Unit Cord Blood Transplantation Research Articles

Cord blood transplantation for AML: Comparable LFS in patients with de novo versus secondary AML in CR1, an ALWP/EBMT study.

We investigated whether secondary versus de novo acute myeloid leukaemia (AML) would be associated with poor outcomes in adult acute AML patients in first complete remission (CR1) receiving unrelated cord blood transplantation (CBT). This is a retrospective study from the acute leukaemia working party of the European Society for Blood and Marrow Transplantation. Inclusion criteria included adult at first allogeneic haematopoietic cell transplantation between 2000 and 2021, unrelated single or double unit CBT, AML in CR1, no ex vivo T-cell depletion and no post-transplant cyclophosphamide. The primary end-point of the study was leukaemia-free survival (LFS). A total of 879 patients with de novo (n = 696) or secondary (n = 183) AML met the inclusion criteria. In multivariable analyses, sAML patients had non-significantly different LFS (HR = 0.98, p = 0.86), overall survival (HR = 1.07, p = 0.58), relapse incidence (HR = 0.74, p = 0.09) and non-relapse mortality (HR = 1.26, p = 0.13) than those with de novo AML. Our results demonstrate non-significantly different LFS following CBT in adult patients with secondary versus de novo AML.

Abstract 15 A State-Run Public Cord Blood Collection Program

Abstract Introduction The Arizona Public Cord Blood Program was created in 2011 by the Arizona Biomedical Research Centre, a sub-section of the Arizona Department of Health Services, to advance the collection and increase the number of racially and ethnically diverse cord blood units available for transplantation, as well as promote awareness of the benefits of cord blood stem cells through our educational partner, Save the Cord Foundation (STCF). Objectives Create a sustainable program for women of all racial and ethnic backgrounds to have the opportunity to donate cord blood, with the primary goal of transplantation, and secondary goal of providing non-transplantable cord blood units for research. A second objective was to educate the residents of the state of Arizona about cord blood stem cells and the need for their preservation. Methods A portion of state lottery funds supports the program monetarily. Those funds are provided to four collection hospitals who employ "cord blood consenters" whose responsibility it is to consent patients, assist delivery providers with collections, and package and ship cord blood units to our partner cord blood bank at MD Anderson Cancer Center. There are also two clinical coordinators who educate and train hospital staff on quality collection practices, with special emphasis on the importance of high volume, sterile collections. STCF provides education across the state to expectant parents, healthcare providers, schools, and the public about the need for cord blood stem cell donation for transplant and research. Results Since 2011, the Arizona Public Cord Blood Program has banked hundreds of racially and ethnically diverse cord blood units with the National Marrow Donor Program, and has had 86 life-saving cord blood units matched with patients in need around the globe. This innovative program has not only expanded cord blood awareness and promoted the preservation of cord blood; it has resulted in the creation of an economic engine for the state of Arizona that is an attractant for STEM based businesses and careers. Discussion A decade later, the Arizona Public Cord Blood Program has proven to be a sustainable model for collecting and providing suitable cord blood units for transplant to diverse patient populations.

Abstract 33 A Diverse and Sustainable State-Run Public Cord Blood Program

IntroductionThe Arizona Public Cord Blood Program was created in 2011 by the Arizona Biomedical Research Centre, a subsection of the Arizona Department of Health Services, to advance the collection and increase the number of racially and ethnically diverse cord blood units available for transplantation, as well as to promote awareness of the benefits of cord blood stem cells through our educational partner, Save the Cord Foundation (STCF).ObjectiveThe main objective of this study was to create a sustainable program for women of all racial and ethnic backgrounds to have the opportunity to donate cord blood, with the primary goal of transplantation and the secondary goal of providing non-transplantable cord blood units for research. A second objective was to educate the residents of the state of Arizona about cord blood stem cells and the need for their preservation.MethodsA portion of state lottery funds support the program monetarily. Those funds are provided to four partner collection hospitals employing "cord blood consenters," whose responsibility it is to consent patients, assist delivery providers with collections, and package and ship cord blood units to our partner cord blood bank at MD Anderson Cancer Center. There are also two clinical coordinators who educate and train hospital staff on quality collection practices, with special emphasis on the importance of high-volume, sterile collections. STCF provides education across the state to expectant parents, health care providers, schools, and the public about the need for cord blood stem cell donation for transplant and research.ResultsSince 2011, the Arizona Public Cord Blood Program has banked several hundreds of racially and ethnically diverse cord blood units with the National Marrow Donor Program (Figure 1) and has had 80 life-saving cord blood units matched with patients in need around the globe. This innovative program has expanded cord blood awareness and promoted the preservation of cord blood, and it also has resulted in the creation of an economic engine for the state of Arizona that is an attractant for STEM-based businesses and careers.Figure 1.Pie chart showing percentage of collections by race/ethnicity. Abbreviation: AI/AN, American Indian/Alaskan Native.DiscussionA decade later, the Arizona Public Cord Blood Program has proven to be a sustainable model for collecting and providing suitable cord blood units for transplant to diverse patient populations.

