Background: The prevalence and determinants of QRS transition zones are not well established. Methods: We examined the distributions of Normal, clockwise (CW) and counterclockwise (CCW)) QRS transition zones and their relations to disease, body size and demographics in 4624 black and white men and women free of cardiovascular disease and major ECG abnormalities enrolled in the NHANES-III survey. Results: CW transition zones were least observed (6.2%) and CCW were most prevalent (60.1%) with Normal in an intermediate position (33.7%). In multivariable logistic regression analysis, the adjusted, significant predictors for CCW compared to Normal were a greater proportion of blacks and women, fewer thin people (BMI < 20, thin), a greater ratio of chest depth to chest width, and an LVMass index <80 g. By contrast, CW persons were older, had larger QRS/T angles, smaller ratio of chest depth to chest width, had a greater proportion of subjects with low voltage QRS, more pulmonary disease, a greater proportion with high heart rates, shorter QRS duration and were more obese (BMI 30). Conclusions: Normal rather than being the most prevalent transition zone was intermediate in frequency between the most frequently encountered CCW and the least frequently encountered transition zone CW. Differences in the predictors of CW and CCW exist. This requires further investigation to examine how far these differences explain the differences in the published prognostic differences between CW and CCW. (C) 2017 Elsevier Inc. All rights reserved.

Prevention of hepatitis B virus (HBV) transmission from infected mothers to their newborns is critical to HBV control and eventual eradication. Mother-to-child perinatal transmission causes the highest chronic carrier rate (>85%) with a high rate of subsequent chronic liver disease and hepatocellular carcinoma. This risk is reduced by 90% with HBV vaccine given along with hepatitis B immune globulin (HBIG) starting at birth. New analyses of our data from US trials of HBIG and HBV vaccine in high-risk infants revealed better efficacy with yeast-recombinant vaccine than plasma-derived vaccine, especially in preventing late onset infections, with evidence that vaccine prevented transmission of maternal HBV infection with the glycine to arginine mutation in surface antigen codon 145 (sG145R). Most late infections with sG145R were in vaccine non-responders, suggesting escape from HBIG rather than from vaccine-induced antibody. Our findings also help explain survey results from Taiwan following universal childhood immunization implemented in the mid-1980s. We conclude that current vaccines will remain effective against surface antigen mutants. Anti-viral drugs in high-risk pregnant women, in combination with newborn HBIG and vaccine, show promise for eliminating residual breakthrough neonatal infections, critical to meeting WHO 2030 goals and for eradicating HBV.

RJ Prineas,1 SG Fraser,2 CE Stevens31Division of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, USA; 2Sunderland Eye Infirmary, Sunderland, UK; 3Department of Epidemiology, New York Blood Center, New York, NY, USAThe case report has a secure place in medical reporting and medical history stretching back to hand-written manuscripts, early medical texts, and earliest medical scientific publications. As scientific methods took hold, fewer case histories were accepted for publication, being replaced by case series and then analyses from epidemiologic studies, clinical trials (controlled and otherwise), and reports of laboratory clinical practice. Clinicopathology conferences around reporting and presentation of separate cases continue to be convened for regular meetings in hospitals and medical schools for teaching purposes. Case reports appear regularly in sections of medical journals or, more recently, as separate journals devoted entirely to them. Further, open-access case report journals have increased in number markedly in the past decade in parallel with International Medical Case Reports Journal (IMCRJ) submissions.1Since the beginning of the publication, the number of journal articles published in IMCRJ has increased steadily from 3 in the inauguration year (2008) to 69 in the latest full year of publication (Table 1), indicating the growing interest in disseminating such reports.The Journal, established by Dove Press, started publishing in 2008. During the first 8 years (until July 2016), published reports came from 50 separate countries (including articles from Africa, Asia, Europe UK, and USA). Sixty one percent of submitted reports (235/387) have been published, and 152 reports were rejected.The number of “reviewers” for each report ranged from 2 to 6, with an average of 3. The 3 leading countries submitting articles were the United States, Japan, and Turkey. Most papers have come from a single author or group, but 29 author groups submitted 2 or more reports and one group has submitted 6.

