injury influenced by high-dose total body irradiation, graft source, and delayed engraftment or graft failure. The survival of patients with diffuse alveolar hemorrhage after hematopoietic stem cell transplantation remains poor. Clinical interventions or experimental studies (e.g., cell expansion for umbilical cord blood transplants or thrombopoietin use) that modulate these risk factors may limit the incidence and improve the outcomes of diffuse alveolar hemorrhage.