Abstract 32 Low Incidence of Product Complaints and Adverse Events Support Safety of Cord Blood Units

IntroductionAs an important cellular therapy source for many patients, the safe and timely delivery of cord blood units (CBU) is paramount. The National Marrow Donor Program (NMDP) investigates product complaints received for CBUs distributed under the 10-CBA investigational new drug application that may impact the safety, quality, identity, purity, or potency of the product. NMDP also receives reports of any patient adverse events or serious complications resulting from the transplantation of CBUs. Information on product complaints and adverse events provides insight into areas related to product integrity, patient safety, and customer satisfaction and highlights opportunities for improvement.ObjectiveWe analyzed all product complaints and adverse events reports submitted to NMDP for CBUs distributed under the NMDP 2010 Cord Blood Access Protocol (10-CBA) from October 2019 through March 2022. These investigations offer visibility into factors associated with product quality and integrity discovered after shipment.MethodsA total of 1,578 CBUs from 38 cord blood banks were shipped from October 2019 through March 2022 (30 months). Data on CBU product complaints reported to NMDP were compiled and analyzed. Data were grouped into categories based upon the primary reason for the product complaint or adverse event. The outcome of NMDP investigations and resolutions is relayed quarterly to the Quality Subgroup of the Cord Blood Advisory Group.ResultsOf the 1,578 CBUs shipped between October 2019 and March 2022, 98% had no reported incidents (32 reports of product complaints and 4 of adverse events). The most common reasons for product complaints investigated by NMDP were related to shipping/transportation (n = 15, 47%), quality issues such as lower than expected potency or bag breaks (n = 11, 34%), and labeling errors (n = 3, 9%). Three of the four adverse events were associated with infusion (two hypertensive episodes and one anaphylaxis) and one was a secondary cancer following transplant.DiscussionTransplant centers report very few quality incidents, product complaints, or adverse events when using cord blood units. We remain vigilant for opportunities to improve. Clinicians and patients can be assured that CBUs are a safe product with high likelihood of arriving to the transplant center without incident or causing adverse events once transplanted.

Primary graft failure, but not relapse, may be identified by early chimerism following double cord blood unit transplantation

AbstractUmbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double umbilical cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism after RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage-specific chimerism after DUCBT in adult patients with hematologic malignancies in the United Kingdom. Fifty-eight patients with a median age of 52 years were recruited, with overall and progression-free survivals of 59% (95% confidence interval [CI], 45%-71%) and 52% (95% CI, 39%-64%), respectively, at 2 years. Nonrelapse mortality was 4% (95% CI, 1%-13%) at day 100, and the relapse rate was 31% (95% CI, 21%-45%) at 1 year. Peripheral blood lineage-specific chimerism was feasible from day 7 after transplant onward. Five patterns of chimerism were observed including (1) complete single unit dominance (39 patients), (2) sustained donor-donor mixed chimerism (3 patients), (3) sustained donor-recipient mixed chimerism (5 patients), (4) dominance reversion (1 patient), and (5) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematologic malignancies to safely access UCBT in the United Kingdom and provided novel insights into the kinetics of donor and recipient chimerism after RIC DUCBT that are clinically relevant. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003845-41/GB as #NCT00959231 and EudraCT 2004-003845-41.

Optimizing selection of double cord blood units for transplantation of adult patients with malignant diseases.

Double-unit unrelated cord blood transplantation (DUCBT) is an option in patients for whom a single unit is not sufficient to provide an adequate number of cells. As current guidelines on UCB unit selection are mainly based on single-unit UCB data, we performed a retrospective analysis of 1375 adult recipients of DUCBT for hematologic malignancies to determine optimal criteria for graft selection. Cryopreserved total nucleated cells (TNCs; ≤3.5 vs >3.5 × 107/kg: hazard ratio [HR], 1.53; 30% vs 45%; P = .01), number of HLA mismatches (≥2 vs 0-1: HR, 1.28; 42% vs 48%; P = .01), and ABO compatibility (minor/major ABO incompatibility vs compatibility: HR, 1.28; P = .04) were independent risk factors for OS. Cryopreserved CD34+ cell dose ≥0.7 × 105/kg in the winning UCB was associated with improved OS (HR, 1.34; P = .03). Low TNC (≤3.5 × 107/kg) and CD34+ (≤1.4 × 105/kg) cell doses were related to decreased neutrophil recovery (HR, 0.65 [P = .01] and HR, 0.81 [P = .01], respectively). DUCBT recipients with ≥2 HLA mismatches had a higher incidence of grade II-IV and III-IV acute graft-versus-host disease (HR, 1.26 [P = .03] and 1.59 [P = .02], respectively). Low TNC dose (HR, 1.57; P = .02) and receiving UCB with ≥2 HLA mismatches (HR, 1.35; P = .03) were associated with increased transplant-related mortality. Our data support selecting adequately HLA-matched UCB units with a double-unit cryopreserved TNC dose >3.5 × 107/kg and CD34+ cell dose of ≥0.7 × 105/kg per unit in DUCBT candidates.

Reducing ethnic disparity in access to high-quality HLA-matched cord blood units for transplantation: analysis of the Canadian Blood Services' Cord Blood Bank inventory.