Sustained hematopoiesis after double-unit cord blood transplantation (dCBT) is mediated by 1 unit in nearly all patients. To investigate the associations between nondominant unit characteristics and neutrophil engraftment, we studied 129 consecutive myeloablative dCBT recipients. Ninety-five percent (95% confidence interval, 90 to 98) of patients engrafted. Detection of the nondominant unit 21 to 28 days after dCBT was not associated with improved neutrophil engraftment. In univariate analyses, nondominant unit characteristics (infused total nucleated cell [TNC] and viable CD3(+) cell doses) were significantly associated with speed and success of neutrophil engraftment as were dominant unit characteristics (infused TNC; viable CD34(+), viable CD3(+), and viable CD3-56(+)16(+) cell doses; and post-thaw CD34(+) cell viability). In multivariate analysis, higher infused TNC dose of the nondominant unit was independently associated with improved neutrophil engraftment, even when this unit did not contribute to donor hematopoiesis. In further subgroup analysis, this association was only evident when the infused viable CD34(+) cell dose of the dominant unit was low (<1.20 × 10(5)/kg). These findings suggest nondominant units mediate a dose-dependent facilitation of engraftment in myeloablative dCBT and support continued investigation of dCBT biology and the clinical practice of dCBT in adults in whom low cell dose grafts are common.

We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34(+) cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34(+) cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34(+) cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34(+) cell counts (r(2) = 0.73). Median CD34(+) cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34(+) cell viability was 92%, 33 (8%) units had <75% viableCD34(+) cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0mLwere more likely to have poor postthaw viability. Precryopreservation CD34(+) cell dose and banking practices should be incorporated into CB unit selection.

During pregnancy women can develop B- and T-cell immunity against the inherited paternal antigens (IPAs) of the fetus, such as HLA, peptides of minor histocompatibilty antigens, and possibly onco-fetal antigens. The biological and pathological role of these pregnancy-induced immunological events is only understood in part. However, anti-IPA immunity in the mother persists for many decades after delivery and may reduce relapse in offspring with leukemia after HLA-haploidentical transplantation of maternal hematopoietic stem cells (HSC). We hypothesized that maternal anti-IPA immune elements cross the placenta and might confer a potent graft-versus-leukemia effect when cord blood (CB) is used in unrelated HSC transplantation. In a retrospective study of single-unit CB recipients with all grafts provided by the New York Blood Center, we show that patients with acute myeloid or lymphoblastic leukemia ( n = 845) who shared one or more HLA-A, -B, or -DRB1 antigens with their CB donor's IPAs had a significant decrease in leukemic relapse posttransplantation [hazard ratio (HR) = 0.38, P < 0.001] compared with those that did not. Remarkably, relapse reduction in patients receiving CB with one HLA mismatch (HR = 0.15, P < 0.001) was not associated with an increased risk of severe acute graft-versus-host disease (HR = 1.43, P = 0.730). Our findings may explain the unexpected low relapse rate after CB transplantation, open new avenues in the study of leukemic relapse after HSC transplantation (possibly of malignancies in general), and have practical implications for CB unit selection.