Launched in 2013, Canadian Blood Services' Cord Blood Bank (CBS' CBB) has built a high-quality, ethnically diverse cord blood repository that aims to reduce ethnic disparity in accessing suitable units for transplantation. As of December 2016, 2000 units have been banked. The self-reported maternal ethnicity was 58% non-Caucasian. Overall, 26% of units were classified as multi-ethnicity with Caucasian (84%) most frequently observed in combination with Asian, First Nations (predominant indigenous peoples in Canada south of the Arctic Circle), or African ethnicity. Utilization scores that incorporate total nucleated and CD34+ cell counts in the CBS' CBB were associated with greater likelihood of utilization compared with the international inventory of units (p < 0.05). The distribution of utilization scores was similar for Caucasians compared with non-Caucasians (p < 0.05). Using HLA genotypes of cord blood units and their mothers, we determined probable ethnic assignments for each haplotype using HaploStats (National Marrow Donor Program). Significant increases in HLA-match likelihoods are predicted for all ethnicities as the inventory grows to its target of 10,000 units and the gap in HLA-match likelihoods for Caucasian and non-Caucasian patients progressively declines. The CBS' CBB inventory is predicted to have high HLA-matching likelihoods across a broad spectrum of ethnic groups, improving access to high-quality stem cell products for all patients.

Repurposing the public cord blood bank inventory in Korea to enhance cord blood use

To enhance public cord blood (CB) use, we examined the current status of CB banking and tried to suggest revision of the banking standard. We retrospectively analyzed the use of stored public CB units between 2011 and 2016 using data from the CB information center in Korea. A total of 19,871 CB units were registered, and 363 units were selected for transplantation. The transplanted CB units contained significantly higher numbers of CD34+ cells than the average numbers in the stored CB units (5.5 × 10^6 vs. 3.2 × 10^6, p < 0.01). They also contained more total nucleated cells (TNCs) than the average of the stored CB units (13.7 × 10^8 vs. 10.7 × 10^8, p < 0.01). Only 49% of the stored CB units contained>10 × 10^8 TNCs, while 81% of the units transplanted contained >10 × 10^8 TNCs. The average length of cryopreservation of the transplanted CB units was 4.58 years and 95% of them had been stored for less than 10 years. During the study period, 18,763 CB units were requested for research, but only 5,888 were released. This discrepancy was mostly due to errors in regulatory and/or networking elements of the CB supply system. The data suggest that preserving CB units for less than 10 years and increasing the required minimum TNC count to 10 × 10^8 would produce an inventory containing units that were more useful for CBT. CB units that did not meet the requisite quality standards could be used for research, and systems for their fair distribution to researchers are needed.

GVHD Prophylaxis Using Tacrolimus and Mini-Dose Methotrexate Improves Engraftment and Reduces Mortality in Cord Blood Transplantation

Background A combination of calcineurin inhibitor and methotrexate (MTX) is one of a standard GVHD prophylaxis in allogeneic hematopoietic stem cell transplantation. However, MTX delays engraftment particularly in cord blood transplantation (CBT). Methods We conducted a retrospective study to evaluate an efficacy of mini-dose of MTX as a GVHD prophylaxis in single unit CBT. We compared the clinical outcome of patients with hematological malignancies in our institution who received standard-dose MTX (St-MTX, 15 mg/m2 of MTX on day 1 and 10 mg/m2 on days 3 and 6) as a GVHD prophylaxis in CBT between 2004 and 2013 and those who received mini-dose MTX (Mini-MTX, 5 mg/m2 of MTX on days 1, 3 and 6) between 2013 and 2018. Results Thirty-two patients received St-MTX and 26 patients received Mini-MTX. There was no statistically significant difference between 2 groups except for patients’ age (St-MTX; 46.5 years, Mini-MTX; 55.0 years, P = 0.0215). Cumulative incidence of neutrophil engraftment was significantly higher in Mini-MTX group (St-MTX; 71.9 %, Mini-MTX; 96.2 %, P = 0.0157). Cumulative incidence of grade II to IV and grade III to IV of acute graft-versus-host disease (GVHD) were 34.4 % and 6.2 % in St-MTX group, and 34.6 % and 7.7 % in Mini-MTX group with no statistical significance. Day 180 non-relapse mortality (NRM) rate was significantly lower in Mini-MTX group compared to St-MTX group (25.0 % vs 3.8 %, P = 0.0279), whereas relapse rate was almost equivalent between these groups. Multivariate analysis also indicated that Mini-MTX significantly improved engraftment (HR, 0.1368; 95% CI, 0.01902 to 0.9841; P = 0.048), and reduced the risk of NRM (HR, 0.1234; 95% CI, 0.01624 to 0.9380; P = 0.043). Day 180 OS were 71.9 % in St-MTX group, and 88.5 % in Mini-MTX group (P = 0.121), and PFS were 62.5 % in St-MTX group, and 80.8 % in Mini-MTX group (P = 0.136). Conclusion Our study suggests that GVHD prophylaxis using mini-dose MTX is feasible and associated with improvement of engraftment and decrease of transplant-related complication early after CBT.

An Analysis of the Correlation between Gastro-Intestinal (GI) Symptoms, Macroscopic Appearance, Histology & Acute Gvhd (aGVHD) Treatment Responses in Cord Blood Transplant (CBT) Recipients: Significant Implications for aGVHD Management

Background GI symptoms are common after CBT & GI aGVHD is frequent. The correlation between symptoms, macroscopic appearance (macro), histology, aGVHD severity & therapy response, however, is not established. Methods We analyzed 1st endoscopies done days +21-180 in engrafted adult double unit CBT recipients transplanted 10/2009-12/2017 with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. All patients (pts) received fungal prophylaxis, early CMV pre-emptive therapy & C. difficile/ viral PCR stool assays (& blood for adenovirus) were routinely performed. Abnormal histology was defined as mild (grade 1-2) vs severe (grade 3-4). Results Of 156 pts, 88 pts (56%) [median 49 years (range 22-66), 65 leukemia, 5 MDS/ MPD, 18 NHL/ HL] were scoped. Their median donor-recipient HLA-allele match was 5/8 (range 3-7) & 36 (38%) pts also received haplo-CD34+ cells. Pts had 44 upper, 2 lower & 42 combined upper/ lower scopes at a median of 52 days (range 22-176) post-CBT. Of 86 pts who had upper scopes (Table 1), 67/86 (78%) were treated for upper GI aGVHD & only 3 had infection (Figure). The majority (51/67,76%) of aGVHD treated pts had normal macro appearance & the majority (49/67, 73%) had aGVHD compatible histology (typically apoptotic epithelial cells, mild in all but 2). Overall, the majority of treated pts (48/67, 72%) had a day 28 CR (37 budesonide, 11 high dose corticosteroids). Of 18 treated pts with normal macro & histology, 11 had CR & 7 PR. Nearly all (40/44, 91%) pts who had lower GI scopes (Table 2) were treated for aGVHD & none had infection (Figure). Most (33/40, 83%) were stage I-II ( Conclusions With pre-emptive CMV therapy, yeast prophylaxis, & stool PCR studies, the majority of CBT pts who required endoscopies had aGVHD & infection was very rare. This was especially true in pts with diarrhea. Normal mucosal appearance was frequent in aGVHD treated pts & nearly all pts with diarrhea & abnormal macro had aGVHD. Most had aGVHD compatible histology (usually mild). Notably, 9/23 treated pts with normal histology only had a PR supporting aGVHD is a clinical diagnosis. Moreover, pts with severe histologic abnormality were at high risk for PR/ refractory disease. This data supports early corticosteroid therapy if aGVHD compatible symptoms & not waiting for biopsy results. This is critical in pts with diarrhea. Correlation of this data with serum biomarkers & microbiota to improve the efficiency of diagnosis & risk stratification are needed.

Adult Cord Blood Transplantation (CBT) Recipients Have a High Incidence of Early Acute Kidney Injury (AKI) and AKI Increases Long-Term Chronic Kidney Disease (CKD) Risk

Introduction While adult double unit CBT (dCBT) has disease-free survival comparable to that of HLA-matched adult donor allografts, frequent patient (pt) comorbidities combined with chemotherapy/TBI & cyclosporine-A (CSA) contribute to AKI risk. Using KDIGO criteria, we analyzed renal injury incidence & risk factors in adults undergoing dCBT. Methods Adult dCBT pts transplanted 2006-2016 for hematologic malignancies using Cy/ Flu/ Thio/ TBI 400 cGy & CSA (therapeutic range 250-450)/ MMF were analyzed. Using day 0 - 100 creatinines, maximum grade (gr.) AKI [gr. 1 (1.5 - 3-fold baseline)] was calculated. If pts had multiple episodes, the highest grade was analyzed. The 2-yr CKD incidence (> 90 days of GFR Results 153 pts [median 51 years (range 23-65), 114/153 (75%) acute leukemia, 27/153 (18%) African, 88/153 (58%) CMV seropositive] were transplanted. No patient had chronic kidney disease pre-dCBT; 32/153 (21%) had hypertension & 12/153 (8%) were diabetic. Median aaHCT-CI was 3 (range 0-9) with 92/153 (60%) pts having a score > 3. 34 (22%) pts had High-Very High rDRI diagnoses. Median pre-dCBT albumin was 4 (range 2.6 - 5.2). 96% of pts engrafted, 76% had grade II-IV acute GVHD by day 100 & 90% were alive & disease-free at day 100 (11 TRM, 3 relapse). 127 pts had AKI (45 gr. 1, 60 gr. 2, & 22 gr. 3) for a day 100 grade 1-3 AKI cumulative incidence of 83% (95%CI: 77-89) (median onset 40 days, range 0-96) & 54% (95%CI: 46-62) for gr. 2-3 AKI (median onset 43 days, range 0-96) (Figure 1). The mean of the 3-day mean CSA level preceding AKI onset was high at 360 ng/ml. African ancestry, CMV seropositivity & low day -7 albumin level & post-dCBT variables of ICU admission, nephrotoxic drug exposure & bacteremia were associated with gr. 1-3 AKI (Table 1A). In multivariate analysis, low day -7 albumin, ICU admission & nephrotoxic drugs were significant (Table 1B). With a median 40 months (range 12-125) survivor follow-up, 34/109 (31%) evaluable pts had CKD at 2-yrs with 1 pt requiring long-term dialysis. Grade 2-3 AKI prior to day 100 was associated with a higher likelihood of having CKD at 2-yrs: 38% vs 25% (Figure 2). Conclusion dCBT recipients are at significant risk for AKI which increases the likelihood of long-term CKD. Early recognition of impending AKI & prompt intervention is critical to mitigate severe kidney injury & long-term impairment. Prevention strategies include adequate hydration, tight CSA level control & substitution of non-nephrotoxic medications (e.g. Letermovir CMV prophylaxis instead of pre-emptive foscarnet, non-aminoglycosides antibiotics, azoles rather than amphotericin, PO cidofovir instead of IV). Investigation of novel GVHD prophylaxis that could permit lower CSA dosing & early AKI detection using biomarkers should also be investigated.