Delayed or failed engraftment is a concern after CBT, even when using double unit grafts. Therefore, we analyzed the ability of the day 21 bone marrow (BM) composition and percent donor chimerism to predict sustained donor neutrophil engraftment in 56 recipients of myeloablative double unit CBT. Patients (median age 29 years, range 2-64) were transplanted for hematological malignancies, predominantly acute leukemia. Units had infused cell doses of 2.7 × 107 TNC/kg/ 1.2 × 105 CD34+ cells/kg for the larger unit, and 1.9 × 107 TNC/kg/ 0.7 × 105 CD34+ cells/kg for the smaller unit, with a donor-recipient HLA-match of 6/6 (n3), 5/6 (n59), and 4/6 (n50). The cumulative incidence (CI) of neutrophil engraftment was 95% (95% confidence interval: 89-100), with 47 patients engrafting with 1 unit and 6 engrafting with 2. The percentage of total myeloid precursors in the day 21 BM aspirate (median 40%, range 0-87), and the percent cellularity in the day 21 BM biopsy (median 5%, range 0-80), were both associated with neutrophil engraftment (Table 1). However, the most critical predictor of engraftment was the percent total donor chimerism (unit#1 + unit#2, median 100%, range 65-100), regardless if 1 or 2 units were present (Table 1). Sustained engraftment was seen in 98% of the 41 patients who were 100% donor at day 21 with a median day to absolute neutrophil count (ANC) ≥ 0.5 of 22 days. By contrast, only 87% of the 15 patients < 100% total donor engrafted [median day to ANC ≥ 0.5 31 days with a relative risk (RR) 0.3, p = 0.001]. Patients who were < 90% donor had especially poor engraftment (Table 1). The association between total donor chimerism and engraftment was independent of the percentage of myeloid precursors or BM cellularity. In patients (n = 37) without engraftment by day 21, a sub-group of particular clinical concern, day 21 total donor chimerism was also significantly associated with subsequent engraftment success (p = 0.003). No patient demographic was associated with total donor chimerism, and the only significant graft characteristic was the infused CFU dose of the engrafting unit (p = 0.002). These findings demonstrate the critical importance of the day 21 BM total donor chimerism and are of practical significance in the care of double unit CBT recipients. Further, they give interesting insights into double unit biology and suggest that the hematopoietic potential of the engrafting unit underlies the ability to generate complete donor chimerism.Table 1Cumulative incidence (CI) of neutrophil engraftment and median day to ANC >0.5 according to day 21 bone marrow composition and chimerism (n = 56).Day 21 BMCharacteristicCI Engraftment by BM Characteristic Sub-group (Day ANC ≥ 0.5) (RR , p value)P Valuefor CIComparison% Total Myeloid Precursors in Aspirate (n=56)<10% (n=18)95% (27 days)(RR 0.44, p=0.017)10-50% (n=18)89% (27 days)(RR 0.47, p=0.028)>50% (n=20)100%(22 days)Reference0.017% Cellularity in Core (n=56)<5% (n=21)91% (30 days)(RR 0.39, p=0.005)5-9% (n=15)100% (27 days)(RR 0.83, p=0.596)>10% (n=20)95%(21 days)Reference0.005% Total Donor Chimerism (n=56)<90% (n=6)67% (38 days)(RR 0.16, p=0.001)90-99% (n=9)100% (29 days)(RR 0.42, p=0.026)100% (n=41)98% (22 days)Reference0.001 Open table in a new tab

Measuring patient satisfaction in the outpatient clinic of one of the largest stem cell transplant centers in the country is important to ongoing improvement of the program. It is also a key activity of clinical administrative staff in their quest to improve clinic functions. Nursing leaders in the Stem Cell Transplant Outpatient Clinic identified and measured three targeted patient satisfaction areas, and based on their findings, implemented changes. The focus areas included phone communication, continuity of care, and "wait times". A patient survey process and questions were developed. Survey questions included items about ease of contacting clinic staff, how long they were placed on hold, and if staff returned calls. Patients were asked if they knew their team, were informed of tests, and received consistent information. They were also surveyed about length of wait times and time from arrival to seeing their physician, perceptions of acceptable wait times and whether they were kept informed. Over 100 patients have been surveyed at 6-month intervals with return rates exceeding 80%. Based on survey findings in these areas, improvements were made including installation of a new phone system, voicemail guidelines, a team member sheet, and revision of education materials. Measurement and evaluation of patient satisfaction continues to be an important role for the SCT leaders. Utilizing the survey process, the team is able to review results and implement action plans for improvement. Staff involvement has been key to the success of this process. Discussion of results, action plans, and outcomes are done at staff meetings. Continual follow-up and evaluation are necessary to assure improvements are sustained. The findings and improvements made by the SCT leadership team may be useful to other nurse leaders and staff in their efforts to improve patient satisfaction, a key component to the success of the SCT journey.

Both total nucleated cell (TNC) dose and human leukocyte antigen (HLA)-match affect the outcome of cord blood (CB) transplantation. However, how to prioritize these characteristics in unit selection is not established. Therefore, we analyzed the outcomes of 1061 patients who received single-unit myeloablative CB transplantation for leukemia or myelodysplasia. TNC dose and HLA-match each affected survival via their effect on transplant-related mortality (TRM); neither was associated with relapse. Therefore, TRM was the focus of multivariate analyses combining dose and HLA-match. Compared with our 1 HLA-mismatch (MM) reference group with TNC 2.5 to 4.9 x 10(7)/kg, recipients of 0 MM units had the lowest TRM regardless of dose (relative risk [RR] = 0.4, P = .019). TRM for recipients of 1- or 2-MM units with TNC 5.0 x 10(7)/kg or greater was similar to the reference group (RR = 0.8, P = .391 and RR = 1.0, P = .847) despite their greater dose. Recipients of 2 MM units with TNC 2.5 to 4.9 x 10(7)/kg had a greater TRM (RR = 1.5, P = .014), and those with 1 or 2 MM and TNC less than 2.5 x 10(7)/kg or 3 MM did substantially worse. These findings support new unit selection criteria that take into account both TNC dose and HLA-match and have important implications for the size of the global CB inventory needed to find an optimum CB graft.

Cord blood (CB) hematopoietic stem cell transplantation can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result from tolerance-inducing events during pregnancy but to date this concept has not been tested in CB transplantation. Hence we analyzed the impact of fetal exposure to noninherited maternal antigens (NIMA) of the HLA-A, -B antigens, or -DRB1 alleles on the outcome of CB transplants. The 1,121 patients studied were transplanted for hematological malignancy with a single CB unit: 1,059 received grafts mismatched for one or two HLA antigens. Of these patients, 79 patients had a mismatched antigen that was identical to a donor NIMA, 25 with one HLA mismatch (MM), and 54 with two. If there was a NIMA match, transplant-related mortality (TRM) was improved, especially in patients ≥10 years ( P = 0.012) as were overall mortality and treatment failure ( P = 0.022 and 0.020, respectively, in the older subset), perhaps related to improved neutrophil recovery, especially in patients who received a low total nucleated cell (TNC) dose ( P = 0.031). Posttransplant relapse rate also tended to be reduced, especially in patients with myelogenous malignancies given units with a single HLA mismatch ( P = 0.074). These findings represent unique evidence that donor exposure to NIMA can improve survival in unrelated CB transplantation and might reduce relapse, indicating that cord blood cells can mount an antileukemic effect. By matching for donor NIMAs in search algorithms of CB inventories, the probability of selecting a graft with an optimal outcome will increase significantly.

Abstract Abstract 661 CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365 Disclosures: No relevant conflicts of interest to declare.

BACKGROUND: Human cord blood (CB) units donated for transplantation require testing for various markers in blood and plasma aliquots. Although the identity link between the CB unit and the labeled aliquots with the same identifiers can be confirmed by HLA‐DNA assays, these methods have not been used for CB plasma. We have previously reported that viral DNA sequences are present in the CB plasma of carrier babies and now hypothesize that human genomic DNA may also be present in CB plasma.

Cryopreserved, banked CB is being increasingly used for allogeneic bone marrow reconstitution of unrelated transplant recipients. The effect of long-term storage on the viability and function of CB hematopoietic stem cells has been addressed only with in vitro assays and immunodeficient mouse models (Broxmeyer et al, PNAS 2003; 100:645–50), but not in clinical transplantation. To evaluate the quality of CB units after prolonged storage in liquid nitrogen freezers, we compared the transplantation outcomes of patients that received CB grafts from the New York Blood Center NCBP stored for 8 years or more (Group 1, N=43, median time from unit collection to transplant: 9.2 years) to those transplanted with units stored < 2 years (Group 2, N=300, median time: 1.1 years). Patients were included in the study if they were transplanted in the period 2001–2006, received a single or double unexpanded unit graft and had no prior transplant in the 6 months preceding the CB graft. Double unit recipients were evaluated if the unit of interest was the one that engrafted, as demonstrated by post-transplant chimerism studies. The two groups were similar with respect to disease category (malignant diseases: 74% in Group 1, 69% in Group 2), location of transplant center (transplant in the US: 60% and 68%, respectively), use of non-myeloablative regimens (19% and 12%, respectively) and double unit transplants (14% and 10%, respectively). More patients in Group 1 were adults (42% and 27%, respectively, p = 0.035). Detailed information on CB thawing was available for all units in Group 1 and 217 in Group 2. Two units of the first Group and 3 of the second were reported to have problems at thawing (clots/leak). No immediate post-infusion complications were reported. Post-transplant ANC recovery was at a median of 25 days in Group 1 and 22 days in Group 2 (multivariate RR = 0.9, p = 0.6). Among patients who survived for 28 days or longer, 8/36 in Group 1 and 42/260 in Group 2 failed to achieve ANC500 (p = 0.3). Overall survival was not different in the two Groups (both 49% at 5 years). These results indicate that “old” CB units can be used effectively in clinical transplantation. Therefore, long-term cryopreservation of CB stem cells is feasible without compromising the quality and engraftment ability of the CB units, supporting the creation of a National Cord Blood Inventory with high quality units. However, these findings need to be viewed with caution: cryopreservation and storage procedures, equipment and devices vary significantly among different Banks. Thus, the results of the NCBP may not apply to all Cord Blood Banks.