Prospective Cohort Study Comparing Intravenous Busulfan Versus Total Body Irradiation in Cord Blood Transplantation

Intravenous busulfan (IV-Bu) or total body irradiation (TBI) based regimens are currently the most widely used myeloablative conditioning regimens for patients with hematologic malignancies undergoing allogeneic stem-cell transplantation(allo-SCT). Numerous trials have been undertaken on the clinical outcomes between IV Bu and TBI, but there are no comparative data for cord blood transplantation(CBT). We conducted a prospective registry-based study to analysis the outcomes of IV Bu and TBI in CBT patients with hematologic malignancies.From May 1, 2008 to Mar 31, 2016, a total of 331 consecutive patients with hematologic malignancies recieved singe unrelated CBT were involved in the study. Eligibility criteria for this analysis included:(1)Weigh ≧35 kilograms and age ≦ 60 years; (2)All patients recieved a single unit CBT but not a double units CBT; (3)Consensus criteria preparative regimens were based on full dose IV Bu(total 12.8 mg/kg, 0.8mg/kg every 6 h for 4 days) or TBI(total 12 Gy, 4 fractions) combined with Cy(60mg/kg × 2d); (4)GVHD prophylaxis regimens include cyclosporine(CSA) and mycophenolate mofetil(MMF) without Antithymocyte Globulin(ATG). Patients who has recieved a previous autologous or allogeneic transplantation was excluded in the study. The cumulative incidence of neutrophil engraftment were 91.6% in IV Bu/Cy cohort and 98.0% in Cy/TBI cohort(P < .001), respectively. The median follow-up time in IV Bu/Cy and Cy/TBI cohorts was 28.7(range, 12.2 to 91.3) months and 55.5(range, 13.1 to 117.1) months, respectively(P<.001). Of them, 200 patients received Cy/TBI, and 131 patients received IV Bu/Cy. The median dose of infused total nucleated cells were 4.51(range, 2.19 to 12.06 )× 107/kg and 3.77(range, 2.14 to 9.05)(P < .001), respectively. And the median number of CD34+ cells was 2.61(range, 0.91 to 9.64) ×105/kg and 2.01(range, 1.12 to 8.71)(P < .001), respectively. The median times to neutrophil engraftment were 16 days and 19 days(P < .001). The estimated DFS at 3 years were not statistically different between the conditioning regimens in univariate analysis. 63.9%±4.21% in patients undergoing conditioning with IV Bu/Cy and 54.4%±3.57% in patients undergoing conditioning with Cy/TBI(P = .21).These results were similar in multivariable analysis (HR, 1.03; 95% CI, 0.68 to 1.54; P = .905). Univariate analysis and multivariable analysis demonstrated that estimated OS and GRFS at 3 years were also not different between those two conditioning regimens.Our resluts demonstrates that, compared with TBI, IV Bu regimen was associated with a higher incidence of graft rejection in CBT. But there was no difference in survival with no increased risk for NRM or relapse between two regimens. For those centers lack of radiation facilities, IV Bu may be a valid and efficient alternative to TBI. With the restriction of a retrospective registry analysis and limited patient munbers, rigorously designed prospective randomized controlled trials are needed to further investigated the availability of IV Bu and TBI for CBT. DisclosuresNo relevant conflicts of interest to declare.

Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor–Enriched Cord Blood, to Double Cord Blood Unit Transplantation

Umbilical cord blood (UCB) transplantation has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20% to 50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the unmanipulated fraction after myeloablative conditioning. The primary endpoint was 100-day survival, which was compared with a contemporaneous double-unit cord blood transplantation (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n = 295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34+ were 3.06 × 107 cell dose/kg and 1.64 × 105 cell dose/kg. Median NC and CD34+ fold expansion were 400 and 77, with a mean total CD34 infused of 9.7 × 105/kg. The 100-day survival was 84.2% for the carlecortemcel-L study group versus 74.6% for the DUCBT group (odds ratio, .50; 95% CI, .26 to .95; P = .035). Survival at day 180 was similar for the 2 groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 days versus 28 days; P < .0001), and platelet (54 days versus 105 days; P = .008) engraftment was seen in the carlecortemcel-L study group; acute and chronic graft-versus-host disease rates were similar. In this multinational comparative study, transplanting expanded CD34+ stem cells from a portion of a single UCB unit, with the remaining unmanipulated fraction improved 100-day survival compared with DUCBT control patients while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729.

Umbilical Cord Blood Cytomegalovirus Serostatus Does Not Have an Impact on Outcomes of Umbilical Cord Blood Transplantation for Acute Leukemia

Several studies have reported an impact of adult hematopoietic stem cell donor cytomegalovirus (CMV) serostatus on allogeneic hematopoietic cell transplantation outcomes. Limited data, however, are available on the impact of cord blood unit (CBU) CMV serostatus on allogeneic umbilical cord blood transplantation (UCBT) outcomes. We analyzed, retrospectively, the impact of CBU CMV serostatus on relapse incidence (RI) and 2-year nonrelapse mortality (NRM) of single-unit CBU transplantation for acute leukemia. Data from 1177 de novo acute leukemia pediatric and adult patients transplanted within European Group for Blood and Marrow Transplantation centers between 2000 and 2012 were analyzed. CBUs were provided by the European Cord Blood Banks. The median follow-up time for live patients was 59.9 months. The recipients of CMV-seropositive and -seronegative CBUs showed a comparable RI (33% versus 35%, respectively, P = .6) and 2-year cumulative incidence of NRM (31% versus 32%, respectively, P = .5). We conclude that CBU CMV serostatus did not influence RI and NRM in de novo acute leukemia patients after allo-UCBT and should not be included as a criteria for cord blood choice.