Background: Banked CB is an effective source of hematopoietic stem cells for allogeneic bone marrow reconstitution. Critical indices of engraftment potential and quality of a CB graft are the nucleated cell dose, CD34 + cell content and total CFU. Determination of CD34 + cell viability by flow cytometry depends on 7-actinomicin D (7-AAD) exclusion, but its diffusion into cells depends on permeability of the cell membrane. Earlier stages of the death pathway (apoptosis) escape detection by 7-AAD. Aims of our study: to establish a sensitive method for detection of early apoptosis in CB cells and to evaluate their ultrastructural morphology, to determine the extent to which early apoptosis may disclose reduced functionality of CD34 + and CD3 + cells and therefore, whether early apoptosis should be investigated routinely in CB grafts before transplantation and to investigate the presence and degree of apoptosis in CD34 + and CD3 + cells upon CB storage at RT and after cryopreservation/thawing, as well as the effect of post-thaw DMSO removal. Results: After CB storage over 48 hrs, evaluation by multiparameter flow cytometry with the mitochondrial potential (MP) marker DILC, Annexin V, 7-AAD and surface cell markers, identified 3 populations with decreasing MP and negative 7-AAD: 1. DILC with high MP (MP High )/Annexin(−); 2. DILC with intermediate MP (MP Interm )/Annexin(−) and 3. MP Interm /Annexin(+). Groups were sorted for CD3 + and CD34 + cells, ultrastructural morphology was evaluated by electron microscopy (EM) and their function by culture with Phytohemaglutinin/IL-2 (PHA) for CD3 + and by CFU assay for CD34 + cells. EM revealed lymphocyte shrinkage, nuclei with condensed chromatin and polarized clusters of organelles, findings suggestive of early stages of apoptosis. In addition, CD3 + cells with MP High had higher stimulation than those with MP Interm and impaired more when cells became Annexin(+) (ratio MP High /MP Interm =54; p + cells with MP High showed higher CFU than those with MP Interm /Annexin(−) and those with Annexin(+), (CFU ratio MP High /MP Interm = 17.7 and 35.6 respectively, p + and CD34 + cells upon CB storage over 48hrs and after cryopreservation/thawing showed decreased CD3 + cell viability (p + cells (range 37–79%). In contrast, there were no significant variations in viability or function of CD34 + cells after cryopreservation/thawing. Thawed cells with DMSO dilution down to 2% concentration or DMSO removal (Dextran/Albumin wash) effected no significant change in viability or function. Summary: CB cells with decreased mitochondrial potential have impaired function and morphological characteristics of early apoptosis; A combination of 7-AAD with a marker of mitochondrial potential (DILC) allows for the detection of early apoptotic cells which are not detected by 7-AAD; CB-lymphocytes have immature appearance by ultrastructural morphology compared to those of adult peripheral blood; Viability and function of CB-CD34 + cells were not significantly reduced by cryopreservation/thawing but those of CD3 cells were. Lower viability and decreased function of CB-CD3 cells may affect the immunological interactions in double or multiple CB transplants as well as clonal expansion post-transplant.