Allele-level HLA matching for umbilical cord blood transplantation for non-malignant diseases in children: a retrospective analysis

The standard for selecting unrelated umbilical cord blood units for transplantation for non-malignant diseases relies on antigen-level (lower resolution) HLA typing for HLA-A and HLA-B, and allele-level for HLA-DRB1. We aimed to study the effects of allele-level matching at a higher resolution-HLA-A, HLA-B, HLA-C, and HLA-DRB1, which is the standard used for adult unrelated volunteer donor transplantation for non-malignant diseases-for umbilical cord blood transplantation. We retrospectively studied 1199 paediatric donor-recipient pairs with allele-level HLA matching who received a single unit umbilical cord blood transplantation for non-malignant diseases reported to the Center for International Blood and Marrow Transplant Research or Eurocord and European Group for Blood and Marrow Transplant. Transplantations occurred between Jan 1, 2000, and Dec 31, 2012. The primary outcome was overall survival. The effect of HLA matching on survival was studied using a Cox regression model. Compared with HLA-matched transplantations, mortality was higher with transplantations mismatched at two (hazard ratio [HR] 1·55, 95% CI 1·08-2·21, p=0·018), three (2·04, 1·44-2·89, p=0·0001), and four or more alleles (3·15, 2·16-4·58, p<0·0001). There were no significant differences in mortality between transplantations that were matched and mismatched at one allele (HR 1·18, 95% CI 0·80-1·72, p=0·39). Other factors associated with higher mortality included recipient cytomegalovirus seropositivity (HR 1·40, 95% CI 1·13-1·74, p=0·0020), reduced intensity compared with myeloablative conditioning regimens (HR 1·36, 1·10-1·68, p=0·0041), transplantation of units with total nucleated cell dose of more than 21 × 107 cells per kg compared with 21 × 107 cells per kg or less (HR 1·47, 1·11-1·95, p=0·0076), and transplantations done in 2000-05 compared with those done in 2006-12 (HR 1·64, 1·31-2·04, p<0·0001). The 5-year overall survival adjusted for recipient cytomegalovirus serostatus, conditioning regimen intensity, total nucleated cell dose, and transplantation period was 79% (95% CI 74-85) after HLA matched, 76% (71-81) after one allele mismatched, 70% (65-75) after two alleles mismatched, 62% (57-68) after three alleles mismatched, and 49% (41-57) after four or more alleles mismatched transplantations. Graft failure was the predominant cause of mortality. These data support a change from current practice in that selection of unrelated umbilical cord blood units for transplantation for non-malignant diseases should consider allele-level HLA matching at HLA-A, HLA-B, HLA-C, and HLA-DRB1. National Cancer Institute; National Heart, Lung, and Blood Institute; National Institute for Allergy and Infectious Diseases; US Department of Health and Human Services-Health Resources and Services Administration; and US Department of Navy.

Umbilical Cord Blood (UCB) Transplantation in Children with Acute Leukemia: Impact of Conditioning Regimen on Transplant Outcomes

The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0501; NCT00412360) randomized children with hematologic malignancy to one or two cord blood unit transplantation between December 2006 and February 2012. While the trial concluded that survival was similar regardless of number of units infused, results were generally better than those previously reported after single UCB transplant. The apparently improved survival in recipients of BMT CTN 0501 compared to prior studies in children transplanted with a single UCB unit prompted a comparison of trial versus non-trial treatment outcomes to determine 1) the generalizability of trial results and 2) whether survival was better for patients treated with the trial regimen. Using data reported to the Center for International Blood and Marrow Transplant Research during the trial period, 396 recipients of one UCB unit transplant met the broad eligibility criteria for BMT CTN 0501 (i.e. aged 1- 21 years, high-risk acute leukemia, performance score ≥70). Trial and non-trial patients were comparable in their HCT-CI score. Trial patients (n=100) received total body irradiation (TBI) 1320 cGy, cyclophosphamide 120 mg/kg, and fludarabine 75 mg/m2 (TCF). Non-trial patients either received the same regimen as in the trial (N=62; non-trial TCF) or an alternative regimen (N=334; non-trial non-TCF regimen). Excluded were 13 patients on BMT CTN 0501 randomized to receive a single UCB unit for malignant diseases other than acute leukemia. Patient and disease characteristics of those treated on BMT CTN 0501 and others were similar except that those who received non-trial TCF regimen were more likely to report performance scores of 80 or 70 (24% versus 11%, p=0.04) and transplanted in relapse (18% vs. 5%, p=0.02) and those that received non-TCF regimens were more likely to 1-10 years of age (76% versus 53%, p<0.0001). Sixty-three percent of non-trial non-TCF regimens included TBI (≥1000 cGy) and the predominant non-TBI regimen was busulfan and cyclophosphamide. All patients received a calcineurin inhibitor for graft-versus-host disease (GVHD) prophylaxis. Donor-recipient HLA-match, median infused total nucleated cells and median follow up times were similar across the groups. Three-year survival rates were similar between patients receiving TCF regimen either on (A) or off trial (B), Figure1A, p=0.83. Similarly, there were no differences in hematopoietic recovery, relapse or non-relapse mortality between trial and non-trial TCF. However, compared to TCF on trial (A), overall survival rates were significantly lower with non-TCF non-TBI (C) and TBI (D) containing regimens after adjusting for age, CMV serostatus, disease and disease status; Figure 1B, 68% versus 55% (p=0.001) and 68% versus 50% (p=0.04), respectively. Results of multivariate analysis are shown in Table 1. Compared to patients treated on trial (TCF regimen; 20% at 3-years) relapse rates were higher with non-TCF non-TBI (42%, p=0.003) but not TBI-containing regimens (25%, p=0.38) after adjusting for age, disease, disease status and CMV seropositivity. Among non-TCF patients, relapse risk was higher for non-TBI compared to TBI-containing regimens (hazard ratio [HR] 1.61, p=0.02) but not mortality risk (HR 0.93, p=0.74). Cytogenetic risk features were not associated with relapse or survival. There were no differences in hematopoietic recovery, acute and chronic GVHD. The results of BMT CTN 0501 appear generalizable to the population of trial eligible patients. The survival differences between the trial specified and other conditioning regimens support use of the TCF regimen to improve survival. It also indicates the importance of conditioning regimen for outcome and may serve as a stimulus to design trials to identify the optimal regimen for children with acute leukemia undergoing UCB transplantation. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Preclinical Development of a Cord Blood (CB)-Derived Hematopoietic Stem Cell (HSC) Product for Allogeneic Transplantation in Patients with Hematological Malignancies