Background: Engraftment and survival in cord blood transplantation is affected by total nucleated cell (TNC) dose and HLA match grade. Thus, patients need assess to more cord blood units (CBUs) to provide for better matches and higher cell dose.Purpose: To examine the effect of HLA match grade and direction of mistmatch on outcome of cord blood transplantation with the aim to improve match algorithms and cord blood unit selection strategies. To apply the match algorithms in an empirical analysis of the chance of finding a CBU match by match grade, taking into account inventory size and donor ethnic background.Materials and Methods: Engraftment, GvHD, relapse, TRM and overall survival was evaluated in 1511 recipients of single CBU from the NYBC National Cord Blood Program transplanted through June 2005 (data available on 91% of eligible patients). The empirical chance of finding a full or 1 antigen mismatch (HLA-A, B at intermediate level and DRB1 at high resolution ) CBU was assessed for 14,378 patients on an inventory 25,917 CBUs from ethnically diverse donors (16.5% African-American, 17.0% Hispanic, 6.6% Asian, 50.4% Caucasian and 9.6% mixed).Results: HLA match grade correlated with engraftment, GvHD, relapse, TRM and overall survival, independent of the effect of TNC dose and other contributing factors. TNC dose/kg patient body weight (range 0.7 to >10.0 x 10^7/kg) did not affect outcome in fully matched CBU grafts. A two-fold increase in TNC dose, on average, was required to overcome differences in TRM and survival for 2 antigen mismatched grafts compared to 1 mismatch. Unidirectional mismatches in GvHD direction only (CBU homozygous at the mismatched loci) provided engraftment, TRM and survival rates that were the same as fully matched grafts, also with no apparent relationship to TNC dose. Patients with leukemia given CBU grafts with a GvHD only ismatch had a relapse rate that was the same at that of fully matched CBUs, whereas those with rejection only mismatches had a significantly higher relpase rate. In the empirical analysis of the chance of finding a match, including mismatch direction, 10.6% of patients could find a full match in an ethnically diverse CBU inventory. Including CBUs with 1 or 2 antigen mismatches only in the GvHD direction more than doubled the chance of finding a "good" match. The chance of finding a match or a CBU with 1 antigen mismatch correlated with patient ethnicity (patients had the best chance of finding a good match within their own ethnic group). African-American patients were the least likely of any group to find a suitable CBU (more than 5-fold less likely than Caucasions to find a full match), in part, because of their smaller numbers in the inventory and, in part, because of their greater HLA diversity. Increasing inventory size increased the chance of finding a full or 1 antigen matched CBU for all ethnic groups, but the improvement diminished progressively.Conclusions: HLA match level, including direction of mismatches, was associated with success of CBU transplantation. As with marrow donor registries, improvement in the probability of matching requires a progressively larger inventory size and depends on the donor ethnic diversity. Quantitatively larger number of donors are required for ethnic minority patients. Thus, the US National Cord Blood Inventory (planned for 150,000 new, high quality CBUs) should be enriched with ethnical diverse donors in order to meet the needs of ethnic minority patients who lack an HLA identical sibling donor.

This study assessed the incidence of cytomegalovirus (CMV) infection after transplantation of cord blood (CB) from unrelated donors and evaluated strategies for screening CB donors. Posttransplantation CMV infection, reported in 23% of 1221 CB recipients, was associated with patient pretransplantation CMV serology (P < .001), but not with CMV serology in CB donors or their mothers. A total of 26 988 infant CB donors were evaluated by viral culture of saliva. Subgroups were evaluated by polymerase chain reaction in CB (CB-PCR) in 2 case-control studies. In the first study, 33 of 47 saliva culture-positive CB donors were confirmed by CB-PCR. All mothers of the 33 infants with confirmed CMV infection were CMV-total antibody positive, but only 1 of 3 had CMV-IgM antibody. The second study evaluated infants born to mothers with CMV-IgM antibody. Of these, 5 of 170 saliva culture-negative infants were positive by CB-PCR. The incidence of congenital CMV infection in CB donors was low (0.12%). Maternal serology had poor predictive value for CMV infection in their infant CB donors and bore no detected relationship to CMV infection in CB recipients. Saliva culture for CMV had both false-positive and -negative results. CB-PCR was a useful alternative for detecting CMV in CB donors.