Umbilical CB is an established source of HSC for allogeneic transplantation in patients lacking HLA-matched donors. The major limitation of CB transplantation is the relatively low number HSCs within a single CB unit (CBU) resulting in delayed engraftment, infections and ultimately increased mortality. Because of this, double CBU transplantation has been used to reach the required cell doses but this approach has not led to an improved overall outcome and often results in an increased rate of GVHD. These findings have prompted the development of ex vivo expansion strategies to increase the number of HSCs, so that a single CBU can be transplanted. Most of these techniques, however, result in enrichment of short term marrow repopulating cells (ST-RC) at the expense of long term (LT)-RC which may impact durable long term engraftment. In addition, they require 2-3 weeks of culture which complicates the timing of transplant and increases the risk of contamination. Our laboratory has developed a novel approach to expand the numbers of functional HSCs, by transiently influencing the epigenetic determinants of HSCs self-renewal. A 7-day treatment of CB CD34+ cells with valproic acid (VPA) results in a dramatic increase in the number of HSCs capable of durable hematopoietic engraftment in animal model recipients (Chaurasia et al. JCI, 2014). Here we report the pre-clinical development of a VPA-expanded HSC product for utilization in the treatment of patients with hematological malignancies. In the place of using freshly collected CBU as starting sources of CD34+ cells, we validated, optimized and scaled-up the expansion procedure utilizing cryopreserved CBU procured from FDA-licensed Cord Blood Banks and clinically relevant GMP reagents and materials. CBUs from 5 different donors were subjected to thawing followed by positive CD34+ cell selection using a Miltenyi CliniMACS Prodigy®. The total number of nucleated cells (TNC), CD34+ cells, viability, clonogenic potential (i.e. CFU number) and the frequency of various HSC sub-classes were determined post-thawing after which each CBU was subjected to CD34+ cell selection. CD34+ cells counts varied between 1.6 and 13.6x106 (mean of 4.5x106/CBU) and had a purity ranging from 69.2-82.8%. CD34+ cells were treated with cytokines for 16-18h, followed by addition of VPA and ex vivo expansion for 7 days. The generated cell product was characterized phenotypically and functionally and the results were compared to the unmanipulated CBU (uCBU) (Table 1). First, the expanded grafts had greater than 90% viability (range 91.4 to 97%) as compared to 68.2% in the uCBUs after thawing. The average number of CD34+ cells generated was 494.8x106 CD34+ cells (i.e. 126-fold greater than uCBU) which is the equivalent of 61.8x105/Kg/ body weight from a single CBU for an 80 kg individual. The fraction of CD34+ cells, which represented over 60% of the expanded graft, was further assessed for the presence ST-RC, intermediate-term (IT)-RC and LT-RC defined phenotypically as CD34+/CD45RA-/CD90-/CD49f-, CD34+/CD45RA-/CD90+/CD49f-, and CD34+/CD45RA-/CD90+/CD49f+, respectively. The average numbers of each of these HSC sub-classes per expanded CBU were 64, 217 and 265 fold higher than their respective numbers found in the uCBUs. Notably, the expanded grafts contained the equivalent of 22.38x105 IT-RC/kg and 16.98x105 LT-RC/kg where as uCBUs contained only 0.1x105 IT-RC/kg and 0.06x105 LT-RC/kg. Considering the ability of these HSC sub-classes to contribute to intermediate and long term hematopoietic engraftment, their presence in such high number gives the VPA-expanded grafts improved potential to lead to durable hematopoietic and immune reconstitution after transplantation. In addition, the expanded graft has a phenotype which would also be anticipated to lead to rapid hematopoietic recovery since lineage committed precursors (i.e. CD33+, CD15+, CD235a+ and CD41+ cells) represented 35-45% of its composition. Finally, as compared to uCBUs, the expanded HSC product contained 20 times more assayable CFUs consisting predominately of CFU-GEMM which are capable of contributing to multilineage engraftment. In summary, we report the generation of an ex vivo expanded CB HSCs product highly enriched in primitive HSCs sub-classes and which is currently being developed for a Phase I clinical trial for allogeneic CB transplantation in patients with hematological malignancies. [Display omitted] DisclosuresBhardwaj:Parker Institute of Cancer Immunotherapy: Membership on an entity's Board of Directors or advisory committees; Checkpoint Sciences: Membership on an entity's Board of Directors or advisory committees.

Genetic diversity of Umbilical Cord Blood Units for transplant of the National Center of Blood Transfusion (Mexico)

IntroductionThe Umbilical Cord Blood Units (UCBU) for transplant are a therapeutic possibility for patients with a wide range of onco-hematologic disorders, especially in children. In Mexico, 48.5% of oncological diseases in children from 1 to 4 years old are leukemias; while in patients from 5 to 14 and 15 to 24 years of age lymphomas and leukemias are predominant and represent the second and third causes of death in these age groups, respectively. Therefore, is it necessary to have registries of UCBU to ensure the representation of the genetic diversity in Mexico in order to attend this requirement. ObjectiveTo estimate the genetic diversity of HLA Class I (A, B) and Class II (DRB1) loci in cryopreserved UCBU of the Cord Blood Bank (CBB) at the National Center of Blood Transfusion (NCBT). MethodsHLA typing of 533 UCBU for transplant was performed at the Research Department (evaluated by “Los Angeles Ca. Inmunogenetics Center”). Class I HLA-A, HLA-B and Class II HLA-DRB1 typing was performed using medium resolution Sequence-Specific Primer (SSP). In cases of an ambiguity by SSP; Sequence-Specific Oligonucleotide (SSO) method was carried out. Results46.5% of the UCBU were obtained from Mexico City donors, 30.95% from the State of Mexico, 8.06% Puebla, 6.37% Morelos and 3.37% from Veracruz. The remaining UCBU 4.75% were represented by other states of the country. The most frequent loci for the HLA-A founded were *02/24, *02/68, *02/02, *02/30, *01/02, *02/31; for HLA-B, *35/39, *15/35, *35/40, *39/44, *07/35, *35/48, *39/40 and for HLA-DRB1, *04/08, *04/07, *04/15, *04/15, *04/03, *04/14. The genetic distances analysis showed that the top five populations analyzed in this study are significatively different from each other. ConclusionsThe majority of the genotypes found suggest Amerindian and European origins and in a lesser proportion Oriental and African. The NCBT is therefore establishing agreements with different states of Mexico to promote the donation of UCBU in order to enrich the genetic diversity in the archives of the NCBT.

Detection of antibiotic resistance genes β-lactamics in bacterial strains isolated from Umbilical Cord Blood Units for transplant

IntroductionAmong the risks associated with hematopoietic stem cells transplantation of umbilical cord blood are bacterial infections. This becomes dangerous when bacterial sepsis is related to resistance to antibiotics commonly used to eliminate of this type infections. Among the widely used antibiotics are those of the β-lactam family. Among the genes responsible for the resistance are designated “bla genes” which encode for broad-spectrum lactamases. Its detection in the laboratory shown the importance in the manufacture of cord blood units. ObjectiveTo correlate the antibiotic resistance in bacterial contaminants isolated from Umbilical Cord Blood Units (UCBU), with detection of genes encoding resistance of β-lactamics antibiotics. Materials and methodsTest of resistance to antibiotics was determined in 107 bacterial strains using disk diffusion method according to the recommendations of “The Clinical and Laboratory Standards Institute (CLSI)” and multiplex amplification by PCR of genes blaTEM, blaSHV and blaCTX-M were performed in order to detect genetic elements associated to antimicrobial resistance tested. ResultsBroad-spectrum penicillins showed lower inhibitory activity on the tested strains. Gene detection by multiplex PCR of encoding antimicrobial resistance (β-lactamases) revealed the presence of bla–HSV, blaCTX-M and bla–TEM genes in most strains tested even when these genes have been reported in Enterobacteriaceae family members. ConclusionsThe genotype detection encoding antibiotic resistance in isolates of UCBU clearly indicates the potential risk of sepsis difficult to eradicate in the patient, if present in a UCBU available for transplant. Additionally, the existence of these genes reveals horizontal transfer events of genetic material between bacteria. So the importance to realize this studies before transplant.

Cord blood transplant for acute myeloid leukaemia.

Umbilical cord blood is a haematopoietic progenitor cell source for patients with acute myeloid leukaemia (AML), other haematological malignancies and metabolic diseases who can be cured by allogeneic haematopoietic cell transplantation, but who do not have a human leucocyte antigen compatible related or unrelated donor. Although the first cord blood transplants were done in children, there are currently more cord blood transplants performed in adults. In this review, we explore the history of umbilical cord blood transplantation, paediatric and adult outcome results, and novel trends to improve engraftment and reduce infection. Umbilical cord blood transplantation cures approximately 30-40% of adults and 60-70% of children with AML. Controversial issues, including the use of double versus single cord blood units for transplantation, optimal cord blood unit selection, infection prophylaxis, conditioning regimens and graft versus host disease prophylaxis, will be reviewed. Finally, comparison to other graft sources, cost, access to care, and the ideal graft source are discussed.