Experience with unrelated allogeneic UCB stem cell transplantation in the non-myeloablative setting is limited because of concerns of graft failure due to limited cell content. Dual UCB graft infusion has been explored to overcome cell dose limitations, but influence on engraftment is unclear. This single institution phase I trial examined RIC followed by single UCB transplantation for patients unable to tolerate fully myeloablative regimens and lacking a matched adult donor. Conditioning consisted of TBI 200 cGy, fludarabine 175 mg/m², cyclophosphamide 2 gm/m², ATG 60 mg/kg. Trial design specified selection of UCB grafts to be matched at 4/6 HLA loci or better with one unit infused if cryopreserved nucleated cell dose exceeded 2.5 x 107/kg recipient weight. If no adequate single UCB unit to meet these criteria was available, study patients received 2 UCB units containing a combined cell dose exceeding 1.5 x 107/kg. Grafts were analyzed via flow cytometry post thaw for stem cell and lymphocyte expression of surface antigens, among them CD4, CD8, CD7, CD34, CD38, CD45RA, CD45RO. 23 patients have been enrolled, the majority diagnosed with AML (n=17). Median age was 47 (range 25–68) years. Single UCB units meeting stated criteria were identified for all but one study patient, who was excluded from graft analysis. The time to engraftment was measured from the date of transplantation to the date of 3 successive days ANC≥500/μL attained. In addition, we assessed time to peripheral blood donor lymphocyte chimerism ≥ 60%. Patients were censored at the date of last follow-up or the date of death. 94% (95%CI: 77-.99%) of patients achieved ANC≥500/μL by T+36 with median of 26.5 ( range 11–55) days. 68% (95%CI: 48–85%) of patients (n=15) achieved >60% donor derived chimerism by median of 22 (range 14–35) days. Median cryopreserved and infused total nucleated cell dose was 2.85 x 107 and 2.5 x 107 cells/kg, respectively. Median infused CD34 cell dose was 1.71 (range 0.21–5.39) x 105 cells/kg. By univariate analysis the dose of infused UCB graft T-cells including CD4 and CD8 T-cells co-expressing CD45RO, and CD34 stem cells co-expressing CD7 and CD38 correlated with neutrophil recovery, p=0.046, 0.008, and 0.033, respectively. Median overall survival at this early interim analysis has not been reached; with 86% and 65% survival at 3 and 24 months, respectively. Event free survival is 78% and 44.5% at 3 and 24 months, respectively. In summary, in this heavily pretreated group of advanced age patients, RIC and single unit unrelated allogeneic UCB stem cell transplantation is safe. Identification of a single UCB graft of HLA match 4/6 meeting cell dose requirement 2.5x107/kg is identified in the vast majority of full size adult patients. Engraftment and survival rates are higher than reported in single UCB transplants following administration of myeloablative regimens and similar to recent reports for RIC with double UCB graft infusion. The potential benefit of infusion of 1 vs. 2 UCB units after RIC in adult patients remains to be fully evaluated.

Purpose To describe outcomes after unrelated donor stem cell transplantation (HCT) in children (< 18 months at diagnosis) with acute leukemia and compare these with outcomes after human leukocyte antigen (HLA)-matched sibling donor HCT. Patients and Methods We compared the results of unrelated donor HCT with bone marrow (n = 85) or cord blood grafts (n = 81) and HLA-matched sibling donor HCT with bone marrow grafts (n = 101) for acute myeloid or acute lymphoblastic leukemia using Cox proportional hazards models. Unrelated donor HCT recipients were younger, more likely to have MLL gene rearrangement, to have advanced leukemia, and to receive irradiation before HCT. Results Treatment-related mortality rates were 6%, 15%, and 31% after matched sibling, unrelated donor bone marrow, and cord blood HCT, respectively. Risks of relapse, overall and leukemia-free survival were significantly associated with disease status at transplantation. Though leukemia recurrence was lowest after unrelated donor HCT in first clinical remission (CR), overall survival, and leukemia-free survival rates were similar after matched sibling and unrelated donor HCT, after adjustment for disease status. Relapse, overall and leukemia-free survival did not differ by graft type (bone marrow v cord blood) or type of leukemia. Three-year probabilities of leukemia-free survival were 49% and 54% after HLA-matched sibling and unrelated donor transplantation in first CR, respectively. Corresponding rates for those with advanced leukemia were 20% and 30%. Conclusion Unrelated donor HCT should be considered for infants with acute leukemia in first CR using the same eligibility criteria as are currently used for those with HLA matched sibling donors.

With the recognition of the critical importance of UCB cell dose upon hematopoietic recovery, neutrophil recovery after UCB transplantation (UCBT) has improved. However, TRM in the early post-engraftment period (days 30–180) remains a barrier to transplant success. Therefore, how graft characteristics impact upon the risk for TRM during this period is important but has not been well characterized. Therefore, we analyzed the impact of cell dose and HLA-match upon TRM between days 30–180 in recipients of single unit 3–6/6 HLA-A,B antigen and DRB1-allele matched UCBT who were transplanted for leukemia or myelodysplasia with units from the NYBC’s National Cord Blood Program and achieved sustained donor engraftment. Patients dying from days 0 to 29 or those with primary or secondary graft failure were excluded, and patients were censored at the time of relapse. 608 patients fulfilled study criteria and had a median age of 9.0 years (range 0.4–58 years). The cumulative incidence of TRM was 36% (95%CI: 32–39). Using 2.5–4.9 x 107 TNC/kg as the reference (n = 229), the impact of cell dose was analyzed. While patients (n = 141) receiving a lower dose of 0.7–2.4 had a relative risk (RR) of TRM of 1.5 (p = 0.009) during this period, TRM in patients receiving higher doses were similar to the reference [5.0–9.9 (n = 160) RR 0.9, p = 0.4; and ≥ 10.0 (n = 78) RR 0.8, p = 0.4)]. However, HLA-match had an impact upon TRM at all levels of match [reference: 5/6 recipients (n = 194); 6/6 (n = 32) RR 0.3, p = 0.063; 4/6 (n = 342) RR 1.7, p = 0.001; and 3/6 (n = 40) RR 2.2, p = 0.003]. To exclude the possibility that disease stage accounted for this finding, a multivariate Cox regression analysis was performed including TNC dose, HLA-match and disease stage, and showed that low dose and HLA-mismatch remained the significant predictors of TRM. Further, when patients were divided into those without significant aGVHD (only grade 0 or 1) (n = 292) vs patients with grade 2–4 aGVHD (n = 301), the effect of HLA-match on TRM was most pronounced in those without significant aGVHD [reference: 5/6 recipients (n = 102); 6/6 (n = 25) RR 0.0, p = NS; 4/6 (n = 151) RR 2.4, p = 0.004; 3/6 (n = 14) RR 2.8, p = 0.050]. Of the transplant-related deaths (n = 60) from days 30–180 in this “without significant aGVHD” group, infection was reported to be a major cause of death in 36 (60%). In summary, above the threshold of 2.5 x 107 TNC/kg, cell dose has no demonstrable effect on the risk for day 180 TRM in the post-engraftment period, whereas the adverse impact of HLA-mismatch is both striking and retained even in the absence of aGVHD. We postulate that the adverse effect of HLA-mismatch is mediated not only by induction of aGVHD, but also by an effect on immune reconstitution as manifested by death from infection. This data has significant implications for graft selection implying that both dose and HLA-match should be considered, and investigation of how to “trade-off” each of these factors should be a priority. Further, it argues that recipients of HLA-mismatched grafts will require aggressive supportive care and strategies to augment immune reconstitution. Finally, improved outcome in UCBT may be dependent upon the ability to obtain units that are both of sufficient size and match which will require an increase in the global UCB inventory.

BACKGROUND:Data regarding the outcome of cord-blood transplantation in adults are scant, despite the fact that these grafts are increasingly used in adults. METHODS:We compared the outcomes of the transplantation of hematopoietic stem cells from unrelated donors in adults with leukemia who had received cord blood that was mismatched for one HLA antigen (34 patients) or two antigens (116 patients), bone marrow that had one HLA mismatch (83 patients), and HLA-matched bone marrow (367 patients). We used Cox proportional-hazards models to analyze the data. RESULTS:Cord-blood recipients were younger and more likely to have advanced leukemia than were bone marrow recipients, and they received lower doses of nucleated cells. Hematopoietic recovery was slower with transplantation of mismatched bone marrow and cord blood than with matched marrow transplantations. Acute graft-versus-host disease (GVHD) was more likely to occur after mismatched marrow transplantation, and chronic GVHD was more likely to occur after cord-blood transplantation. The rates of treatment-related mortality, treatment failure, and overall mortality were lowest among patients who received matched marrow transplants. Patients who received mismatched bone marrow transplants and those who received mismatched cord-blood transplants had similar rates of treatment-related mortality (P=0.96), treatment failure (P=0.69), and overall mortality (P=0.62). There were no differences in the rate of recurrence of leukemia among the groups. There were no differences in outcome after cord-blood transplantation between patients with one HLA mismatch and those with two HLA mismatches. CONCLUSIONS:HLA-mismatched cord blood should be considered an acceptable source of hematopoietic stem-cell grafts for adults in the absence of an HLA-matched adult donor.